Diabetes Care Volume 48, Supplement 1, January 2025 S59

4. Comprehensive Medical American Diabetes Association

Professional Practice Committee*
Evaluation and Assessment of
Comorbidities: Standards of Care
in Diabetes—2025

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

Diabetes Care 2025;48(Suppl. 1):S59–S85 | https://doi.org/10.2337/dc25-S004

4. MEDICAL EVALUATION AND COMORBIDITIES

The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes
the ADA’s current clinical practice recommendations and is intended to provide the
components of diabetes care, general treatment goals and guidelines, and tools to
evaluate quality of care. Members of the ADA Professional Practice Committee, an
interprofessional expert committee, are responsible for updating the Standards of
Care annually, or more frequently as warranted. For a detailed description of ADA
standards, statements, and reports, as well as the evidence-grading system for
ADA’s clinical practice recommendations and a full list of Professional Practice Com-
mittee members, please refer to Introduction and Methodology. Readers who wish
to comment on the Standards of Care are invited to do so at professional.diabetes
.org/SOC.

PERSON-CENTERED COLLABORATIVE CARE

Recommendations
4.1 A communication style that uses person-centered, culturally sensitive, and
strength-based language and active listening; elicits individual preferences and
beliefs; and assesses literacy, numeracy, and potential barriers to care should be
used to optimize health outcomes and health-related quality of life. B
4.2 People with diabetes can benefit from a coordinated interprofessional
team that may include but is not limited to diabetes care and education spe-
cialists, primary care and subspecialty clinicians, nurses, registered dietitian
nutritionists, exercise specialists, pharmacists, dentists, podiatrists, and behav-
ioral health professionals. C

*A complete list of members of the American

Diabetes Association Professional Practice Committee
A successful medical evaluation depends on beneficial interactions and care coor- can be found at https://doi.org/10.2337/dc25-SINT.
dination between the person with diabetes and the care team (1). The Chronic Duality of interest information for each author is
Care Model (2–4) (see Section 1, “Improving Care and Promoting Health in available at https://doi.org/10.2337/dc25-SDIS.
Populations”) is a person-centered approach to care that requires a close working Suggested citation: American Diabetes Association
Professional Practice Committee. 4. Comprehensive
relationship between the person with diabetes and clinicians involved in treat-
medical evaluation and assessment of com-
ment planning. People with diabetes should receive health care from a coordi- orbidities: Standards of Care in Diabetes—2025.
nated interprofessional team that may include but is not limited to diabetes care Diabetes Care 2025;48(Suppl. 1):S59–S85
and education specialists, primary care and subspecialty clinicians, nurses, regis- The BONE HEALTH subsection has received endorsement
tered dietitian nutritionists, exercise specialists, pharmacists, dentists, podiatrists, from the American Society for Bone and Mineral
behavioral health professionals, and community partners such as community Research.
health workers and community paramedics. Individuals with diabetes and their © 2024 by the American Diabetes Association.
care partners must assume an active role in their care. Based on the preferences Readers may use this article as long as the
work is properly cited, the use is educational
and values of the person with diabetes, elicited by the care team, the person with
and not for profit, and the work is not altered.
diabetes, their family or support group, and the health care team together formu- More information is available at https://www
late the management plan, which includes lifestyle management (see Section 5, .diabetesjournals.org/journals/pages/license.
S60 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

“Facilitating Positive Health Behaviors with routine reassessment as necessary diabetes in “following doctor’s orders,”
and Well-being to Improve Health given their changing circumstances across which is at odds with the active role peo-
Outcomes”) and pharmacotherapy, as the life span. Various strategies and techni- ple with diabetes take in the day-to-day
appropriate. ques should be used to support the person’s decision-making, planning, monitoring,
The goals of treatment for diabetes self-management efforts, including pro- evaluation, and problem-solving involved
are to prevent or delay complications viding education on problem-solving and in diabetes self-management. Using a
and optimize quality of life (Fig. 4.1). coping skills for all aspects of diabetes nonjudgmental approach that normal-
Treatment goals and plans should be co- management. izes periodic lapses in management may
created by the care team and people Communication by health care professio- help minimize the person’s resistance to
with diabetes based on their individual nals with people with diabetes and their reporting problems with self-management.
preferences, values, and goals. This indi- families should acknowledge that multiple Empathizing and using active listening tech-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

vidualized management plan should take factors impact glycemic management but niques, such as open-ended questions, re-
into account the person’s age, cognitive also emphasize that collaboratively devel- flective statements, and summarizing what
abilities, school/work schedule and condi- oped treatment plans and a healthy lifestyle the person said, can help facilitate commu-
tions, health beliefs, support systems, eating can significantly improve disease outcomes nication. Perceptions of people with diabe-
patterns, physical activity, social situation, fi- and well-being (5–10). Thus, the goal of tes about their own ability, or self-efficacy,
nancial concerns, cultural factors, literacy communication between health care pro- to self-manage diabetes constitute one
and numeracy (mathematical literacy), dia- fessionals and people with diabetes is to es- important psychosocial factor related to
betes history (duration, complications, and tablish a collaborative relationship and to improved diabetes self-management and
current use of medications), comorbidities, assess and address self-management bar- treatment outcomes in diabetes (12–14)
disabilities, health priorities, other medical riers without blaming people with diabetes and should be a goal of ongoing assess-
conditions, preferences for care, access to for “noncompliance” or “nonadherence” ment, education, and treatment planning.
health care services, and life expectancy. when the outcomes of self-management Language has a strong impact on per-
People living with diabetes should be en- are not optimal (11). The familiar terms ceptions and behavior. Empowering lan-
gaged in conversation about these aspects noncompliance and nonadherence denote guage can help to inform and motivate,
of their lives and diabetes management, a passive, obedient role for a person with while shame and judgement can be

Decision Cycle for Person-Centered Glycemic

Management in Type 2 Diabetes

• Review management plan

• Mutually agree on changes
• The individual’s priorities
• Ensure agreed modification of therapy is implemented in
• Current lifestyle and health behaviors
a timely fashion to avoid therapeutic inertia
• Comorbidities (i.e., CVD, CKD, and HF)
• Undertake decision cycle regularly (at least once or twice
• Clinical characteristics (i.e., age, A1C, and weight)
a year)
• Issues such as motivation, depression, and cognition
• Operate in an integrated system of care
• Social determinants of health

GOALS • Individualized glycemic and weight goals

• Impact on weight, hypoglycemia, and cardiovascular
•
•
Emotional well-being
Lifestyle and health behaviors
OF CARE and kidney protection
• Underlying physiological factors
• Tolerability of medications • Prevent complications • Side effect profiles of medications
• Biofeedback including BGM and CGM, • Complexity of treatment plan (i.e., frequency, and
weight, step count, A1C, BP, and lipids
• Optimize quality of life mode of administration)
• Treatment choice to optimize medication use and
reduce treatment discontinuation
• Access, cost, availability of medication, and lifestyle
choices

• Ensure there is regular review;

more frequent contact initially is
often desirable for DSMES • Ensure access to DSMES
• Involve an educated and informed person
(and the individual’s family or caregiver)
• Explore personal preferences
• Specify SMART goals: • Language matters (include person-first,
- Specific strengths-based, empowering language)
- Measurable • Include motivational interviewing, goal
- Achievable setting, and shared decision-making
- Realistic
- Time limited

Figure 4.1—Decision cycle for person-centered glycemic management in type 2 diabetes. BGM, blood glucose monitoring; BP, blood pressure;
CGM, continuous glucose monitoring; CKD, chronic kidney disease; CVD, cardiovascular disease; DSMES, diabetes self-management education and
support; HF, heart failure. Adapted from Davies et al. (324).
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S61

discouraging. The American Diabetes Associ- health and functional status, diabetes “Cardiovascular Disease and Risk
ation (ADA) and the Association of Diabetes complications, cardiovascular risk, hy- Management”), chronic kidney disease
Care & Education Specialists (ADCES) (for- poglycemia risk, and shared decision- (CKD) staging (see Section 11, “Chronic
merly called the American Association of Di- making to set therapeutic goals. B Kidney Disease and Risk Management”),
abetes Educators) joint consensus report, presence of retinopathy and neuropathy
“The Use of Language in Diabetes Care and (see Section 12, “Retinopathy, Neuro-
Education,” provides the authors’ expert The comprehensive medical evaluation pathy, and Foot Care”), and risk of treat-
opinion regarding the use of language by includes the initial and follow-up evalua- ment-associated hypoglycemia should be
health care professionals when speaking or tions, which comprise assessment of used to individualize goals for glycemia (see
writing about diabetes for people with di- complications, psychosocial assessment, Section 6, “Glycemic Goals and Hypo-
abetes or for professional audiences (15). management of comorbid conditions, over- glycemia”), blood pressure, and lipids and

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

Although further research is needed to all health, functional and cognitive status, to select specific glucose-lowering medica-
address the impact of language on diabe- and engagement of the person with diabe- tion(s) (see Section 9, “Pharmacologic
tes outcomes, the report includes five tes throughout the process. While a com- Approaches to Glycemic Treatment”),
key consensus recommendations for lan- prehensive list is provided in Table 4.1, in antihypertension medications, and lipid-
guage use: clinical practice the health care professional lowering treatment intensity.
may need to prioritize the components of Additional referrals should be arranged
• Use language that is neutral, non- the medical evaluation given the available as necessary (Table 4.2). Clinicians should
judgmental, and based on facts, ac- resources and time. Engaging other mem- ensure that people with diabetes are ap-
tions, physiology, or biology. bers of the health care team can also sup- propriately screened for complications,
• Use language free from stigma. port comprehensive diabetes care. The goal
comorbidities, and treatment burden. Dis-
• Use language that is strength based, of these recommendations is to provide
cussing and implementing an approach to
respectful, and inclusive and that the health care team information so it can
glycemic management with the person is
imparts hope. optimally support people with diabetes and
a part, not the sole goal, of the clinical
• Use language that fosters collabora- their care partners. In addition to the
encounter.
tion between people with diabetes medical history, physical examination, and
and health care professionals. laboratory tests, health care professionals
• Use language that is person cen- IMMUNIZATIONS
should assess diabetes self-management
tered (e.g., “person with diabetes” is behaviors, nutrition, social determinants Recommendation
preferred over “diabetic”). of health, and psychosocial health (see 4.5 Provide routinely recommended
Section 5, “Facilitating Positive Health vaccinations for children and adults
COMPREHENSIVE MEDICAL Behaviors and Well-being to Improve with diabetes as indicated by age
EVALUATION Health Outcomes”) and give guidance on (see Table 4.3). A
routine immunizations. The assessment of
Recommendations
sleep pattern and duration should also be
4.3 A complete medical evaluation Children and adults with diabetes should
considered, as this may affect glycemic
should be performed at the initial visit receive vaccinations according to age-
management. Interval follow-up visits
and follow-up, as appropriate, to: appropriate recommendations (16,17).
should occur at least every 3–6 months in-
• Confirm the diagnosis and classify The Centers for Disease Control and Pre-
dividualized to the person and then at
diabetes. A vention (CDC) provides vaccination sched-
least annually.
• Assess glycemic status and previ- ules specifically for children, adolescents,
Lifestyle management and behavioral
ous treatment. A and adults with diabetes (cdc.gov/
health care are cornerstones of diabetes
• Evaluate for diabetes complications, vaccines/). The CDC Advisory Committee
management. People with diabetes should
potential comorbid conditions, and on Immunization Practices (ACIP) makes
be referred for diabetes self-management
overall health status. A recommendations based on its own review
education and support, medical nutrition
• Identify care partners and sup- and rating of the evidence, provided in
therapy, and assessment of behavioral
port system. E Table 4.3 for selected vaccinations. The
health concerns as appropriate. People
• Assess social determinants of health ACIP evidence review has evolved over
with diabetes should receive recom-
and structural barriers to optimal time with the adoption of Grading of Rec-
mended preventive care services (e.g., im-
health and health care. A ommendations Assessment, Development,
munizations and age- and sex-appropriate
• Review risk factor management and Evaluation (GRADE) in 2010 and then
cancer screening); smoking cessation
in the person with diabetes. A
counseling; and ophthalmological, den- the Evidence to Decision or Evidence to
• Begin engagement with the person
tal, podiatric, and other referrals, as Recommendation frameworks in 2020 (18).
with diabetes in the formulation of
needed. Here, we discuss the particular importance
a care management plan including
The assessment of risk of acute and of specific vaccines.
initial goals of care. A
chronic diabetes complications and treat-
• Develop a plan for continuing
ment planning are key components of ini- COVID-19
care. A
tial and follow-up visits (Table 4.2). The People with underlying medical condi-
4.4 Ongoing management should be
risk of atherosclerotic cardiovascular dis- tions, including diabetes, are more likely
guided by the assessment of overall
ease and heart failure (see Section 10, to become severely ill with coronavirus
S62 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

disease 2019 (COVID-19). COVID-19 vac-

Table 4.1—Components of the comprehensive diabetes medical evaluation at
initial, follow-up, and annual visits cination using an appropriate number
of doses of updated vaccines is recom-
Visit mended for everyone aged 6 months
Initial Every follow-up Annual and older in the U.S. (18).
Past medical and family history
Diabetes history Hepatitis B

Characteristics at onset (e.g., age and  Compared with the general population,
symptoms and/or signs) people with type 1 or type 2 diabetes

Review of previous treatment plans and 
have higher rates of hepatitis. Because of
response

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

Assess frequency, cause, and severity of  the higher likelihood of transmission of
past hospitalizations the disease, hepatitis B vaccine is recom-
Family history mended for adults with diabetes aged

Family history of diabetes in a first-  <60 years. For adults aged $60 years,
degree relative hepatitis B vaccine may be administered

Family history of autoimmune disorders 
Personal history of complications and
at the discretion of the treating clinician
common comorbidities based on the person’s likelihood of ac-

Common comorbidities (e.g., obesity,   quiring hepatitis B infection (19).
OSA, and MASLD)

High blood pressure or abnormal lipids   Influenza

Macrovascular and microvascular  
Influenza is a common, preventable infec-
complications

Hypoglycemia: awareness, frequency,    tious disease associated with high mortality
causes, and timing of episodes and morbidity in vulnerable populations,

Presence of hemoglobinopathies or   including youth, older adults, and people
anemias with chronic diseases. Influenza vaccination

Last dental visit  
in people with diabetes has been found to

Last dilated eye exam  

Visits to specialists  significantly reduce influenza and diabetes-

Disability assessment and use of    related hospital admissions (20). In people
assistive devices (e.g., physical, with diabetes, the influenza vaccine has
cognitive, vision and auditory, history of been associated with lower risk of all-cause
fractures, and podiatry)
mortality, cardiovascular mortality, and car-

Personal history of autoimmune disease 
Surgical and procedure history diovascular events (21). Given the benefits

Surgeries (e.g., metabolic surgery and    of the annual influenza vaccination, it is rec-
transplantation) ommended for all individuals $6 months
Interval history of age who do not have a contraindication.

Changes in medical or family history  
The live attenuated influenza vaccine, which
since last visit
is delivered by nasal spray, is an option for
Behavioral factors
people who are 2–49 years of age and are

Eating patterns and weight history   
not pregnant, but people with chronic con-

Assess familiarity with carbohydrate  
counting (e.g., type 1 diabetes or type 2 ditions such as diabetes are cautioned
diabetes treated with MDI) against taking the live attenuated influenza

Physical activity and sleep behaviors;    vaccine and are instead recommended to
screen for OSA receive the inactive or recombinant influ-

Tobacco, alcohol, and substance use  
enza vaccination. As of the 2024–2025 sea-
Medications and vaccinations son, all influenza vaccines offered in the

Current medication plan    U.S. are trivalent (22).

Medication-taking behavior, including   
rationing of medications and/or medical
equipment Pneumococcal Pneumonia

Medication intolerance or side effects    Like influenza, pneumococcal pneumonia

Complementary and alternative medicine    is a common, preventable disease. People
use with diabetes are at increased risk for

Vaccination history and needs  
pneumococcal infection and have been re-
Technology use ported to have a high risk of hospitalization

Assess use of health apps, online    and death, with a mortality rate as high as
education, patient portals, etc.

Glucose monitoring (meter/CGM): results   
50% (23). All people with diabetes should
and data use receive one of the CDC-recommended
pneumococcal vaccines (24). See details in
Continued on p. S63
Table 4.3.
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S63

Respiratory Syncytial Virus

Table 4.1—Continued Respiratory syncytial virus (RSV) is a cause
Visit
of respiratory illness in some individuals,
including older adults. People with chronic
Initial Every follow-up Annual
conditions such as diabetes have a higher

Review insulin pump settings and use and   
risk of severe illness. The U.S. Food and
connected pen and glucose data
Drug Administration (FDA) approved the
Social life assessment
first vaccines for prevention of RSV-associ-
Social network

Identify existing social supports  
ated lower respiratory tract disease in

Identify surrogate decision maker and   adults aged $60 years. On 26 June 2024,
advanced care plan ACIP voted to recommend that all adults

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

Identify social determinants of health   aged $75 years and adults aged 60–74
(e.g., food security, housing stability and years who are at increased risk for severe
homelessness, transportation access, RSV should receive a single dose of RSV
financial security, and community safety)

Assess daily routine and environment,   
vaccine (25).
including school or work schedules and
ability to engage in diabetes self- ASSESSMENT OF COMORBIDITIES
management
Besides assessing diabetes-related compli-
Physical examination cations, clinicians and people with diabetes

Height, weight, and BMI; growth and    need to be aware of common comorbid-
pubertal development in children and
ities that affect people with diabetes and
adolescents

Blood pressure determination   
that may complicate management (26–28).

Orthostatic blood pressure measures   Diabetes comorbidities are conditions that
(when indicated) affect people with diabetes more often

Fundoscopic examination (refer to eye   than age-matched people without diabe-
specialist) tes. This section discusses many of the

Thyroid palpation  
common comorbidities observed in people

Skin examination (e.g., acanthosis   
nigricans, insulin injection or insertion with diabetes but is not necessarily inclu-
sites, and lipodystrophy) sive of all the conditions that have been

Comprehensive foot examination   reported.

Visual inspection (e.g., skin integrity,   
callous formation, foot deformity or ulcer, Autoimmune Diseases
and toenails)*

Check pedal pulses and screen for PAD   Recommendations
with ABI testing if a PAD diagnosis would 4.6 Screen people with type 1 diabe-
change management tes for autoimmune thyroid disease

Determination of temperature, vibration or   soon after diagnosis and thereafter
pinprick sensation, and 10-g monofilament
at repeated intervals if clinically indi-
exam

Screen for depression, anxiety, diabetes   cated. B
distress, fear of hypoglycemia, and 4.7 Adults with type 1 diabetes should
disordered eating be screened for celiac disease in the

Assessment for cognitive performance if   presence of gastrointestinal symptoms,
indicated† signs, laboratory manifestations, or clin-

Assessment for functional performance if  
ical suspicion suggestive of celiac dis-
indicated†

Consider assessment for bone health (e.g.,  
ease. B
loss of height and kyphosis)
Laboratory evaluation People with type 1 diabetes are at in-

A1C, if the results are not available within    creased risk for other autoimmune dis-
the past 3 months
eases, with thyroid disease, celiac disease,

Lipid profile, including total, LDL, and HDL  ^
cholesterol and triglycerides‡ and pernicious anemia (vitamin B12 defi-

Liver function tests (i.e., FIB-4)‡   ciency) being among the most common

Spot urinary albumin-to-creatinine ratio   (29). Other autoimmune conditions asso-

Serum creatinine and estimated glomerular   ciated with type 1 diabetes include auto-
filtration rate§ immune liver disease, primary adrenal

Thyroid-stimulating hormone in people  
with type 1 diabetes‡
insufficiency (Addison disease), vitiligo,

Celiac disease in people with type 1  collagen vascular diseases, and myasthe-
diabetesjj nia gravis (30–33). Type 1 diabetes may
Continued on p. S64
also occur with other autoimmune dis-
eases in the context of specific genetic
S64 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

Organization–defined T-score of #–2.5 SD.

Table 4.1—Continued
However, it is now established that the
Visit consideration of other risk factors im-
proves the categorization of fracture risk
Initial Every follow-up Annual
(Table 4.4). There are factors beyond

Vitamin B12 if taking metformin for >5  
years
BMD that contribute to bone strength in

CBC with platelets   people with diabetes.

Serum potassium levels in people with   A low-trauma hip/pelvis, vertebral, or
diabetes on ACE inhibitors, ARBs, or forearm fracture in people aged $65 years
diuretics§ is diagnostic for osteoporosis independent

Calcium, vitamin D, and phosphorous for   of BMD and is one of the strongest risk

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

appropriate people with diabetes
factors for subsequent fractures, especially
ABI, ankle brachial index; ARBs, angiotensin receptor blockers; CBC, complete blood count; in the first 1–2 years after a fracture
CGM, continuous glucose monitor; FIB-4: fibrosis-4 index; MASLD, metabolic-associated stea- (37,38). Osteoporotic hip fractures are as-
totic liver disease; MDI, multiple daily injections; OSA, obstructive sleep apnea; PAD, periph- sociated with significant morbidity, mortal-
eral arterial disease. *Should be performed at every visit in people with diabetes with
ity, and societal costs (39). It is estimated
sensory loss, previous foot ulcers, or amputations. †At 65 years of age or older. ‡May also
need to be checked after initiation or dose changes of medications that affect these labora- that 20% of individuals do not survive to 1
tory values (i.e., diabetes medications, blood pressure medications, cholesterol medications, year after hip fracture, while 60% do not
or thyroid medications). ^In people without dyslipidemia and not on cholesterol-lowering regain their prior functionality, living with
therapy, testing may be less frequent. §May be needed more frequently in people with dia- permanent disability (40).
betes with known chronic kidney disease or with changes in medications that affect kidney Hip fractures in people with diabetes
function and serum potassium (see Table 11.2). jjIn people with presence of gastrointestinal
are associated with higher risk of mor-
symptoms, signs, laboratory manifestations, or clinical suspicion suggestive of celiac disease.
tality (28% in women and 57% in men),
longer recovery, and delayed healing
(41) compared with individuals without
disorders such as polyglandular autoim- a known association with higher diabetes.
mune syndromes (34). Given the high fracture risk (e.g., thiazolidinediones
prevalence, nonspecific symptoms, and in- and sulfonylureas) is recommended, Epidemiology and Risk Factors
sidious onset of primary hypothyroidism, particularly for those at elevated Age-specific fracture risk is significantly
routine screening for thyroid dysfunction risk for fractures. B increased in people with type 1 or type 2
is recommended for all people with type 1 4.11 To reduce the risk of falls and diabetes in both sexes, with a 34% in-
diabetes. Screening for celiac disease fractures, glycemic management goals crease in fracture risk compared with
should be considered in adults with dia- should be individualized for people those without diabetes (42).
betes with suggestive symptoms (e.g., with diabetes at a higher risk of fracture.
diarrhea, malabsorption, and abdominal C Prioritize use of glucose-lowering Type 1 Diabetes. Fracture risk in people
pain) or signs (e.g., osteoporosis, vitamin medications that are associated with with type 1 diabetes is increased by 4.35
deficiencies, and iron deficiency anemia) low risk for hypoglycemia to avoid times for hip fractures, 1.83 times for up-
(35,36). Measurement of vitamin B12 lev- falls. B per limb fractures, and 1.97 times for an-
els should be considered for people with 4.12 Advise people with diabetes kle fractures (43). Fractures occur even
type 1 diabetes and peripheral neuropa- on their intake of calcium (1,000– at young ages, 10–15 years earlier than
thy or unexplained anemia. 1,200 mg/day) and vitamin D to en- they do in people without diabetes, and
sure it meets the recommended are less frequent at the vertebral level.
Bone Health daily allowance for those at risk for Type 1 diabetes is often associated with
Recommendations fracture, either through their diet or low bone mass, although BMD underes-
4.8 Assess fracture risk in older adults supplemental means. B timates the high risk of fracture observed
with diabetes as a part of routine care 4.13 Antiresorptive medications and in young individuals (43). Risk of fracture is
in diabetes clinical practice, according osteoanabolic agents should be recom- increased in people with type 1 diabetes
to risk factors and comorbidities. A mended for older adults with diabetes with microvascular complications or neurop-
4.9 Monitor bone mineral density us- who are at higher risk of fracture, in- athy (41). Moreover, average A1C >7.9%
ing dual-energy X-ray absorptiometry cluding those with low bone mineral (risk ratio [RR] 3.57 [CI 1.08–11.78]), dura-
in older adults with diabetes (aged density with a T-score #2.0, history tion of diabetes >26 years (RR 7.6 [CI
$65 years) and younger individuals of fragility fracture, or elevated Frac- 1.67–34.6]), and family history of fractures
ture Risk Assessment Tool score ($3% (RR 2.64 [CI 1.15–6.09]) have been inde-
with diabetes and multiple risk factors
for hip fracture or $20% for major os- pendently associated with high risk of non-
every 2–3 years (Table 4.4). A
teoporotic fracture). B vertebral fractures (44).
4.10 Consider the potential adverse
impact on skeletal health when se-
Type 2 Diabetes. In people with type 2 di-
lecting pharmacological options to
Determination of fracture risk traditionally abetes, even with normal or higher BMD,
lower glucose levels in people with
has relied on measurements of bone min- hip fracture risk is increased by 1.79
diabetes. Avoiding medications with
eral density (BMD) and the World Health times, and risk throughout life is 40–70%
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S65

[95% CI 1.65–3.01]) (58,59). According to

Table 4.2—Essential components for assessment, planning, and referral
the Action to Control Cardiovascular Risk
Assessing risk of diabetes complications in Diabetes (ACCORD) study, reduced risk

ASCVD and heart failure history is noted in women who had discontinued

ASCVD risk factors and 10-year ASCVD risk assessment

Staging of chronic kidney disease (see Table 11.2)
TZD use for 1–2 years (HR 0.57 [95% CI

Hypoglycemia risk (see Section 6, “Glycemic Targets and Hypoglycemia Prevention”) 0.35–0.92]) or >2 years (HR 0.42 [95% CI

Assessment for retinopathy 0.24–0.74]) compared with current users

Assessment for neuropathy (60). Furthermore, individuals with type 2

Assessment for MASLD and MASH diabetes on insulin (RR 1.49 [95% CI
Goal setting 1.29–1.73]) or sulfonylurea (RR 1.30

Set A1C, blood glucose, and time in range goals [95% CI 1.18–1.43]) treatment exhibit a

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

Set lipid goal heightened fracture risk (61).

If hypertension is present, establish blood pressure goal

Weight management and physical activity goals
Screening

Diabetes self-management goals
Most evidence on screening in individuals
Therapeutic treatment plans
at risk for fracture is available from peo-

Lifestyle management (e.g., registered dietitian nutritionist)

Pharmacologic therapy: glucose lowering
ple with type 2 diabetes; fracture risk

Pharmacologic therapy: cardiovascular and kidney disease risk factors prediction using BMD in type 1 diabetes

Weight management with pharmacotherapy or metabolic surgery, as appropriate has not been extensively studied. Health

Use of glucose monitoring and insulin delivery devices care professionals should assess fracture

Referral to diabetes education and medical specialists (as needed) history and risk factors in people with di-
Referrals for initial care management abetes and recommend measurement of

Eye care professional for annual dilated eye exam BMD if appropriate according to the indi-

Family planning for individuals of childbearing potential vidual’s age and sex.

Registered dietitian nutritionist for medical nutrition therapy

Diabetes self-management education and support

Dentist for comprehensive dental and periodontal examination
Type 2 Diabetes. People with type 2 diabe-

Behavioral health professional, if indicated tes have 5–10% higher BMD than people

Audiology, if indicated without diabetes, although they present

Social worker and community resources, if indicated with lower bone strength, impaired bone

Rehabilitation medicine or another relevant health care professional for physical and microarchitecture, and accelerated bone
cognitive disability evaluation, if indicated
loss (49,62–64). A T-score adjustment of

Other appropriate health care professionals
0.5 has been proposed to improve frac-
Assessment and treatment planning are essential components of initial and all follow-up vis- ture prediction by dual-energy X-ray ab-
its. ASCVD, atherosclerotic cardiovascular disease; MASH, metabolic dysfunction–associated sorptiometry (DXA). For example, a T-score
steatohepatitis; MASLD, metabolic dysfunction–associated steatotic liver disease.
#–2.0 should be interpreted as equivalent
to –2.5 in a person without diabetes (50).
higher than in it is in individuals without skeletal sites (RR 1.52 [95% CI 1.23–1.88]) Notably, the Fracture Risk Assessment Tool
diabetes (42,45–47). According to a meta- (51). A Japanese study echoed these find- (FRAX), although useful, does not factor in
analysis that included 15 studies, people ings, showing a fracture risk increase (haz- type 2 diabetes; an inclusion of the condi-
with type 2 diabetes had a 35% higher in- ard ratio [HR] 2.24 [95% CI 1.56–3.21]) tion is estimated to mirror the effect of ei-
cidence of vertebral fractures, causing in- with severe hypoglycemia episodes (53). ther a 10-year age increase or a 0.5 SD
creased risk of mortality (HR 2.11 [95% CI Longer disease duration further ele- reduction in BMD T-score (65). Fracture
1.72–2.59]) (48). Fracture risk is also in- vates fracture risk (54); data indicate indi- risk was higher in large observational stud-
creased in the upper limbs and ankle. viduals who have had type 2 diabetes for ies in participants with diabetes compared
However, bone loss is accelerated, and >10 years face significantly higher frac- with those without diabetes for a given
low BMD remains an independent risk ture risks, which are largely attributed to T-score and age or for a given FRAX score
factor for fractures (49,50). ensuing microvascular and macrovascular (50). One method to potentially improve
Glycemic management significantly im- damage affecting the skeleton. Additionally, fracture risk prediction for people with
pacts fracture risk in people with diabetes. high fracture risk is seen in people with type 2 diabetes involves using the FRAX
A meta-analysis revealed an 8% increased cardiovascular disease (CVD), nephropathy, “rheumatoid arthritis” input as a proxy for
fracture risk per 1% rise in A1C level (RR retinopathy, neuropathy, poor physical diabetes risk (66,67). Additionally, perfor-
1.08 [95% CI 1.03–1.14]) (51). Poor glyce- function, and frequent falls (55–57). mance of FRAX can be improved by using
mic management (A1C >9%) over 2 years Certain glucose-lowering medications 1) trabecular bone score adjustment, 2)
in individuals with type 2 diabetes corre- also factor into fracture risk. Studies have lowering femoral neck T-score input by
lated with a 29% heightened fracture risk reported increased fracture incidences in 0.5 SD, or 3) increasing the age by 10
(52). Notably, this risk was higher among women using thiazolidinediones (TZD), years (66). Growing evidence suggests
White individuals than in other racial with the risk doubling with 1–2 years of that fracture risk prediction is enhanced
groups. Hypoglycemia also escalated the TZD use compared with placebo or other by use of trabecular bone score (65,66),
risk of fractures at the hip and other glucose-lowering medications (HR 2.23 although such studies are not available for
S66 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

Table 4.3—Highly recommended immunizations for adults with diabetes (from the Advisory Committee on Immunization
Practices and Centers for Disease Control and Prevention)
Vaccine Recommended ages Schedule GRADE evidence type* References
COVID-19 All people 6 months of age and Current initial vaccination Centers for Disease Control and
older and boosters Prevention, Interim Clinical
Considerations for Use of COVID-19
Vaccines in the United States (318)
Hepatitis B Adults with diabetes aged Weng et al., Universal Hepatitis B
<60 years; for adults aged Vaccination in Adults Aged 19–59
$60 years, hepatitis B vaccine Years: Updated Recommendations
may be administered at the of the Advisory Committee on

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

discretion of the treating Immunization Practices—United
clinician based on the person’s States, 2022 (19)
likelihood of acquiring
hepatitis B infection

Influenza All people with diabetes advised Annual Centers for Disease Control and
to receive a trivalent influenza Prevention, Prevention and Control
vaccine and not to receive live of Seasonal Influenza with Vaccines:
attenuated influenza vaccine Recommendations of the Advisory
Committee on Immunization
Practices—United States, 2024–25
Influenza Season (22)

Pneumonia (PPSV23 19–64 years of age, vaccinate One dose is recommended for those who 2 Centers for Disease Control and
[Pneumovax]) with Pneumovax previously received PCV13; if PCV15 Prevention, Updated
was used, follow with PPSV23 $1 year Recommendations for Prevention of
later; PPSV23 is not indicated after Invasive Pneumococcal Disease
PCV20; adults who received only Among Adults Using the 23-Valent
PPSV23 may receive PCV15 or PCV20 Pneumococcal Polysaccharide
$1 year after their last dose Vaccine (PPSV23) (24,319)
$65 years of age One dose is recommended for those 2 Falkenhorst et al., Effectiveness of the
who previously received PCV13; if 23-Valent Pneumococcal
PCV15 was used, follow with PPSV23 Polysaccharide Vaccine (PPV23)
$1 year later; PPSV23 is not Against Pneumococcal Disease in
indicated after PCV20; adults who the Elderly: Systematic Review and
received only PPSV23 may receive Meta-analysis (24,320)
PCV15 or PCV20 $1 year after their
last dose

PCV20 or PCV15 Adults 19–64 years of age with One dose of PCV15 or PCV20 is Kobayashi et al., Use of 15-Valent
an immunocompromising recommended by the Centers for Pneumococcal Conjugate Vaccine
condition (e.g., chronic renal Disease Control and Prevention and 20-Valent Pneumococcal
failure), cochlear implant, or Conjugate Vaccine Among U.S.
cerebrospinal fluid leak Adults: Updated Recommendations
Adults 19–64 years of age, For those who have never received any of the Advisory Committee on
immunocompetent pneumococcal vaccine, the Centers Immunization Practices—United
for Disease Control and Prevention States, 2022 (24, 321)
recommends one dose of PCV15 or
PCV20
$65 years of age, One dose of PCV15 or PCV20; PCSV23
immunocompetent, have may be given $8 weeks after PCV15;
shared decision-making PPSV23 is not indicated after PCV20
discussion with health care
professionals
RSV Older adults $60 years of age Adults aged $75 years and those aged Centers for Disease Control and
with diabetes appear to be a $60 years and at high risk may Prevention, CDC Recommends RSV
risk group receive a single dose of an RSV Vaccine for Older Adults (25)
vaccine

Tetanus, diphtheria, All adults; pregnant individuals Booster every 10 years 2 for effectiveness, Havers et al., Use of Tetanus Toxoid,
pertussis (Tdap) should have an extra dose 3 for safety Reduced Diphtheria Toxoid, and
Acellular Pertussis Vaccines:
Updated Recommendations of the
Advisory Committee on
Immunization Practices—United
States, 2019 (322)

Continued on p. S67
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S67

Table 4.3—Continued
Vaccine Recommended ages Schedule GRADE evidence type* References
Zoster $50 years of age Two-dose Shingrix, even if previously 1 Dooling et al., Recommendations of
vaccinated the Advisory Committee on
Immunization Practices for Use of
Herpes Zoster Vaccines (323)

For a comprehensive list of vaccines, refer to the Centers for Disease Control and Prevention web site at cdc.gov/vaccines/. Advisory Commit-
tee on Immunization Practices recommendations can be found at cdc.gov/vaccines/acip/recommendations. GRADE, Grading of Recommenda-
tions Assessment, Development, and Evaluation; PCV13, 13-valent pneumococcal conjugate vaccine; PCV15, 15-valent pneumococcal
conjugate vaccine; PCV 20, 20-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine. *Evidence
type: 1, randomized controlled trials (RCTs) or overwhelming evidence from observational studies; 2, RCTs with important limitations or excep-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

tionally strong evidence from observational studies; 3, observational studies or RCTs with notable limitations; 4, clinical experience and obser-
vations, observational studies with important limitations, or RCTs with several major limitations.

individuals with type 1 diabetes and are are commonly used in clinical practice to to factors like poor vision, neuropathy, sar-
based on data from the U.S. or Canada. monitor bone formation and bone re- copenia, and impaired gait. Health care
In people with type 2 diabetes, BMD sorption, although they are suppressed professionals should advocate moderate
should be monitored by DXA scan in in people with diabetes and have not physical activity to enhance muscle health,
older adults (aged $65 years) in the been shown to predict fracture risk (69). gait coordination, and balance as part of
absence of other comorbidities and in fracture preventive strategies (56,57,71).
younger individuals (>50 years of age) Type 1 Diabetes. Because hip fracture Aerobic and weight-bearing exercise
with bone or diabetes-related risk factors, risk in type 1 diabetes starts to increase should be recommended to counteract
such as insulin use or diabetes duration after the age of 50, clinicians may consider the potential negative effect of weight
>10 years (Table 4.4). Reassessment is assessing BMD after the 5th decade of loss on bone; specific guidelines have
recommended every 2–3 years (65), life (43). In people with type 1 diabetes, been published for older adults with
depending on the screening evaluation BMD underestimates fracture risk, but type 2 diabetes (72).
and the presence of additional risk fac- studies do not address the extent of un- Osteoporosis and fracture prevention
tors, although the evidence on how fre- derestimation of fracture risk. are first based on measures applied to
quently DXA should be repeated is less According to the International Society the general population. All people with
robust. According to the European Asso- for Pediatric and Adolescent Diabetes diabetes should receive an adequate daily
ciation for the Study of Obesity (EASO), (ISPAD), regular assessment of bone health intake of proteins, calcium, and vitamin D,
DXA should be performed every 2 years using bone densitometry in youth with stop smoking, and have regular physical
in subjects undergoing bariatric-metabolic type 1 diabetes is still controversial and not activity (73–75).
surgery. recommended, but it may be considered in Intake of calcium should reflect the
DXA-assisted vertebral fracture assess- association with celiac disease (70). age-specific recommendations for the
ment is a convenient and low-cost method general population and should be ob-
to assess vertebral fractures, although tradi- Management tained through diet and/or oral supple-
tional lateral thoracic/lumbar spine X-ray is Appropriate glycemic management and ments (76).
still considered the gold standard (68). MRI minimizing hypoglycemic episodes are cru- The optimal level of 25-hydroxyvita-
or computed tomography imaging studies cial for bone health in people with diabe- min D is a matter of controversy (77),
performed for other purposes should be tes. Individuals with prolonged disease, although serum levels 20–30 ng/mL are
analyzed for presence of vertebral frac- microvascular and macrovascular complica- generally thought to be sufficient (78).
tures as well as chest X-rays in hospital- tions, or frequent hypoglycemic episodes The safe upper limit is also a matter of
ized individuals. Bone turnover markers face higher fracture risks and fall risks due debate, and there is substantial disagree-
ment over whether to treat to a specified
Table 4.4—Diagnostic assessment
serum level. In the U.S., the recommended
daily allowance of vitamin D is 600 IU for
Individuals who should receive BMD testing
people aged 51–70 years and 800 IU for
People aged $65 years people aged >70 years (78). In clinical
Postmenopausal women and men aged $50 years with history of adult-age fracture or practice, this dose of supplement may not
with diabetes–specific risk factors: be sufficient to reach recommended se-

Frequent hypoglycemic events rum levels of vitamin D, particularly in

Diabetes duration >10 years
those at risk for vitamin D deficiency, and

Diabetes medications: insulin, thiazolidinediones, sulfonylureas

A1C >8% therefore supplementation should be

Peripheral or autonomic neuropathy, retinopathy, nephropathy individualized.

Frequent falls Fractures are important determinants

Glucocorticoid use of frailty, a predisability condition that
should be mitigated with individualized
S68 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

interventions to prevent falls, maintain There are some additional considera- bone metabolism. Medications other than
mobility, and delay disability (72). In many tions related to medication selection in TZDs are advisable for postmenopausal
circumstances, conservative management people with diabetes. Data from a phase 3 women or older men with type 2 diabetes
(calcium, vitamin D, and lifestyle meas- trial, Future Revascularization Evaluation due to their safer bone health profiles.
ures) are not enough to reduce fracture in Patients With Diabetes Mellitus: Opti- While several studies have shown metfor-
risk. When pharmacological treatment is mal Management of Multivessel Disease min to have a safe profile, special atten-
needed, treatment initiation strategies are (FREEDOM), and its 10-year extension tion should be paid to the wide use of
the same as those used for the general have shown that people with diabetes sulfonylureas because of the high risk of
population. Antiosteoporosis medications treated with denosumab experienced pos- hypoglycemic events leading to falls and
reduce bone resorption (bisphosphonates, itive effects on fasting glucose (82) and sig- fractures (87). Dipeptidyl peptidase 4 in-
selective estrogen receptor modulators, nificant improvements in BMD and lower hibitors and glucagon-like peptide 1 re-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

and denosumab), stimulate bone forma- vertebral fracture risk (67). However, ac- ceptor agonists (GLP-1 RAs) have been
tion (teriparatide and abaloparatide), or cording to a post hoc subgroup analysis, a used in clinical practice for more than
have dual actions by stimulating bone higher risk of nonvertebral fractures was 15 years, and both clinical trials and
formation and reducing bone resorption observed in people with diabetes treated postmarketing data suggest a neutral im-
(romosozumab). These agents improve with denosumab (67). Romosozumab re- pact on bone health (88,89). Tirzepatide
bone density and reduce the risk of ver- ceived FDA approval with a box warning may play a positive effect through glucose-
tebral and nonvertebral fractures. Al- because it may increase risk of myocardial dependent insulinotropic polypeptide (GIP)
though there are no studies specifically infarction, stroke, or cardiovascular death receptor agonism, preventing bone loss as-
designed for people with diabetes, data on and should not be prescribed in women sociated with weight loss (90), although
antiresorptive and osteoanabolic agents who experienced a myocardial infarction bone outcomes have not yet been reported
suggest efficacy in type 2 diabetes is similar or a stroke within the past year (83,84). in clinical data.
to that for individuals without diabetes Use of sodium–glucose cotransporter 2
(79–81). Using individual participant data Secondary Prevention of Fragility Frac-
(SGLT2) inhibitors has raised some con-
from randomized trials, antiresorptive ther- tures. The risk of subsequent fracture in
cerns. The Canagliflozin Cardiovascular As-
apies show similar effects in people with individuals with hip or vertebral fracture
sessment Study (CANVAS) study showed
and without type 2 diabetes for vertebral, is high, especially in the first 1–2 years
that the proportion of subjects with frac-
hip, and nonvertebral fractures (79). No after a fracture. Antiosteoporosis treat-
ture was higher in the canagliflozin groups
similar studies of efficacy of antiosteoporo- ment reduces the risk of fracture in older
than the noncanagliflozin groups (2.7% vs.
sis treatment in people with type 1 diabe- individuals with prior hip or vertebral
1.9%, respectively). Further analyses from
tes have been published. fracture.
the same trial and from the Canagliflozin
As in the general population, people
and Renal Events in Diabetes with Estab-
Primary Prevention of Fragility Fractures with diabetes who experience fragility
lished Nephropathy Clinical Evaluation
in People With Diabetes. In the general fracture should 1) be given the diagnosis
population, a T-score #–2.5 is the thresh- (CREDENCE) study found a neutral effect
of osteoporosis regardless of DXA data
old to consider pharmacological treatment on fracture risk (91–94). Although few
and 2) receive the appropriate work-up
for osteoporosis. In type 2 diabetes, since and therapy to prevent future fractures data are available, use of empagliflozin,
T-score underestimates fracture risk (as (85). Individuals on long-term treatment ertugliflozin, or dapagliflozin has not been
discussed above), a T-score #–2.0 may be with antiosteoporosis medications, with associated with negative effects on bone
more appropriate for considering initiation multiple fragility fractures, or with multi- health (93–95). Use of insulin has been
of a first-line drug, including bisphospho- ple comorbidities should be referred to a shown to be associated with a doubling of
nates (alendronate, risedronate, and zole- bone metabolic specialist. In these more the risk of hip fractures (87), likely because
dronic acid) or denosumab. complicated cases, a bone specialist may of higher risk of hypoglycemia, longer du-
Denosumab is preferred in individuals choose to initiate an osteoanabolic agent ration of the disease, and comorbidities
with estimated glomerular filtration rate to optimize bone formation and reduce that may contribute to diminished bone
<30–35 mL/min/1.73 m2, although the immediate fracture risk (86). It is strongly strength.
FDA has recently issued a boxed warning recommended that all individuals with a In conclusion, glucose-lowering medica-
for increased risk of severe hypocalcemia fragility fracture be started on antiosteo- tions with a good bone safety profile are
in individuals with advanced chronic kid- porosis therapy and adequate calcium preferred. This is especially true in older
ney disease. Self-management abilities of and vitamin D supplementation (if re- adults, in people with longer duration of
the person with diabetes should be con- quired) as soon as possible. In the appro- disease, or in people with complications.
sidered in medication selection, recom- priate individual, therapy may even be Aggressive therapeutic approaches should
mending strict medication-taking behavior, initiated during an inpatient stay to re- be avoided in those who are frail and in
as there can be rebound bone loss causing duce care delays (85). older adults to prevent hypoglycemic
multiple vertebral fractures with missed events and falls.
doses of denosumab or delays in care. Glucose-Lowering Medications and Bone
Bisphosphonate therapy (oral or intrave- Health Cancer
nous) may be more appropriate in individ- Care plans for type 2 diabetes treatment Diabetes is associated with increased
uals with poor medication-taking behavior should consider individual fracture risk risk of cancers of the liver, pancreas, en-
or gaps in access to medical care. and the potential effect of medications on dometrium, colon and rectum, breast,
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S69

and bladder (96). The association may diabetes than people without Alzheimer In type 2 diabetes, severe hypoglycemia
result from shared risk factors between dementia. In a 15-year prospective study is associated with reduced cognitive func-
type 2 diabetes and cancer (older age, of community-dwelling people >60 years tion, and those with poor cognitive function
obesity, and physical inactivity) but may of age, the presence of diabetes at base- have more severe or repeated episodes of
also be due to diabetes-related factors line significantly increased the age-and hypoglycemia. Multiple observational stud-
(97), such as underlying disease physiol- sex-adjusted incidence of all-cause demen- ies of adults with diabetes have found an
ogy or diabetes treatments, although evi- tia, Alzheimer dementia, and vascular de- association between severe hypoglyce-
dence for these links is scarce. People mentia compared with rates in those with mic episodes and cognitive decline or in-
with diabetes should be encouraged normal glucose tolerance (105). A new cident dementia (113–116). Decreased
to undergo recommended age-and sex- clinical entity of diabetes-related dementia cognitive function also increases the risk
appropriate cancer screenings, coordinated is being recognized as distinct from for severe hypoglycemia, likely through

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

with their primary health care professional, Alzheimer dementia or vascular dementia. impaired ability to recognize and respond
and to reduce their modifiable cancer It is characterized by slow progression of appropriately to hypoglycemic symptoms
risk factors (obesity, physical inactivity, dementia, absence of typical neuroimag- (113,117,118). Additionally, long-term follow-
and smoking). New onset of atypical dia- ing findings seen in Alzheimer or vascu- up of Diabetes Control and Complica-
betes (lean body habitus and negative lar dementia, old age, high A1C levels, tions Trial/Epidemiology of Diabetes In-
family history) in a middle-aged or older long duration of diabetes, high fre- terventions and Complications (DCCT/
person may precede the diagnosis of quency of insulin use, frailty, and sarco- EDIC) showed recurrent severe hypogly-
pancreatic adenocarcinoma (98). Addi- penia or dynapenia (106). See Section cemia was associated with the highest
tionally, in a nationwide cancer registry in 13, “Older Adults,” for a more detailed risk of long-term psychomotor and men-
New Zealand, postpancreatitis diabetes discussion regarding assessment of tal function decline (119). Simplifying or
mellitus was associated with significantly cognitive impairment. deintensifying glycemic therapy and/or
higher risk (2.4-fold) of pancreatic cancer
liberalizing A1C goals may prevent hypo-
compared with pancreatitis after type 2 Glycemic Status and Cognition glycemia in individuals with cognitive dys-
diabetes (99). However, in the absence In individuals with diabetes, higher A1C function. See Section 13, “Older Adults,”
of other symptoms (e.g., weight loss and level is associated with lower cognitive for more detailed discussion of hypogly-
abdominal pain), routine screening for function (107). A meta-analysis of ran- cemia in older people with type 1 and
pancreatic cancer is not currently recom- domized trials found that intensive glyce- type 2 diabetes.
mended. Metformin and sulfonylureas mic management, compared with higher
may have anticancer properties. Data for
A1C goals, was associated with a slightly Dental Care
pioglitazone are mixed, with a previous
lower rate of cognitive decline (108). How-
concern for bladder cancer association. Recommendations
ever, these findings were driven by an 4.15 People with diabetes should be
Recommendations cannot be made at
this time (100–102). Thus far, the use of older study with an A1C goal of <7.0% in referred for a dental exam at least
GLP-1 RAs has not been shown to be as- the intensive treatment arm. Analyses once per year. E
sociated with the incidence of thyroid within the ACCORD, Action in Diabetes and 4.16 Coordinate efforts between the
cancer, pancreatic cancer, or any other Vascular Disease: Preterax and Diamicron medical and dental teams to appropri-
type of cancer in humans (103). MR Controlled Evaluation (ADVANCE), and ately adjust glucose-lowering medica-
Veterans Affairs Diabetes Trial (VADT) studies tion and treatment plans prior to and
Cognitive Impairment/Dementia found that intensive glycemic management in the post–dental procedure period
(A1C goal of <6.0–6.5%) resulted in no dif- as needed. B
Recommendation
4.14 In the presence of cognitive im- ferences in cognitive outcomes compared
pairment, diabetes treatment plans with standard control (108–110). Therefore,
Periodontal disease is more severe, and
should be simplified as much as pos- intensive glycemic management should not
may be more prevalent, in people with
sible and tailored to minimize the be advised for the improvement of cogni-
diabetes than in those without and has
risk of hypoglycemia. B tive function in individuals with type 2
been associated with higher A1C levels
diabetes. Additionally, people with type 2 (120–122). Longitudinal studies suggest
diabetes and dementia are at heightened that people with periodontal disease
Diabetes is associated with a significantly
risk for experiencing hyperglycemic crises have higher rates of incident diabetes.
increased risk and rate of cognitive de-
(diabetic ketoacidosis and hyperglycemic Current evidence suggests that periodon-
cline and an increased risk of dementia
hyperosmolar state) compared with people tal disease adversely affects diabetes out-
(104). A meta-analysis of prospective ob-
servational studies found that individuals without dementia (111), underscoring the comes, and periodontal treatment using
with diabetes had a 43% higher risk of all importance of supporting diabetes man- subgingival instrumentation may improve
types of dementia, a 43% higher risk of agement for individuals experiencing cogni- glycemic outcomes (123,124). In a ran-
Alzheimer dementia, and a 91% higher tive decline and diminished capacity for domized controlled trial (RCT), intensive
risk of vascular dementia compared with self-care. In addition, these individuals have periodontal treatment was associated
individuals without diabetes (104). The re- increased difficulty with complex treatment with better glycemic outcomes (A1C 8.3%
verse is also true: people with Alzheimer and monitoring plans and are at risk of vs. 7.8% in control subjects and the inten-
dementia are more likely to develop frailty, hypoglycemia, and disability (112). sive-treatment group, respectively) and
S70 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

reduction in inflammatory markers after A disability is defined as a physical or retinopathy, autonomic neuropathy, and
12 months of follow-up (125). mental impairment that substantially peripheral neuropathy, it is important to
Dental health professionals should be limits one or more major life activities recognize the disabilities caused by macro-
included in the diabetes care team (126). of an individual (131,132). Activities of vascular complications of diabetes. These
Early detection of oral health problems by daily living (ADLs) and instrumental ac- macrovascular complications, which include
clinicians may be helpful to promote tivities of daily living (IADLs) comprise coronary heart disease, stroke, and periph-
prompt referral to dental care and mitigate basic and complex life care tasks, re- eral arterial disease, can lead to further im-
the expensive and extensive procedures spectively. The capacity to accomplish pairments (134).
needed to treat advanced oral disease such tasks serves as an important mea- An assessment of disability should be per-
(127,128). Clinical assessment of people sure of function. Diabetes is associated formed as necessary with referrals made
with diabetes should include a dental his- with an increase in the risk of work and to appropriate health care professionals

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

tory, and dental professionals should be in- physical disability, with estimates of specializing in disability (e.g., physical
formed about key aspects of the person’s 50–80% increased risk of disability for medicine and rehabilitation physician,
health and diabetes treatment plan, in- people with diabetes compared with physical therapist, occupational therapist,
cluding glycemic goals, medications, and people without diabetes (133). Reviews or speech-language pathologist) (133,141,
comorbid conditions (127,128). It is impor- have shown that lower-body functional 142). Customized rehabilitation interven-
tant for dental professionals to know limitation was the most prevalent dis- tions for individuals with a disability from
when people with diabetes have high A1C ability (47–84%) among people with dia- diabetes can recover function, allowing for
levels, as this population may have lower betes (134,135). In a systematic review safe physical activity (143), and improve
oral healing capacity (129,130). Hepatic, and meta-analysis, the presence of dia- quality of life (144). Additionally, frailty is
renal, and pulmonary conditions should betes increased the risk of mobility dis- commonly associated with diabetes, with
also be known by dental professionals to ability (15 studies; odds ratio [OR] 1.71 progression to disability, morbidity, and
assist in appropriate dosing of antibiotics [95% CI 1.53–1.91]; RR 1.51 [95% CI mortality in older adults. People with dia-
and other medications. Coordination be- 1.38–1.64]), of IADL disability (10 stud- betes as well as frailty or disability may
tween dental professionals and the diabe- ies; OR 1.65 [95% CI 1.55–1.74]), and of contend with comorbid conditions such as
tes care team will be especially important ADL disability (16 studies; OR 1.82 [95% CI hypoglycemia, sarcopenia, falls, and cogni-
for people treated with insulin, sulfonylur- 1.63–2.04]; RR 1.82 [95% CI 1.40–2.36]) tive dysfunction. A thorough medical eval-
eas, or meglitinides who are at risk of hy- (133). The mechanisms underlying disabil- uation is imperative to identify the best
poglycemia during dental procedures, ity are multifactorial and include obesity, approaches to preventative and therapeu-
especially if fasting. The risk of hypoglyce- coronary artery disease, stroke, lower ex- tic interventions for frailty and diabetes
mia can be mitigated by coordination be- tremity complications, and physiological management (145).
tween the dentist and treating clinician factors such as hyperglycemia, sarcopenia, To assess the impact of diabetes on an
prior to the procedure to make a hypogly- inflammation, and insulin resistance (136). individual’s daily functioning, clinicians
cemia prevention plan, which may include Diabetic peripheral neuropathy (DPN) should consider evaluating their ability to
medication adjustment, blood glucose is a common complication of both type 1 perform ADLs and IADLs, ensuring they
monitoring before and during the proce- and 2 diabetes and may cause impaired can manage basic self-care and more
dure, and treatment of hypoglycemia if ap- postural balance and gait kinematics complex tasks necessary for specific living
propriate. Therefore, dental professionals (137), leading to functional disability. situations, services, and supports. A psy-
caring for people with diabetes should DPN can be found in up to half of peo- chosocial assessment should be conducted
have access to blood glucose monitors ple with type 1 or type 2 diabetes, result- to screen for behavioral health conditions
during procedures as well as carbohy- ing in physical disability, and neuropathic like depression and anxiety and to under-
drates and glucagon to treat any hypo- pain, resulting in a diminished quality of stand the individual’s social support and
glycemia that occurs. life (138). Glycemic management pre- coping mechanisms. Functional capacity
vents DPN development in type 1 diabe- evaluations, involving tests for physical en-
Disability tes; in contrast, glycemic management durance and strength, are used to gauge
Recommendation
has modest or no benefit in individuals the ability of the person with diabetes to
with type 2 diabetes, possibly due to the work and carry out daily activities. Addi-
4.17 Assess for disability at the initial
combined effect of coexisting comorbid- tionally, standardized disability question-
visit and for decline in function at
each subsequent visit in people with ities (138). People with lower-extremity naires and scales, such as the Diabetes
diabetes. If a disability is impacting involvement due to DPN have 3 times Distress Scale (DDS) and the World Health
functional ability or capacity to man- more risk of restricted mobility, resulting Organization Disability Assessment Sched-
age their diabetes, a referral should in people with DPN experiencing more ule (WHODAS 2.0), are employed to mea-
be made to an appropriate health physical dysfunctions and impairments sure the emotional burden of diabetes and
care professional specializing in disabil- than people who have diabetes but not overall disability (146,147). These sug-
ity (e.g., physical medicine and reha- neuropathy (139). Furthermore, DPN may gested structured assessments are particu-
bilitation specialist, physical therapist, progress to nontraumatic lower-limb am- larly relevant if individuals have fallen, had
occupational therapist, or speech- putation, which significantly impacts qual- emergency department visits, missed ap-
language pathologist). C ity of life (140). pointments, made significant errors in the
In addition to complications of diabetes treatment plan, or exhibit apathy and de-
from microvascular conditions such as CKD, pressed mood.
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S71

Moreover, when treating people with replacement in men with symptomatic hy- factor (159), although the most likely pri-
an acquired disability from diabetes, it pogonadism may have benefits, including mary underlying risk factor is vascular dis-
is vital to consider social determinants improved sexual function, well-being, mus- ease (159).
of health, race and ethnicity, and socio- cle mass and strength, and bone density Men with diabetes are at increased
economic status (148). Rates of diabetes- (156). In men with diabetes who have risk for both CVD and ED, and ED is a pre-
related major amputations are higher in symptoms or signs of low testosterone (hy- dictor of cardiovascular events in men
individuals who are from racial and ethnic pogonadism), a morning total testosterone with diabetes (163,164) as well as in
minoritized groups (149), live in rural level should be measured using an accu- men without diabetes. The significant
areas, and are from regions with the low- rate and reliable assay (157). In men who factors associated with ED in men with
est socioeconomic levels (150). Address- have total testosterone levels close to the diabetes are age, peripheral or auto-
ing the complex challenges faced by lower limit, it is reasonable to determine nomic neuropathy, presence of micro-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

individuals with acquired disabilities from free testosterone concentrations either di- vascular disease including retinopathy,
diabetes requires a multifaceted approach rectly from equilibrium dialysis assays or by CVD, duration of diabetes, poor glycemic
involving solutions from both within and calculations that use total testosterone, sex management, hypogonadism, and diuretic
outside the health care system. By hormone binding globulin, and albumin therapy (165). Physical activity may be pro-
focusing on social determinants of health, concentrations (157). Further tests (such tective. Men with diabetes and ED report
health care professionals can develop as luteinizing hormone and follicle- a significant decline in quality-of-life meas-
appropriate interventions, provide advo- stimulating hormone levels) may be needed ures and an increase in depressive symp-
cacy, and establish support systems that to further evaluate the individual. Testoster- toms (166), and depression is a well-
cater to the specific needs of this popu- one replacement in older men with hypogo- recognized risk factor for ED. Given the
lation. See Section 1, “Improving Care nadism has been associated with increased bidirectional relationship between ED
and Promoting Health in Populations.” coronary artery plaque volume, with no and depression, treatment of either one
conclusive evidence that testosterone sup- can result in improvement in the other
Hepatitis C plementation is associated with increased condition. CKD is also a risk factor for
Infection with hepatitis C virus (HCV) is as- cardiovascular risk in all men with hypogo- CVD and ED, with prevalence rates of ED
sociated with a higher prevalence of type 2 nadism (157). Furthermore, erectile dys- >75% in men on hemodialysis (167).
diabetes, which is present in up to one- function (ED) is also common in people Awareness and identification of these
third of individuals with chronic HCV infec- with diabetes (158), and it is reasonable to characteristics, factors, and behaviors can
tion. HCV may impair glucose metabolism measure and correct testosterone levels guide clinicians in early screening, treat-
by several mechanisms, including directly close to the lower limit to address the de- ment, prevention, and counseling in all
via viral proteins and indirectly by altering sire component that contributes to erectile men with diabetes and particularly those
proinflammatory cytokine levels (151). The difficulties (159) (see ERECTILE DYSFUNCTION, be- at higher risk for ED (165). Given the evi-
use of newer direct-acting antiviral drugs low, for more information on evaluation dence that ED is strongly associated with
produces a sustained virological response and further discussion). diabetes and CVD, men with ED should
(cure) in nearly all cases and has been re- be evaluated and managed for cardiovas-
ported to improve glucose metabolism in Erectile Dysfunction cular and endocrine risk factors. Glycemic
individuals with diabetes (152). A meta- assessment in men not previously diag-
Recommendation
analysis of mostly observational studies nosed with diabetes, lipid profile, and
4.19 In men with diabetes or predia-
found a mean reduction in A1C levels of morning total testosterone should be
betes, screen for ED, particularly in
0.45% (95% CI –0.60 to –0.30) and reduced considered mandatory in all men newly
those with high cardiovascular risk,
requirement for glucose-lowering medica- presenting with ED (168).
retinopathy, cardiovascular disease,
tion use following successful eradication of In a recent meta-analysis, testosterone
chronic kidney disease, peripheral or
HCV infection (153). was superior to placebo in improving
autonomic neuropathy, longer dura-
erectile function in men with testoster-
tion of diabetes, depression, and hy-
Low Testosterone in Men one deficiency; however, the magnitude
pogonadism, and in those who are
of the effect was lower in the presence of
Recommendation not meeting glycemic goals. B
diabetes and obesity (169).
4.18 In men with diabetes or predi-
Meta-analyses show that all phosphodi-
abetes, inquire about sexual health
The most common sexual dysfunction in esterase type 5 inhibitors (PDE5Is) are su-
(e.g., low libido and erectile dys-
men is ED, with an estimated prevalence perior to placebo in treating ED, lower
function [ED]). If symptoms and/or
of 52.5% in men with diabetes (160). The dosages had effects comparable with those
signs of hypogonadism are detected
best predictors of ED are age (>40 years), of higher dosages, and various PDE5Is
(e.g., low libido, ED, and depres-
CVD, diabetes, hypertension, obesity, dys- show comparable efficacy (159). PDE5Is
sion), screen with a morning serum
lipidemia, metabolic syndrome, hypogo- are associated with an increased risk of
total testosterone level. B
nadism, smoking, depression, and use of headaches, flushing, and dyspepsia (159).
medications such as antidepressants and First-line therapy for ED in men with diabe-
Mean levels of testosterone are lower in opioids (161,162). Because diabetes, poor tes is PDE5Is, but men with diabetes may
men with diabetes than in age-matched nutrition, obesity, lack of exercise, and be less responsive than men without diabe-
men without diabetes, but obesity is a CVD are often interrelated, it may be tes (160). Strategies to improve response
major confounder (154,155). Testosterone challenging to identify the primary risk to PDE5Is include daily therapy and
S72 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

optimization of comorbidities. In men with problems with arousal, and 33–84% (vs. resulting in lack of initiation, and physi-
diabetes not responding to PDEIs, other po- 2–39%) report problems with orgasm; cal challenges such as pain, vaginal dry-
tentially effective treatments may include 33–66% (vs. 4–28%) report problems ness, and impaired sensitivity. Several
intracavernosal injections, intraurethral with lubrication, and 33–46% (vs. 8–39%) women explained that vaginal dryness
prostaglandin, vacuum erection devices, report problems with pain (173). was an obstacle during sexual inter-
and penile prosthetic surgery (160). The Diabetes MILES (Management and course, leading to pain or even refraining
Impact for Long-term Empowerment and from sexual activity. Sexual challenges
Female Sexual Dysfunction Success) study examined the prevalence of were perceived to become a source of
sexual dysfunction in sexually active women disappointment to the partners and con-
Recommendations
with type 1 or type 2 diabetes and the asso- sequential guilt for the women. Women
4.20 In women with diabetes or predi-
ciations between sexual dysfunction and also reported fear of hypoglycemia during

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

abetes, inquire about sexual health by
clinical and psychological variables. Over- sex, and some reported trying to maintain
screening for desire (libido), arousal,
all, 33% of women reported sexual dys- mild hyperglycemia. Technology devices,
and orgasm difficulties, particularly in
function (type 1, 36.0%; type 2, 26.2%). such as glucose monitors and insulin
those who experience depression
The prevalence of specific FSDs accord- pumps, could be perceived as both a phys-
and/or anxiety and those with recur-
ing to diabetes type was decreased de- ical and mental obstacle during sexual ac-
rent urinary tract infections. B
sire (type 1, 22%; type 2, 15%), decreased tivity (176).
4.21 In postmenopausal women with
arousal (type 1, 9%; type 2, 11%), lubrica- Women with type 2 (25%) or type 1
diabetes or prediabetes, screen for
tion problems (type 1, 19%; type 2, 14%), (17%) diabetes would like their health
symptoms and/or signs of genitouri-
and orgasmic dysfunction (type 1, 16%; care professional to initiate a discussion
nary syndrome of menopause, includ-
type 2, 15%) (173). on how diabetes is affecting their sex life
ing vaginal dryness and dyspareunia. B
Medical comorbidities that are risk fac- (177). Women with type 1 diabetes almost
tors for FSD include hypertension, obesity, unanimously endorsed that sexual health
Female sexual dysfunction (FSD) is common metabolic syndrome, smoking, and hyper- should be addressed, that they would find
in women with diabetes. In an epidemio- lipidemia. Clinical factors for consideration it a relief that they were not alone, that
logic cross-sectional study of community- include longer duration of diabetic retinop- they should be provided with information
residing middle-aged and older adults athy and neuropathy and individuals not when they are young, and that it would be
(57–85 years), women with diagnosed dia- meeting glycemic goals. The prevalence of difficult to address the topic themselves
betes were less likely than men with diag- FSD in women with end-stage kidney dis- (176). Unfortunately, many health care pro-
nosed diabetes (adjusted OR 0.28 [95% CI ease is 74% (174). fessionals do not actively discuss sexual
0.16–0.49]) and women without diabetes In women with diabetes, social and psy- functioning in consultations, meaning that
(0.63 [0.45–0.87]) to be sexually active chological components play a major role when the topic is discussed it is mostly the
(170). Older women with diabetes are as in FSD. Depression, anxiety, and emotional person with diabetes who initiates the con-
likely as men to have sexual problems but adjustments to diabetes have been found versation (170). This leads to a marked un-
are significantly less likely to have discussed to be associated with sexual dysfunctions derdiagnosis and undertreatment of sexual
sex with a physician (170). in women with diabetes. A study from dysfunctions in people with diabetes.
While studies showing the association Norway reported that women with type 1 While no specific guidelines are avail-
between diabetes and FSD are less conclu- diabetes with scores on the Female Sexual able for the treatment of FSD in this pop-
sive than those in men, most have reported Function Index (FSFI) (a validated instru- ulation, women with type 1 or type 2
a higher prevalence of FSD in women with ment) indicating sexual dysfunction were diabetes should be encouraged to engage
diabetes compared with women without more likely than women without sexual in lifestyle interventions and, in the ab-
diabetes (171). A meta-analysis found that dysfunction to have diabetes distress, de- sence of contraindications, may benefit
sexual dysfunctions are more common in pression, and menopausal symptoms. They from already-approved treatments for
women with type 1 and type 2 diabetes (OR were also older and more likely to be single FSD (178). The Look AHEAD (Action for
2.27 and 2.49, respectively) than in women and postmenopausal (175). Another study Health in Diabetes) study on intervention
without diabetes (172). also showed that women with sexual dys- demonstrated statistical improvements in
Reviews report a wide range of preva- function were significantly more likely to the FSFI total score and all domains of
lence rates of sexual dysfunctions in report impaired well-being, have elevated sexual dysfunction (179). Lifestyle factors
women with diabetes. In women with diabetes distress, have poor adjustment to that enhance desire and sexual function in-
type 1 diabetes, 16–85% (vs. 0–66% in diabetes, and have more moderate to se- clude nutrition (such as the Mediterranean
women without diabetes) report prob- vere anxiety than women without sexual eating pattern), exercise (such as walking),
lems with desire, 11–76% (vs. 0–41%) re- dysfunctions (173). and smoking cessation. Other interventions
port problems with arousal, and 9–66% In a qualitative study exploring the include improving glycemic management
(vs. 0–39%) report problems with orgasm; experiences of sexual health and sexual and prevention of diabetes complications;
9–57% (vs. 0–28%) report problems with challenges, women with type 1 diabetes diagnosis and treatment of menopausal
lubrication, and 7–61% (vs. 5–39%) report reported that diabetes affected their re- symptoms with hormonal therapies; ad-
problems with pain. In women with type 2 lationship, including sex life, and had an dressing vaginal dryness and dyspareunia
diabetes, 70–82% (vs. 10–66% in women impact on their partner. Challenges in- as well as urinary tract and mycotic genital
without diabetes) report problems with cluded reduced sexual desire, decline infections; screening and addressing de-
desire, 54–68% (vs. 3–41%) report in frequency, less spontaneous desire pression, anxiety, diabetes distress, and
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S73

related psychosocial issues; and considering over a 2-year period preceding evalua- is 20% and is driven by obesity, which is
FDA-approved centrally acting medications tion) or other secondary causes of he- becoming more common in this popula-
for hypoactive sexual desire disorder, in- patic steatosis (181). It is estimated that tion (194), with a large variability across
cluding flibanserin and bremelanotide. in adults in the U.S., the prevalence of studies using different steatosis measure-
MASLD is >70% of people with type 2 di- ment methods (195). The prevalence of
Metabolic Dysfunction–Associated abetes (182–184). This is consistent with liver steatosis in a population with type 1
Steatotic Liver Disease and Metabolic studies from other countries (185,186). diabetes by MRI (i.e., the gold standard)
Dysfunction–Associated Steatohepatitis The new definition of MASLD aims to re- with low prevalence of obesity was only
Screening move potential stigma from the term 8.8% compared with 68% in people with
Recommendations “fatty” when referring to steatosis, high- type 2 diabetes (196). The prevalence of
4.22a Screen adults with type 2 diabe- lights the role of prediabetes and type 2 clinically significant fibrosis ($F2) is esti-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

tes or with prediabetes, particularly diabetes in MASLD, and provides a posi- mated to be 5% (197), which is much
those with obesity or other cardiome- tive diagnosis by using cardiometabolic lower than the prevalence in type 2 diabe-
tabolic risk factors or established car- risk factors as surrogates for insulin resis- tes (182,183,189). Therefore, screening for
diovascular disease, for their risk of tance, the main driver for the develop- fibrosis in people with type 1 diabetes
having or developing cirrhosis related ment of steatosis. The new definition should only be considered in the presence
to metabolic dysfunction–associated correlates well with the past definition of additional risk factors for MASLD, such as
steatohepatitis (MASH) using a calcu- of MASLD for people with prediabetes or obesity, incidental hepatic steatosis on imag-
lated fibrosis-4 index (FIB-4) (derived type 2 diabetes (who already have, by ing, or elevated plasma aminotransferases.
from age, ALT, AST, and platelets definition, one cardiometabolic risk factor) Clinicians underestimate the preva-
[mdcalc.com/calc/2200/fibrosis4-fib-4- (187,188). A separate category outside of lence of at-risk MASH and do not consis-
index-liver-fibrosis]), even if they have MASLD, named metabolic dysfunction and tently implement appropriate screening
normal liver enzymes. B alcoholic liver disease, was created for cir- strategies in people with prediabetes or
4.22b Adults with diabetes or predi- cumstances in which alcohol intake is type 2 diabetes, thus missing a chance to
abetes with persistently elevated greater than that allowed for MASLD but establish an early diagnosis (198). This
plasma aminotransferase levels for less than that attributed to alcoholic liver pattern of underdiagnosis is compounded
>6 months and low FIB-4 should disease. More research is needed to better by sparse referral to specialists and inade-
be evaluated for other causes of characterize the predictive value for meta- quate prescription of medications with
liver disease. B bolic dysfunction–associated steatohepati- potential efficacy in MASH (199,200). The
4.23 Adults with type 2 diabetes or tis (MASH) of different cardiometabolic goal of screening for MASLD is to identify
prediabetes with a FIB-4 $1.3 should risk factors and the natural history of met- people with at-risk MASH to prevent fu-
have additional risk stratification by abolic dysfunction and alcoholic liver dis- ture cirrhosis, HCC, liver transplantation,
liver stiffness measurement with tran- ease or steatosis in young adults without and all-cause mortality (201–204). This
sient elastography, or, if unavailable, cardiometabolic risk factors. risk is higher in people who have central
the enhanced liver fibrosis (ELF) test. B Diabetes is a major risk factor for de- obesity and cardiometabolic risk factors or
4.24 Refer adults with type 2 diabetes veloping MASH (formerly nonalcoholic insulin resistance, are >50 years of age,
or prediabetes at higher risk for signifi- steatohepatitis, or NASH) and worse liver and/or have persistently elevated plasma
cant liver fibrosis (i.e., as indicated by outcomes (185,186). MASH is defined his- aminotransferases (AST and/or ALT
FIB-4, liver stiffness measurement, or tologically as having $5% hepatic steato- >30 units/L for >6 months) (205,206).
ELF) to a gastroenterologist or hepa- sis with inflammation and hepatocyte Some genetic variants that alter hepato-
tologist for further evaluation and injury (hepatocyte ballooning), with or cyte triglyceride metabolism may also in-
management. B without evidence of liver fibrosis (181). crease the risk of MASH progression and
Steatohepatitis is estimated to affect more cirrhosis (207,208), amplifying the impact
than half of people with type 2 diabetes of obesity, but the role of genetic testing
Metabolic dysfunction–associated stea- with MASLD (189,190). Fibrosis stages are in clinical practice remains to be estab-
totic liver disease (MASLD) has replaced classified histologically as the following: lished. Individuals with MASLD also are
the term nonalcoholic fatty liver disease F0, no fibrosis; F1, mild; F2, moderate (sig- at a greater risk of developing extrahe-
(NAFLD) to identify steatotic liver dis- nificant); F3, severe (advanced); and F4, patic cancer (192), type 2 diabetes (209),
ease. The definition includes the pres- cirrhosis. In the U.S., between 12% and and CVD (210,211). Emerging evidence
ence of steatotic liver disease and at 20% of people with type 2 diabetes have suggests that MASLD increases the risk
least one cardiometabolic risk factor as- “at-risk” MASH (i.e., steatohepatitis with of CKD in people with type 2 diabetes,
sociated with insulin resistance (e.g., clinically significant fibrosis [$F2] and at particularly when liver fibrosis is present
prediabetes, diabetes, atherogenic dysli- risk for cirrhosis) (182,183,189). A similar (212,213), although the association of
pidemia, or hypertension) without other or higher prevalence has been observed MASLD with diabetic retinopathy is less
identifiable causes of steatosis (180). worldwide (185,186,190). People with clear (214).
This is in the absence of ongoing or re- type 2 diabetes and at-risk MASH are at The fibrosis-4 index (FIB-4) is the
cent consumption of significant amounts an increased risk of future cirrhosis, hepa- most cost-effective strategy for the ini-
of alcohol (defined as ingestion of >21 tocellular carcinoma (HCC) (191,192), and tial screening of people with prediabe-
standard drinks per week in men and liver transplantation (193). The prevalence tes and cardiometabolic risk factors or
>14 standard drinks per week in women of MASLD in people with type 1 diabetes with type 2 diabetes for at-risk MASH in
S74 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

primary care and diabetes clinical set- at-risk MASH clinically significant fibrosis Transient elastography (LSM) is the best-
tings (186,200,205,206,215–217). The ($F2) and increased risk of adverse liver validated imaging technique for fibrosis
diagnostic algorithm for the screening outcomes. A value of >2.67 confers a high risk stratification, and it predicts future cir-
and liver fibrosis risk stratification of peo- risk of having advanced fibrosis (F3–F4), rhosis and all-cause mortality in MASLD
ple with prediabetes or type 2 diabetes is and referral to the liver specialist is war- (205,206,227). An LSM value of <8.0 kPa
shown in Fig. 4.2. A screening strategy ranted without additional testing. FIB-4 has a good negative predictive value
relying on elevated plasma aminotrans- predicts changes over time in hepatic fi- to exclude advanced fibrosis ($F3–F4)
ferases >40 units/L would miss most in- brosis (221,222) and allows risk stratifi- (228–230) and indicates lower risk for
dividuals with MASH in these settings, as cation of individuals in terms of future clinically significant fibrosis. Such individ-
at-risk MASH with clinically significant liver-related morbidity and mortality (223). uals with prediabetes or type 2 diabetes
fibrosis ($F2) is frequently observed

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

FIB-4 has reasonable specificity but low can be followed in nonspecialty clinics
with plasma aminotransferases below the sensitivity, hence a negative result rules with repeat surveillance testing every
commonly used cutoff of 40 units/L out fibrosis while a positive result requires $2 years, although the precise time in-
(182–184,189,218,219). The American Col- confirmatory testing (222,224,225). Its terval remains to be established. If the
lege of Gastroenterology considers the low cost, simplicity, and good specificity LSM is $8.0 kPa, the risk for advanced fi-
upper limit of normal ALT levels to be make it the initial test of choice (Fig. 4.2). brosis ($F3–F4) is higher and such individ-
29–33 units/L for male individuals and FIB-4 has not been validated in pediatric uals should be referred to the hepatologist
19–25 units/L for female individuals (220), populations or in adults aged <35 years. (181,189,205,206) within the framework
as higher levels are associated with in- In people with diabetes $65 years of age, of an interprofessional team (231–233).
creased liver-related mortality. The FIB-4 es- higher cutoffs for FIB-4 have been recom- FIB-4 followed by LSM helps stratify peo-
timates the risk of hepatic cirrhosis and is mended (1.9–2.0 rather than $1.3) (226). ple with diabetes by risk level and mini-
calculated from the computation of age, In people with a FIB-4 $1.3, there is mize specialty referrals (227,234–237) (Fig.
plasma aminotransferases (AST and ALT), need for additional risk stratification with 4.2). Given the lack of widespread avail-
and platelet count (mdcalc.com/calc/2200/ a liver stiffness measurement (LSM) by ability of LSM, the ELF test is a good alter-
fibrosis-4-fib-4-index-liver-fibrosis). A value transient elastography (Fig. 4.2). Use of a native (238). Individuals with ELF <9.8 are
of <1.3 is considered low risk of having ad- second nonproprietary diagnostic panel is considered at low risk for adverse liver
vanced fibrosis (F3–F4) and for developing not recommended (e.g., MASLD fibrosis outcomes. Individuals with ELF $9.8 are
adverse liver outcomes, while $1.3 is con- score and others), as they generally do not considered at high risk of having MASH
sidered as having a higher probability of perform better than FIB-4 (181,184,224). with advanced liver fibrosis ($F3–F4) and

Diagnostic Algorithm for the Prevention of Cirrhosis in People With

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Managed by primary care

(and interprofessional team)
Lower risk of
future cirrhosis • Repeat FIB-4 every 1-2 years
• Optimize lifestyle and treatment
of comorbidities
Groups with the highest risk of
future cirrhosis
No
No
Type 2 diabetes

Is LSM
8.0 kPa*?
Prediabetes Rule out 3?
secondary
causes of
steatosis Yes
Obesity or ↑ ALT
Yes
actors

Managed by liver specialist

(and interprofessional team)
Higher risk of
*Consider vailable. Refer to future cirrhosis • Additional imaging and biomarker
liver .8 risk stratification
67 • Treatment + long-term follow-up

Figure 4.2—Diagnostic algorithm for risk stratification and the prevention of cirrhosis in individuals with metabolic dysfunction–associated steatotic
liver disease (MASLD). CV, cardiovascular; ELF, enhanced liver fibrosis test; FIB-4, fibrosis-4 index; LSM, liver stiffness measurement, as measured
by vibration-controlled transient elastography. *In the absence of LSM, consider ELF a diagnostic alternative. If ELF $9.8, an individual is at high
risk of metabolic dysfunction–associated steatohepatitis with advanced liver fibrosis ($F3–F4) and should be referred to a liver specialist.
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S75

therefore are at risk for adverse liver because of potential beneficial effects diabetes B and to improve cardio-
outcomes (181,217). They should be re- on MASH. B vascular outcomes. B
ferred to a gastroenterologist or hepa- 4.27b Combination therapy with piogli- 4.32b Metabolic surgery should be
tologist. The optimal cutoff for clinical tazone plus GLP-1 RA can be considered used with caution in adults with type 2
use of ELF in primary care and endocri- for the treatment of hyperglycemia in diabetes with compensated cirrhosis
nology settings is evolving (239–242). adults with type 2 diabetes with biopsy- from MASLD B and is not recom-
An ELF <9.8 suggests an individual is at proven MASH or those at high risk of mended in decompensated cirrhosis. B
low risk of advanced liver fibrosis and liver fibrosis (identified with noninva-
may be followed in the nonspecialty sive tests) because of potential bene-
clinic with repeat testing in $2 years ficial effects on MASH.B
While steatohepatitis and cirrhosis occur in
but may need repeat testing more often lean people with diabetes and are believed
4.28 For consideration of treatment

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

if ELF is between 9.2 and 9.7. to be linked to genetic predisposition, insu-
with a thyroid hormone receptor-b
Specialists may order additional tests lin resistance, and environmental factors
agonist in adults with type 2 diabe-
for fibrosis risk stratification in MASH tes or prediabetes with MASLD with
(244,245), ample evidence implicates excess
(180,205,206,217), including magnetic visceral fat and overall adiposity in people
moderate (F2) or advanced (F3) liver
resonance elastography (MRE) (best over- with overweight and obesity in the patho-
fibrosis on liver histology, or by a vali-
all performance, particularly for early genesis of the disease (246,247). Obesity
dated imaging-based or blood-based
fibrosis stages) or multiparametric iron- test, refer to a gastroenterologist or
in the setting of type 2 diabetes worsens
corrected T1 MRI (cT1) (243) and pat- insulin resistance and steatohepatitis,
hepatologist with expertise in MASLD
ented blood-based fibrosis biomarkers. management. A
promoting the development of cirrhosis
While liver biopsy remains the gold stan- (248). Therefore, clinicians should enact
4.29 Treatment initiation and monitor-
dard for the diagnosis of MASH, its indi- evidence-based interventions (as dis-
ing should be individualized and within
cation is reserved to the discretion of cussed in Section 5, “Facilitating Positive
the context of an interprofessional
the specialist within an interprofessional Health Behaviors and Well-being to
team that includes a gastroenterolo-
team approach due to high costs and po- Improve Health Outcomes”) to promote
gist or hepatologist, consideration of
tential for morbidity associated with this healthy lifestyle change and weight loss
individual preferences, and a careful
procedure. for people with overweight or obesity
shared-decision cost-benefit discus-
and MASLD. There is consensus that a
sion. B
Management minimum weight loss goal of 5%, prefer-
4.30a In adults with type 2 diabetes
ably $10%, is needed to improve liver
Recommendations and MASLD, use of glucose-lowering
histology (181,205,206,217), with fibro-
4.25 Adults with type 2 diabetes or therapies other than pioglitazone
sis requiring the larger weight reduction
prediabetes, particularly with over- or GLP-1 RAs may be continued as
to promote change (249,250). However,
weight or obesity, who have meta- clinically indicated, but these ther-
there is significant individual variability in
bolic dysfunction–associated steatotic apies lack evidence of benefit in
histological outcomes with weight loss. In-
liver disease (MASLD) should be rec- MASH. B
dividualized, structured weight loss and
ommended lifestyle changes using an 4.30b Insulin therapy is the pre-
exercise programs offer greater benefit
interprofessional approach that pro- ferred agent for the treatment of
than standard counseling in people with
motes weight loss, ideally within a hyperglycemia in adults with type 2
MASLD (251).
structured nutrition plan and physical diabetes with decompensated cir-
Dietary recommendations to induce
activity program for cardiometabolic rhosis. C
an energy deficit are not different from
benefits B and histological improve- 4.31a Adults with type 2 diabetes
those for people with diabetes with
ment. C and MASLD are at increased cardio-
obesity without MASLD and should in-
4.26 In adults with type 2 diabetes, vascular risk; therefore, comprehen-
clude a reduction of macronutrient con-
MASLD, and overweight or obesity, sive management of cardiovascular
tent, limiting saturated fat, starch, and
consider using a glucagon-like peptide 1 risk factors is recommended. B
added sugar, with adoption of healthier
(GLP-1) receptor agonist (RA) or a 4.31b Statin therapy is safe in adults
eating patterns. The Mediterranean eat-
dual glucose-dependent insulinotropic with type 2 diabetes and compensated
ing pattern has the best evidence for im-
polypeptide (GIP) and GLP-1 RA for cirrhosis from MASLD and should be
proving liver and cardiometabolic health
the treatment of obesity with poten- initiated or continued for cardiovascu-
(205,215–217,251). Both aerobic and
tial benefits in MASH as an adjunctive lar risk reduction as clinically indicated.
resistance training improve MASLD in pro-
therapy to lifestyle interventions for B In people with decompensated cir-
portion to treatment engagement and in-
weight loss. B rhosis, statin therapy should be used
tensity of the program (252). Obesity
4.27a In adults with type 2 diabetes with caution, and close monitoring is
pharmacotherapy may assist with weight
and biopsy-proven MASH or those needed, given limited safety and effi-
loss in the context of lifestyle modification
at high risk for liver fibrosis (based cacy data. B
if not achieved by lifestyle modification
on noninvasive tests), pioglitazone, 4.32a Consider metabolic surgery in
alone (see Section 8, “Obesity and Weight
a GLP-1 RA, or a dual GIP and GLP-1 RA appropriate candidates as an option
Management for the Prevention and
is preferred for glycemic management to treat MASH in adults with type 2
Treatment of Type 2 Diabetes”).
S76 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) Treatment Algorithm

Obesity Diabetes MASH

pharmacotherapy pharmacotherapy pharmacotherapy

MASLD Prefer GLP-1 RA,

Prefer GLP-1 RA,
with F0-F1 dual GIP and GLP-1 RA dual GIP and GLP-1 RA, Not indicated
pioglitazone, SGLT2i

Individualize
care, targeting Obesity Diabetes MASH
the following: MASLD pharmacotherapy pharmacotherapy pharmacotherapy
• Adoption of a with F2-F3
Prefer GLP-1 RA,

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

healthy lifestyle (“at risk” Prefer GLP-1 RA,
dual GIP and GLP-1 RA, Resmetirom
dual GIP and GLP-1 RA
• Weight loss (if indicated) MASH) pioglitazone

• Optimal diabetes
management
Obesity Diabetes MASH
• Cardiovascular pharmacotherapy pharmacotherapy pharmacotherapy
risk reduction Compensated
cirrhosis
• Need for metabolic
surgery (as recommended
MASLD As with F2-F3
with caution*
As with F2-F3
with caution*
 AVOID

by guidelines)

Obesity Diabetes MASH

Decompensated pharmacotherapy pharmacotherapy pharmacotherapy
cirrhosis
 AVOID Only use insulin  AVOID

*Individualized care and close monitoring needed in compensated cirrhosis given limited safety data available.

Figure 4.3—Metabolic dysfunction–associated steatotic liver disease (MASLD) treatment algorithm. F0-F1, no to minimal fibrosis; F2-F3, moderate
fibrosis; F4, cirrhosis; GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA, glucagon-like peptide 1 receptor agonist; MASH, metabolic
dysfunction–associated steatohepatitis; SGLT2i, sodium–glucose cotransporter 2 inhibitor.

Given the high prevalence of at-risk to treat hyperglycemia with GLP-1 RAs and/or trial data) from other oral glucose-lower-
MASH (12–20%) (182–184,186,189), pioglitazone in people with type 2 diabetes ing therapies in MASLD. In the context of
higher risk of disease progression and and MASLD is based on consistent histo- treating hyperglycemia in people with
liver-related mortality (185,204,253), and logical benefit for steatohepatitis in sev- type 2 diabetes with MASLD, where the
the lack of pharmacological treatments eral phase 2 RCTs with GLP-1 RAs and low cost of pioglitazone and any liver im-
once cirrhosis is established (254,255), with pioglitazone (264–268) compared provement would be an added benefit to
optimizing the pharmacological manage- with no benefit with metformin or other glycemic management, these plans would
ment of hyperglycemia and obesity in glucose-lowering medications in MASH be potentially cost-effective for the treat-
people with type 2 diabetes and MASH (181,205,206). ment of MASLD (273,274). Vitamin E may
could serve the dual purpose of address- Pioglitazone improves glucose and lipid be beneficial for the treatment of MASH
ing these comorbidities while treating metabolism and reverses steatohepatitis in people without diabetes (266). How-
the liver disease (Fig. 4.3). Therefore, in people with prediabetes or type 2 dia- ever, in people with type 2 diabetes, vita-
early diagnosis and treatment of MASLD betes (261,264,265) and even in individu- min E monotherapy was found to be
offers the best opportunity for cirrhosis als without diabetes (266–268) (Fig. 4.3). ineffective in a small RCT (261), and it did
prevention. In phase 2 clinical trials, Fibrosis also improved in some trials not seem to enhance pioglitazone’s effi-
pioglitazone and some GLP-1 RAs have (265,267). A meta-analysis (260) concluded cacy when used in combination, as re-
been shown to be potentially effective that pioglitazone treatment results in reso- ported in an earlier trial in this population
to treat steatohepatitis (205,256–259) and lution of MASH and may improve fibrosis. (265). Pioglitazone causes dose-dependent
to slow fibrosis progression (260–262). Furthermore, combination therapy with weight gain (15 mg/day, mean weight
They may also decrease CVD (257), which pioglitazone plus a GLP-1 RA has been gain of 1–2%; 45 mg/day, mean weight
is the number one cause of death in peo- reported safe and effective for the treat- gain of 3–5%), which can be blunted or
ple with type 2 diabetes and MASLD ment of hyperglycemia in adults with reversed if combined with SGLT2 inhibi-
(210). Evidence from phase 3 clinical trials type 2 diabetes (269–272) as well as in tors or GLP-1 RAs (257,271,272,275).
still are not fully published (e.g., a phase reducing hepatic steatosis (269,271), sug- Pioglitazone increases fracture risk, may
3 study on semaglutide, The Effect of Sem- gesting additive benefit in individuals with promote heart failure if used in individu-
aglutide in Subjects With Non-cirrhotic MASLD. It is important to note that these als with preexisting congestive heart fail-
Non- alcoholic Steatohepatitis [ESSENSE] studies are based on phase 2 clinical trials ure, and may increase the risk of bladder
trial, is predicted to be published in 2025) and await further phase 3 evidence. How- cancer, although this remains controversial
(263), and no glucose-lowering or weight ever, these plans are attractive because (181,205,206,257,258).
management medication is FDA approved for they offer potential benefit compared GLP-1 RAs are effective at inducing
the treatment of MASH. The recommendation with lack of histological benefit (or clinical weight loss and ameliorating elevated
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S77

plasma aminotransferases and steatosis diabetes and MASLD for glycemic man- Insulin is the preferred glucose-lowering
(256) (Fig. 4.3). However, there are few agement, as clinically indicated. However, agent for the treatment of hyperglycemia
phase 2 RCTs of GLP-1 RAs in individuals these agents have either failed to im- in adults with type 2 diabetes with decom-
with MASH proven by biopsy. A small prove steatohepatitis in paired-biopsy pensated cirrhosis given the lack of robust
RCT reported that liraglutide improved studies (metformin) or have no RCTs with evidence about the safety and efficacy of
some features of MASH and may delay liver histological end points (i.e., sulfonyl- oral agents and noninsulin injectables (i.e.,
fibrosis progression (276). Subcutaneous ureas, glitinides, dipeptidyl peptidase 4 GLP-1 RAs and dual GIP and GLP-1 RAs)
semaglutide treatment in 320 people inhibitors, or acarbose). (255), although a recent 48-week study
with MASH (62% having type 2 diabe- Resmetirom is a thyroid hormone re- suggested that GLP-1 RAs are safe in indi-
tes) led to resolution of steatohepatitis ceptor-b agonist approved by the FDA viduals with MASH and compensated cir-
without worsening of fibrosis in 59% of for the treatment of adults with MASLD rhosis (287).

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

individuals at the higher dose (equiva- with moderate (F2) or advanced (F3) Metabolic surgery leading to sustained
lent to 2.4 mg/week semaglutide) com- liver fibrosis on liver histology or a vali- weight loss and improvement of type 2 di-
pared with 17% in the placebo group dated imaging- or blood-based test. In a abetes can improve MASH and cardiome-
(P < 0.001) (262). Cumulatively, sema- phase 3 RCT, resmetirom for 52 weeks in tabolic health, altering the natural history
glutide did not significantly affect the 966 adults at the highest dose of 100 mg of the disease (288). Meta-analyses report
stage of liver fibrosis in this group of (or placebo) met the primary end point that 70–80% of people have improvement
people but, over 72 weeks, slowed the of MASH resolution without worsening in hepatic steatosis, 50–75% of people
progression of liver fibrosis (4.9% with of fibrosis in 29.9% of participants com- have improvement in inflammation and
the GLP-1 RA at the highest dose com- pared with 9.7% on placebo (P < 0.001) hepatocyte ballooning (necrosis), and
pared with 18.8% on placebo). Tirzepa- (283). Fibrosis improved in up to 25.9% 30–40% of people have improvement in fi-
tide is a dual GIP and GLP-1 RA known and 14.2%, respectively (P < 0.001). Nau- brosis (289,290). It may also reduce the
to reduce liver steatosis in MASLD sea, vomiting, and diarrhea occurred risk of HCC (290). It is important to note
(277), and a phase 2 paired-biopsy study more often with resmetirom. The gastro- that currently metabolic surgery is not
of 190 adults with overweight or obesity intestinal side effects are dose dependent indicated solely for treatment of MASH.
with MASH (50–60% of whom had type 2 and improve with continued treatment. Given that many individuals with MASH
diabetes) recently reported that doses of 5, Resmetirom decreased free thyroxine (T4) have metabolic risks (type 2 diabetes
10, and 15 mg/day resulted in resolution levels by 20% and increased sex hor- and obesity) that are indications for met-
of steatohepatitis without worsening of fi- mone-binding protein levels two- to three- abolic surgery, the improvement in liver
brosis in 44%, 56%, and 62% of partici- fold. Although a recent review of the data health is expected, but surgical indication
pants, respectively, compared with 10% of concluded that there is little concern should follow current practice guidelines.
participants receiving placebo (P < 0.001 about these changes, long-term postmar- Metabolic surgery should be used with
for all three comparisons) (278). Improve- keting data must be collected (284,285). caution in individuals with compensated
ment of at least one fibrosis stage without Guidance by the American Association for cirrhosis (i.e., asymptomatic stage of cir-
worsening of MASH occurred in 55%, 51%, the Study of Liver Diseases (AASLD) about rhosis without associated liver complica-
and 61% of participants, respectively, com- optimal individual identification for treat- tions), but with experienced surgeons the
pared with 30% of participants receiving ment, safety, and long-term monitoring risk of hepatic decompensation is similar
placebo. Survodutide is a dual GLP-1 and has recently been published (286). This is to that for individuals with less advanced
glucagon RA that is in development, and a especially relevant because hypothyroid- liver disease. Because of the paucity of
phase 2 paired-biopsy trial recently re- ism and hypogonadism are more preva- safety and outcome data, metabolic sur-
ported benefit in MASH (279). In summary, lent in people with MASLD than in the gery is not recommended in individuals
GLP-1–based therapies and/or pioglitazone is general population (181,205), and clini- with decompensated cirrhosis (i.e., cir-
recommended to treat type 2 diabetes in cians should monitor all individuals with rhosis stage with complications such as
adults with MASH based on histological MASLD for symptoms of endocrine defi- variceal hemorrhage, ascites, hepatic en-
benefit for steatohepatitis in several ciency and manage according to clinical cephalopathy, or jaundice) who also have
phase 2 RCTs (278,279) compared practice guidelines. Per its label, candi- a much higher risk of postoperative devel-
with no benefit with metformin or dates for resmetirom treatment are those opment of these liver-related complica-
other glucose-lowering or weight loss with MASLD and moderate (F2) to ad- tions (181,205,206).
medications. Within the context of their vanced (F3) liver fibrosis but not with cir- Adults with type 2 diabetes and MASLD
approved indication (e.g., obesity or type 2 rhosis or other active liver disease (i.e., are at an increased risk of CVD and
diabetes), these medications are cost- alcohol-related liver disease, autoimmune require comprehensive management of
effective to treat the comorbidity, while hepatitis, or primary biliary cholangitis) or cardiovascular risk factors (181,205,206).
potentially improving MASH, which be- unmanaged hypothyroidism or hyperthy- Within an interprofessional approach,
comes an added benefit. roidism. Given complexities associated statin therapy should be initiated or con-
SGLT2 inhibitors (280–282) and insulin with selection of an individual for therapy, tinued for cardiovascular risk reduction as
(258) reduce hepatic steatosis, but their ef- drug cost, and treatment monitoring, ther- clinically indicated. Overall, its use appears
fects on steatohepatitis remain unknown. apy should be individualized and initiated to be safe in adults with type 2 diabetes
The use of glucose-lowering agents other by a hepatologist or gastroenterologist and MASH, including in the presence of
than pioglitazone or GLP-1 RAs may be with expertise in MASH within an interpro- compensated cirrhosis (Child-Pugh class A
continued in individuals with type 2 fessional team. or B cirrhosis) from MASLD. Some studies
S78 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

even suggest that statin use in people Postpancreatitis diabetes may include ei- high-frequency impairment (316). Impair-
with chronic liver disease may reduce epi- ther new-onset disease or previously ment in smell, but not taste, has also
sodes of hepatic decompensation and/or unrecognized diabetes (302). Studies of been reported in individuals with diabe-
overall mortality (291,292). Statin therapy individuals treated with incretin-based tes (317).
is not recommended in decompensated therapies for diabetes have also reported
cirrhosis given limited safety and efficacy that pancreatitis may occur more fre- References
data (181,205,206). quently with these medications, but re- 1. Northwood M, Shah AQ, Abeygunawardena
sults have been mixed and causality has C, Garnett A, Schumacher C. Care coordination of
not been established (303–306). older adults with diabetes: a scoping review. Can
Obstructive Sleep Apnea J Diabetes 2023;47:272–286
Age-adjusted rates of obstructive sleep Islet autotransplantation should be 2. Stellefson M, Dipnarine K, Stopka C. The
apnea, a risk factor for CVD, are signifi- considered for individuals requiring total chronic care model and diabetes management in

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

cantly higher (4- to 10-fold) with obesity, pancreatectomy for medically refractory US primary care settings: a systematic review.
especially with central obesity (293) (see chronic pancreatitis to prevent postsur- Prev Chronic Dis 2013;10:E26
3. Coleman K, Austin BT, Brach C, Wagner EH.
Section 5, “Facilitating Positive Health gical diabetes. Approximately one-third Evidence on the Chronic Care Model in the new
Behaviors and Well-being to Improve of individuals undergoing total pancrea- millennium. Health Aff (Millwood) 2009;28:75–85
Health Outcomes”). The prevalence of ob- tectomy with islet autotransplantation 4. Gabbay RA, Bailit MH, Mauger DT, Wagner
structive sleep apnea in the population are insulin free 1 year postoperatively, EH, Siminerio L. Multipayer patient-centered
medical home implementation guided by the
with type 2 diabetes may be as high as and observational studies from different chronic care model. Jt Comm J Qual Patient Saf
23%, and the prevalence of any sleep-di- centers have demonstrated islet graft 2011;37:265–273
sordered breathing may be as high as 58% function up to a decade after the surgery 5. Adler AI, Coleman RL, Leal J, Whiteley WN,
(294,295). In participants with obesity en- in some individuals (307–311). Both per- Clarke P, Holman RR. Post-trial monitoring of a
rolled in the Look AHEAD trial, the preva- randomised controlled trial of intensive glycaemic
sonal factors for the individual with dia-
control in type 2 diabetes extended from 10 years
lence exceeded 80% (296). Obstructive betes and disease factors should be to 24 years (UKPDS 91). Lancet 2024;404:
sleep apnea should be evaluated in indi- carefully considered when deciding the 145–155
viduals with suggestive symptoms (e.g., indications and timing of this surgery. 6. Nathan DM, Genuth S, Lachin J, et al.; Diabetes
excessive daytime sleepiness, snoring, Control and Complications Trial Research Group.
Surgeries should be performed in skilled
and witnessed apnea) (297). Sleep apnea The effect of intensive treatment of diabetes on
facilities that have demonstrated exper- the development and progression of long-term
treatment (lifestyle modification, continu- tise in islet autotransplantation. complications in insulin-dependent diabetes mellitus.
ous positive airway pressure, oral applian- N Engl J Med 1993;329:977–986
ces, and surgery) significantly improves Sensory Impairment 7. Lachin JM, Genuth S, Nathan DM, Zinman B,
quality of life and blood pressure man- Rutledge BN; DCCT/EDIC Research Group. Effect of
Hearing impairment, both in high-fre- glycemic exposure on the risk of microvascular
agement. Recently, two phase 3 random- quency and low- to midfrequency ranges, complications in the diabetes control and comp-
ized trials found that among adults with is more common in people with diabetes lications trial–revisited. Diabetes 2008;57:995–1001
obesity and moderate-to-severe obstruc- than in those without, with stronger as- 8. White NH, Cleary PA, Dahms W, Goldstein D,
tive sleep apnea but without diabetes, sociations found in studies of younger
Malone J, Tamborlane WV. Diabetes Control
treatment with the dual GIP and GLP-1 and Complications Trial (DCCT)/Epidemiology of
people (312). Proposed pathophysiologic Diabetes Interventions and Complications (EDIC)
RA tirzepatide substantially reduced sleep
mechanisms include the combined contri- Research Group. Beneficial effects of intensive
apnea severity (298). More research is therapy of diabetes during adolescence: outcomes
butions of hyperglycemia and oxidative
needed to determine the effects of GLP-1 after the conclusion of the Diabetes Control and
stress with cochlear microangiopathy and
and dual GIP and GLP-1 RAs on sleep ap- Complications Trial (DCCT). J Pediatr 2001;139:
auditory neuropathy (313). In a National 804–812
nea in people with diabetes.
Health and Nutrition Examination Survey 9. Rodriguez K, Ryan D, Dickinson JK, Phan V.
(NHANES) analysis, hearing impairment Improving quality outcomes: the value of diabetes
Pancreatitis care and education specialists. Clin Diabetes 2022;
Diabetes is linked to diseases of the exo- was about twice as prevalent in people
40:356–365
crine pancreas, such as pancreatitis, which with diabetes as in those without, after 10. Nathan DM, Bayless M, Cleary P, et al.; DCCT/
may disrupt the global architecture or adjusting for age and other risk factors for EDIC Research Group. Diabetes control and com-
hearing impairment (314). Low HDL cho- plications trial/epidemiology of diabetes inter-
physiology of the pancreas, often resulting
lesterol, coronary heart disease, periph- ventions and complications study at 30 years:
in both exocrine and endocrine dysfunc- advances and contributions. Diabetes 2013;62:
tion. Up to half of individuals with diabetes eral neuropathy, and general poor health 3976–3986
may have some degree of impaired exo- have been reported as risk factors for 11. Anderson RM, Funnell MM. Compliance and
crine pancreas function (299). People with hearing impairment for people with dia- adherence are dysfunctional concepts in diabetes
betes, but an association of hearing loss care. Diabetes Educ 2000;26:597–604
diabetes are at an approximately twofold 12. Sarkar U, Fisher L, Schillinger D. Is self-efficacy
higher risk of developing acute pancreatitis with glycemia has not been consistently associated with diabetes self-management across
(300). observed (315). In the DCCT/EDIC cohort, race/ethnicity and health literacy? Diabetes Care
Conversely, prediabetes and/or diabe- increases in the time-weighted mean A1C 2006;29:823–829
tes has been found to develop in approx- was associated with increased risk of 13. King DK, Glasgow RE, Toobert DJ, et al. Self-
efficacy, problem solving, and social-environmental
imately one-third of individuals after an hearing impairment when tested after support are associated with diabetes self-
episode of acute pancreatitis (301); thus, long-term (>20 years) follow-up, with ev- management behaviors. Diabetes Care 2010;33:
the relationship is likely bidirectional. ery 10% increase in A1C leading to 19% 751–753
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S79

14. Nouwen A, Urquhart Law G, Hussain S, across the disease course: diabetes & aging diabetes mellitus and risk of fracture. Am J
McGovern S, Napier H. Comparison of the role of study. J Gen Intern Med 2012;27:1674–1681 Epidemiol 2007;166:495–505
self-efficacy and illness representations in relation 29. Nederstigt C, Uitbeijerse BS, Janssen LGM, 46. Napoli N, Conte C, Pedone C, et al. Effect of
to dietary self-care and diabetes distress in Corssmit EPM, de Koning EJP, Dekkers OM. insulin resistance on BMD and fracture risk in older
adolescents with type 1 diabetes. Psychol Health Associated auto-immune disease in type 1 adults. J Clin Endocrinol Metab 2019;104:3303–3310
2009;24:1071–1084 diabetes patients: a systematic review and meta- 47. Napoli N, Schwartz AV, Schafer AL, et al.;
15. Dickinson JK, Guzman SJ, Maryniuk MD, analysis. Eur J Endocrinol 2019;180:135–144 Osteoporotic Fractures in Men (MrOS) Study
et al. The use of language in diabetes care and 30. De Block CE, D, Leeuw IH, V, Gaal LF. High Research Group. Vertebral fracture risk in diabetic
education. Diabetes Care 2017;40:1790–1799 prevalence of manifestations of gastric auto- elderly men: the MrOS study. J Bone Miner Res
16. Wodi AP, Murthy N, McNally VV, Daley MF, immunity in parietal cell antibody-positive type 1 2018;33:63–69
Cineas S. Advisory Committee on Immunization (insulin-dependent) diabetic patients. The Belgian 48. Koromani F, Oei L, Shevroja E, et al.
Practices recommended immunization schedule Diabetes Registry. J Clin Endocrinol Metab 1999; Vertebral fractures in individuals with type 2
for children and adolescents aged 18 years or 84:4062–4067 diabetes: more than skeletal complications alone.

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

younger - United States, 2024. MMWR Morb 31. Triolo TM, Armstrong TK, McFann K, et al. Diabetes Care 2020;43:137–144
Mortal Wkly Rep 2024;73:6–10 Additional autoimmune disease found in 33% of 49. Faraj M, Schwartz AV, Burghardt AJ, et al. Risk
17. Murthy N, Wodi AP, McNally VV, Daley MF, patients at type 1 diabetes onset. Diabetes Care factors for bone microarchitecture impairments in
Cineas S. Advisory Committee on Immunization 2011;34:1211–1213 older men with type 2 diabetes - the MrOS study. J
Practices recommended immunization schedule 32. Hughes JW, Riddlesworth TD, DiMeglio LA, Clin Endocrinol Metab. 12 July 2024 [Epub ahead
for adults aged 19 years or older - United States, Miller KM, Rickels MR, McGill JB; T1D Exchange of print]. DOI: 10.1210/clinem/dgae452
2024. MMWR Morb Mortal Wkly Rep 2024;73: Clinic Network. Autoimmune diseases in children 50. Schwartz AV, Vittinghoff E, Bauer DC, et al.;
11–15 and adults with type 1 diabetes from the T1D Osteoporotic Fractures (SOF) Research Group;
18. Centers for Disease Control and Prevention, Exchange Clinic Registry. J Clin Endocrinol Metab Osteoporotic Fractures in Men (MrOS) Research
Advisory Committee on Immunization Practice 2016;101:4931–4937 Group; Health, Aging, and Body Composition
(ACIP). ACIP Evidence to Recommendation User’s 33. Kahaly GJ, Hansen MP. Type 1 diabetes (Health ABC) Research Group. Association of
Guide. 2020. Accessed 8 October 2024. Available associated autoimmunity. Autoimmun Rev 2016; BMD and FRAX score with risk of fracture in older
from https://stacks.cdc.gov/view/cdc/127248 15:644–648 adults with type 2 diabetes. JAMA 2011;305:
19. Weng MK, Doshani M, Khan MA, et al. 34. Eisenbarth GS, Gottlieb PA. Autoimmune 2184–2192
Universal hepatitis B vaccination in adults aged polyendocrine syndromes. N Engl J Med 2004;350: 51. Hidayat K, Fang Q-L, Shi B-M, Qin L-Q.
19-59 years: updated recommendations of the 2068–2079 Influence of glycemic control and hypoglycemia
Advisory Committee on Immunization Practices - 35. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood on the risk of fracture in patients with diabetes
United States, 2022. MMWR Morb Mortal Wkly mellitus: a systematic review and meta-analysis
AH, Murray JA. ACG clinical guidelines: diagnosis
Rep 2022;71:477–483
and management of celiac disease. Am J of observational studies. Osteoporos Int 2021;32:
20. Goeijenbier M, van Sloten TT, Slobbe L, et al.
Gastroenterol 2013;108:656–676 1693–1704
Benefits of flu vaccination for persons with diabetes
36. Husby S, Murray JA, Katzka DA. AGA clinical 52. Wang B, Wang Z, Poundarik AA, et al.
mellitus: a review. Vaccine 2017;35:5095–5101
practice update on diagnosis and monitoring of Unmasking fracture risk in type 2 diabetes: the
21. Yedlapati SH, Khan SU, Talluri S, et al. Effects of
celiac disease-changing utility of serology and association of longitudinal glycemic hemoglobin
influenza vaccine on mortality and cardiovascular
histologic measures: expert review. Gastroenterology level and medications. J Clin Endocrinol Metab
outcomes in patients with cardiovascular disease: a
2019;156:885–889 2022;107:e1390–e1401
systematic review and meta-analysis. J Am Heart
37. Cauley JA, Hochberg MC, Lui L-Y, et al. Long- 53. Komorita Y, Iwase M, Fujii H, et al. Both
Assoc 2021;10:e019636
term risk of incident vertebral fractures. JAMA hypo- and hyperglycaemia are associated with
22. Grohskopf LA, Ferdinands JM, Blanton LH,
2007;298:2761–2767 increased fracture risk in Japanese people with
Broder KR, Loehr J. Prevention and control of
38. Kanis JA, Johnell O, De Laet C, et al. A meta- type 2 diabetes: the Fukuoka Diabetes Registry.
seasonal influenza with vaccines: recommen-
dations of the Advisory Committee on Immuni- analysis of previous fracture and subsequent Diabet Med 2020;37:838–847
zation Practices-United States, 2024-25 influenza fracture risk. Bone 2004;35:375–382 54. Majumdar SR, Leslie WD, Lix LM, et al.
season. MMWR Recomm Rep 2024;73:1–25 39. Pedersen AB, Ehrenstein V, Sz
epligeti SK, Longer duration of diabetes strongly impacts
23. Kornum JB, Thomsen RW, Riis A, Lervang H-H, et al. Thirty-five-year trends in first-time fracture risk assessment: the Manitoba BMD
Schønheyder HC, Sørensen HT. Diabetes, glycemic hospitalization for hip fracture, 1-year mortality, cohort. J Clin Endocrinol Metab 2016;101:4489–
control, and risk of hospitalization with pneumonia: and the prognostic impact of comorbidity: a 4496
a population-based case-control study. Diabetes Danish nationwide cohort study, 1980-2014. 55. Vavanikunnel J, Charlier S, Becker C, et al.
Care 2008;31:1541–1545 Epidemiology 2017;28:898–905 Association between glycemic control and risk of
24. Kobayashi M, Pilishvili T, Farrar JL, et al. 40. Tajeu GS, Delzell E, Smith W, et al. Death, fracture in diabetic patients: a nested case-
Pneumococcal vaccine for adults aged $19 years: debility, and destitution following hip fracture. J control study. J Clin Endocrinol Metab 2019;
recommendations of the Advisory Committee on Gerontol A Biol Sci Med Sci 2014;69:346–353 104:1645–1654
Immunization Practices, United States, 2023. 41. Miao J, Brismar K, Nyr
en O, Ugarph-Morawski 56. Strotmeyer ES, Cauley JA, Schwartz AV, et al.
MMWR Recomm Rep 2023;72:1–39 A, Ye W. Elevated hip fracture risk in type 1 Nontraumatic fracture risk with diabetes mellitus and
25. Britton A, Roper LE, Kotton CN, et al. Use of diabetic patients: a population-based cohort study impaired fasting glucose in older white and black
respiratory syncytial virus vaccines in adults aged in Sweden. Diabetes Care 2005;28:2850–2855 adults: the health, aging, and body composition
$60 years: updated recommendations of the 42. Wang H, Ba Y, Xing Q, Du J-L. Diabetes study. Arch Intern Med 2005;165:1612–1617
Advisory Committee on Immunization Practices - mellitus and the risk of fractures at specific sites: 57. Schwartz AV, Vittinghoff E, Sellmeyer DE,
United States, 2024. MMWR Morb Mortal Wkly a meta-analysis. BMJ Open 2019;9:e024067 et al.; Health, Aging, and Body Composition
Rep 2024;73:696–702 43. Weber DR, Haynes K, Leonard MB, Willi SM, Study. Diabetes-related complications, glycemic
26. Grant RW, Ashburner JM, Hong CS, Chang Y, Denburg MR. Type 1 diabetes is associated with control, and falls in older adults. Diabetes Care
Barry MJ, Atlas SJ. Defining patient complexity an increased risk of fracture across the life span: 2008;31:391–396
from the primary care physician’s perspective: a a population-based cohort study using The 58. Loke YK, Singh S, Furberg CD. Long-term use
cohort study. Ann Intern Med 2011;155:797–804 Health Improvement Network (THIN). Diabetes of thiazolidinediones and fractures in type 2
27. Tinetti ME, Fried TR, Boyd CM. Designing Care 2015;38:1913–1920 diabetes: a meta-analysis. CMAJ 2009;180:32–39
health care for the most common chronic 44. Leanza G, Maddaloni E, Pitocco D, et al. Risk 59. Dormandy J, Bhattacharya M, van
condition–multimorbidity. JAMA 2012;307:2493– factors for fragility fractures in type 1 diabetes. Troostenburg de Bruyn A-R; PROactive Investigators.
2494 Bone 2019;125:194–199 Safety and tolerability of pioglitazone in high-risk
28. Sudore RL, Karter AJ, Huang ES, et al. 45. Janghorbani M, Van Dam RM, Willett WC, patients with type 2 diabetes: an overview of data
Symptom burden of adults with type 2 diabetes Hu FB. Systematic review of type 1 and type 2 from PROactive. Drug Saf 2009;32:187–202
S80 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

60. Schwartz AV, Chen H, Ambrosius WT, et al. A scoping review. J Nutr Health Aging 2017;21: biomarkers in patients with type 2 diabetes
Effects of TZD use and discontinuation on 527–538 treated with canagliflozin. J Clin Endocrinol Metab
fracture rates in ACCORD bone study. J Clin 76. National Institutes of Health. Calcium—fact 2016;101:44–51
Endocrinol Metab 2015;100:4059–4066 sheet for health professionals. Accessed 19 92. Watts NB, Bilezikian JP, Usiskin K, et al.
61. Hidayat K, Du X, Wu M-J, Shi B-M. The use August 2024. Available from https://ods.od.nih. Effects of canagliflozin on fracture risk in patients
of metformin, insulin, sulphonylureas, and gov/factsheets/Calcium-HealthProfessional with type 2 diabetes mellitus. J Clin Endocrinol
thiazolidinediones and the risk of fracture: 77. Rosen CJ, Abrams SA, Aloia JF, et al. IOM Metab 2016;101:157–166
systematic review and meta-analysis of obser- committee members respond to Endocrine 93. Perkovic V, Jardine MJ, Neal B, et al.;
vational studies. Obes Rev 2019;20:1494–1503 Society vitamin D guideline. J Clin Endocrinol CREDENCE Trial Investigators. Canagliflozin and
62. Piccoli A, Cannata F, Strollo R, et al. Sclerostin Metab 2012;97:1146–1152 renal outcomes in type 2 diabetes and nephro-
regulation, microarchitecture, and advanced 78. National Institutes of Health. Vitamin D— pathy. N Engl J Med 2019;380:2295–2306
glycation end-products in the bone of elderly fact sheet for health professionals. Accessed 19 94. Neal B, Perkovic V, Matthews DR. Can-
women with type 2 diabetes. J Bone Miner Res August 2024. Available from https://ods.od.nih agliflozin and cardiovascular and renal events in

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

2020;35:2415–2422 .gov/factsheets/VitaminD-HealthProfessional type 2 diabetes. N Engl J Med 2017;377:2099
63. Leanza G, Cannata F, Faraj M, et al. Bone 79. Eastell R, Vittinghoff E, Lui L-Y, et al. Diabetes 95. Li X, Li T, Cheng Y, et al. Effects of SGLT2
canonical Wnt signaling is downregulated in type 2 mellitus and the benefit of antiresorptive therapy inhibitors on fractures and bone mineral density
diabetes and associates with higher advanced on fracture risk. J Bone Miner Res 2022;37: in type 2 diabetes: an updated meta-analysis.
glycation end-products (AGEs) content and 2121–2131 Diabetes Metab Res Rev 2019;35:e3170
reduced bone strength. Elife 2024;12:RP90437 80. Langdahl BL, Silverman S, Fujiwara S, et al. 96. Suh S, Kim KW. Diabetes and cancer: cancer
64. Tramontana F, Napoli N, Litwack-Harrison S, Real-world effectiveness of teriparatide on should be screened in routine diabetes assessment.
et al. More rapid bone mineral density loss in fracture reduction in patients with osteoporosis Diabetes Metab J 2019;43:733–743
older men with diabetes: the Osteoporotic and comorbidities or risk factors for fractures: 97. Giovannucci E, Harlan DM, Archer MC, et al.
Fractures in Men (MrOS) study. J Clin Endocrinol integrated analysis of 4 prospective obser- Diabetes and cancer: a consensus report. CA
Metab. 24 February 2024 [Epub ahead of print]. vational studies. Bone 2018;116:58–66 Cancer J Clin 2010;60:207–221
DOI: 10.1210/clinem/dgae045 81. Schwartz AV, Pavo I, Alam J, et al. 98. Aggarwal G, Kamada P, Chari ST. Prevalence of
65. Ferrari SL, Abrahamsen B, Napoli N, et al.; Teriparatide in patients with osteoporosis and diabetes mellitus in pancreatic cancer compared
Bone and Diabetes Working Group of IOF. type 2 diabetes. Bone 2016;91:152–158 to common cancers. Pancreas 2013;42:198–201
82. Napoli N, Pannacciulli N, Vittinghoff E, et al. 99. Cho J, Scragg R, Petrov MS. Postpancreatitis
Diagnosis and management of bone fragility in
Effect of denosumab on fasting glucose in diabetes confers higher risk for pancreatic cancer
diabetes: an emerging challenge. Osteoporos Int
women with diabetes or prediabetes from the than type 2 diabetes: results from a nationwide
2018;29:2585–2596
FREEDOM trial. Diabetes Metab Res Rev 2018; cancer registry. Diabetes Care 2020;43:2106–2112
66. Leslie WD, Johansson H, McCloskey EV,
34:e2991 100. Ninomiya I, Yamazaki K, Oyama K, et al.
Harvey NC, Kanis JA, Hans D. Comparison of
83. Langdahl BL, Hofbauer LC, Forfar JC. Pioglitazone inhibits the proliferation and metastasis
methods for improving fracture risk assessment
Cardiovascular safety and sclerostin inhibition. J of human pancreatic cancer cells. Oncol Lett 2014;
in diabetes: the Manitoba BMD registry. J Bone
Clin Endocrinol Metab 2021;106:1845–1853 8:2709–2714
Miner Res 2018;33:1923–1930
84. Cosman F, Crittenden DB, Adachi JD, et al. 101. Hendriks AM, Schrijnders D, Kleefstra N,
67. Ferrari S, Eastell R, Napoli N, et al.
Romosozumab treatment in postmenopausal et al. Sulfonylurea derivatives and cancer, friend
Denosumab in postmenopausal women with
women with osteoporosis. N Engl J Med 2016; or foe? Eur J Pharmacol 2019;861:172598
osteoporosis and diabetes: subgroup analysis of
375:1532–1543 102. Hua Y, Zheng Y, Yao Y, Jia R, Ge S, Zhuang A.
FREEDOM and FREEDOM extension. Bone 2020; 85. Conley RB, Adib G, Adler RA, et al. Secondary Metformin and cancer hallmarks: shedding new
134:115268 fracture prevention: consensus clinical recom- lights on therapeutic repurposing. J Transl Med
68. LeBoff MS, Greenspan SL, Insogna KL, et al. The mendations from a multistakeholder coalition. J 2023;21:403
clinician’s guide to prevention and treatment of Bone Miner Res 2020;35:36–52 103. Wang L, Xu R, Kaelber DC, Berger NA.
osteoporosis. Osteoporos Int 2022;33:2049–2102 86. Hofbauer LC, Rachner TD. More DATA to Glucagon-like peptide 1 receptor agonists and 13
69. Napoli N, Conte C, Eastell R, et al. Bone guide sequential osteoporosis therapy. Lancet obesity-associated cancers in patients with type 2
turnover markers do not predict fracture risk in 2015;386:1116–1118 diabetes. JAMA Netw Open 2024;7:e2421305
type 2 diabetes. J Bone Miner Res 2020;35: 87. Napoli N, Strotmeyer ES, Ensrud KE, et al. 104. Xue M, Xu W, Ou Y-N, et al. Diabetes
2363–2371 Fracture risk in diabetic elderly men: the MrOS mellitus and risks of cognitive impairment and
70. International Society for Pediatric and study. Diabetologia 2014;57:2057–2065 dementia: a systematic review and meta-analysis
Adolescent Diabetes. ISPAD Clinical Practice 88. Hidayat K, Du X, Shi B-M. Risk of fracture of 144 prospective studies. Ageing Res Rev 2019;
Consensus Guidelines 2022. Accessed 19 August with dipeptidyl peptidase-4 inhibitors, glucagon- 55:100944
2024. Available from https://www.ispad.org/ like peptide-1 receptor agonists, or sodium- 105. Ohara T, Doi Y, Ninomiya T, et al. Glucose
page/ISPADGuidelines2022 glucose cotransporter-2 inhibitors in real-world tolerance status and risk of dementia in the
71. Armamento-Villareal R, Aguirre L, Napoli N, use: systematic review and meta-analysis of community: the Hisayama study. Neurology 2011;
et al. Changes in thigh muscle volume predict observational studies. Osteoporos Int 2019;30: 77:1126–1134
bone mineral density response to lifestyle 1923–1940 106. Hanyu H. Diabetes-related dementia. Adv
therapy in frail, obese older adults. Osteoporos 89. Chai S, Liu F, Yang Z, et al. Risk of fracture Exp Med Biol 2019;1128:147–160
Int 2014;25:551–558 with dipeptidyl peptidase-4 inhibitors, glucagon- 107. Gudala K, Bansal D, Schifano F, Bhansali A.
72. Sinclair AJ, Abdelhafiz A, Dunning T, et al. like peptide-1 receptor agonists, or sodium- Diabetes mellitus and risk of dementia: a meta-
An international position statement on the glucose cotransporter-2 inhibitors in patients analysis of prospective observational studies. J
management of frailty in diabetes mellitus: with type 2 diabetes mellitus: a systematic Diabetes Investig 2013;4:640–650
summary of recommendations. J Frailty Aging review and network meta-analysis combining 108. Tang X, Cardoso MA, Yang J, Zhou J-B, Sim
o
2017;7:10–20 177 randomized controlled trials with a median R. Impact of intensive glucose control on brain
73. Ebeling PR, Adler RA, Jones G, et al. follow-up of 26 weeks. Front Pharmacol 2022; health: meta-analysis of cumulative data from
Management of endocrine disease: therapeutics of 13:825417 16,584 patients with type 2 diabetes mellitus.
vitamin D. Eur J Endocrinol 2018;179:R239–R259 90. Rosenstock J, Wysham C, Fr
ıas JP, et al. Diabetes Ther 2021;12:765–779
74. Maddaloni E, Cavallari I, Napoli N, Conte C. Efficacy and safety of a novel dual GIP and GLP-1 109. Cukierman-Yaffe T, Gerstein HC, Williamson
Vitamin D and diabetes mellitus. Front Horm Res receptor agonist tirzepatide in patients with type 2 JD, et al.; Action to Control Cardiovascular Risk in
2018;50:161–176 diabetes (SURPASS-1): a double-blind, randomised, Diabetes-Memory in Diabetes (ACCORD-MIND) In-
75. Iolascon G, Gimigliano R, Bianco M, et al. Are phase 3 trial. Lancet 2021;398:143–155 vestigators. Relationship between baseline glycemic
dietary supplements and nutraceuticals effective 91. Bilezikian JP, Watts NB, Usiskin K, et al. control and cognitive function in individuals with
for musculoskeletal health and cognitive function? Evaluation of bone mineral density and bone type 2 diabetes and other cardiovascular risk factors:
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S81

the Action to Control Cardiovascular Risk in observational evidence. J Periodontol 2013;84: 139. Selvarajah D, Kar D, Khunti K, et al. Diabetic
Diabetes-Memory in Diabetes (ACCORD-MIND) trial. S135–S152 peripheral neuropathy: advances in diagnosis
Diabetes Care 2009;32:221–226 124. Simpson TC, Clarkson JE, Worthington HV, and strategies for screening and early inter-
110. Launer LJ, Miller ME, Williamson JD, et al.; et al. Treatment of periodontitis for glycaemic vention. Lancet Diabetes Endocrinol 2019;7:
ACCORD MIND Investigators. Effects of intensive control in people with diabetes mellitus. 938–948
glucose lowering on brain structure and function in Cochrane Database Syst Rev 2022;4:CD004714 140. Fatma S, Noohu MM. Classification of
people with type 2 diabetes (ACCORD MIND): a 125. D’Aiuto F, Gkranias N, Bhowruth D, et al.; functionality of people with diabetic peripheral
randomised open-label substudy. Lancet Neurol TASTE Group. Systemic effects of periodontitis neuropathy based on international classification
2011;10:969–977 treatment in patients with type 2 diabetes: a of functioning, disability and health core set (ICF-
111. McCoy RG, Galindo RJ, Swarna KS, et al. 12 month, single-centre, investigator-masked, ran- CS) of diabetes mellitus. J Diabetes Metab Disord
Sociodemographic, clinical, and treatment- domised trial. Lancet Diabetes Endocrinol 2018;6: 2020;19:213–221
related factors associated with hyperglycemic 954–965 141. Zhang Y, Lazzarini PA, McPhail SM, van
crises among adults with type 1 or type 2 126. Elangovan S, Hertzman-Miller R, Karimbux Netten JJ, Armstrong DG, Pacella RE. Global

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

diabetes in the US from 2014 to 2020. JAMA N, Giddon D. A framework for physician-dentist disability burdens of diabetes-related lower-
Netw Open 2021;4:e2123471 collaboration in diabetes and periodontitis. Clin extremity complications in 1990 and 2016.
112. Mair ML, Athavale R, Abdelhafiz AH. Practical Diabetes 2014;32:188–192 Diabetes Care 2020;43:964–974
considerations for managing patients with diabetes 127. Herrera D, Sanz M, Shapira L, et al. 142. Tsai Y-H, Chuang L-L, Lee Y-J, Chiu C-J. How
and dementia. Expert Rev Endocrinol Metab 2017; Association between periodontal diseases and does diabetes accelerate normal aging? An
12:429–440 cardiovascular diseases, diabetes and respiratory examination of ADL, IADL, and mobility disability
113. Punthakee Z, Miller ME, Launer LJ, et al.; diseases: consensus report of the Joint Workshop in middle-aged and older adults with and without
ACCORD-MIND Investigators. Poor cognitive by the European Federation of Periodontology diabetes. Diabetes Res Clin Pract 2021;182:
function and risk of severe hypoglycemia in type 2 (EFP) and the European arm of the World 109114
diabetes: post hoc epidemiologic analysis of the Organization of Family Doctors (WONCA Europe). 143. Streckmann F, Balke M, Cavaletti G, et al.
ACCORD trial. Diabetes Care 2012;35:787–793 J Clin Periodontol 2023;50:819–841 Exercise and neuropathy: systematic review with
114. Lacy ME, Gilsanz P, Eng C, Beeri MS, Karter 128. Lalla E, Papapanou PN. Diabetes mellitus and meta-analysis. Sports Med 2022;52:1043–1065
AJ, Whitmer RA. Severe hypoglycemia and periodontitis: a tale of two common interrelated 144. Jing X, Chen J, Dong Y, et al. Related factors
cognitive function in older adults with type 1 diseases. Nat Rev Endocrinol 2011;7:738–748 of quality of life of type 2 diabetes patients: a
diabetes: the Study of Longevity in Diabetes 129. Christgau M, Palitzsch KD, Schmalz G, systematic review and meta-analysis. Health
(SOLID). Diabetes Care 2020;43:541–548 Kreiner U, Frenzel S. Healing response to non- Qual Life Outcomes 2018;16:189
115. Lee AK, Rawlings AM, Lee CJ, et al. Severe surgical periodontal therapy in patients with 145. Yoon S-J, Kim K-I. Frailty and disability in
diabetes. Ann Geriatr Med Res 2019;23:165–169
hypoglycaemia, mild cognitive impairment, diabetes mellitus: clinical, microbiological, and
146. World Health Organization. WHO Disability
dementia and brain volumes in older adults with immunologic results. J Clin Periodontol 1998;25:
Assessment Schedule 2.0 (WHODAS 2.0).
type 2 diabetes: the Atherosclerosis Risk in 112–124
Accessed 26 September 2024. Available from
Communities (ARIC) cohort study. Diabetologia 130. Retzepi M, Donos N. The effect of diabetes
https://www.who.int/standards/classifications/
2018;61:1956–1965 mellitus on osseous healing. Clin Oral Implants
international-classification-of-functioning-disability-
116. Ye M, Yang Q, Zhang L, et al. Effect of Res 2010;21:673–681
and-health/who-disability-assessment-schedule
hypoglycemic events on cognitive function in 131. United States Code. Americans with
147. Diabetes Distress Assessment and Resource
individuals with type 2 diabetes mellitus: a dose- Disabilities Act of 1990. Pub. L. No. 101–336 42
Center. Diabetes Distress Scale (DDS). Accessed 26
response meta-analysis. Front Neurol 2024;15: U.S.C. § 2. 104 Stat. 328. p. 101-336.
September 2024. Available from https://
1394499 132. United States Code. Americans with
diabetesdistress.org/take-dd-survey/
117. Mattishent K, Loke YK. Bi-directional Disabilities Act Amendments Act of 2008. Pub. L.
148. Hill-Briggs F, Adler NE, Berkowitz SA, et al.
interaction between hypoglycaemia and cognitive No. 110–325 42 U.S.C.A. § 12101 et seq.
Social determinants of health and diabetes: a
impairment in elderly patients treated with 133. Wong E, Backholer K, Gearon E, et al.
scientific review. Diabetes Care 2020;44:258–279
glucose-lowering agents: a systematic review and Diabetes and risk of physical disability in adults: a 149. Tan T-W, Shih C-D, Concha-Moore KC, et al.
meta-analysis. Diabetes Obes Metab 2016;18: systematic review and meta-analysis. Lancet Disparities in outcomes of patients admitted with
135–141 Diabetes Endocrinol 2013;1:106–114 diabetic foot infections. PLoS One 2019;14:
118. Giorda CB, Ozzello A, Gentile S, et al.; 134. Tomic D, Shaw JE, Magliano DJ. The burden e0215532
HYPOS-1 Study Group of AMD. Incidence and risk and risks of emerging complications of diabetes 150. Skrepnek GH, Mills JL, Armstrong DG. A
factors for severe and symptomatic hypoglycemia mellitus. Nat Rev Endocrinol 2022;18:525–539 diabetic emergency one million feet long:
in type 1 diabetes. Results of the HYPOS-1 study. 135. Lisy K, Campbell JM, Tufanaru C, Moola S, disparities and burdens of illness among diabetic
Acta Diabetol 2015;52:845–853 Lockwood C. The prevalence of disability among foot ulcer cases within emergency departments
119. Jacobson AM, Ryan CM, Braffett BH, et al.; people with cancer, cardiovascular disease, in the United States, 2006-2010. PLoS One 2015;
DCCT/EDIC Research Group. Cognitive performance chronic respiratory disease and/or diabetes: a 10:e0134914
declines in older adults with type 1 diabetes: results systematic review. Int J Evid Based Healthc 151. Lecube A, Hern
andez C, Genesca J, Sim
o R.
from 32 years of follow-up in the DCCT and EDIC 2018;16:154–166 Proinflammatory cytokines, insulin resistance, and
study. Lancet Diabetes Endocrinol 2021;9:436–445 136. Gregg EW, Menke A. Diabetes and insulin secretion in chronic hepatitis C patients:
120. Khader YS, Dauod AS, El-Qaderi SS, disability. In Diabetes in America, 3rd ed. Cowie a case-control study. Diabetes Care 2006;29:
Alkafajei A, Batayha WQ. Periodontal status of CC, Casagrande SS, Menke A, et al., Eds. 1096–1101
diabetics compared with nondiabetics: a meta- Bethesda, MD, National Institute of Diabetes and 152. Hum J, Jou JH, Green PK, et al. Improvement
analysis. J Diabetes Complications 2006;20:59–68 Digestive and Kidney Diseases, 2018. Available in glycemic control of type 2 diabetes after
121. Casanova L, Hughes FJ, Preshaw PM. from https://www.ncbi.nlm.nih.gov/pubmed/ successful treatment of hepatitis C virus. Diabetes
Diabetes and periodontal disease: a two-way 33651544 Care 2017;40:1173–1180
relationship. Br Dent J 2014;217:433–437 137. Khan KS, Andersen H. The impact of 153. Carnovale C, Pozzi M, Dassano A, et al. The
122. Eke PI, Thornton-Evans GO, Wei L, diabetic neuropathy on activities of daily living, impact of a successful treatment of hepatitis C
Borgnakke WS, Dye BA, Genco RJ. Periodontitis postural balance and risk of falls - a systematic virus on glyco-metabolic control in diabetic
in US adults: National Health and Nutrition review. J Diabetes Sci Technol 2022;16:289–294 patients: a systematic review and meta-analysis.
Examination Survey 2009-2014. J Am Dent Assoc 138. Elafros MA, Andersen H, Bennett DL, et al. Acta Diabetol 2019;56:341–354
2018;149:576–588.e576 Towards prevention of diabetic peripheral 154. Dhindsa S, Miller MG, McWhirter CL, et al.
123. Borgnakke WS, Yl€ ostalo PV, Taylor GW, neuropathy: clinical presentation, pathogenesis, Testosterone concentrations in diabetic and non-
Genco RJ. Effect of periodontal disease on and new treatments. Lancet Neurol 2022;21: diabetic obese men. Diabetes Care 2010;33:
diabetes: systematic review of epidemiologic 922–936 1186–1192
S82 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

155. Grossmann M. Low testosterone in men function based on international index of erectile and nonalcoholic fatty liver disease. Obesity
with type 2 diabetes: significance and treatment. function scores. Eur Urol 2017;72:1000–1011 (Silver Spring) 2021;29:1950–1960
J Clin Endocrinol Metab 2011;96:2341–2353 170. Lindau ST, Tang H, Gomero A, et al. 185. Younossi ZM, Golabi P, Price JK, et al. The
156. Bhasin S, Cunningham GR, Hayes FJ, et al.; Sexuality among middle-aged and older adults global epidemiology of nonalcoholic fatty liver
Task Force, Endocrine Society. Testosterone with diagnosed and undiagnosed diabetes: a disease and nonalcoholic steatohepatitis among
therapy in men with androgen deficiency national, population-based study. Diabetes Care patients with type 2 diabetes. Clin Gastroenterol
syndromes: an Endocrine Society clinical practice 2010;33:2202–2210 Hepatol 2024;22:1999–2010.e8
guideline. J Clin Endocrinol Metab 2010;95: 171. Maiorino MI, Bellastella G, Esposito K. 186. Stefan N, Cusi K. A global view of the
2536–2559 Diabetes and sexual dysfunction: current interplay between non-alcoholic fatty liver disease
157. Bhasin S, Brito JP, Cunningham GR, et al. perspectives. Diabetes Metab Syndr Obes 2014;7: and diabetes. Lancet Diabetes Endocrinol 2022;
Testosterone therapy in men with hypogonadism: 95–105 10:284–296
an Endocrine Society clinical practice guideline. J 172. Pontiroli AE, Cortelazzi D, Morabito A. 187. Song SJ, Lai JC-T, Wong GL-H, Wong VW-S,
Clin Endocrinol Metab 2018;103:1715–1744 Female sexual dysfunction and diabetes: a Yip TC-F. Can we use old NAFLD data under the

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

158. Shindel AW, Lue TF, Anawalt B, et al. Medical systematic review and meta-analysis. J Sex Med new MASLD definition? J Hepatol 2024;80:
and surgical therapy of erectile dysfunction. In 2013;10:1044–1051 e54–e56
Endotext. Feingold KR, Anawalt B, Blackman MR, 173. Van Cauwenberghe J, Enzlin P, Nefs G, et al. 188. Younossi ZM, Paik JM, Stepanova M, Ong J,
et al., Eds. South Dartmouth, MA, MDText.com, Prevalence of and risk factors for sexual Alqahtani S, Henry L. Clinical profiles and mortality
2000. Available from https://www.ncbi.nlm.nih dysfunctions in adults with type 1 or type 2 rates are similar for metabolic dysfunction-
.gov/pubmed/25905163 diabetes: results from Diabetes MILES - Flanders. associated steatotic liver disease and non-alcoholic
159. Allen MS, Walter EE. Erectile dysfunction: Diabet Med 2022;39:e14676 fatty liver disease. J Hepatol 2024;80:694–701
an umbrella review of meta-analyses of risk- 174. Pyrgidis N, Mykoniatis I, Tishukov M, et al. 189. Harrison SA, Gawrieh S, Roberts K, et al.
factors, treatment, and prevalence outcomes. J Sexual dysfunction in women with end-stage Prospective evaluation of the prevalence of non-
Sex Med 2019;16:531–541 renal disease: a systematic review and meta- alcoholic fatty liver disease and steatohepatitis in
160. Kouidrat Y, Pizzol D, Cosco T, et al. High analysis. J Sex Med 2021;18:936–945 a large middle-aged US cohort. J Hepatol 2021;
prevalence of erectile dysfunction in diabetes: a 175. Haugstvedt A, Jørgensen J, Strandberg RB, 75:284–291
systematic review and meta-analysis of 145 et al. Sexual dysfunction in women with type 1 190. Castera L, Laouenan C, Vallet-Pichard A,
studies. Diabet Med 2017;34:1185–1192 diabetes in Norway: a cross-sectional study on et al.; QUID-NASH Investigators. High prevalence
161. Araujo AB, Mohr BA, McKinlay JB. Changes the prevalence and associations with physical of NASH and advanced fibrosis in type 2 diabetes:
in sexual function in middle-aged and older men: and psychosocial complications. Diabet Med 2022; a prospective study of 330 outpatients undergoing
longitudinal data from the Massachusetts Male 39:e14704 liver biopsies for elevated ALT, using a low
176. Buskoven MEH, Kjørholt EKH, Strandberg threshold. Diabetes Care 2023;46:1354–1362
Aging Study. J Am Geriatr Soc 2004;52:1502–
RB, Søfteland E, Haugstvedt A. Sexual dysfunction 191. Paik JM, Golabi P, Younossi Y, Mishra A,
1509
in women with type 1 diabetes in Norway: a Younossi ZM. Changes in the global burden of
162. Grover SA, Lowensteyn I, Kaouache M,
qualitative study of women’s experiences. Diabet chronic liver diseases from 2012 to 2017: the
et al. The prevalence of erectile dysfunction in
Med 2022;39:e14856 growing impact of NAFLD. Hepatology 2020;72:
the primary care setting: importance of risk
177. Hendrieckx C, Halliday JA, Russell-Green S, 1605–1616
factors for diabetes and vascular disease. Arch
et al. Adults with diabetes distress often want to 192. Simon TG, Roelstraete B, Khalili H, Hagstr€ om
Intern Med 2006;166:213–219
talk with their health professionals about it: H, Ludvigsson JF. Mortality in biopsy-confirmed
163. Ma RC-W, So W-Y, Yang X, et al. Erectile
findings from an audit of 4 Australian specialist nonalcoholic fatty liver disease: results from a
dysfunction predicts coronary heart disease in
diabetes clinics. Can J Diabetes 2020;44:473–480 nationwide cohort. Gut 2021;70:1375–1382
type 2 diabetes. J Am Coll Cardiol 2008;51:2045–
178. Di Stasi V, Maseroli E, Vignozzi L. Female 193. Burra P, Becchetti C, Germani G. NAFLD
2050
sexual dysfunction in diabetes: mechanisms, and liver transplantation: disease burden, current
164. Gazzaruso C, Solerte SB, Pujia A, et al. Erectile
diagnosis and treatment. Curr Diabetes Rev management and future challenges. JHEP Rep
dysfunction as a predictor of cardiovascular events
2022;18:e171121198002 2020;2:100192
and death in diabetic patients with angiographically 179. Wing RR, Bond DS, Gendrano IN, 3rd, et al.; 194. Corbin KD, Driscoll KA, Pratley RE, Smith SR,
proven asymptomatic coronary artery disease: Sexual Dysfunction Subgroup of the Look AHEAD Maahs DM, Mayer-Davis EJ; Advancing Care for
a potential protective role for statins and Research Group. Effect of intensive lifestyle Type 1 Diabetes and Obesity Network (ACT1ON).
5-phosphodiesterase inhibitors. J Am Coll Cardiol intervention on sexual dysfunction in women Obesity in type 1 diabetes: pathophysiology,
2008;51:2040–2044 with type 2 diabetes: results from an ancillary clinical impact, and mechanisms. Endocr Rev 2018;
165. Kalter-Leibovici O, Wainstein J, Ziv A, et al.; Look AHEAD study. Diabetes Care 2013;36: 39:629–663
Israel Diabetes Research Group (IDRG) Investigators. 2937–2944 195. de Vries M, Westerink J, Kaasjager KHAH,
Clinical, socioeconomic, and lifestyle parameters 180. Rinella ME, Lazarus JV, Ratziu V, et al. A de Valk HW. Prevalence of nonalcoholic fatty liver
associated with erectile dysfunction among diabetic multisociety Delphi consensus statement on new disease (NAFLD) in patients with type 1 diabetes
men. Diabetes Care 2005;28:1739–1744 fatty liver disease nomenclature. Hepatology 2023; mellitus: a systematic review and meta-analysis. J
166. De Berardis G, Pellegrini F, Franciosi M, 78:1966–1986 Clin Endocrinol Metab 2020;105:3842–3853
et al.; QuED (Quality of Care and Outcomes in 181. Rinella ME, Neuschwander-Tetri BA, 196. Cusi K, Sanyal AJ, Zhang S, et al. Non-
Type 2 Diabetes) Study Group. Longitudinal Siddiqui MS, et al. AASLD practice guidance on alcoholic fatty liver disease (NAFLD) prevalence
assessment of quality of life in patients with the clinical assessment and management of and its metabolic associations in patients with
type 2 diabetes and self-reported erectile nonalcoholic fatty liver disease. Hepatology 2023; type 1 diabetes and type 2 diabetes. Diabetes
dysfunction. Diabetes Care 2005;28:2637–2643 77:1797–1835 Obes Metab 2017;19:1630–1634
167. Navaneethan SD, Vecchio M, Johnson DW, 182. Lomonaco R, Godinez Leiva E, Bril F, et al. 197. Ciardullo S, Perseghin G. Prevalence of
et al. Prevalence and correlates of self-reported Advanced liver fibrosis is common in patients elevated liver stiffness in patients with type 1 and
sexual dysfunction in CKD: a meta-analysis of with type 2 diabetes followed in the outpatient type 2 diabetes: a systematic review and meta-
observational studies. Am J Kidney Dis 2010; setting: the need for systematic screening. Diabetes analysis. Diabetes Res Clin Pract 2022;190:109981
56:670–685 Care 2021;44:399–406 198. Cusi K. Nonalcoholic fatty liver disease in
168. Hackett G, Kirby M, Wylie K, et al. British 183. Ciardullo S, Monti T, Perseghin G. High diabetes: a call to action. Diabetes Spectr 2024;
society for sexual medicine guidelines on the prevalence of advanced liver fibrosis assessed by 37:5–7
management of erectile dysfunction in men- transient elastography among U.S. adults with 199. Younossi ZM, Ong JP, Takahashi H, et al.;
2017. J Sex Med 2018;15:430–457 type 2 diabetes. Diabetes Care 2021;44:519–525 Global Nonalcoholic Steatohepatitis Council. A
169. Corona G, Rastrelli G, Morgentaler A, 184. Barb D, Repetto EM, Stokes ME, Shankar global survey of physicians knowledge about
Sforza A, Mannucci E, Maggi M. Meta-analysis of SS, Cusi K. Type 2 diabetes mellitus increases the nonalcoholic fatty liver disease. Clin Gastroenterol
results of testosterone therapy on sexual risk of hepatic fibrosis in individuals with obesity Hepatol 2022;20:e1456–e1468
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S83

200. Kanwal F, Shubrook JH, Younossi Z, et al. with chronic kidney disease: a systematic review assessing steatosis and fibrosis in patients with
Preparing for the NASH epidemic: a call to action. and meta-analysis. PLoS Med 2014;11:e1001680 nonalcoholic fatty liver disease. Gastroenterology
Diabetes Care 2021;44:2162–2172 214. Song D, Li C, Wang Z, Zhao Y, Shen B, Zhao 2019;156:1717–1730
201. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver W. Association of non-alcoholic fatty liver disease 229. M
ozes FE, Lee JA, Selvaraj EA, et al.;
fibrosis, but no other histologic features, is associated with diabetic retinopathy in type 2 diabetic LITMUS Investigators. Diagnostic accuracy of
with long-term outcomes of patients with non- patients: a meta-analysis of observational studies. non-invasive tests for advanced fibrosis in
alcoholic fatty liver disease. Gastroenterology 2015; J Diabetes Investig 2021;12:1471–1479 patients with NAFLD: an individual patient data
149:389–397.e310

215. Arab JP, Dirchwolf M, Alvares-da-Silva MR, meta-analysis. Gut 2022;71:1006–1019
202. Ekstedt M, Hagstr€ om H, Nasr P, et al. Fibrosis et al. Latin American Association for the Study of 230. Elhence A, Anand A, Biswas S, et al.
stage is the strongest predictor for disease-specific the Liver (ALEH) practice guidance for the Compensated advanced chronic liver disease in
mortality in NAFLD after up to 33 years of follow- diagnosis and treatment of non-alcoholic fatty nonalcoholic fatty liver disease: two-step strategy
up. Hepatology 2015;61:1547–1554 liver disease. Ann Hepatol 2020;19:674–690 is better than Baveno criteria. Dig Dis Sci 2023;
203. Taylor RS, Taylor RJ, Bayliss S, et al. 216. Eslam M, Sarin SK, Wong VW-S, et al. The 68:1016–1025

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

Association between fibrosis stage and outcomes Asian Pacific Association for the Study of the 231. Wong VWS, Zelber-Sagi S, Cusi K, et al.
of patients with nonalcoholic fatty liver disease: Liver clinical practice guidelines for the diagnosis Management of NAFLD in primary care settings.
a systematic review and meta-analysis. Gas- and management of metabolic associated fatty Liver Int 2022;42:2377–2389
troenterology 2020;158:1611–1625.e1612 liver disease. Hepatol Int 2020;14:889–919 232. Lazarus JV, Anstee QM, Hagstr€ om H, et al.
204. Sanyal AJ, Van Natta ML, Clark J, et al.; NASH 217. European Association for the Study of the Defining comprehensive models of care for
Clinical Research Network (CRN). Prospective Liver (EASL); European Association for the Study of NAFLD. Nat Rev Gastroenterol Hepatol 2021;18:
study of outcomes in adults with nonalcoholic fatty Diabetes (EASD); European Association for the 717–729
liver disease. N Engl J Med 2021;385:1559–1569 Study of Obesity (EASO); European Association for 233. Cusi K, Budd J, Johnson E, Shubrook J.
205. Cusi K, Isaacs S, Barb D, et al. American the Study of the Liver (EASL). EASL-EASD-EASO Making sense of the nonalcoholic fatty liver
Association of Clinical Endocrinology clinical Clinical Practice Guidelines on the management of disease clinical practice guidelines: what clinicians
practice guideline for the diagnosis and man- metabolic dysfunction-associated steatotic liver need to know. Diabetes Spectr 2024;37:29–38
agement of nonalcoholic fatty liver disease in disease (MASLD). J Hepatol 2024;81:492–542 234. Anstee QM, Lawitz EJ, Alkhouri N, et al.
primary care and endocrinology clinical settings: 218. Portillo-Sanchez P, Bril F, Maximos M, et al. Noninvasive tests accurately identify advanced
co-sponsored by the American Association for the High prevalence of nonalcoholic fatty liver fibrosis due to NASH: baseline data from the
Study of Liver Diseases (AASLD). Endocr Pract disease in patients with type 2 diabetes mellitus STELLAR trials. Hepatology 2019;70:1521–1530
2022;28:528–562 and normal plasma aminotransferase levels. J 235. Lee J, Vali Y, Boursier J, et al. Prognostic
206. Kanwal F, Shubrook JH, Adams LA, et al. Clin Endocrinol Metab 2015;100:2231–2238 accuracy of FIB-4, NAFLD fibrosis score and APRI
219. Maximos M, Bril F, Portillo Sanchez P, et al. for NAFLD-related events: a systematic review.
Clinical care pathway for the risk stratification
The role of liver fat and insulin resistance as Liver Int 2021;41:261–270
and management of patients with nonalcoholic
determinants of plasma aminotransferase elevation 236. Chan W-K, Treeprasertsuk S, Goh GB-B,
fatty liver disease. Gastroenterology 2021;161:
in nonalcoholic fatty liver disease. Hepatology 2015; et al. Optimizing use of nonalcoholic fatty liver
1657–1669
61:153–160 disease fibrosis score, fibrosis-4 score, and liver
207. Gellert-Kristensen H, Richardson TG, Davey
220. Kwo PY, Cohen SM, Lim JK. ACG clinical stiffness measurement to identify patients with
Smith G, Nordestgaard BG, Tybjaerg-Hansen A,
guideline: evaluation of abnormal liver chemistries. advanced fibrosis. Clin Gastroenterol Hepatol
Stender S. Combined effect of PNPLA3, TM6SF2,
Am J Gastroenterol 2017;112:18–35 2019;17:2570–2580.e2537
and HSD17B13 variants on risk of cirrhosis and
221. Younossi ZM, Anstee QM, Wai-Sun Wong V, 237. Petta S, Wai-Sun Wong V, Bugianesi E, et al.
hepatocellular carcinoma in the general po-
et al. The association of histologic and noninvasive Impact of obesity and alanine aminotransferase
pulation. Hepatology 2020;72:845–856
tests with adverse clinical and patient-reported levels on the diagnostic accuracy for advanced
208. Stender S, Kozlitina J, Nordestgaard BG,
outcomes in patients with advanced fibrosis due liver fibrosis of noninvasive tools in patients with
Tybjærg-Hansen A, Hobbs HH, Cohen JC.
to nonalcoholic steatohepatitis. Gastroenterology nonalcoholic fatty liver disease. Am J Gastroenterol
Adiposity amplifies the genetic risk of fatty liver 2019;114:916–928
2021;160:1608–1619.e1613
disease conferred by multiple loci. Nat Genet 222. Siddiqui MS, Yamada G, Vuppalanchi R, 238. Vali Y, Lee J, Boursier J, et al.; LITMUS
2017;49:842–847 et al.; NASH Clinical Research Network. Diagnostic Systematic Review Team. Enhanced liver fibrosis
209. Mantovani A, Byrne CD, Bonora E, Targher accuracy of noninvasive fibrosis models to detect test for the non-invasive diagnosis of fibrosis in
G. Nonalcoholic fatty liver disease and risk of change in fibrosis stage. Clin Gastroenterol Hepatol patients with NAFLD: a systematic review and
incident type 2 diabetes: a meta-analysis. Diabetes 2019;17:1877–1885.e1875 meta-analysis. J Hepatol 2020;73:252–262
Care 2018;41:372–382 223. Unalp-Arida A, Ruhl CE. Liver fibrosis scores 239. Srivastava A, Gailer R, Tanwar S, et al.
210. Duell PB, Welty FK, Miller M, et al.; American predict liver disease mortality in the United Prospective evaluation of a primary care referral
Heart Association Council on Arteriosclerosis, States population. Hepatology 2017;66:84–95 pathway for patients with non-alcoholic fatty
Thrombosis and Vascular Biology; Council on 224. Qadri S, Ahlholm N, Lønsmann I, et al. liver disease. J Hepatol 2019;71:371–378
Hypertension; Council on the Kidney in Car- Obesity modifies the performance of fibrosis 240. Saarinen K, F€arkkil€a M, Jula A, et al.
diovascular Disease; Council on Lifestyle and biomarkers in nonalcoholic fatty liver disease. J Enhanced liver fibrosis test predicts liver-related
Cardiometabolic Health; and Council on Peripheral Clin Endocrinol Metab 2022;107:e2008–e2020 outcomes in the general population. JHEP Rep
Vascular Disease. Nonalcoholic fatty liver disease 225. Bril F, McPhaul MJ, Caulfield MP, et al. 2023;5:100765
and cardiovascular risk: a scientific statement from Performance of plasma biomarkers and diagnostic 241. Kjaergaard M, Lindvig KP, Thorhauge KH,
the American Heart Association. Arterioscler panels for nonalcoholic steatohepatitis and et al. Using the ELF test, FIB-4 and NAFLD fibrosis
Thromb Vasc Biol 2022;42:e168–e185 advanced fibrosis in patients with type 2 diabetes. score to screen the population for liver disease. J
211. Mantovani A, Csermely A, Petracca G, et al. Diabetes Care 2020;43:290–297 Hepatol 2023;79:277–286
Non-alcoholic fatty liver disease and risk of fatal 226. McPherson S, Hardy T, Dufour J-F, et al. Age 242. Zoncape M, Liguori A, Tsochatzis EA. Non-
and non-fatal cardiovascular events: an updated as a confounding factor for the accurate non- invasive testing and risk-stratification in patients
systematic review and meta-analysis. Lancet invasive diagnosis of advanced NAFLD fibrosis. with MASLD. Eur J Intern Med 2024;122:11–19
Gastroenterol Hepatol 2021;6:903–913 Am J Gastroenterol 2017;112:740–751 243. Andersson A, Kelly M, Imajo K, et al. Clinical
212. Ciardullo S, Ballabeni C, Trevisan R, Perseghin 227. Castera L, Friedrich-Rust M, Loomba R. utility of magnetic resonance imaging biomarkers
G. Liver stiffness, albuminuria and chronic kidney Noninvasive assessment of liver disease in for identifying nonalcoholic steatohepatitis patients
disease in patients with NAFLD: a systematic patients with nonalcoholic fatty liver disease. at high risk of progression: a multicenter pooled
review and meta-analysis. Biomolecules 2022; Gastroenterology 2019;156:1264–1281.e1264 data and meta-analysis. Clin Gastroenterol Hepatol
12:105 228. Eddowes PJ, Sasso M, Allison M, et al. 2022;20:2451–2461
213. Musso G, Gambino R, Tabibian JH, et al. Accuracy of FibroScan controlled attenuation 244. Long MT, Noureddin M, Lim JK. AGA clinical
Association of non-alcoholic fatty liver disease parameter and liver stiffness measurement in practice update: diagnosis and management of
S84 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 48, Supplement 1, January 2025

nonalcoholic fatty liver disease in lean individuals: trial of subcutaneous semaglutide in nonalcoholic patients with type 2 diabetes: a 24-week, ran-
expert review. Gastroenterology 2022;163:764– steatohepatitis. N Engl J Med 2021;384:1113–1124 domized, placebo-controlled trial. Diabetes Obes
774.e761 263. National Library of Medicine, National Metab 2014;16:147–158
245. Cusi K. Nonalcoholic steatohepatitis in Center for Biotechnology Information. Research 276. Armstrong MJ, Gaunt P, Aithal GP, et al.;
nonobese patients: not so different after all. Study on Whether Semaglutide Works in People LEAN Trial Team. Liraglutide safety and efficacy in
Hepatology 2017;65:4–7 With Non-Alcoholic Steatohepatitis (NASH) patients with non-alcoholic steatohepatitis (LEAN):
246. Loomba R, Friedman SL, Shulman GI. (ESSENCE). Accessed 23 September 2024. a multicentre, double-blind, randomised, placebo-
Mechanisms and disease consequences of non- Available from https://clinicaltrials.gov/study/ controlled phase 2 study. Lancet 2016;387:679–
alcoholic fatty liver disease. Cell 2021;184:2537– NCT04822181 690
2564 264. Belfort R, Harrison SA, Brown K, et al. A 277. Gastaldelli A, Cusi K, Fern
andez Land
o L,
247. Cusi K. Role of obesity and lipotoxicity in placebo-controlled trial of pioglitazone in Bray R, Brouwers B, Rodr
ıguez A
. Effect of
the development of nonalcoholic steatohepatitis: subjects with nonalcoholic steatohepatitis. N tirzepatide versus insulin degludec on liver fat
pathophysiology and clinical implications. Gas- Engl J Med 2006;355:2297–2307 content and abdominal adipose tissue in people

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

troenterology 2012;142:711–725.e716 265. Cusi K, Orsak B, Bril F, et al. Long-term with type 2 diabetes (SURPASS-3 MRI): a
248. Schuppan D, Surabattula R, Wang XY. pioglitazone treatment for patients with substudy of the randomised, open-label, parallel-
Determinants of fibrosis progression and regression nonalcoholic steatohepatitis and prediabetes or group, phase 3 SURPASS-3 trial. Lancet Diabetes
in NASH. J Hepatol 2018;68:238–250 type 2 diabetes mellitus: a randomized trial. Ann Endocrinol 2022;10:393–406
249. Promrat K, Kleiner DE, Niemeier HM, et al. Intern Med 2016;165:305–315 278. Loomba R, Hartman ML, Lawitz EJ, et al.;
Randomized controlled trial testing the effects of 266. Sanyal AJ, Chalasani N, Kowdley KV, et al.; SYNERGY-NASH Investigators. Tirzepatide for
weight loss on nonalcoholic steatohepatitis. NASH CRN. Pioglitazone, vitamin E, or placebo for metabolic dysfunction-associated steatohepatitis
Hepatology 2010;51:121–129 nonalcoholic steatohepatitis. N Engl J Med 2010; with liver fibrosis. N Engl J Med 2024;391:
250. Vilar-Gomez E, Martinez-Perez Y, Calzadilla- 362:1675–1685 299–310
Bertot L, et al. Weight loss through lifestyle 267. Aithal GP, Thomas JA, Kaye PV, et al. 279. Sanyal AJ, Bedossa P, Fraessdorf M, et al.;
modification significantly reduces features of Randomized, placebo-controlled trial of pioglitazone 1404-0043 Trial Investigators. A phase 2 randomized
nonalcoholic steatohepatitis. Gastroenterology in nondiabetic subjects with nonalcoholic steato- trial of survodutide in MASH and fibrosis. N Engl J
2015;149:367–378.e365 hepatitis. Gastroenterology 2008;135:1176–1184 Med 2024;391:311–319
251. Younossi ZM, Zelber-Sagi S, Henry L, Gerber 268. Huang J-F, Dai C-Y, Huang C-F, et al. First-in- 280. Cusi K, Bril F, Barb D, et al. Effect of
LH. Lifestyle interventions in nonalcoholic fatty Asian double-blind randomized trial to assess the canagliflozin treatment on hepatic triglyceride
liver disease. Nat Rev Gastroenterol Hepatol 2023; efficacy and safety of insulin sensitizer in content and glucose metabolism in patients with
nonalcoholic steatohepatitis patients. Hepatol Int
20:708–722 type 2 diabetes. Diabetes Obes Metab 2019;21:
2021;15:1136–1147
252. Sargeant JA, Gray LJ, Bodicoat DH, et al. 812–821
269. Sathyanarayana P, Jogi M, Muthupillai R,
The effect of exercise training on intrahepatic 281. Kahl S, Gancheva S, Straßburger K, et al.
Krishnamurthy R, Samson SL, Bajaj M. Effects of
triglyceride and hepatic insulin sensitivity: a Empagliflozin effectively lowers liver fat content
combined exenatide and pioglitazone therapy on
systematic review and meta-analysis. Obes Rev in well-controlled type 2 diabetes: a randomized,
hepatic fat content in type 2 diabetes. Obesity
2018;19:1446–1459 double-blind, phase 4, placebo-controlled trial.
(Silver Spring) 2011;19:2310–2315
253. Kanwal F, Kramer JR, Li L, et al. Effect of Diabetes Care 2020;43:298–305
270. Abdul-Ghani M, Migahid O, Megahed A,
metabolic traits on the risk of cirrhosis and 282. Latva-Rasku A, Honka M-J, Kullberg J, et al.
DeFronzo RA, Al-Ozairi E, Jayyousi A. Combination
hepatocellular cancer in nonalcoholic fatty liver The SGLT2 inhibitor dapagliflozin reduces liver fat
therapy with pioglitazone/exenatide improves
disease. Hepatology 2020;71:808–819 but does not affect tissue insulin sensitivity: a
beta-cell function and produces superior glycaemic
254. Younossi Z, Stepanova M, Sanyal AJ, et al. randomized, double-blind, placebo-controlled
control compared with basal/bolus insulin in
The conundrum of cryptogenic cirrhosis: adverse poorly controlled type 2 diabetes: a 3-year follow- study with 8-week treatment in type 2 diabetes
outcomes without treatment options. J Hepatol up of the Qatar study. Diabetes Obes Metab patients. Diabetes Care 2019;42:931–937
2018;69:1365–1370 2020;22:2287–2294 283. Harrison SA, Bedossa P, Guy CD, et al.;
255. Castera L, Cusi K. Diabetes and cirrhosis: 271. Lavynenko O, Abdul-Ghani M, Alatrach M, MAESTRO-NASH Investigators. A phase 3, ran-
current concepts on diagnosis and management. et al. Combination therapy with pioglitazone/ domized, controlled trial of resmetirom in NASH
Hepatology 2023;77:2128–2146 exenatide/metformin reduces the prevalence of with liver fibrosis. N Engl J Med 2024;390:497–509
256. Patel Chavez C, Cusi K, Kadiyala S. The hepatic fibrosis and steatosis: the efficacy and 284. Cusi K. Selective agonists of thyroid
emerging role of glucagon-like peptide-1 receptor durability of initial combination therapy for type 2 hormone receptor beta for the treatment of
agonists for the management of NAFLD. J Clin diabetes (EDICT). Diabetes Obes Metab 2022;24: NASH. N Engl J Med 2024;390:559–561
Endocrinol Metab 2022;107:29–38 899–907 285. Noureddin M, Charlton MR, Harrison SA,
257. Gastaldelli A, Cusi K. From NASH to diabetes 272. Ahr
en B, Masmiquel L, Kumar H, et al. et al. Expert panel recommendations: practical
and from diabetes to NASH: mechanisms and Efficacy and safety of once-weekly semaglutide clinical applications for initiating and monitoring
treatment options. JHEP Rep 2019;1:312–328 versus once-daily sitagliptin as an add-on to resmetirom in patients with MASH/NASH and
258. Budd J, Cusi K. Role of agents for the metformin, thiazolidinediones, or both, in patients moderate to noncirrhotic advanced fibrosis. Clin
treatment of diabetes in the management of with type 2 diabetes (SUSTAIN 2): a 56-week, Gastroenterol Hepatol. 20 July 2024 [Epub ahead
nonalcoholic fatty liver disease. Curr Diab Rep double-blind, phase 3a, randomised trial. Lancet of print]. DOI: 10.1016/j.cgh.2024.07.003
2020;20:59 Diabetes Endocrinol 2017;5:341–354 286. Chen VL, Morgan TR, Rotman Y, et al.
259. Ussher JR, Drucker DJ. Glucagon-like peptide 1 273. Noureddin M, Jones C, Alkhouri N, Gomez Resmetirom therapy for metabolic dysfunction-
receptor agonists: cardiovascular benefits and EV, Dieterich DT, Rinella ME; NASHNET. Screening associated steatotic liver disease: October 2024
mechanisms of action. Nat Rev Cardiol 2023;20: for nonalcoholic fatty liver disease in persons updates to AASLD Practice Guidance. Hepatology.
463–474 with type 2 diabetes in the United States is cost- 18 October 2024 [Epub ahead of print]. DOI:
260. Musso G, Cassader M, Paschetta E, Gambino effective: a comprehensive cost-utility analysis. 10.1097/HEP.0000000000001112
R. Thiazolidinediones and advanced liver fibrosis Gastroenterology 2020;159:1985–1987.e1984 287. Loomba R, Abdelmalek MF, Armstrong MJ,
in nonalcoholic steatohepatitis: a meta-analysis. 274. Mahady SE, Wong G, Craig JC, George J. et al.; NN9931-4492 Investigators. Semaglutide 2.4
JAMA Intern Med 2017;177:633–640 Pioglitazone and vitamin E for nonalcoholic mg once weekly in patients with non-alcoholic
261. Bril F, Kalavalapalli S, Clark VC, et al. Response steatohepatitis: a cost utility analysis. Hepatology steatohepatitis-related cirrhosis: a randomised,
to pioglitazone in patients with nonalcoholic 2012;56:2172–2179 placebo-controlled phase 2 trial. Lancet Gas-
steatohepatitis with vs without type 2 diabetes. Clin 275. Kovacs CS, Seshiah V, Swallow R, et al.; EMPA- troenterol Hepatol 2023;8:511–522
Gastroenterol Hepatol 2018;16:558–566.e552 REG PIO Trial Investigators. Empagliflozin improves 288. Aminian A, Al-Kurd A, Wilson R, et al.
262. Newsome PN, Buchholtz K, Cusi K, et al.; glycaemic and weight control as add-on therapy to Association of bariatric surgery with major adverse
NN9931-4296 Investigators. A placebo-controlled pioglitazone or pioglitazone plus metformin in liver and cardiovascular outcomes in patients with
diabetesjournals.org/care Comprehensive Medical Evaluation and Assessment of Comorbidities S85

biopsy-proven nonalcoholic steatohepatitis. JAMA 301. Das SLM, Singh PP, Phillips ARJ, Murphy R, Examination Survey 1999-2004. Diabetes Care
2021;326:2031–2042 Windsor JA, Petrov MS. Newly diagnosed diabetes 2011;34:1540–1545
289. Fakhry TK, Mhaskar R, Schwitalla T, mellitus after acute pancreatitis: a systematic 316. Schade DS, Lorenzi GM, Braffett BH, et al.;
Muradova E, Gonzalvo JP, Murr MM. Bariatric review and meta-analysis. Gut 2014;63:818–831 DCCT/EDIC Research Group. Hearing impairment
surgery improves nonalcoholic fatty liver disease: 302. Petrov MS. Diabetes of the exocrine pancreas: and type 1 diabetes in the Diabetes Control and
a contemporary systematic review and meta- American Diabetes Association-compliant lexicon. Complications Trial/Epidemiology of Diabetes
analysis. Surg Obes Relat Dis 2019;15:502–511 Pancreatology 2017;17:523–526 Interventions and Complications (DCCT/EDIC)
290. Ramai D, Singh J, Lester J, et al. Systematic 303. Thomsen RW, Pedersen L, Møller N, Kahlert cohort. Diabetes Care 2018;41:2495–2501
review with meta-analysis: bariatric surgery J, Beck-Nielsen H, Sørensen HT. Incretin-based 317. Rasmussen VF, Vestergaard ET, Hejlesen O,
reduces the incidence of hepatocellular carcinoma. therapy and risk of acute pancreatitis: a nationwide Andersson CUN, Cichosz SL. Prevalence of taste
Aliment Pharmacol Ther 2021;53:977–984 population-based case-control study. Diabetes Care and smell impairment in adults with diabetes: a
291. Kim RG, Loomba R, Prokop LJ, Singh S. Statin 2015;38:1089–1098 cross-sectional analysis of data from the National
use and risk of cirrhosis and related complications 304. Tk
ac I, Raz I. Combined analysis of three Health and Nutrition Examination Survey (NHANES).

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S59/791510/dc25s004.pdf by Nicaragua Institution user on 25 April 2025

in patients with chronic liver diseases: a systematic large interventional trials with gliptins indicates Prim Care Diabetes 2018;12:453–459
review and meta-analysis. Clin Gastroenterol increased incidence of acute pancreatitis in 318. Centers for Disease Control and Prevention.
Hepatol 2017;15:1521–1530.e1528 patients with type 2 diabetes. Diabetes Care Interim Clinical Considerations. Accessed 19
292. Kaplan DE, Serper MA, Mehta R, et al.; VOCAL 2017;40:284–286 August 2024. Available from https://www.cdc.gov/
Study Group. Effects of hypercholesterolemia and 305. Egan AG, Blind E, Dunder K, et al. Pancreatic vaccines/covid-19/clinical-considerations/covid-19-
statin exposure on survival in a large national cohort safety of incretin-based drugs–FDA and EMA vaccines-us.html
of patients with cirrhosis. Gastroenterology 2019; assessment. N Engl J Med 2014;370:794–797 319. Centers for Disease Control and Prevention
156:1693–1706.e1612 306. Drucker DJ. Efficacy and safety of GLP-1 (CDC); Advisory Committee on Immunization
293. Li C, Ford ES, Zhao G, Croft JB, Balluz LS, medicines for type 2 diabetes and obesity. Diabetes Practices. Updated recommendations for prevention
Mokdad AH. Prevalence of self-reported clinically Care 2024; of invasive pneumococcal disease among adults
diagnosed sleep apnea according to obesity 307. Bellin MD, Gelrud A, Arreaza-Rubin G, et al. using the 23-valent pneumococcal polysaccharide
Total pancreatectomy with islet autotransplantation: vaccine (PPSV23). MMWR Morb Mortal Wkly Rep
status in men and women: National Health and
summary of an NIDDK workshop. Ann Surg 2015; 2010;59:1102–1106
Nutrition Examination Survey, 2005-2006. Prev
261:21–29 320. Falkenhorst G, Remschmidt C, Harder T,
Med 2010;51:18–23
308. Sutherland DER, Radosevich DM, Bellin Hummers-Pradier E, Wichmann O, Bogdan C.
294. West SD, Nicoll DJ, Stradling JR. Prevalence
MD, et al. Total pancreatectomy and islet Effectiveness of the 23-valent pneumococcal poly-
of obstructive sleep apnoea in men with type 2
autotransplantation for chronic pancreatitis. J Am saccharide vaccine (PPV23) against pneumococcal
diabetes. Thorax 2006;61:945–950
Coll Surg 2012;214:409–424 disease in the elderly: systematic review and
295. Resnick HE, Redline S, Shahar E, et al.;
309. Quartuccio M, Hall E, Singh V, et al. Glycemic meta-analysis. PLoS One 2017;12:e0169368
Sleep Heart Health Study. Diabetes and sleep
predictors of insulin independence after total 321. Kobayashi M, Farrar JL, Gierke R, et al. Use
disturbances: findings from the Sleep Heart pancreatectomy with islet autotransplantation. J of 15-valent pneumococcal conjugate vaccine
Health Study. Diabetes Care 2003;26:702–709 Clin Endocrinol Metab 2017;102:801–809 and 20-valent pneumococcal conjugate vaccine
296. Foster GD, Sanders MH, Millman R, et al.; 310. Webb MA, Illouz SC, Pollard CA, et al. Islet among U.S. adults: updated recommendations of
Sleep AHEAD Research Group. Obstructive sleep auto transplantation following total pan- the Advisory Committee on Immunization Practices -
apnea among obese patients with type 2 createctomy: a long-term assessment of graft United States, 2022. MMWR Morb Mortal Wkly Rep
diabetes. Diabetes Care 2009;32:1017–1019 function. Pancreas 2008;37:282–287 2022;71:109–117
297. Bibbins-Domingo K, Grossman DC, Curry SJ, 311. Wu Q, Zhang M, Qin Y, et al. Systematic 322. Havers FP, Moro PL, Hunter P, Hariri S,
et al.; US Preventive Services Task Force. Screening review and meta-analysis of islet autotrans- Bernstein H. Use of tetanus toxoid, reduced
for obstructive sleep apnea in adults: US plantation after total pancreatectomy in chronic diphtheria toxoid, and acellular pertussis vaccines:
Preventive Services Task Force recommendation pancreatitis patients. Endocr J 2015;62:227–234 updated recommendations of the Advisory
statement. JAMA 2017;317:407–414 312. Baiduc RR, Helzner EP. Epidemiology of Committee on Immunization Practices - United
298. Malhotra A, Grunstein RR, Fietze I, et al.; diabetes and hearing loss. Semin Hear 2019;40: States, 2019. MMWR Morb Mortal Wkly Rep
SURMOUNT-OSA Investigators. Tirzepatide for 281–291 2020;69:77–83
the treatment of obstructive sleep apnea and 313. Helzner EP, Contrera KJ. Type 2 diabetes 323. Dooling KL, Guo A, Patel M, et al.
obesity. N Engl J Med 2024;391:1193–1205 and hearing impairment. Curr Diab Rep 2016; Recommendations of the Advisory Committee on
299. Piciucchi M, Capurso G, Archibugi L, Delle 16:3 Immunization Practices for use of herpes zoster
Fave MM, Capasso M, Delle Fave G. Exocrine 314. Hicks CW, Wang D, Lin FR, Reed N, vaccines. MMWR Morb Mortal Wkly Rep 2018;
pancreatic insufficiency in diabetic patients: Windham BG, Selvin E. Peripheral neuropathy 67:103–108
prevalence, mechanisms, and treatment. Int J and vision and hearing impairment in US adults 324. Davies MJ, Aroda VR, Collins BS, et al.
Endocrinol 2015;2015:595649 with and without diabetes. Am J Epidemiol 2023; Management of hyperglycemia in type 2 diabetes,
300. Lee Y-K, Huang M-Y, Hsu C-Y, Su Y-C. 192:237–245 2022. A consensus report by the American
Bidirectional relationship between diabetes and 315. Bainbridge KE, Hoffman HJ, Cowie CC. Risk Diabetes Association (ADA) and the European
acute pancreatitis: a population-based cohort study factors for hearing impairment among U.S. adults Association for the Study of Diabetes (EASD).
in Taiwan. Medicine (Baltimore) 2016;95:e2448 with diabetes: National Health and Nutrition Diabetes Care 2022;45:2753–2786