CASE STUDIES:

Managing Type 2 Diabetes From Diagnosis Through Disease Progression:

Role of GLP-1 Receptor Agonists in Therapy

About This Activity 3. Explain the differences between GLP-1 receptor

agonist therapy and DPP-4 inhibitor therapy in
This enduring activity was developed in part from a
patient-centered language
CE-certified symposium held on Thursday, October
3, 2013, during OMED 2013 Osteopathic Medical 4. Describe how GLP-1 receptor agonists may be
Conference & Exposition in Las Vegas, Nevada. used as monotherapy, part of combination therapy
strategies, with insulin, and over the course of
Target Audience
diabetes
This CE activity is intended for osteopathic physicians
and other healthcare professionals involved in the care Credit Designation Statement
of patients with type 2 diabetes.
The American Osteopathic Association designates
Learning Objectives this activity for a maximum of 1.50 hours of Category-
After completing this activity learners should be better 1B credit.
able to:
Planning Committee Disclosures
1. I dentify different concerns and pathophysiologic Laurie Ermentrout states that she has no relevant
considerations that exist for patients at different financial relationship to disclose.
times in the course of diabetes progression
Kate Mann, PharmD, states that she has no relevant
2. D
 ifferentiate GLP-1 receptor agonists from financial relationship to disclose.
traditional glucose-lowering agents with respect to
A1C lowering effects, weight effects, and risks of This enduring activity is supported by an educational
hypoglycemia grant from Novo Nordisk Inc.
Managing Recent-Onset Diabetes:
Choosing Well-Tolerated Therapies
With Durability to Add to Metformin
or in Metformin-Intolerant Patients
Jay H. Shubrook, Jr., DO, FACOFP, FAAFP
Director, Diabetes Endocrine Center
Director, Diabetes Fellowship
The Diabetes Institute at Ohio University, Athens, Ohio

Introduction
Current treatment algorithms for type 2 diabetes mellitus
(T2DM) recommend promptly starting pharmacotherapy,
Figure 1. Kaplan-Meier plot of secondary failure of metformin mono-
usually with metformin, for patients with moderate therapy by categories of duration of diabetes at metformin initiation,
hyperglycemia in whom lifestyle changes are anticipated adjusted for age and A1C level at initiation and the percent per year
(95% confidence intervals [CIs]) experiencing secondary failure.
to be unsuccessful when used alone.1,2 Metformin, the
most widely used first-line T2DM drug, has a long record
of safety. This oral agent has been associated with
improved glycemic, microvascular and cardiovascular
outcomes, reduction in diabetes-related complications,
a low risk of hypoglycemia and weight gaining, and is also
available generically. Clinical data supporting metformin’s
use soon after diabetes diagnosis suggest that earlier
use might preserve beta-cell function, and prolong the
effectiveness of metformin, reduce lifetime glycemic
burden, and thus prevent diabetes complications.3

Figure 1 shows categories of duration of diabetes at

metformin initiation (adjusted for age and A1C level
at initiation) and the percent per year experiencing
secondary failure. If metformin was started within 3
months of diagnosis, the failure rate was 12.2%, but if Figure 2. Kaplan-Meier plot of secondary failure of metformin mono-
it was started at 12 months from diagnosis, the failure therapy by categories of A1C level at metformin initiation, adjusted for
age and diabetes duration at initiation and the percent per year (95%
was 21.4%. The separation is clearer in Figure 2,
CIs) experiencing secondary failure.
when looking at the level of A1C. If one waits to initiate
metformin until the A1C level is above 9%, the failure
rate is 19.4% per year, whereas the failure rate is much Diabetes care by American Diabetes Association Reproduced with
lower if metformin is started at an A1C level closer to permission of AMERICAN DIABETES ASSOCIATION in the format
Continuing Education via Copyright Clearance Center.
7%.3

Metformin is associated with initial gastrointestinal (GI)

side effects and may not be tolerated by all patients,
especially at higher doses. Caution is advised in using it
in patients at risk for lactic acidosis especially in people
advanced renal insufficiency, cirrhosis or alcoholism.4

2
Case Study patients enrolled in the study, physicians assigned the
highest treatment priority to glucose control (for 68% of
Clinton is a 40-year-old African-American man, married
patients, followed far behind by lipids in 11% of patients
with 4 children, who works as a foreman of a loading
and BP in 9% of patients).6 The historical rationale for
dock. He was diagnosed with T2DM 3 months ago. He
improving glycemia was the estimated 37% reduction
weighs 220.5 lb and has a body mass index (BMI) of 31.6
in microvascular complications for each 1% reduction in
kg/m2. He is a current smoker. He is on no prescription
A1C levels.7 While this is important, most patients with
medications. His current A1C level is 7.8%. He complains
type 2 diabetes die from cardiovascular disease and
of sleep disturbance.
cardiovascular risk factors must be addressed.
Biometrics: Social history:
A meta-analysis performed by Huang found that
• Height: 70 in. • Loading dock foreman
in patients who had concurrent hyperglycemia,
• Weight: 220.5 lb (100 kg) • Married; 4 children, ages
hypertension and dyslipidemia the greatest benefit with
• BMI: 31.6 kg/m2 4, 6, 8, and 9
hypertension, then dyslipidemia, then finally glucose
•S  moker (½ pack a day x 15
Vital signs:
years) lowering.8 Hypertension is the most common among
• Pulse: 55 bpm •S  ocial alcohol use (beer on the comorbid disease conditions, occurring in 90% of
• Respirations: 22/minute weekends) patients with diabetes,9 and further increases the risk
• Blood pressure (BP): • Denies illicit drug use for disease- and treatment-related complications.10 The
148/92 mm Hg combination of hypertension and diabetes accelerates
Current medications:
Medical history: the progression of diabetes-related complications such
• Multivitamin daily as diabetic nephropathy, retinopathy, left ventricular
• Appendectomy 5 • Occasional over-the-
years ago hypertrophy, and diastolic heart failure, and doubles the
counter (OTC) medicines
• No history of alcoholism risk of stroke and cardiovascular disease and all-cause
for headache
• No history of pancreatitis mortality compared with non-diabetic patients with
hypertension.11
Family history:
• Two brothers, both A comprehensive approach to the person with T2DM
withT2DM, controlled with is the most effective. In the Steno-2 study, intensified
oral medications therapy of modifiable risk factors in patients with T2DM
and microalbuminuria was compared with standard
treatment. The target limits for A1C, fasting cholesterol
Question 1: and triglycerides (TGs), and BP were much stricter than
What is your priority for treating this patient? in the control group. In addition to lifestyle changes and
diet modifications, all patients in this group received
A. Focus on BP ACE inhibitors (ACEIs) or angiotensin receptor blockers
B. Focus on glucose (ARBs). This multifactorial approach led to significant
C. Focus on lipids reductions in both micro- and macrovascular event
D. Focus on weight rates as well as death (Figure 3),12 and was found to
E. All of the above be cost-effective.13 Treatment guidelines now suggest
All of Clinton’s parameters need attention. One could a comprehensive approach to patients with diabetes,
argue that addressing his weight would improve the rather than a solely glucose-centric approach.2,4,14
other 3 parameters, but it is known that unless a patient
is ready and willing to make a change in lifestyle and to
address weight, such efforts are not likely to succeed. It
has also been shown that physicians are often reluctant
to bring up the topic of weight during an office visit.5

Bergenstal and colleagues studied physician approaches

to patients with diabetes and with adverse CV risk factors
and found that, after evaluating the metabolic profiles of

3
 He is counseled on the fact that diabetes is a progressive
disease, that his medications will change over time, and
that these changes will be discussed with him.
Medications 3 months later:
• Lisinopril 20 mg daily
• Atorvastatin 40 mg daily
• He is tolerating metformin 1000 mg twice daily
• A1C level = 7.4%
• Smoking reduced to 2 packs/week
• Weight increased to 228 lb
Figure 3. Kaplan-Meier estimates of the risk of death from any cause
• BMI is 26.3 kg/m2
and from CV causes and the number of CV events, according to treat-
ment group. From Gaede P et al. N Engl J Med. 2008;358:580-591. • BP = 128/72 mm Hg
The New England journal of medicine by MASSACHUSETTS MEDICAL • Total cholesterol = 147 mg/dL
SOCIETY Reproduced with permission of MASSACHUSETTS MEDICAL • LDL = 78 mg/dL
SOCIETY, in the format reuse in CME materials via Copyright Clearance
• High-density lipoprotein (HDL) = 37 mg/dL
Center.
• TGs = 148 mg/dL

Question 2: Clinton thinks he has gained weight because he is using

hard candy and chewing gum in place of cigarettes.
According to the current treatment guidelines, what is
the recommended class of BP agent for Clinton? Question 3:
A. ACEI or ARB How would you adjust Clinton’s therapy to avoid further
B. Calcium channel blocker weight gain? Which is most likely to avoid further
C. Loop diuretic weight gain?
D. Thiazide diuretic A. Discontinue metformin, start a sulfonylurea
The American Diabetes Association (ADA) Standards of B. Continue metformin, start a dipeptidyl peptidase-4
Medical Care15 and the American Association of Clinical (DPP-4) inhibitor
Endocrinologists (AACE) Comprehensive Diabetes C. Continue metformin, start a thiazolidinedione
Treatment Algorithm2 recommend the use of blockers of D. Discontinue metformin, start a basal insulin
the renin-angiotensin system (eg, an ACEI or ARB) for the The full algorithm from the ADA and the European
prevention of CV and renal complications.16 Statins are Association for the Study of Diabetes (EASD) position
the mainstay for the management of dyslipidemia and statement on the Management of Hyperglycemia in Type
the prevention of atherosclerosis.17 Smoking cessation 2 Diabetes: A Patient-Centered Approach is shown in
will also be a key factor in reducing CV risk.15 Figure 4,4 An abbreviated algorithm showing treatment
Clinton is started on the following medications: options when the goal is to avoid weight gain is shown
• Lisinopril 20 mg daily in Figure 5,4 suggesting that the best answer from the
• Atorvastatin 40 mg daily ones above is to continue metformin and to start a DPP-4
• Metformin 500 mg daily to be increased in 1 week to inhibitor. DPP-4 inhibitors are once-daily oral agents that
500 mg twice daily if tolerated, then to 1000 mg twice are well tolerated and are not associated with weight
daily over the ensuing month gain or hypoglycemia. They are considered weight
neutral. Adding a sulfonylurea or a thiazolidinedione
He is counseled on his therapeutic targets for reducing might increase the chances of further weight gain. Use
the risks of diabetes complications (A1C level <7%, BP of basal insulin in the absence of metformin can also be
<140/90 mm Hg, low-density lipoprotein [LDL] <100 mg/ associated with weight gain.
dL). Clinton understands that he must stop smoking and is
referred to a smoking cessation program. He is referred to
a registered dietitian for nutrition counseling. He agrees to
begin walking 15 minutes a day after dinner with his wife.

4
Figure 4. ADA/EASD treatment algorithm. From Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379; Inzucchi SE et al. Diabetologia. 2012;55:1577-1596
Reproduced with permission of AMERICAN DIABETES ASSOCIATION in the format Continuing Education via Copyright Clearance Center.

Figure 5 contains another option with high efficacy in Question 4:

A1C lowering and is associated with possible weight
While you are willing to work with Clinton on this and
loss: a glucagon-like peptide-1 (GLP-1) receptor agonist
revisit the situation at his next 3-month visit, you tell him
(RA). GLP-1 RAs are given by subcutaneous injection,
that GLP-1 RAs have which of the following effects that
but unlike insulin, they are not associated with a risk of
DPP-4 inhibitors don’t? (Choose all that apply.)
hypoglycemia (unless, as is also true for DPP-4 inhibitors,
they are used with insulin or insulin secretagogues, in A. Can cause slow, steady weight loss
which case the dose of the other agent may need to be B. Decrease glucagon secretion
reduced). C. Enhance feelings of fullness
D. Increase insulin secretion
You explain both options to Clinton; at the moment, he
E. Slow gastric empting
prefers an oral agent, explaining that he has a lot going
on with his efforts and lifestyle modification, including Both DPP-4 inhibitors and GLP-1 RA increase insulin
smoking cessation, as well as trying to get his family to secretion and decrease glucagon secretion by virtue of
work with him to change their meal habits. their physiologic effects of GLP-1. Because GLP-1 RAs
provide supraphysiological (or pharmacologic) levels of
GLP-1, they also slow gastric emptying, enhance satiety
(feelings of fullness), and can result in weight loss that is
slow and steady. These supraphysiological levels that are
positive in causing greater A1C lowering also come with
transient GI adverse effects that patients must expect.
5
Figure 5. When goal is to avoid weight gain. Adapted from Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379; Inzucchi SE et al.
Diabetologia. 2012;55:1577-1596
Diabetes care by AMERICAN DIABETES ASSOCIATION Reproduced with permission of AMERICAN DIABETES ASSOCIATION in the format Continuing
Education via Copyright Clearance Center.

Medications 3 months further along: Question 5:

• Lisinopril 20 mg daily What action do you take with regard to Clinton’s
• Atorvastatin 40 mg daily glycemic control?
• Metformin 1000 mg twice daily
• Sitagliptin 100 mg/day A. Do nothing, continue on current regimen for another
• A1C level = 7.8% 3-6 months
• Weight back to 220 lb B. Switch from a DPP-4 inhibitor to a GLP-1 RA
• BP = 120/70 mm Hg C. Switch from a DPP-4 inhibitor to a basal insulin
• LDL = 80 mg/dL D. Increase the dose of the DPP-4 inhibitor or take
DPP-4 and GLP-1 at some time—this might allow an
Clinton has further intensified his walking and has started important teaching point about not taking together
some resistance training. His family is working with him
on nutrition. Everyone is pleased that he has stopped Doing nothing would be considered clinical inertia,
smoking. He is somewhat frustrated that despite his allowing Clinton to languish at an unacceptably high level
efforts he is not achieving his A1C goal. He still blames of glucose for too long.18,19 Current guidelines suggest
his sugar intake (too many sodas) from the good work he that if patients are not achieving goal in 3 months, then
has done with smoking. therapy should be intensified.1,2,4 Clinton should be
praised for the positive efforts he has made in his overall
health and be offered effective tools to achieve his
glycemic targets, an A1C level <7%. At this juncture, he
is still obese and would do well with a weight-beneficial
agent with greater glucose-lowering potential. Consider
a GLP-1 RA, with the knowledge that patients who
switch from a DPP-4 inhibitor to a GLP-1 RA20,21 show
further decreases in A1C level, decreases in weight,
and increases in patient satisfaction,22 despite having to
use an injectable agent. Show Clinton the injectable pen
device and the ultrafine needle.

6
Case Study at 1 Year for microvascular complications such as blindness,
nerve damage, and kidney disease should help patients
Biometrics: Relevant measurements appreciate the need for a multifactorial approach to care.
• Height: 70 in. and laboratory values:
• Weight: 209 lb • A1C level = 6.8% The use of metformin early in the course of diabetes
• BMI: 30 kg/m2 • FPG = 116 mg/dL reduces the rate of treatment failure; combination
• BP = 120/70 mm Hg therapy with drugs with complementary mechanisms
Current medications: • Total cholesterol = 136 of action, such as the incretin-based therapies (DPP-4
• Multivitamin daily mg/dL inhibitors or GLP-1RAs), when A1C goals are not being
• Occasional OTC • LDL = 66 mg/dL met reduces the exposure of patients to uncontrolled
medicines for headache • HDL = 45 mg/dL
hyperglycemia. We want to be clear that we are adding
• Lisinopril 20 mg daily • TGs = 100 mg/dL
• Atorvastatin 40 mg daily
metformin with incretins—not incretins with incretins.
• Metformin 1000 mg twice Being able to explain the differences between DPP-4
daily inhibitors and GLP-1 RAs can help with the appropriate
• Exenatide 10 mcg twice use of the right agent, for the right patient, at the right
daily (1 hour before time. GLP-1 RAs can be especially beneficial in patients
breakfast, 1 hour before when a low risk of hypoglycemia and the opportunity for
dinner) weight loss is desirable.

Clinton is pleased with his progress; his A1C level is References

under control, as are his BP and lipids. He has quit 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of
smoking. He has lost weight and almost reached the hyperglycaemia in type 2 diabetes: a patient-centered approach.
Position statement of the American Diabetes Association (ADA)
point of no longer being obese. He may now consider and the European Association for the Study of Diabetes (EASD).
a Web-based/remote or structured multidisciplinary Diabetologia. Jun 2012;55(6):1577-1596.
program, or even medical therapy for weight loss. 2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE
Clinton understands that he is not a candidate for Comprehensive Diabetes Management Algorithm 2013. Endocr
surgery (BMI ≥35 kg/m2). He wonders why his lipids Pract. Mar-Apr 2013;19(2):327-336.

have improved. Some of the improvement can be 3. Brown JB, Conner C, Nichols GA. Secondary failure of
metformin monotherapy in clinical practice. Diabetes Care.
explained by his weight loss but GLP-1 RAs have shown
Mar 2010;33(3):501-506.
some modest improvements in CV risk markers (both
4. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of
BP and lipids).23 However, these do not take the place of hyperglycemia in type 2 diabetes: a patient-centered approach:
statins or antihypertensive agents. position statement of the American Diabetes Association (ADA)
and the European Association for the Study of Diabetes (EASD).
You congratulate Clinton on all of his hard work; he thanks Diabetes Care. Jun 2012;35(6):1364-1379.
you for working with him slowly, surely, and steadily to 5. Kraschnewski JL, Sciamanna CN, Stuckey HL, et al. A silent
stay motivated and to keep moving toward his goals. You response to the obesity epidemic: decline in US physician weight
remind Clinton that T2DM is a progressive disease and counseling. Med Care. Feb 2013;51(2):186-192.
that other changes may need to occur over time, but that 6. Bergenstal RM, Nag SS, Reusch JE, Sajjan SG, Alexander CM.
you are sure that by working together, control can be Macrovascular risk factors in patients with diabetes: physician
treatment strategies and extent of control. Endocr Pract. May-Jun
maintained. 2005;11(3):172-179.

Summary 7. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with
macrovascular and microvascular complications of type 2 diabetes
Involving patients with T2DM in treatment decision- (UKPDS 35): prospective observational study. BMJ. Aug 12
2000;321(7258):405-412.
making and taking a patient-centered approach to care,
with attention to CV risk factors in addition to glucose 8. Huang ES, Meigs JB, Singer DE. The effect of interventions to
prevent cardiovascular disease in patients with type 2 diabetes
control, can enhance the chances of therapeutic mellitus. Am J Med. Dec 1 2001;111(8):633-642.
success. Knowing that CV disease is the primary cause
9. Bramlage P, Binz C, Gitt AK, et al. Diabetes treatment patterns
of mortality for these patients, that obesity contributes and goal achievement in primary diabetes care (DiaRegis) - study
to CV risk, and that glycemic control reduces the risk protocol and patient characteristics at baseline. Cardiovasc
Diabetol. 2010;9:53.

7
10 Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality 17. Jellinger PS, Smith DA, Mehta AE, et al. American Association
from coronary heart disease in subjects with type 2 diabetes and in of Clinical Endocrinologists’ Guidelines for Management of
nondiabetic subjects with and without prior myocardial infarction. Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract.
N Engl J Med. Jul 23 1998;339(4):229-234. Mar-Apr 2012;18 Suppl 1:1-78.
11.Gitt AK, Schmieder RE, Duetting E, et al. Achievement of 18. Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ.
recommended glucose and blood pressure targets in patients Clinical Inertia in People With Type 2 Diabetes: A retrospective
with type 2 diabetes and hypertension in clinical practice - study cohort study of more than 80,000 people. Diabetes Care. Jul 22
rationale and protocol of DIALOGUE. Cardiovasc Diabetol. 2013.
2012;11:148.
19. Mata-Cases M, Benito-Badorrey B, Roura-Olmeda P, et al. Clinical
12.Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a inertia in the treatment of hyperglycemia in type 2 diabetes
multifactorial intervention on mortality in type 2 diabetes. N Engl J patients in primary care. Curr Med Res Opin. Aug 14 2013.
Med. Feb 7 2008;358(6):580-591.
20. Pratley RE, Nauck MA, Bailey T, et al. Efficacy and safety of
13.Gaede P, Valentine WJ, Palmer AJ, et al. Cost-effectiveness of switching from the DPP-4 inhibitor sitagliptin to the human GLP-1
intensified versus conventional multifactorial intervention in type 2 analog liraglutide after 52 weeks in metformin-treated patients
diabetes: results and projections from the Steno-2 study. Diabetes with type 2 diabetes: a randomized, open-label trial. Diabetes
Care. Aug 2008;31(8):1510-1515. Care. Oct 2012;35(10):1986-1993.
14.Handelsman Y, Mechanick JI, Blonde L, et al. American 21. Wysham C, Bergenstal R, Malloy J, et al. DURATION-2:
Association of Clinical Endocrinologists Medical Guidelines for efficacy and safety of switching from maximum daily sitagliptin
Clinical Practice for developing a diabetes mellitus comprehensive or pioglitazone to once-weekly exenatide. Diabet Med. Jun
care plan. Endocr Pract. Mar-Apr 2011;17 Suppl 2:1-53. 2011;28(6):705-714.
15. S
 tandards of medical care in diabetes--2013. Diabetes Care. Jan 22. Davies M, Pratley R, Hammer M, Thomsen AB, Cuddihy R.
2013;36 Suppl 1:S11-66. Liraglutide improves treatment satisfaction in people with
Type 2 diabetes compared with sitagliptin, each as an add on to
16. H
 andelsman Y. Diabetes and hypertension: a comprehensive
metformin. Diabet Med. Mar 2011;28(3):333-337.
report on management and the prevention of cardiovascular
and renal complications. J Clin Hypertens (Greenwich). Apr 23. Lorber D. GLP-1 receptor agonists: Effects on cardiovascular risk
2011;13(4):221-223. reduction. Cardiovasc Ther. Aug 2013; 31(4):238-49.

8
What to Do When There is a Loss of
Glycemic Control: Insulin or Incretins?
Thomas B. Repas, DO, FACP, FACE, FACOI, FNLA, CDE
Clinical Assistant Professor
Department of Medicine
Sanford School of Medicine
University of South Dakota
Rapid City, South Dakota

Introduction
The Centers for Disease Control and Prevention report
that individuals aged 45-64 years comprise the largest
group of newly diagnosed patients with diabetes
(Figure 1),1 although patients aged 65 and older still
constitute the greatest absolute number of patients with
diabetes.2 Middle-aged patients with type 2 diabetes Figure 2. Natural history ofT2DM. Three pathophysiologic defects likely
mellitus (T2DM), particularly women and those younger responsible for the progressive nature and deterioration of glycemic
control in patients withT2DM: insulin resistance, insulin deficiency, and
than 55, have a 2-3 times higher risk of all-cause and impaired incretin effect. IFG = impaired fasting glucose; IGT = impaired
cardiovascular (CV) mortality than people without glucose tolerance.4
diabetes,3 even after adjusting for smoking history. The American Journal of Medicine by Association of Professors of
Medicine (Washington, D.C.) Reproduced with permission of EXCERP-
TA MEDICA, INC. in the format reuse in CME Materials via Copyright
Clearance Center.

Case Study
Hannah is a 54-year-old Caucasian woman with a 5-year
history of T2DM. She is divorced, has 2 children, and works
as a headhunter. She weighs 181 lb (82 kg) and has a body
mass index (BMI) of 32.2 kg/m2, which classifies her as
obese. Although Hannah indicates a desire and readiness
to lose weight and has attended medical nutritional
counseling, she has been unable to substantially change
her habits and lose any significant amount of weight. Her
Figure 1. Estimated number of new cases of diagnosed diabetes among comorbidities include hypertension, dyslipidemia, and
people aged 20 years or older, by age group, United States, 2010.1
osteoarthritis. Her current fasting blood glucose (FBG)
level is 174 mg/dL, postprandial glucose (PPG) levels
T2DM is a progressive disease characterized by gradual (2 hr) are approximately 240 mg/dL, and her glycated
defects in both insulin sensitivity (increasing insulin hemoglobin (A1C) level is 8.6%.
resistance) and insulin secretion by pancreatic beta cells,
as well as excessive secretion of glucagon by alpha cells
and an impaired incretin effect (Figure 2).4

Numerous drugs are now available for the treatment of

T2DM that target different pathophysiological aspects
of the disease. Combination therapy may therefore
offer advantages for achieving or maintaining glycemic
control, specifically when agents with complementary
mechanisms of action are used.

9
 Hannah has CV risk factors (dyslipidemia, hypertension)
Biometrics: Current medications:
but no evidence of CVD. She is already showing some
• Height: 62 in. • Metformin 1000 mg daily
evidence of microvascular complications of T2DM,
• Weight: 181 lb x 4 years
• BMI: 32.2 kg/m2 • Glyburide 5 mg daily
specifically diabetic retinopathy, which is often the first
x 3 years complication to appear.5 This serious microvascular
Vital signs: complication is a leading cause of blindness in the United
• Lisinopril/
• Pulse: 66 bpm hydrochlorothiazide States.6 Randomized, controlled clinical trials in patients
• Respirations: 15/minute 20/12.5 mg/day x 8 years with type 1 diabetes and those with T2DM have shown
• Blood pressure (BP): • Atorvastatin 40 mg/day the beneficial effects of intensive glycemic control7,8 and
130/78 mm Hg x 4 years intensive treatment of elevated BP8 on the progression
Medical history: Known allergies:
of diabetic retinopathy.
• Postmenopausal • Peanuts According to Healthy People 2020, only 53.4% of adults
• Hypertension
Physical examination:
aged 18 years and older with diagnosed diabetes in
• Dyslipidemia
2008 had a dilated eye examination in the past year. The
• No history of pancreatitis, • Obese-no other signs of
national goal is to improve this by 10% by 2020.9 Healthy
thyroid cancer peripheral resistance or
endocrinopathy People 2020 is also seeking to improve the percentage of
Family history: patients with diabetes with an A1C level <7%. Hannah’s
• Diminished lower-
• Father with T2DM; extremity reflexes A1C level is above the general goal recommended by
mother died at age 52 of a • Fundoscopic examination the American Diabetes Association (ADA) of 7% and
myocardial infarction. reveals bilateral her PPG level is well above that recommended by ADA
• Her older sister (age 60) background diabetic (<180 mg/dL). FBG levels are also not well controlled
has T2DM treated with retinopathy with no (recommended target range 70-130 mg/dL). 10 It is
insulin evidence of macular therefore safe to say that her glucose regimen should
edema be intensified.
Social history:
• Occupation: headhunter Pertinent laboratory
• Past smoker (quit 20 years values: Question 2:
ago) • A1C level = 8.6%, What is your A1C goal for Hannah?
• Social alcohol use (a glass FPG = 174 mg/dL,
of wine with dinner, most PPG = 240 mg/dL
1. <8%
nights) • BP = 130/78 mm Hg 2. <7.5%
• Denies illicit drug use • Serum creatinine = 3. <7%
• Water aerobics twice a 1.4 mg/dL 4. ≤6.5%
week • Low-density lipoprotein 5. <6% if achievable without hypoglycemia
• Divorced, 2 children ages (LDL) = 94 mg/dL;
14 and 12, both in good triglycerides (TG) = The key to successful treatment of diabetes is
health 189 mg/dL; high-density individualization of glycemic targets and therapeutic
lipoprotein (HDL) = choices. Results of recent clinical trials have shown
37 mg/dL that treatment is no longer a case of “one size fits all.”11
Although treatment goals in general are to achieve an
Question 1: A1C level <7% (ADA) or ≤6.5% (American Association
of Clinical Endocrinologists [AACE]), 12 choosing a
What is your assessment of Hannah’s current status?
specific A1C target range for a given patient requires
Choose all that apply.
taking several factors into consideration, including an
A. She has microvascular complications assessment of the patient’s risk for hyperglycemia-
B. She has cerebrovascular disease related complications versus the risks of therapy, all
C. She has CV risk factors in the context of the overall clinical setting. Comorbid
D. She has postprandial hypoglycemia-this is true as well conditions, psychological status, capacity for self-care,
E. Her glucose regimen should be intensified economic considerations, and family and social support
systems also play a key role in the intensity of therapy

10
 Framework for Setting Individualized Glycemic Targets

Most Intensive Level, Least Intensive Level

Approximately 6.0% Approximately 8.0%
- Highly motivated, adherent, knowledgeable, - Less motivated, nonadherent, less knowledgeable,
strong self-care capability weak self-care capability
- Adequate resources or support systems - Inadequate resources or support systems
- Low risk of hypoglycemia - High risk of hypoglycemia
- Short duration of T2DM (+ legacy effect) - Long duration of T2DM (- legacy effect)
- Long life expectancy - Short life expectancy
- No microvascular disease - Advanced microvascular diesase
- No CVD - Established CVD
- No coexisting conditions - Multiple, severe coexisting conditions, or both

A1C Range
ADA: 7% in general;
AACE: 6.5% in general

Figure 3. Framework for setting individualized glycemic targets. From Ismail-Beigi F. N Engl J Med. 2012;366:1319-1327.

(Figure 3).13 In Hannah’s case, and with her input, an A1C she started insulin and is against this option. Hannah
goal of <7% is chosen, with an interim goal of <7.5% to has heard of newer medications that might be more
be achieved as a first mark. “weight friendly.”15 Although she has struggled with
her weight, she is becoming receptive to a discussion of
Question 3: other options and actions that she can take. This appears
Hannah’s A1C level is 8.6% on metformin and glyburide. to be a good time to reintroduce the topic of lifestyle
What change in therapy would you make to achieve the modification.
goal that you have set for her?
Remind patients that reducing caloric intake and
A. Add basal insulin increasing physical activity is key to achieving and
B. Add a dipeptidyl peptidase-4 (DPP-4) inhibitor maintaining weight loss. A hypocaloric diet is essential for
C. Add a glucagon-like peptide-1 (GLP-1) receptor initial weight loss.16 Physical activity recommendations
agonist (RA) include for patients with diabetes according to AACE
D. Add a thiazolidinedione (TZD) include ≥150 minutes/week of moderate-intensity
exercise that may include flexibility and strength training,
Although many physicians feel comfortable with
aerobic exercise, or cross-training, where the heart rate
traditional agents such as TZDs, their use may be
increases to 70% of maximum.16 Hannah is willing
associated with weight gain and may worsen fluid
to commit to embark on a slow but steady increase in
retention, both of which would be undesirable in
walking from 20 minutes every other day to being able to
Hannah. Recall that Hannah has pedal edema and is
achieve a brisk walk and a total of ≥150 minutes/week of
obese. Furthermore, there are some concerns about
moderate-intensity exercise.
osteoporosis with TZDs. Recent data suggest that
pioglitazone inhibits bone formation but does not seem to Regarding glucose control, you introduce the idea
affect bone resorption. Postmenopausal women rather of an injectable GLP-1 RA, which can lower blood
than premenopausal women or men are particularly glucose levels by ~1% and may also be associated with
vulnerable to this side effect.14 Furthermore, a TZD is weight loss. You tell Hannah that she may experience
unlikely to lower her A1C level by >1%. gastrointestinal (GI) distress (eg, nausea) temporarily as
she titrates up to a dose that will be effective in bringing
You discuss starting insulin with Hannah. Insulin is the
her glucose levels down. This agent affects feelings of
most potent treatment of hyperglycemia and the most
fullness (satiety) in addition to increasing insulin and
likely to get her to goal. Her sister gained 10 lb when
suppressing glucagon. In fact, you tell Hannah, these
11
agents have been compared with basal insulin and work Hannah is tolerating the 1.2-mg dose of liraglutide. She
just about as well in terms of A1C lowering, will target had minimal nausea for 1 week. The dose was then
her postprandial hyperglycemia to a greater extent, and titrated to a maximal dose of 1.8 mg per the prescribing
will not have risks of hypoglycemia or weight gain.17-19 information after another week, as was needed to bring
With this introduction and the hope for weight loss that her A1C level towards her goal.
is accompanied with improved glucose control she is
At 1 month: Pertinent laboratory values:
willing to give this a try.
• A1C level = 7.5%, FPG = 118 mg/dL, PPG = 180 mg/dL
Hannah is started on 0.6 mg of liraglutide in a prefilled • BP = 120/78 mm Hg
pen, injected subcutaneously once daily for 1 week, in • LDL = 70 mg/dL; TG = 132 mg/dL; HDL = 42 mg/dL
addition to her current glucose-lowering medications. At
1 week, she should increase the dose to a therapeutic At 2 months: Pertinent laboratory values:
dose of 1.2 mg, if she is able to do so without intolerable • A1C level = 6.9%, FPG = 114 mg/dL, PPG = 138 mg/dL
GI side effects. At this point, consider discontinuing the • BP = 120/78 mm Hg
sulfonylurea if the glucose is responding to the GLP-1RA. • LDL = 70 mg/dL; TG = 132 mg/dL; HDL = 42 mg/dL
Although hypoglycemia does not occur with liraglutide • Weight = (-5 kg)
monotherapy because of its glucose-dependent insulin
Question 5:
secretory effects, hypoglycemia may occur when used
with insulin secretagogues. A medication that globally Which of the following is correct about GLP-1 RAs?
increases insulin secretion will overwhelm the glucose
A. Nausea and weight loss are linked
dependent insulin secretion.
B. Weight loss and glycemic control are linked
Question 4: C. Every patient loses weight on a GLP-1 RA
D. Patients with greater BMI tend to lose more weight
Hannah asks if there is an oral form of the GLP-1 RA you than those with lower BMI
prescribed for her. What do you tell her?
Patients should be counseled that the main goal of
A. Yes, DPP-4 inhibitors and GLP-1 RAs work the same GLP-1–based therapy is to prevent diabetes-related
way have the same side effect profile and efficacy complications through good glycemic control. Lowering
B. No, beyond the differences in route of administration, A1C levels reduces the risk of serious complications
GLP-1 RAs are associated with greater glucose such as retinopathy, nephropathy, neuropathy, and
lowering, and may also cause weight loss, whereas macrovascular disease (Figure 4).7,8,25
DPP-4 inhibitors are weight neutral
Not every patient will lose weight with GLP-1 RAs,
Although DPP-4 inhibitors and GLP-1 RAs are more although patients with greater BMI’s tend to lose more
similar to each other than other agents, as they both weight than those with lower BMI values.26
affect the incretin system but have different mechanisms
of action, there are important differences. One works by Lifestyle modification remains important. The ADA has
inhibiting the enzyme that breaks down whatever GLP-1 just issued new dietary guidelines,27 and Hannah may
exists in the system (DPP-4 inhibitors). The other acts benefit from a referral to a dietitian. Therapeutic lifestyle
directly on the receptor to increase the level of GLP-1 and changes are important throughout the progression of
stimulate insulin secretion and decrease glucagon levels disease.
(GLP-1 RAs).20 Head-to-head studies have shown that
It has been shown that weight loss effects of GLP-1 RAs
GLP-1 RAs are more effective in lowering blood glucose
are independent of glucose lowering (that is, patients will
levels than DPP-4 inhibitors.21-24 The 2 classes of drugs
show improvement is A1C levels whether or not they lose
both work only in the presence of high blood glucose
weight). Although the mechanism of action of weight
levels-this is called glucose dependent insulin secretion,
loss with GLP-1 RAs is not completely understood,
so both are associated with a low risk of hypoglycemia.
these effects occur in the presence or absence of GI
Because of the greater potency, GLP-1 RAs also have
side effects, that is, they are not dependent on them. In
weight loss effects. DPP-4 inhibitors do not cause weight
addition to slowing of GI emptying, there appear to be
gain.15 However, they are also associated with higher
central effects on satiety.28
levels of GI side effects including nausea and vomiting.
12
 Lowering A1C Reduces Summary
Complications in Diabetes Treating the patient who has loss of glycemic control
will typically require combination therapy to address
DCCT Kumamoto UKPDS
the multifactorial and progressive nature of T2DM.
A1C 9.1% g 7.3% 9.4% g 7.1% 7.9% g 7.0%
An individualized approach is necessary, taking into
Retinopathy i63% i69% i17%-21%
account specific patient concerns and comorbid
Nephropathy i54% i70% i24%-33% conditions, whether these be hypoglycemia, weight
Neuropathy i60% Significantly — gain, medication cost, or CV risk. Newer agents such
improved
as incretin-based therapies offer the physician effective
Macrovascular i41%* — i16%* options for therapy that complement metformin, with
disease low risks of hypoglycemia and low risks of weight gain.
*Not statistically significant GLP-1 RAs are particularly effective when greater A1C
Figure 4. Lowering A1C levels reduces complications in diabetes.7,8,24 lowering is required and when avoidance of weight gain
or when weight loss is desirable. Given by subcutaneous
injection by pen devices, these agents are relatively
Question 6:
simple to administer and titrate to effective doses;
You and Hannah begin a discussion about weight loss. adverse effects of nausea should be a major point of
She asks which of the following diets would work best counseling to ensure that the patient will be able to
for her; you respond that which of the following will result adhere to treatment. An understanding that weight loss
in the most weight loss: and glycemic control are independent of each other
A. Atkins and are separate goals, and that lifestyle modification
B. The Zone remains a critical aspect of diabetes self-management,
C. Ornish remains central to successful outcomes.
D. Weight Watchers
E. It doesn’t matter, as long as you stick with it References
1. National diabetes fact sheet: national estimates and general
The answer is, it doesn’t matter, as long as patients information on diabetes and prediabetes in the United States,
2011. U.S. Department of Health and Human Services, Centers for
persevere. In a randomized study, each popular diet Disease Control and Prevention, 2011, (2011).
modestly reduced body weight and several cardiac risk
2. CDC. Diabetes Report Card 2012. In: Prevention CfDCa, ed.
factors at 1 year.29 Overall dietary adherence rates were Atlanta: US Department of Health and Human Services; 2012.
low beyond a year, although increased adherence was 3. Taylor KS, Heneghan CJ, Farmer AJ, et al. All-cause and
associated with greater weight loss and cardiac risk cardiovascular mortality in middle-aged people with type 2 diabetes
factor reductions for each popular diet.30 Typically people compared with people without diabetes in a large U.K. primary care
database. Diabetes Care. Aug 2013;36(8):2366-2371.
struggle to keep on a specialized diet and have high rates
of weight regain. It may serve people better to make 4. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of
incretin-based therapy: therapeutic potential, patient selection and
more moderate changes that may be easier to maintain clinical use. Am J Med. Jun 2009;122(6 Suppl):S37-50.
over a lifetime.
5. Kohner EM. Microvascular disease: what does the UKPDS tell us
about diabetic retinopathy? Diabet Med. Aug 2008;25 Suppl 2:20-
On a program of modest exercise and nutrient-dense
24.
but calorie-restricted diet, along with use of a weight-
6. Kempen JH, O’Colmain BJ, Leske MC, et al. The prevalence of
beneficial treatment for her diabetes (eg, metformin and diabetic retinopathy among adults in the United States. Arch
a GLP-1 RA), Hannah observes benefits in her glycemic Ophthalmol. Apr 2004;122(4):552-563.
control, weight, as well as small improvements in her 7. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy
cardiometabolic risk factors.31,32 prevents the progression of diabetic microvascular complications in
Japanese patients with non-insulin-dependent diabetes mellitus: a
randomized prospective 6-year study. Diabetes Res Clin Pract. May
1995;28(2):103-117.
8. Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes
Study (UKPDS) Group. Lancet. Sep 12 1998;352(9131):837-853.

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9. Heatlhypeople.gov. Dilated Eye Exams Objectives. 2013. 22. Pratley R, Nauck M, Bailey T, et al. One year of liraglutide
treatment offers sustained and more effective glycaemic
10. S
 tandards of medical care in diabetes--2013. Diabetes Care. Jan
control and weight reduction compared with sitagliptin, both in
2013;36 Suppl 1:S11-66.
combination with metformin, in patients with type 2 diabetes: a
11. I smail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth randomised, parallel-group, open-label trial. Int J Clin Pract. Apr
S. Individualizing glycemic targets in type 2 diabetes mellitus: 2011;65(4):397-407.
implications of recent clinical trials. Ann Intern Med. Apr 19
23. Bergenstal RM, Wysham C, Macconell L, et al. Efficacy
2011;154(8):554-559.
and safety of exenatide once weekly versus sitagliptin or
12. R
 odbard HW, Jellinger PS, Davidson JA, et al. Statement by an pioglitazone as an adjunct to metformin for treatment of type
American Association of Clinical Endocrinologists/American 2 diabetes (DURATION-2): a randomised trial. Lancet. Aug 7
College of Endocrinology consensus panel on type 2 diabetes 2010;376(9739):431-439.
mellitus: an algorithm for glycemic control. Endocr Pract. Sep-Oct
24. Malloy J, Meloni A, Han J. Efficacy and tolerability of exenatide
2009;15(6):540-559.
once weekly versus sitagliptin in patients with type 2 diabetes
13. I smail-Beigi F. Clinical practice. Glycemic management of type 2 mellitus: a retrospective analysis of pooled clinical trial data.
diabetes mellitus. N Engl J Med. Apr 5 2012;366(14):1319-1327. Postgrad Med. May 2013;125(3):58-67.
14. X
 iao WH, Wang YR, Hou WF, et al. The effects of pioglitazone on 25. The effect of intensive treatment of diabetes on the development
biochemical markers of bone turnover in the patients with type 2 and progression of long-term complications in insulin-dependent
diabetes. Int J Endocrinol. 2013;2013:290734. diabetes mellitus. The Diabetes Control and Complications Trial
15. M
 eneghini LF, Orozco-Beltran D, Khunti K, et al. Weight beneficial Research Group. N Engl J Med. Sep 30 1993;329(14):977-986.
treatments for type 2 diabetes. J Clin Endocrinol Metab. Nov 26. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of
2011;96(11):3337-3353. exenatide therapy over 82 weeks on glycaemic control and weight
16. H
 andelsman Y, Mechanick JI, Blonde L, et al. American in over-weight metformin-treated patients with type 2 diabetes
Association of Clinical Endocrinologists Medical Guidelines for mellitus. Diabetes Obes Metab. Jul 2006;8(4):419-428.
Clinical Practice for developing a diabetes mellitus comprehensive 27. Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy
care plan. Endocr Pract. Mar-Apr 2011;17 Suppl 2:1-53. recommendations for the management of adults with diabetes.
17. A
 schner P, Chan J, Owens DR, et al. Insulin glargine versus Diabetes Care. Nov 2013;36(11):3821-3842.
sitagliptin in insulin-naive patients with type 2 diabetes mellitus 28. Drucker DJ, Nauck MA. The incretin system: glucagon-like
uncontrolled on metformin (EASIE): a multicentre, randomised peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors
open-label trial. Lancet. Jun 16 2012;379(9833):2262-2269. in type 2 diabetes. Lancet. Nov 11 2006;368(9548):1696-1705.
18. B
 levins T, Han J, Nicewarner D, Chen S, Oliveira JH, Aronoff 29. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer
S. Exenatide is non-inferior to insulin in reducing HbA1c: an EJ. Comparison of the Atkins, Ornish, Weight Watchers, and
integrated analysis of 1423 patients with type 2 diabetes. Zone diets for weight loss and heart disease risk reduction: a
Postgrad Med. May 2010;122(3):118-128. randomized trial. JAMA : the journal of the American Medical
19. R
 ussell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin Association. Jan 5 2005;293(1):43-53.
glargine and placebo in combination with metformin and 30. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer
sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): EJ. Comparison of the Atkins, Ornish, Weight Watchers, and
a randomised controlled trial. Diabetologia. Oct 2009;52(10):2046- Zone diets for weight loss and heart disease risk reduction: a
2055. randomized trial. JAMA. Jan 5 2005;293(1):43-53.
20. C
 ornell S. Differentiating among incretin therapies: a multiple- 31. Mundil D, Cameron-Vendrig A, Husain M. GLP-1 receptor
target approach to type 2 diabetes. J Clin Pharm Ther. Oct agonists: a clinical perspective on cardiovascular effects. Diab
2012;37(5):510-524. Vasc Dis Res. Apr 2012;9(2):95-108.
21. P
 ratley RE, Nauck M, Bailey T, et al. Liraglutide versus 32. Lorber D. GLP-1 Receptor Agonists: Effects on Cardiovascular
sitagliptin for patients with type 2 diabetes who did not have Risk Reduction. Cardiovasc Ther. Aug 2013; 31(4):238-49.
adequate glycaemic control with metformin: a 26-week,
randomised, parallel-group, open-label trial. Lancet. Apr 24
2010;375(9724):1447-1456.

14
Managing Diabetes in Patients With gestational diabetes Current medications:
Disease of Long Duration: GLP-1 during her first pregnancy • Metformin 1000 mg daily x
10 years
Receptor Agonists and Insulin in Social history:
• Pioglitazone 30 mg daily x
Combination • Occupation: real estate
3 years
agent (semi-retired)
Etie S. Moghissi, MD, FACP, FACE • Lisinopril 20 mg/day x 8
• Non-smoker
Associate Clinical Professor years
• Social alcohol use (~2-3
Department of Medicine drinks/week) Known allergies:
University of California – Los Angeles • Denies illicit drug use • Pollen
Los Angeles, California • Married, 2 children
ages 32 and 28, both in
good health; walks with
Introduction husband after dinner daily
Among US residents aged 65 years and older, 10.9
million, or 26.9%, had diabetes in 2010.1 Older adults
including patients with long duration of diabetes are often Question 1:
treated with insulin. Recent data show that glucagon-like What is your assessment of Claudia’s current
peptide-1 receptor agonists (GLP-1RAs) may be used diabetes status?
in combination with insulin for patients who have not
achieved glycemic goals. This improved glycemic control A. Impaired glucose tolerance is the predominant issue
has been associated with reductions in the insulin, dose B. Insulin resistance predominates
a low risk of hypoglycemia, and possible weight loss. C. She has limited beta-cell function at this time
D. She is glucotoxic
Case Study E. C and D
Claudia is a 68-year-old Latina of Honduran descent, T2DM is a progressive disease. In T2DM, disease
married with 2 children, who works as a real estate progression that typically starts with insulin resistance
agent. She was diagnosed with type 2 diabetes mellitus and abnormal insulin secretion but then is paralleled by a
(T2DM) 10 years ago and has been a patient of yours for decline in the function of pancreatic beta cells, leading to
the last 3 years. Today, accompanied by her husband, she further impairment of insulin secretion and activity.
comes to see you for routine follow-up of her diabetes
and presents with a complaint of fatigue. Over the past 6 This contributes to the hyperglycemia characteristic
months, she has lost 6 lb without any significant change of the disease in later stages. When glucose is present
in her diet or physical activity. Her current fasting blood in excessive amounts over a prolonged period it exerts
glucose (FBG) level is 195 mg/dL and her hemoglobin negative effects on beta-cell function. This “glucotoxicity”
(A1C) level is 9.1%. sets in motion a cycle of events in which the hyperglycemia
that results from impaired glucose regulation contributes
Biometrics: Medical history: to further beta-cell decline (Figure 1).2,3
• Height: 66 in. • Hypertension, controlled
Question 2:
• Weight: 174 lb (180 lb at a with angiotensin-
visit 6 months prior) converting enzyme (ACE) According to the 2013 American Association of Clinical
• Body mass index (BMI): inhibitor Endocrinologists (AACE) 4 task force on the new
28.1 kg/m2 • No history of pancreatitis comprehensive diabetes management algorithm,
what is the recommended therapy for Claudia, who
Vital signs: Family history:
has an A1C level >9% and symptoms of uncontrolled
• Pulse: 68 bpm • Both parents deceased—
hyperglycemia, and is on 2 oral agents?
• Respirations: 18/minute father (myocardial
• Blood pressure (BP): infarction [MI], T2DM), A. Addition of a basal insulin
128/78 mm Hg mother (hypertension, B. Addition of a GLP-1 RA
T2DM, breast cancer) C. Addition of a sulfonylurea
• Three siblings—all with
D. Any of the above
hypertension, one with
15
 is also important. Data show that less than 20% of
patients are truly unwilling to start insulin therapy. 9
Adding basal insulin is a simple and effective approach to
initiating insulin therapy.

Physicians can promote patient acceptance of insulin by

reviewing the benefits of controlled A1C levels, discuss
the benefits of a effective therapy with few side effects,
and addressing patient concerns. Further, having the
patient give herself her first injection in the office can really
improve initiation and continuation of insulin therapy.

Question 3:
What starting dose of basal insulin, based on
Claudia’s weight, would you prescribe for her if using
recommendations from the AACE algorithm?
Figure 1. Vicious Cycle of Worsening Hyperglycemia and Glucose Toxic-
ity in the Face of Declining Beta-cell Function. Adapted from Del Guerra
S et al. Diabetes Metab Rev Res. Mar 2007;23(3):234-238; Del Guerra S et
A. 10 units
al. Diabetes. Mar 2005;54(3):727-735. B. 8-16 units
C. 16-24 units
In the ADOPT (A Diabetes Outcome Progression Trial) D. 45 units
study,5 the “durability” (that is, the length of time the
AACE recommends weight-based dosing based on the
drug was effective) of sulfonylureas was shown to
level of hyperglycemia (A1C) (Figure 2).4 One important
be the least, that of metformin intermediate, and that
point is that a starting dose of insulin is never likely to be
of thiazolidinediones the longest, suggesting that
the dose on which a patient should remain. Patients can
sulfonylureas required beta-cell function to be effective.
easily be taught to self-titrate their insulin doses based
Thus, many clinicians believe that sulfonylureas are most
on the results of self-monitoring of blood glucose levels;
useful early in the course of diabetes but much less so in
several studies have shown that patients are capable of
diabetes of long duration. Thus, addition of a sulfonylurea
doing this safely and effectively.10-12
would not be recommended at this juncture.
Based on Claudia’s weight of 174 lb (~79 kg) and an A1C
Although the AACE algorithm provides guidance as to
level of 9.1%, a starting dose between 16 and 24 units
what therapies to initiate and add, it respects individual
is indicated. A dose of 20 units is chosen for simplicity,
circumstances that would lead to different choices.4
with instructions to titrate every 2-3 days by adding 2 U to
A GLP-1 RA might be a reasonable choice but would
reach an FBG level between 80 and 110 mg/dL. Claudia
be unlikely to bring the A1C level to goal quickly and is
is to call the office with any concerns and is counseled
more likely to affect postprandial glucose levels. Claudia
about the signs, symptoms, and correction measures for
has high fasting glucose levels, so a basal insulin that
hypoglycemia. Figure 3 shows other titration options, as
targets basal or fasting glucose levels would be most
well as what to do should hypoglycemia occur.4
appropriate.
Claudia titrated her therapy throughout the first month
Furthermore, if at least a 2% reduction is needed to
and 1-month followup is a good idea to prevent overdoing
bring patients to an A1C level <7% (American Diabetes
the basal insulin dose. At her follow-up appointment in 1
Association recommended goals),6 only insulin is likely
month, Claudia is feeling much better. She has titrated
to be effective. Finally in patients who are acutely
her basal insulin dose to 40 units every night. Her meter
symptomatic, insulin is recommended therapy.4,6
download shows fasting glucose levels between 100
Although many physicians prefer to delay initiation of and 110 mg/dL for the past several days. Her most
insulin therapy until absolutely necessary,7,8 not allowing recent blood glucose reading taken 2 hours after lunch
patients to languish at unacceptably high glucose levels is 190 mg/dL. Her A1C level is 8%. She has regained
with the attendant risk for diabetes-related complications some of the weight she had lost when she was severely

16
Figure 2. Algorithm for Adding Basal (Long-acting) Insulin. From AACE Figure 3. Algorithm for Titrating Basal (Long-acting) Insulin. From AACE
Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. Comprehensive Diabetes Management Algorithm 2013. Endocr Pract.
Mar-Apr 2013;19(2):327-336. Mar-Apr 2013;19(2):327-336.

hyperglycemic (current weight is 190 lb). Patients with DPP-4 inhibitors inhibit breakdown of endogenous
severe hyperglycemia often will lose weight as they will incretin hormones. Clinical trial data on the use of insulin
become catabolic and lose calories through glucosuria. with DPP-4 inhibitors suggest that an A1C reduction of
Claudia is feeling less tired and is more willing to pursue between 0.4% and 0.7% can be achieved when the oral
her lifestyle modification efforts. She has joined a local agent is added to insulin after 6 months of therapy.13-16
gym and is taking some strength-training classes. This may not be quite enough to bring Claudia to an
A1C level <7%. Weight change was similar for placebo
Current medications:
and DPP-4 inhibitor arms in these trials.13-16 The risk of
• Lisinopril 20 mg/day x 8 years hypoglycemia is low with addition of DPP-4 inhibitors and
• Metformin/pioglitazone 850/30 mg daily (switched to their tolerability profiles are good.
combination product at last visit)
• Insulin long-acting basal analog 40 units GLP-1RAs act directly on GLP-1receptors to increase
insulin release and suppress glucagon secretion in a
Question 4: glucose-dependent manner, thus providing glycemic
What would be your recommendation for Claudia now? control with a low incidence of hypoglycemia. GLP-
1RAs also promote weight loss, and have beneficial
A. Add a dipeptidyl peptidase -4 (DPP-4) inhibitor effects on markers of beta-cell function, lipid levels, BP,
B. Add a GLP-1 RA and cardiovascular risk markers.17 The combination of a
C. Add prandial insulin GLP-1RA and insulin is effective for optimizing glucose
D. Any of the above are reasonable choices control, working on complementary aspect of diabetes
Any one of the above is a reasonable choice for pathophysiology.18 GLP-1RAs also ameliorate some of
intensifying therapy when patients are achieving FBG the adverse effects typically associated with insulin. Data
goals but are not at A1C goals while on basal insulin from clinical studies support the therapeutic potential of
therapy. The AACE algorithm suggests that prandial GLP-1RA/insulin combination therapy, typically showing
control can be provided by either of the incretin-based beneficial effects on glycemic control and body weight,
treatment options (DPP-4 inhibitors or GLP-1 RAs) or with a low incidence of hypoglycemia and, in patients
by intensification of insulin therapy with prandial insulin on established insulin therapy, facilitating reductions in
If choosing a prandial insulin, the total daily dose of insulin dose.19
insulin (prandial and basal) will be 0.3-0.5 U/kg, divided Minimizing the risk of hypoglycemia is a priority for
approximately evenly between basal analog and prandial physicians and patients alike and should influence
analog insulins. treatment choices as a matter of safety, patient

17
adherence, and ultimately an influence on healthcare Question 6:
costs. Minimizing risk of weight gain is also a priority in
Adding a GLP-1 RA to basal insulin therapy may have
terms of safety, adherence, and cost.4
what effect on the basal insulin dosage requirements?
A patient-centered discussion with Claudia considers
A. Decrease in insulin dose
the risk of hypoglycemia, risk of weight gain, and the
B. Increase in insulin dose
risk of diabetes-related complications from uncontrolled
C. No effect on insulin dose
hyperglycemia. It is decided that she will start a longer-
acting GLP-1 RA. A recent review analyzed the latest randomized
controlled clinical trials of insulin/GLP-1 RA combination
Question 5: therapy and results from “real-world” use of these
In addition to the notation in Claudia’s original medical regimens as reported through observational and clinical
history that she has no history of pancreatitis, what else practice studies.19 The most common finding across all
should be documented before prescribing a longer- types of studies was that combination therapy improved
acting GLP-1 RA? glycemic control without weight gain or an increased
risk of hypoglycemia.19 Many studies reported weight
A. No history of bone marrow dysplasia
loss and a reduction in insulin use when a GLP-1 RA
B. No history of hepatitis C
was added to existing insulin therapy. 19 Thus, it would
C. No family history of medullary thyroid carcinoma
seem important to closely monitor blood glucose levels
(MTC)
and adjust basal insulin levels downward as needed to
D. No history of systemic lupus erythematosus
avoid hypoglycemia. Should hypoglycemia occur, reduce
Cases of pancreatitis have been described in connection the total daily dose of insulin by 10%-20% if the blood
with the use of exenatide, liraglutide, and other GLP- glucose level is <70 mg/dL or by 20%-40% if the level is
1 RAs, although no causal relationship has been <40 mg/dL (personal experience).
established. 20 Patients should know the signs and
It is important that when adding combination therapy
symptoms of pancreatitis and stop taking incretin-
that Claudia knows the signs and symptoms of
based therapies if severe abdominal pain and vomiting
hypoglycemia and that she and her family know how to
occur. If pancreatitis is confirmed, therapy should not be
treat hypoglycemia should it occur.
restarted. Diabetes in and of itself is associated with a
higher risk of pancreatitis.21 If a history of pancreatitis is Claudia does well on her regimen of metformin, a single
noted in a patient’s record, another class of drugs should injection of a long-acting basal insulin analog, and a single
be considered. injection of a GLP-1 RA. She generally chooses to inject
both medications in the evening at different injection
There is no link between the use of GLP-1 RAs and
sites, often one in each thigh. She loses approximately
hepatitis C, bone marrow dysplasia, or systemic lupus
5 lbs over the next 3 months and her A1C level decreased
erythematosus.
to 6.9%. She has continued to monitor her blood glucose
Both of the longer-acting GLP-1 RAs, liraglutide and levels and is able to self-titrate her insulin dose down
exenatide once weekly, are contraindicated in patients to 10 units. She has up-titrated the liraglutide to the
with a personal or family history of MTC or multiple maximal glucose-lowering dose of 1.8 mg with the ability
endocrine neoplasia type 2 (MEN-2). Documentation of to tolerate the transient gastrointestinal side effects (ie,
a negative family or personal history of MTC or MEN-2 is nausea) by eating very slowing and acknowledging the
recommended before prescribing GLP-1 RAs. No special satiety effect.
monitoring (eg, calcitonin or ultrasound) is required when
Return visit 3 months: Current medications:
starting or maintaining a GLP-1RA.
• Lisinopril 20 mg/day x 8 years
Claudia starts on liraglutide 0.6 mg one daily in the • Metformin/pioglitazone 850/30 mg daily
evening. Exenatide once-weekly is not approved for use • Insulin glargine 30 units
with basal insulin. • Liraglutide 1.8 mg

18
Summary 10. Harris SB, Yale JF, Berard L, et al. Does a patient-managed insulin
intensification strategy with insulin glargine and insulin glulisine
The progressive nature of T2DM, with it is changing provide similar glycemic control as a physician-managed strategy?
pathophysiological features, mandates physicians to Results of the START (Self-Titration with Apidra(R) to Reach
Target) Study - A randomized non-inferiority trial. Diabetes Care.
change therapy as the nature of the disease changes Oct 29 2013.
in order to maintain glycemic control. In patients with 11. Khunti K, Davies MJ, Kalra S. Self-titration of insulin in the
long-standing diabetes, beta-cell function is likely to management of people with type 2 diabetes: a practical solution to
be at a minimum, making agents that rely in insulin improve management in primary care. Diabetes Obes Metab. Aug
2013;15(8):690-700.
secretion (secretagogues like sulfonylureas) less
useful. The ADOPT trial demonstrated the durability 12. Meneghini L, Koenen C, Weng W, Selam JL. The usage of a
simplified self-titration dosing guideline (303 Algorithm) for
of thiazolidinediones and metformin in terms of insulin detemir in patients with type 2 diabetes--results of the
maintenance of glycemic control compared to randomized, controlled PREDICTIVE 303 study. Diabetes Obes
sulfonylureas. Eventually, most patients will require Metab. Nov 2007;9(6):902-913.
insulin therapy. Basal insulin therapy is relatively easy 13. Vilsboll T, Rosenstock J, Yki-Jarvinen H, et al. Efficacy and safety
to use to meet background insulin requirements. of sitagliptin when added to insulin therapy in patients with type 2
diabetes. Diabetes Obes Metab. Feb 2010;12(2):167-177.
Prandial glucose control can be achieved with addition of
14. Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect
GLP-1 RAs, which not only increase insulin secretion
of saxagliptin as add-on therapy in patients with poorly controlled
but suppress glucagon-mediated hyperglycemia. They type 2 diabetes on insulin alone or insulin combined with
do this without increasing the risk of hypoglycemia or metformin. Curr Med Res Opin. Apr 2012;28(4):513-523.
increasing the risk of weight gain, in contrast to adding 15. Yki-Jarvinen H, Rosenstock J, Duran-Garcia S, et al. Effects of
prandial insulin injections. Adding Linagliptin to Basal Insulin Regimen for Inadequately
Controlled Type 2 Diabetes: A >=52-week randomized, double-
blind study. Diabetes Care. Dec 2013;36(12):3875-3881.
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