Retinopatia Neuropatia

Diabetes Care Volume 47, Supplement 1, January 2024 S231
12. Retinopathy, Neuropathy, and American Diabetes Association

Professional Practice Committee*
Foot Care: Standards of Care in
Diabetes—2024
Diabetes Care 2024;47(Suppl. 1):S231–S243 | https://doi.org/10.2337/dc24-S012
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12. RETINOPATHY, NEUROPATHY, AND FOOT CARE
The American Diabetes Association (ADA) “Standards of Care in Diabetes” in-
cludes the ADA’s current clinical practice recommendations and is intended to
provide the components of diabetes care, general treatment goals and guide-
lines, 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 Committee 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.
For prevention and management of diabetes complications in children and adoles-

cents, please refer to Section 14, “Children and Adolescents.”
DIABETIC RETINOPATHY
Recommendations
12.1 Implement strategies to help people with diabetes reach glycemic goals
to reduce the risk or slow the progression of diabetic retinopathy. A
12.2 Implement strategies to help people with diabetes reach blood pressure and
lipid goals to reduce the risk or slow the progression of diabetic retinopathy. A
Diabetic retinopathy is a highly specific neurovascular complication of both type 1

and type 2 diabetes, with prevalence strongly related to both the duration of diabe-
*A complete list of members of the American
tes and the level of glycemic control (1). Diabetic retinopathy is the most frequent Diabetes Association Professional Practice Committee
cause of new cases of blindness among adults aged 20–74 years in developed coun- can be found at https://doi.org/10.2337/dc24-SINT.
tries. Glaucoma, cataracts, and other eye disorders occur earlier and more frequently Duality of interest information for each author is
in people with diabetes. available at https://doi.org/10.2337/dc24-SDIS.
In addition to diabetes duration, factors that increase the risk of, or are associated Suggested citation: American Diabetes Associ-
with, retinopathy include chronic hyperglycemia (2,3), nephropathy (4), hypertension ation Professional Practice Committee. 12. Retino-
(5), and dyslipidemia (6). Intensive diabetes management with the goal of achieving pathy, neuropathy, and foot care: Standards of
near-normoglycemia has been shown in large prospective randomized studies to pre- Care in Diabetes—2024. Diabetes Care 2024;47
(Suppl. 1):S231–S243
vent and/or delay the onset and progression of diabetic retinopathy, reduce the
need for future ocular surgical procedures, and potentially improve self-reported vi- © 2023 by the American Diabetes Association.
sual function (2,7–10). A meta-analysis of data from cardiovascular outcomes studies Readers may use this article as long as the
work is properly cited, the use is educational
showed no association between glucagon-like peptide 1 receptor agonist (GLP-1 RA) and not for profit, and the work is not altered.
treatment and retinopathy per se, except through the association between retinopa- More information is available at https://www
thy and average A1C reduction at the 3-month and 1-year follow-up. Long-term .diabetesjournals.org/journals/pages/license.
S232 Retinopathy, Neuropathy, and Foot Care Diabetes Care Volume 47, Supplement 1, January 2024
impact of improved glycemic control on and/or progression of diabetic reti- readily available (15–17). High-quality
retinopathy was not studied in these tri- nopathy. B fundus photographs can detect most clin-
als. However, GLP-1 RAs including lira- 12.8 Individuals with preexisting type 1 ically significant diabetic retinopathy. In-
glutide, semaglutide, and dulaglutide or type 2 diabetes should receive an terpretation of the images should be
have been shown to be associated eye exam before pregnancy and in the performed by a trained eye care profes-
with an increased risk of rapidly wors- first trimester and should be moni- sional. Retinal photography may also en-
ening diabetic retinopathy in random- tored every trimester and for 1 year hance efficiency and reduce costs when
ized trials. Further data from clinical postpartum as indicated by the degree the expertise of ophthalmologists can be
studies with longer follow-up purposefully of retinopathy. B used for more complex examinations
designed for diabetic retinopathy risk as- and for therapy (15,18,19). In-person ex-
sessment, particularly including individu- ams are still necessary when the retinal
als with established diabetic retinopathy, The preventive effects of therapy and photos are of unacceptable quality and
are warranted. Retinopathy status should for follow-up if abnormalities are detected.

the fact that individuals with any level of
be assessed when intensifying glucose- diabetic retinopathy or macular edema Retinal photos are not a substitute for di-
lowering therapies such as those using may be asymptomatic provide strong lated comprehensive eye exams, which
GLP-1 RAs, since rapid reductions in A1C support for screening to detect diabetic should be performed at least initially and
can be associated with initial worsen- at yearly intervals thereafter or more fre-
retinopathy. Prompt diagnosis allows tri-
ing of retinopathy (11). quently as recommended by an eye care
age of people with diabetes and timely
intervention that may prevent vision loss professional. Artificial intelligence systems
Screening
in individuals who are asymptomatic de- that detect more than mild diabetic reti-
Recommendations spite advanced diabetic eye disease. nopathy and diabetic macular edema, au-
12.3 Adults with type 1 diabetes should Diabetic retinopathy screening should thorized for use by the U.S. Food and
have an initial dilated and comprehen- Drug Administration (FDA), represent an
be performed using validated approaches
sive eye examination by an ophthalmol- alternative to traditional screening ap-
and methodologies. Youth with type 1 or
ogist or optometrist within 5 years after proaches (20). There are now three FDA-
type 2 diabetes are also at risk for com-
the onset of diabetes. B approved artificial intelligence algorithms
plications and need to be screened for
12.4 People with type 2 diabetes for diabetic retinopathy screening and
diabetic retinopathy (12) (see Section 14,
examination. These services are now cov-
should have an initial dilated and “Children and Adolescents”). If diabetic
comprehensive eye examination by ered by most insurances. There are pub-
retinopathy is evident on screening,
an ophthalmologist or optometrist at lished prospective multicenter clinical trials
prompt referral to an ophthalmologist
the time of the diabetes diagnosis. B on the diagnostic accuracy for each (21–23).
is recommended. Subsequent examina-
12.5 If there is no evidence of retinopa- However, the benefits and optimal utiliza-
tions for individuals with type 1 or type 2
thy from one or more annual eye ex- tion of this type of screening have yet to be
diabetes are generally repeated annually fully determined. Results of all screening
ams and glycemic indicators are within for individuals with minimal to no reti-
the goal range, then screening every eye examinations should be documented
nopathy. Exams every 1–2 years may be and transmitted to the referring health care
1–2 years may be considered. If any cost-effective after one or more normal
level of diabetic retinopathy is present, professional.
eye exams. In a population with well-
subsequent dilated retinal examinations controlled type 2 diabetes, there was lit- Type 1 Diabetes
should be repeated at least annually by tle risk of development of significant reti- Because retinopathy is estimated to take at
an ophthalmologist or optometrist. If nopathy within a 3-year interval after a least 5 years to develop after the onset of
retinopathy is progressing or sight- normal examination (13), and less fre- hyperglycemia, people with type 1 diabetes
threatening, then examinations will quent intervals have been found in simu- should have an initial dilated and compre-
be required more frequently. B lated modeling to be potentially effective hensive eye examination within 5 years af-
12.6 Programs that use retinal pho- in screening for diabetic retinopathy in ter the diagnosis of diabetes (14).
tography with remote reading or individuals without diabetic retinopathy
the use of U.S. Food and Drug Ad- (14). However, it is important to adjust Type 2 Diabetes
ministration–approved artificial intelli- screening intervals based on the pres- People with type 2 diabetes who may
gence algorithms to improve access ence of specific risk factors for retinop- have had years of undiagnosed diabetes
to diabetic retinopathy screening are athy onset and worsening retinopathy. and have a significant risk of prevalent
appropriate screening strategies for
More frequent examinations by the diabetic retinopathy at the time of diag-
diabetic retinopathy. Such programs
ophthalmologist will be required if reti- nosis should have an initial dilated and
need to provide pathways for timely
nopathy is progressing or risk factors comprehensive eye examination at the
referral for a comprehensive eye ex-
such as uncontrolled hyperglycemia, ad- time of diagnosis.
amination when indicated. B
vanced baseline retinopathy, or diabetic
12.7 Counsel individuals of child-
macular edema are present. Pregnancy
bearing potential with preexisting
Retinal photography with remote read- Individuals who develop gestational di-
type 1 or type 2 diabetes who are
ing by experts has great potential to pro- abetes mellitus do not require eye ex-
planning pregnancy or who are preg-
vide screening services in areas where aminations during pregnancy since they
nant on the risk of development
qualified eye care professionals are not do not appear to be at increased risk of
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S233
developing diabetic retinopathy during Treatment severe vision loss from PDR from 15.9%
pregnancy (24). However, individuals of Recommendations in untreated eyes to 6.4% in treated
childbearing potential with preexisting 12.9 Promptly refer individuals with eyes with the greatest benefit ratio in
type 1 or type 2 diabetes who are plan- any level of diabetic macular edema, those with more advanced baseline dis-
ning pregnancy or who have become moderate or worse nonproliferative di- ease (disc neovascularization or vitreous
pregnant should be counseled on the abetic retinopathy (a precursor of pro- hemorrhage). Later, the ETDRS verified
baseline prevalence and risk of devel- liferative diabetic retinopathy [PDR]), the benefits of panretinal photocoagula-
opment and/or progression of diabetic or any PDR to an ophthalmologist tion for high-risk PDR and in older-onset
retinopathy. In a systematic review and individuals with severe nonproliferative
who is knowledgeable and experi-
meta-analysis of 18 observational stud- diabetic retinopathy or less-than-high-risk
enced in the management of dia-
ies of pregnant individuals with preex- PDR (28). Panretinal laser photocoagula-
betic retinopathy. A
isting type 1 or type 2 diabetes, the tion is still commonly used to manage
12.10 Panretinal laser photocoagu-
complications of diabetic retinopathy that

prevalence of any diabetic retinopathy lation therapy is indicated to reduce
and proliferative diabetic retinopathy involve retinal neovascularization and its
the risk of vision loss in individuals
(PDR) in early pregnancy was 52.3% complications. A more gentle, macular fo-
with high-risk PDR and, in some cases,
and 6.1%, respectively. The pooled pro- cal/grid laser photocoagulation technique
severe nonproliferative diabetic reti-
gression rate per 100 pregnancies for was shown in the ETDRS to be effective
nopathy. A in treating eyes with clinically significant
new diabetic retinopathy development 12.11 Intravitreous injections of anti–
was 15.0 (95% CI 9.9–20.8), worsened macular edema from diabetes (28), but
vascular endothelial growth factor this is now largely considered to be sec-
nonproliferative diabetic retinopathy was (anti-VEGF) are a reasonable alterna-
31.0 (95% CI 23.2–39.2), pooled sight- ond-line treatment for diabetic macular
tive to traditional panretinal laser pho- edema.
threatening progression rate from non- tocoagulation for some individuals
proliferative diabetic retinopathy to PDR with PDR and also reduce the risk of Anti–Vascular Endothelial Growth Factor
was 6.3 (95% CI 3.3–10.0), and worsened vision loss in these individuals. A Treatment
PDR was 37.0 (95% CI 21.2–54.0), demon- 12.12 Intravitreous injections of anti- Data from the DRCR Retina Network
strating that close follow-up should be VEGF are indicated as first-line treat- (formerly the Diabetic Retinopathy Clini-
maintained during pregnancy to prevent ment for most eyes with diabetic mac- cal Research Network) and others dem-
vision loss (25). In addition, rapid imple- ular edema that involves the foveal onstrate that intravitreal injections of
mentation of intensive glycemic man- center and impairs vision acuity. A anti-VEGF agents are effective at re-
agement in the setting of retinopathy is 12.13 Macular focal/grid photocoagu- gressing proliferative disease and lead
associated with early worsening of reti- lation and intravitreal injections of cor- to noninferior or superior visual acuity
nopathy (26). ticosteroid are reasonable treatments outcomes compared with panretinal la-
A systematic review and meta-analysis
in eyes with persistent diabetic macu- ser over 2 years of follow-up (29,30). In
and a controlled prospective study dem-
lar edema despite previous anti-VEGF addition, it was observed that individu-
onstrate that pregnancy in individuals als treated with ranibizumab tended to
therapy or eyes that are not candi-
with type 1 diabetes may aggravate reti- have less peripheral visual field loss, fewer
dates for this first-line approach. A
nopathy and threaten vision, especially vitrectomy surgeries for secondary compli-
12.14 The presence of retinopathy is
when glycemic management is poor or cations from their proliferative disease,
not a contraindication to aspirin ther-
retinopathy severity is advanced at the and a lower risk of developing diabetic
apy for cardioprotection, as aspirin
time of conception (25,26). Laser photo- macular edema (29). However, a poten-
does not increase the risk of retinal
coagulation surgery can minimize the tial drawback in using anti-VEGF therapy
hemorrhage. A
risk of vision loss during pregnancy for to manage proliferative disease is that in-
individuals with high-risk PDR or center- dividuals were required to have a greater
involved diabetic macular edema (26). Two of the main motivations for screen- number of visits and received a greater
The use of anti–vascular endothelial ing for diabetic retinopathy are to pre- number of treatments than is typically
growth factor (anti-VEGF) injections in vent loss of vision and to intervene with required for management with panretinal
pregnant individuals may be justified treatment when vision loss can be pre- laser, which may not be optimal for
only if the potential benefit outweighs vented or reversed. some individuals. The FDA has approved
the potential risk to the fetus and only aflibercept and ranibizumab for the treat-
if clearly indicated. Current anti-VEGF Photocoagulation Surgery ment of eyes with diabetic retinopathy.
medications have been assigned to Two large trials, the Diabetic Retinopa- Other emerging therapies for retinopathy
pregnancy category C by the FDA (ani- thy Study (DRS) in individuals with PDR that may use sustained intravitreal deliv-
mal studies have revealed evidence of and the Early Treatment Diabetic Reti- ery of pharmacologic agents are currently
embryo–fetal toxicity, but there are no nopathy Study (ETDRS) in individuals under investigation. Anti-VEGF treatment
controlled data in human pregnancy), with macular edema, provide the stron- of eyes with nonproliferative diabetic ret-
and caution should be used in pregnant gest support for the therapeutic bene- inopathy has been demonstrated to re-
individuals with diabetes because of fits of photocoagulation surgery. The duce subsequent development of retinal
theoretical risks to the vasculature of DRS (27) showed that panretinal photo- neovascularization and diabetic macular
the developing fetus. coagulation surgery reduced the risk of edema but has not been shown to improve
visual outcomes over 2 years of therapy Visual Rehabilitation

fork (for large-fiber function). All people
and therefore is not routinely recom- Recommendations with diabetes should have annual 10-g
mended for this indication (31). 12.15 People who experience vision monofilament testing to identify feet at
While the ETDRS (28) established the loss from diabetes should be coun- risk for ulceration and amputation. B
benefit of focal laser photocoagulation seled on the availability and scope of 12.19 Symptoms and signs of auto-
surgery in eyes with clinically significant vision rehabilitation care and provided, nomic neuropathy should be assessed
macular edema (defined as retinal edema or referred for, a comprehensive evalu- in people with diabetes starting at di-
located at or threatening the macular cen- ation of their visual impairment by a agnosis of type 2 diabetes and 5 years
ter), current data from well-designed clini- practitioner experienced in vision reha- after the diagnosis of type 1 diabetes,
cal trials demonstrate that intravitreal bilitation. E and at least annually thereafter, and
anti-VEGF agents provide a more effective 12.16 People with vision loss from dia- with evidence of other microvascular
treatment plan for center-involved diabetes should receive educational mate- complications, particularly kidney dis-

betic macular edema than monotherapy rials and resources for eye care support ease and diabetic peripheral neuropa-
with laser (32,33). Most individuals re- in addition to self-management educa- thy. Screening can include asking about
quire near-monthly administration of in- tion (e.g., glycemic management and orthostatic dizziness, syncope, or dry
travitreal therapy with anti-VEGF agents hypoglycemia awareness). E cracked skin in the extremities. Signs of
during the first 12 months of treatment, autonomic neuropathy include ortho-
with fewer injections needed in subse- In the U.S., 12% of adults with diabe- static hypotension, a resting tachycar-
quent years to maintain remission from tes have some level of vision impair- dia, or evidence of peripheral dryness
central-involved diabetic macular edema. ment (38). They may have difficulty or cracking of skin. E
There are currently five anti-VEGF agents controlling their diabetes and perform-
used to treat eyes with central-involved ing many other activities of daily living, Diabetic neuropathies are a heteroge-
diabetic macular edema—bevacizumab, which can lead to depression, anxiety, neous group of disorders with diverse
ranibizumab, aflibercept, brolucizumab and social isolation, and difficulties at home, clinical manifestations. The early recog-
faricimab (1)—and a comparative effective- workplace, school, or workplace (39). nition and appropriate management of
ness study demonstrated that aflibercept People with diabetes are at increased neuropathy in people with diabetes is
provides vision outcomes superior to those risk of chronic vision loss, subsequent important. Points to be aware of in-
of bevacizumab when eyes have moderate functional decline, and resulting dis- clude the following:
visual impairment (vision of 20/50 or ability. Vision impairment has physical,
1. Diabetic neuropathy is a diagnosis
worse) from diabetic macular edema psychological, behavioral, and social con-
of exclusion. Nondiabetic neuropa-
(34). For eyes that have good vision (20/25 sequences that affect people with diabe-
thies may be present in people with
or better) despite diabetic macular edema, tes, their families, friends, and caregivers.
diabetes and may be treatable.
close monitoring with initiation of anti- Health care professionals and stakehold-
2. Up to 50% of diabetic peripheral
VEGF therapy if vision worsens provides ers may not be aware of the overall im-
neuropathy may be asymptomatic.
similar 2-year vision outcomes compared pact of vision loss on an individual’s
If not recognized and if preventive
with immediate initiation of anti-VEGF health and well-being. People with diabe-
foot care is not implemented, peo-
therapy (35). tes-related vision loss should be evaluated
ple with diabetes are at risk for in-
Eyes that have persistent diabetic to determine their potential to benefit
juries as well as diabetic foot ulcers
macular edema despite anti-VEGF treat- from comprehensive vision restoration.
(DFUs) and amputations.
ment may benefit from macular laser Vision rehabilitation can help people with
3. Recognition and treatment of auto-
photocoagulation or intravitreal therapy vision loss achieve maximum function, in-
nomic neuropathy may improve symp-
with corticosteroids. Both of these ther- dependence, and quality of life.
toms, reduce sequelae, and improve
apies are also reasonable first-line ap- quality of life.
proaches for individuals who are not NEUROPATHY
candidates for anti-VEGF treatment Screening Specific treatment to reverse the un-
due to systemic considerations such as derlying nerve damage is currently not
Recommendations
pregnancy. 12.17 All people with diabetes should available. Glycemic management can
be assessed for diabetic peripheral effectively prevent diabetic peripheral
Adjunctive Therapy neuropathy (DPN) and cardiovascular
neuropathy starting at diagnosis of
Lowering blood pressure has been shown autonomic neuropathy (CAN) in type 1
type 2 diabetes and 5 years after the
to decrease retinopathy progression, diabetes (40,41) and may modestly slow
diagnosis of type 1 diabetes and at
although strict goals (systolic blood pres- their progression in type 2 diabetes
least annually thereafter. B
sure <120 mmHg) do not impart addi- (42), but it does not reverse neuronal
12.18 Assessment for distal symmet-
tional benefit (8). In individuals with loss. Treatments of other modifiable risk
ric polyneuropathy should include a
dyslipidemia, retinopathy progression factors (including lipids and blood pres-
careful history and assessment of
may be slowed by the addition of feno- sure) can aid in prevention of DPN pro-
either temperature or pinprick sensa-
fibrate, particularly with very mild non- gression in type 2 diabetes and may
tion (small-fiber function) and vibra-
proliferative diabetic retinopathy at reduce disease progression in type 1 di-
tion sensation using a 128-Hz tuning
baseline (36,37). abetes (43–45). Therapeutic strategies
(pharmacologic and nonpharmacologic) annually for autonomic neuropathy (46). outlet obstruction or peptic ulcer disease
for the relief of painful DPN and symp- The symptoms and signs of autonomic (with esophagogastroduodenoscopy or a
toms of autonomic neuropathy can po- neuropathy should be elicited carefully barium study of the stomach) is needed
tentially reduce pain (46) and improve during the history and physical examina- before considering a diagnosis of or spe-
quality of life. tion. Major clinical manifestations of cialized testing for gastroparesis. The di-
diabetic autonomic neuropathy include agnostic gold standard for gastroparesis
Diagnosis resting tachycardia, orthostatic hypoten- is the measurement of gastric emptying
Diabetic Peripheral Neuropathy sion, gastroparesis, constipation, diarrhea, with scintigraphy of digestible solids at
Individuals with a type 1 diabetes dura- fecal incontinence, erectile dysfunction, 15-min intervals for 4 h after food intake.
tion $5 years and all individuals with neurogenic bladder, and sudomotor The use of 13C octanoic acid breath test is
type 2 diabetes should be assessed an- dysfunction with either increased or an approved alternative.
nually for DPN using the medical history decreased sweating. Screening for symp-
toms of autonomic neuropathy includes Genitourinary Disturbances. Diabetic au-

and simple clinical tests (46). Symptoms
vary according to the class of sensory fi- asking about symptoms of orthostatic in- tonomic neuropathy may also cause gen-
bers involved. The most common early tolerance (dizziness, lightheadedness, or itourinary disturbances, including sexual
symptoms are induced by the involve- weakness with standing), syncope, exer- dysfunction and bladder dysfunction.
ment of small fibers and include pain and cise intolerance, constipation, diarrhea, In men, diabetic autonomic neuropathy
dysesthesia (unpleasant sensations of urinary retention, urinary incontinence, may cause erectile dysfunction and/or
burning and tingling). The involvement of or changes in sweat function. Further retrograde ejaculation (46). Female sex-
testing can be considered if symptoms ual dysfunction occurs more frequently
large fibers may cause numbness and loss
are present and will depend on the end in those with diabetes and presents as
of protective sensation (LOPS). LOPS indi-
organ involved but might include cardio- decreased sexual desire, increased pain
cates the presence of distal sensory poly-
vascular autonomic testing, sweat testing, during intercourse, decreased sexual
neuropathy and is a risk factor for diabetic
urodynamic studies, gastric emptying, or arousal, and inadequate lubrication (50).
foot ulceration. The following clinical tests
endoscopy/colonoscopy. Impaired coun- Lower urinary tract symptoms manifest as
may be used to assess small- and large-
terregulatory responses to hypoglyce- urinary incontinence and bladder dysfunc-
fiber function and protective sensation:
mia in type 1 and type 2 diabetes can tion (nocturia, frequent urination, urina-
lead to hypoglycemia unawareness but tion urgency, and weak urinary stream).
1. Small-fiber function: pinprick and Evaluation of bladder function should be
are not directly linked to autonomic
temperature sensation. performed for individuals with diabetes
neuropathy.
2. Large-fiber function: lower-extremity who have recurrent urinary tract infec-
reflexes, vibration perception, and 10-g tions, pyelonephritis, incontinence, or a
Cardiovascular Autonomic Neuropathy. Car-
monofilament. palpable bladder.
diovascular autonomic neuropathy (CAN)
3. Protective sensation: 10-g monofilament.
is associated with mortality indepen-
dently of other cardiovascular risk factors Treatment
These tests not only screen for the (48,49). In its early stages, CAN may be Recommendations
presence of dysfunction but also predict completely asymptomatic and detected
future risk of complications. Electrophys- 12.20 Optimize glucose management
only by decreased heart rate variability to prevent or delay the development
iological testing or referral to a neurolo- with deep breathing. Advanced disease
gist is rarely needed, except in situations of neuropathy in people with type 1
may be associated with resting tachycar- diabetes A and to slow the progression
where the clinical features are atypical dia (>100 bpm) and orthostatic hypoten-
or the diagnosis is unclear. of neuropathy in people with type 2
sion (a fall in systolic or diastolic blood diabetes. C Optimize blood pressure
In all people with diabetes and DPN, pressure by >20 mmHg or >10 mmHg,
causes of neuropathy other than diabetes and serum lipid control to reduce the
respectively, upon standing without an risk or slow the progression of diabetic
should be considered, including toxins (e.g., appropriate increase in heart rate). CAN
alcohol), neurotoxic medications (e.g., che- neuropathy. B
treatment is generally focused on allevi- 12.21 Assess and treat pain related
motherapy), vitamin B12 deficiency, hypo- ating symptoms. to diabetic peripheral neuropathy B
thyroidism, renal disease, malignancies
and symptoms of autonomic neurop-
(e.g., multiple myeloma, bronchogenic Gastrointestinal Neuropathies. Gastrointes- athy to improve quality of life. E
carcinoma), infections (e.g., HIV), chronic tinal neuropathies may involve any por- 12.22 Gabapentinoids, serotonin-
inflammatory demyelinating neuropathy, tion of the gastrointestinal tract, with norepinephrine reuptake inhibitors,
inherited neuropathies, and vasculitis (47). manifestations including esophageal dys-
tricyclic antidepressants, and sodium
See the American Diabetes Association po- motility, gastroparesis, constipation, diar-
channel blockers are recommended as
sition statement “Diabetic Neuropathy” rhea, and fecal incontinence. Gastroparesis
initial pharmacologic treatments for
for more details (46). should be suspected in individuals with
neuropathic pain in diabetes. A Refer
erratic glycemic management or with up-
to neurologist or pain specialist when
Diabetic Autonomic Neuropathy per gastrointestinal symptoms without
adequate pain management is not
Individuals who have had type 1 diabe- another identified cause. Exclusion of
achieved within the scope of practice
tes for $5 years and all individuals with reversible/iatrogenic causes such as
of the treating clinician. E
type 2 diabetes should be assessed medications or organic causes of gastric
Glycemic Management risk of DPN development with an odds medium-quality studies support the role
Near-normal glycemic management, ratio of 1.58 (61). In the ACCORD trial, in- of duloxetine in the treatment of pain
implemented early in the course of dia- tensive blood pressure intervention de- in DPN. A high-quality study supports
betes, has been shown to effectively decreased CAN risk by 25% (57). the role of venlafaxine in the treatment
lay or prevent the development of DPN of pain in DPN. Only one medium-quality
and CAN in people with type 1 diabetes Neuropathic Pain study supports a possible role for des-
(51–54). Although the evidence for the Neuropathic pain can be severe and can venlafaxine for treatment of pain in DPN
benefit of near-normal glycemic manage- impact quality of life, limit mobility, and (64). Adverse events may be more severe
ment is not as strong that for type 2 dia- contribute to depression and social dys- in older people but may be attenuated
betes, some studies have demonstrated a function (62). No compelling evidence with lower doses and slower titration of
modest slowing of progression without re- exists in support of glycemic or lifestyle duloxetine.
versal of neuronal loss (42,55). Specific management as therapies for neuro- Tapentadol and Tramadol. Tapentadol
glucose-lowering strategies may have dif-

pathic pain in diabetes or prediabetes, and tramadol are centrally acting opioid
ferent effects. In a post hoc analysis, par- which leaves only pharmaceutical inter- analgesics that exert their analgesic ef-
ticipants, particularly men, in the Bypass ventions (63). A recent guideline by the fects through both m-opioid receptor
Angioplasty Revascularization Investiga- American Academy of Neurology rec- agonism and norepinephrine and sero-
tion in Type 2 Diabetes (BARI 2D) trial ommends that the initial treatment of tonin reuptake inhibition. SNRI/opioid
treated with insulin sensitizers had a pain should also focus on the concur-
lower incidence of distal symmetric poly- agents are probably effective in the
rent treatment of both sleep and mood treatment of pain in DPN. However,
neuropathy over 4 years than those disorders because of increased frequency
treated with insulin/sulfonylurea (56). the use of any opioids for manage-
of these problems in individuals with ment of chronic neuropathic pain car-
Additionally, recent evidence from the DPN (64).
Action to Control Cardiovascular Risk in ries the risk of addiction and should
A number of pharmacologic therapies
Diabetes (ACCORD) trial showed clear be avoided.
exist for treatment of pain in diabetes.
benefit of intensive glucose and blood Tricyclic Antidepressants. TCAs have been
The American Academy of Neurology
pressure management on the preven- studied for treatment of pain, and most
update suggested that gabapentinoids,
tion of CAN in type 2 diabetes (57). of the relevant data were acquired from
serotonin-norepinephrine reuptake in-
trials of amitriptyline and include two
hibitors (SNRIs), sodium channel block-
Lipid Management high-quality studies and two medium-
ers, and tricyclic antidepressants (TCAs)
Dyslipidemia is a key factor in the devel- quality studies supporting the treatment
could all be considered in the treatment
opment of neuropathy in people with of pain in DPN (64). These American of pain in DPN (64,66). Anticholinergic
type 2 diabetes and may contribute to side effects may be dose limiting and
Academy of Neurology recommendations
neuropathy risk in people with type 1 di-
offer a supplement to a recent American restrict use in individuals $65 years of
abetes (58,59). Although the evidence for age.
Diabetes Association pain monograph
a relationship between lipids and neurop- Sodium Channel Blockers. Sodium chan-
(65). A recent head-to-head trial sug-
athy development has become increas- nel blockers include lamotrigine, lacosa-
gested therapeutic equivalency for TCAs,
ingly clear in type 2 diabetes, the optimal mide, carbamazepine, oxcarbazepine,
SNRIs, and gabapentinoids in the treat-
therapeutic intervention has not been and valproic acid. Five medium-quality
ment of pain in DPN (66). The trial also
identified. Positive effects of physical ac- studies support the role of sodium
supported the role of combination ther-
tivity, weight loss, and bariatric surgery channel blockers in treating pain in
apy over monotherapy for the treatment
have been reported in individuals with DPN (64).
of pain in DPN.
DPN, but use of conventional lipid-lowering
Gabapentinoids. Gabapentinoids include Capsaicin. Capsaicin has received FDA
pharmacotherapy (such as statins or fenofi-
several calcium channel a2-d subunit approval for treatment of pain in DPN
brates) does not appear to be effective in
ligands. Eight high-quality studies and using an 8% patch, with one high-quality
treating or preventing DPN development
seven medium-quality studies support study reported. One medium-quality study
(60).
the role of pregabalin in treatment of of 0.075% capsaicin cream has been re-
Blood Pressure Management pain in DPN. One high-quality study and ported. In individulas with contraindica-
There are multiple reasons for blood many small studies support the role of tions to oral pharmacotherapy or who
pressure management in people with di- gabapentin in the treatment of pain in prefer topical treatments, the use of topi-
abetes, but neuropathy progression (es- DPN. Two medium-quality studies sug- cal capsaicin can be considered.
pecially in type 2 diabetes) has now gest that microgabalin has a small Lidocaine 5% Plaster/Patch. Lidocaine
been added to this list. Although data effect on pain in DPN (64). Adverse ef- patches have limited data supporting
from many studies have supported the fects may be more severe in older in- their use in DPN and are not effective
role of hypertension in risk of neuropathy dividuals (67) and may be attenuated in more widespread distribution of pain
development, a recent meta-analysis of by lower starting doses and more gradual (although they may be of use in individ-
data from 14 countries in the Interna- titration. uals with nocturnal neuropathic foot
tional Prevalence and Treatment of Diabe- SNRIs. SNRIs include duloxetine, venla- pain). Lidocaine patches cannot be used
tes and Depression (INTERPRET-DD) study faxine, and desvenlafaxine, all selective for more than 12 h in a 24-h period
revealed hypertension as an independent SNRIs. Two high-quality studies and five (68).
a-Lipoic acid, although not

a-Lipoic Acid. regarding the benefits of metoclopra- neuropathy (pain, burning, numbness)
approved for the treatment of painful mide for the management of gastropare- and vascular disease (leg fatigue, clau-
DPN, may be effective and considered sis is weak, and given the risk for serious dication). B
for the treatment of painful DPN (64, adverse effects (extrapyramidal signs such 12.27 Initial screening for peripheral
65). as acute dystonic reactions, drug-induced arterial disease (PAD) should in-
parkinsonism, akathisia, and tardive dyski- clude assessment of lower-extremity
Orthostatic Hypotension nesia), its use in the treatment of gastro- pulses, capillary refill time, rubor on
Treating orthostatic hypotension is chal- paresis beyond 12 weeks is no longer dependency, pallor on elevation, and
lenging. The therapeutic goal is to mini- recommended by the FDA. It should be venous filling time. Individuals with
mize postural symptoms rather than to reserved for severe cases that are unre-
a history of leg fatigue, claudication,
restore normotension. Most individuals sponsive to other therapies (76). Other
and rest pain relieved with depen-
require both nonpharmacologic meas- treatment options include domperidone
dency or decreased or absent pedal
ures (e.g., ensuring adequate salt intake, (available outside the U.S.) and erythro-

pulses should be referred for ankle-
avoiding medications that aggravate hy- mycin, which is only effective for short-
brachial index with toe pressures and
potension, or using compressive gar- term use due to tachyphylaxis (77,78).
for further vascular assessment as
ments over the legs and abdomen) and Gastric electrical stimulation using a surgi-
appropriate. B
pharmacologic measures. Physical activ- cally implantable device has received ap-
12.28 An interprofessional approach
ity and exercise should be encouraged proval from the FDA, although there are
facilitated by a podiatrist in conjunction
to avoid deconditioning, which is known very limited data in DPN and the results
with other appropriate team members
to exacerbate orthostatic intolerance, do not support gastric stimulation as an
is recommended for individuals with
and volume repletion with fluids and effective therapy in diabetic gastroparesis
foot ulcers and high-risk feet (e.g.,
salt is critical. There have been clinical (79).
those on dialysis, those with Charcot
studies that assessed the impact of an
foot, those with a history of prior ulcers
approach incorporating the aforemen- Erectile Dysfunction
In addition to treatment of hypogonad- or amputation, and those with PAD). B
tioned nonpharmacologic measures. Ad-
ism if present, treatments for erectile 12.29 Refer individuals who smoke
ditionally, supine blood pressure tends
dysfunction may include phosphodies- and have a history of prior lower-
to be much higher in these individuals,
terase type 5 inhibitors, intracorporeal extremity complications, loss of pro-
often requiring treatment of blood pres-
or intraurethral prostaglandins, vacuum tective sensation, structural abnormal-
sure at bedtime with shorter-acting drugs
devices, or penile prostheses. As with ities, or PAD to foot care specialists for
that also affect baroreceptor activity such
DPN treatments, these interventions do ongoing preventive care and lifelong
as guanfacine or clonidine, shorter-acting
not change the underlying pathology surveillance. B
calcium blockers (e.g., isradipine), or
and natural history of the disease pro- 12.30 Provide general preventive foot
shorter-acting b-blockers such as ateno-
cess but may improve a person’s quality self-care education to all people with
lol or metoprolol tartrate. Alternatives
of life. diabetes, including those with loss of
can include enalapril if an individual is
protective sensation, on appropriate
unable to tolerate preferred agents
FOOT CARE ways to examine their feet (palpation
(69–71). Midodrine and droxidopa are
or visual inspection with an unbreak-
approved by the FDA for the treat-
Recommendations able mirror) for daily surveillance of
ment of orthostatic hypotension.
12.23 Perform a comprehensive foot early foot problems. B
evaluation at least annually to iden- 12.31 The use of specialized thera-
Gastroparesis
tify risk factors for ulcers and ampu- peutic footwear is recommended for
Treatment for diabetic gastroparesis may
tations. A people with diabetes at high risk for
be very challenging. A low-fiber, low-fat
12.24 The examination should include in- ulceration, including those with loss
eating plan provided in small frequent
spection of the skin, assessment of foot of protective sensation, foot deformi-
meals with a greater proportion of liquid
deformities, neurological assessment ties, ulcers, callous formation, poor
calories may be useful (72–74). In addi-
(10-g monofilament testing with at peripheral circulation, or history of
tion, foods with small particle size may
least one other assessment: pinprick, amputation. B
improve key symptoms (75). Withdraw-
temperature, or vibration), and vas- 12.32 For chronic diabetic foot ulcers
ing drugs with adverse effects on gastro-
cular assessment, including pulses in that have failed to heal with optimal
intestinal motility, including opioids,
the legs and feet. B standard care alone, adjunctive treat-
anticholinergics, TCAs, GLP-1 RAs, and
12.25 Individuals with evidence of ment with randomized controlled trial–
pramlintide, may also improve intestinal
sensory loss or prior ulceration or proven advanced agents should be
motility (72,76). However, the risk of re-
amputation should have their feet considered. Considerations might in-
moval of GLP-1 RAs should be balanced
inspected at every visit. A clude negative-pressure wound therapy,
against their potential benefits. In cases
12.26 Obtain a prior history of ulcera- placental membranes, bioengineered
of severe gastroparesis, pharmacologic
tion, amputation, Charcot foot, angio- skin substitutes, several acellular ma-
interventions are needed. Only metoclo-
plasty or vascular surgery, cigarette trices, autologous fibrin and leukocyte
pramide, a prokinetic agent, is approved
smoking, retinopathy, and renal dis- platelet patches, and topical oxygen
by the FDA for the treatment of gastro-
ease and assess current symptoms of therapy. A
paresis. However, the level of evidence
Foot ulcerations and amputations are com- assessment of skin integrity, assessment performed with at least one other neu-
mon complications associated with diabe- for LOPS using the 10-g monofilament rologic assessment tool (e.g., pinprick,
tes. These may be the consequences of along with at least one other neurologi- temperature perception, ankle reflexes,
several factors, including peripheral neu- cal assessment tool, pulse examination or vibratory perception with a 128-Hz
ropathy, peripheral arterial disease (PAD), of the dorsalis pedis and posterior tibial tuning fork or similar device). Absent
and foot deformities. They represent major arteries, and assessment for foot deformi- monofilament sensation and one other
causes of morbidity and mortality in peo- ties such as bunions, hammertoes, and abnormal test confirms the presence of
ple with diabetes. Early recognition of at- prominent metatarsals, which increase LOPS. Further neurological testing, such
risk feet, preulcerative lesions, and prompt plantar foot pressures and increase risk as nerve conduction, electromyography,
treatment of ulcerations and other lower- for ulcerations. At-risk individuals should nerve biopsy, or intraepidermal nerve
extremity complications can delay or pre- be assessed at each visit and should be fiber density biopsies, are rarely indi-
vent adverse outcomes. referred to foot care specialists for ongo- cated for the diagnosis of peripheral

Early recognition requires an under- ing preventive care and surveillance. The sensory neuropathy (46).
standing of those factors that put peo- physical examination can stratify people
ple with diabetes at increased risk for with diabetes into different categories Evaluation for Peripheral Arterial
ulcerations and amputations. Factors and determine the frequency of these vis- Disease
that are associated with the at-risk foot its (81) (Table 12.1). Initial screening for PAD should include
include the following: a history of leg fatigue, claudication,
Evaluation for Loss of Protective and rest pain relieved with dependency.
• Poor glycemic management Sensation Physical examination for PAD should in-
• Peripheral neuropathy/LOPS The presence of peripheral sensory neu- clude assessment of lower-extremity
• PAD ropathy is the single most common pulses, capillary refill time, rubor on de-
• Foot deformities (bunions, hammer- component cause for foot ulceration. In pendency, pallor on elevation, and ve-
toes, Charcot joint, etc.) a multicenter trial, peripheral neuropa- nous filling time (80,84). Any individual
• Preulcerative corns or calluses thy was found to be a component cause exhibiting signs and symptoms of PAD
• Prior ulceration in 78% of people with diabetes with ul- should be referred for noninvasive arterial
• Prior amputation cerations and that the triad of periph- studies in the form of Doppler ultrasound
• Smoking eral sensory neuropathy, minor trauma, with pulse volume recordings. While
• Retinopathy and foot deformity was present in ankle-brachial indices will be calculated,
• Nephropathy (particularly individuals >63% of participants (82). All people they should be interpreted carefully, as
on dialysis or posttransplant) with diabetes should undergo a com- they are known to be inaccurate in peo-
prehensive foot examination at least an- ple with diabetes due to noncompressible
Identifying the at-risk foot begins nually, or more frequently for those in vessels. Toe systolic blood pressure tends
with a detailed history documenting di- higher-risk categories (80,81). to be more accurate. Toe systolic blood
abetes management, smoking history, LOPS is vital to risk assessment. One pressures <30 mmHg are suggestive of
exercise tolerance, history of claudica- of the most useful tests to determine PAD and an inability to heal foot ulcera-
tion or rest pain, and prior ulcerations LOPS is the 10-g monofilament test. tions (85). Individuals with abnormal pulse
or amputations. A thorough examina- Studies have shown that clinical exami- volume recording tracings and toe pres-
tion of the feet should be performed nation and the 10-g monofilament test sures <30 mmHg with foot ulcers should
annually in all people with diabetes and are the two most sensitive tests in iden- be referred for immediate vascular eval-
more frequently in at-risk individuals tifying the foot at risk for ulceration uation. Due to the high prevalence of
(80). The examination should include (83). The monofilament test should be PAD in people with diabetes, the Society
Table 12.1—International Working Group on the Diabetic Foot risk stratification system and corresponding foot screening
frequency
Category Ulcer risk Characteristics Examination frequency*
0 Very low No LOPS and No PAD Annually
1 Low LOPS or PAD Every 6–12 months
2 Moderate LOPS 1 PAD, or Every 3–6 months
LOPS 1 foot deformity, or
PAD 1 foot deformity
3 High LOPS or PAD and one or more of the following: Every 1–3 months
History of foot ulcer
Amputation (minor or major)
End-stage renal disease
Adapted with permission from Schaper et al. (81). LOPS, loss of protective sensation; PAD, peripheral artery disease. *Examination frequency
suggestions are based on expert opinion and person-centered requirements.
for Vascular Surgery and the American responses will need other people, such as with or without a history of trauma and
Podiatric Medical Association guidelines family members, to assist with their care. without an open ulceration. These indi-
recommend that all people with diabe- The selection of appropriate footwear viduals require a thorough workup for
tes >50 years of age should undergo and footwear behaviors at home should possible Charcot neuroarthropathy (94).
screening via noninvasive arterial studies also be discussed (e.g., no walking bare- Early diagnosis and treatment of this
(84,86). If normal, these should be re- foot, avoiding open-toed shoes). Therapeu- condition is of paramount importance
peated every 5 years (84). tic footwear with custom-made orthotic in preventing deformities and instability
devices have been shown to reduce peak that can lead to ulceration and amputa-
Education for People With Diabetes plantar pressures (89). Most studies use tion. These individuals require total non–
All people with diabetes (and their fami- reduction in peak plantar pressures as an weight-bearing and urgent referral to a
lies), particularly those with the afore- outcome as opposed to ulcer prevention. foot care specialist for further manage-
mentioned high-risk conditions, should Certain design features of the orthoses, ment. Foot and ankle X-rays should be

receive general foot care education, in- such as rocker soles and metatarsal ac- performed in all individuals presenting
cluding appropriate management strate- commodations, can reduce peak plantar with the above clinical findings.
gies (87–89). This education should be pressures more significantly than insoles There have been a number of develop-
provided to all newly diagnosed people alone. A systematic review, however, ments in the treatment of ulcerations over
with diabetes as part of an annual com- showed there was no significant reduc- the years (95). These include negative-
prehensive examination and to individu- tion in ulcer incidence after 18 months pressure therapy, growth factors, bioengi-
als with high-risk conditions at every compared with standard insoles and extra- neered tissue, acellular matrix tissue, stem
visit. Recent studies have shown that depth shoes. Further, it was also noted cell therapy, hyperbaric oxygen therapy,
while education improves knowledge of that evidence to prevent first ulcerations and, most recently, topical oxygen therapy
diabetic foot problems and self-care of was nonexistent (93). (96–98). While there is literature to sup-
the foot, it does not improve behaviors port many modalities currently used to
associated with active participation in Treatment treat diabetic foot wounds, robust ran-
their overall diabetes care and to achieve Treatment recommendations for people domized controlled trials (RCTs) are often
personal health goals (90). Evidence also with diabetes will be determined by lacking. However, it is agreed that the ini-
suggests that while education for people their risk category. No-risk or low-risk in- tial treatment and evaluation of ulcera-
with diabetes and their families is impor- dividuals can often be managed with tions include the following five basic
tant, the knowledge is quickly forgotten education and self-care. People in the principles of ulcer treatment:
and needs to be reinforced regularly (91). moderate to high risk category should
Individuals considered at risk should be referred to foot care specialists for • Offloading of plantar ulcerations
understand the implications of foot de- further evaluation and regular surveil- • Debridement of necrotic, nonviable
formities, LOPS, and PAD; the proper lance as outlined in Table 12.1. This tissue
care of the foot, including nail and skin includes individuals with LOPS, PAD, • Revascularization of ischemic wounds
care; and the importance of foot inspec- and/or structural foot deformities, such when necessary
tions on a daily basis. Individuals with as Charcot foot, bunions, or hammer- • Management of infection: soft tissue
LOPS should be educated on appropriate toes. Individuals with any open ulcera- or bone
ways to examine their feet (palpation or tion or unexplained swelling, erythema, • Use of physiologic, topical dressings
visual inspection with an unbreakable or increased skin temperature should
mirror) for daily surveillance of early foot be referred urgently to a foot care spe- However, despite following the above
problems. People with diabetes should cialist or interprofessional team. principles, some ulcerations will become
also be educated on the importance of Initial treatment recommendations should chronic and fail to heal. In those situa-
referrals to foot care specialists. A recent include daily foot inspection, use of mois- tions, advanced wound therapy can play
study showed that people with diabetes turizers for dry, scaly skin, and avoidance a role. When to use advanced wound
and foot disease lacked awareness of of self-care of ingrown nails and calluses. therapy has been the subject of much
their risk status and why they were be- Well-fitted athletic or walking shoes with discussion, as the therapy is often quite
ing referred to a interprofessional team customized pressure-relieving orthoses expensive. It has been determined that
of foot care specialists. Further, they ex- should be part of initial recommenda- if a wound fails to show a reduction of
hibited a variable degree of interest in tions for people with increased plantar 50% or more after 4 weeks of appropri-
learning further about foot complications pressures (as demonstrated by plantar ate wound management (i.e., the five
(92). calluses). Individuals with deformities such basic principles above), consideration
Individuals’ understanding of these as bunions or hammertoes may require should be given to the use of advanced
issues and their physical ability to con- specialized footwear such as extra-depth wound therapy (99). Treatment of these
duct proper foot surveillance and care shoes. Those with even more significant chronic wounds is best managed in an
should be assessed. Those with visual deformities, as in Charcot joint disease, interprofessional setting.
difficulties, physical constraints preventing may require custom-made footwear. Evidence to support advanced wound
movement, or cognitive problems that Special consideration should be given therapy is challenging to produce and to
impair their ability to assess the condition to individuals with neuropathy who pre- assess. Randomization of trial participants
of the foot and to institute appropriate sent with a warm, swollen, red foot is difficult, as there are many variables
that can affect wound healing. In addi-

Table 12.2—Categories of advanced wound therapies
tion, many RCTs exclude certain cohorts
of people, e.g., individuals with chronic Negative-pressure wound therapy
renal disease or those on dialysis. Finally, Standard electrically powered
Mechanically powered
blinding of participants and clinicians is
not always possible. Meta-analyses and Oxygen therapies
systematic reviews of observational stud- Hyperbaric oxygen therapy
ies are used to determine the clinical Topical oxygen therapy
Oxygen-releasing sprays, dressings
effectiveness of these modalities. Such
studies can augment formal RCTs by in- Biophysical
cluding a greater variety of participants in Electrical stimulation, diathermy
Pulsed electromagnetic fields, pulsed radiofrequency energy
various clinical settings who are typically
Low-frequency noncontact ultrasound
excluded from the more rigidly structured

Extracorporeal shock wave therapy
clinical trials.
Growth factors
Advanced wound therapy can be cate-
Becaplermin: platelet-derived growth factor
gorized into nine broad categories Fibroblast growth factor
(95) (Table 12.2). Topical growth factors, Epidermal growth factor
acellular matrix tissues, and bioengi-
Autologous blood products
neered cellular therapies are commonly Platelet-rich plasma
used in offices and wound care centers Leukocyte, platelet, fibrin multilayered patches
to expedite healing of chronic, more su- Whole blood clot
perficial ulcerations. Numerous clinical Acellular matrix tissues
reports and retrospective studies have Xenograft dermis
demonstrated the clinical effectiveness Bovine dermis
of each of these modalities. Over the years, Xenograft acellular matrices
there has been increased evidence to sup- Small intestine submucosa
port the use of these modalities. Nonethe- Porcine urinary bladder matrix
Ovine forestomach
less, use of those products or agents with
Equine pericardium
robust RCTs or systematic reviews should Fish skin graft
generally be preferred over those without Bovine collagen
level 1 evidence (Table 12.2). Bilayered dermal regeneration matrix
Negative-pressure wound therapy was Human dermis products
first introduced in the early to mid- Human pericardium
1990s. It has become especially useful in Placental tissues
Amniotic tissues/amniotic fluid
wound preparation for skin grafts and
Umbilical cord
flaps and assists in the closure of deep,
large wounds (100,101). A variety of Bioengineered allogeneic cellular therapies
Bilayered skin equivalent (human keratinocytes and fibroblasts)
types exist in the marketplace and
Dermal replacement therapy (human fibroblasts)
range from electrically powered to
mechanically powered in different Stem cell therapies
sizes depending upon the specific Autogenous: bone marrow–derived stem cells
Allogeneic: amniotic matrix with mesenchymal stem cells
wound requirements.
Electrical stimulation, pulsed radiofre- Miscellaneous active dressings
quency energy, and extracorporeal shock- Hyaluronic acid, honey dressings, etc.
Sucrose octasulfate dressing
wave therapy are biophysical modalities
that are believed to upregulate growth Adapted with permission from Frykberg and Banks (95).
factors or cytokines to stimulate wound
healing, while low-frequency noncontact
ultrasound is used to debride wounds. While there had been great interest in DFUs (103,104). While there may be
However, most of the studies advocating this modality being able to expedite some benefit in prevention of amputa-
the use of these modalities have been ret- healing of chronic DFUs, there has only tion in selected chronic neuroischemic
rospective observational or poor-quality been one positive RCT published in the ulcers, recent studies have shown no
RCTs. last decade that reported increased heal- benefit in healing DFUs in the absence of
Hyperbaric oxygen therapy is the de- ing rates at 9 and 12 months compared ischemia and/or infection (98,105).
livery of oxygen through a chamber, ei- with control subjects (102). More recent Topical oxygen therapy has been stud-
ther individual or multiperson, with the studies with significant design deficien- ied rather vigorously in recent years, with
intention of increasing tissue oxygena- cies and participant dropouts have failed several high-quality RCTs and at least five
tion to increase tissue perfusion and to provide corroborating evidence that systematic reviews and meta-analyses all
neovascularization, combat resistant bac- hyperbaric oxygen therapy should be supporting its efficacy in healing chronic
teria, and stimulate wound healing. widely used for managing nonhealing DFUs at 12 weeks (96,97,106–110) Three
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Diabetes Care Volume 47, Supplement 1, January 2024 S231

12. Retinopathy, Neuropathy, and American Diabetes Association

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For prevention and management of diabetes complications in children and adoles-

Diabetic retinopathy is a highly speciﬁc neurovascular complication of both type 1

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visual outcomes over 2 years of therapy Visual Rehabilitation

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a-Lipoic acid, although not

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that can affect wound healing. In addi-

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