S252 Diabetes Care Volume 48, Supplement 1, January 2025

12. Retinopathy, Neuropathy, and American Diabetes Association

Professional Practice Committee*
Foot Care: Standards of Care in
Diabetes—2025
Diabetes Care 2025;48(Suppl. 1):S252–S265 | https://doi.org/10.2337/dc25-S012

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

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-
tes and the level of glycemic management (1). Diabetic retinopathy is the most fre-
quent cause of new cases of blindness among adults aged 20–74 years in developed
countries. Glaucoma, cataracts, and other eye disorders occur earlier and more fre- *A complete list of members of the American
Diabetes Association Professional Practice Committee
quently in people with diabetes. can be found at https://doi.org/10.2337/dc25-SINT.
In addition to diabetes duration, factors that increase the risk of, or are associated
Duality of interest information for each author is
with, retinopathy include chronic hyperglycemia (2,3), nephropathy (4), hypertension available at https://doi.org/10.2337/dc25-SDIS.
(5), and dyslipidemia (6–8). Intensive diabetes management with the goal of achieving
Suggested citation: American Diabetes Association
near-normoglycemia has been shown in large prospective randomized studies to pre- Professional Practice Committee. 12. Retinopathy,
vent and/or delay the onset and progression of diabetic retinopathy, reduce the need neuropathy, and foot care: Standards of Care in
for future ocular surgical procedures, and potentially improve self-reported visual func- Diabetes—2025. Diabetes Care 2025;48(Suppl. 1):
tion (2,6,9–11). A meta-analysis of data from cardiovascular outcomes studies showed S252–S265
no association between glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment © 2024 by the American Diabetes Association.
and retinopathy per se, except through the association between retinopathy and aver- Readers may use this article as long as the
work is properly cited, the use is educational
age A1C reduction at the 3-month and 1-year follow-up. Long-term impact of im- and not for profit, and the work is not altered.
proved glycemic management on retinopathy was not studied in these trials. However, More information is available at https://www
GLP-1 RAs including liraglutide, semaglutide, and dulaglutide have been shown to be .diabetesjournals.org/journals/pages/license.
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S253

associated with a risk of mildly worsening in the first trimester and may need to artificial intelligence (AI) programs that
diabetic retinopathy in randomized trials be monitored every trimester and for are U.S. Food and Drug Administration
(12,13). Further data from clinical studies 1 year postpartum as indicated by the (FDA) approved for this purpose. Retinal
with longer follow-up purposefully de- degree of retinopathy. B photography may also enhance efficiency
signed for diabetic retinopathy risk assess- and reduce costs when the expertise of
ment, particularly including individuals ophthalmologists can be used for more
with established diabetic retinopathy, are Identifying individuals with diabetes- complex examinations and for treatment
needed. Retinopathy status should be as- related eye disease is important because (20,23,24). In-person exams are still nec-
sessed when glucose-lowering therapies people with vision-threatening retinopa- essary when the retinal photos are of un-
are intensified, such as those using GLP-1 thy may be asymptomatic. Additionally, acceptable quality and for follow-up if
RAs, since rapid reductions in A1C can current therapies can not only prevent abnormalities are detected. Retinal photos
be associated with initial worsening of vision loss but also help improve vision are not a substitute for dilated compre-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

retinopathy (14). for many individuals. Prompt diagnosis hensive eye exams, which should be per-
allows triage of people with diabetes and formed at least initially and at yearly
Screening timely intervention that may prevent vi- intervals thereafter or more frequently as
sion loss in individuals who are asymp- recommended by an eye care profes-
Recommendations
tomatic despite advanced diabetes-related sional. AI systems that detect more than
12.3 Adults with type 1 diabetes should
eye disease. mild diabetic retinopathy and diabetic
have an initial dilated and comprehen-
Diabetic retinopathy screening should macular edema that have been autho-
sive eye examination by an ophthal-
be performed using validated approaches rized for use by the FDA represent an
mologist or optometrist within 5 years
and methodologies. Youth with type 1 or alternative to traditional screening ap-
after the onset of diabetes. B
type 2 diabetes are also at risk for compli- proaches (25). Three AI platforms have
12.4 People with type 2 diabetes should
cations and need to be screened for dia- been approved by the FDA for diabetic
have an initial dilated and comprehen-
betic retinopathy (15–17) (see Section 14, retinopathy screening and examination:
sive eye examination by an ophthal-
“Children and Adolescents”). If diabetic ret- AEYE diagnostic screening technology,
mologist or optometrist at the time of
inopathy is evident on screening, prompt or AEYE-DS (AEYE Health); EyeArt AI
the diabetes diagnosis. B
referral to an ophthalmologist is recom- screening system (Eyenuk); and Lumi-
12.5 If there is no evidence of retinop-
mended. Subsequent examinations for in- neticsCore, formerly IDx-DR (Digital Di-
athy from one or more annual eye ex-
dividuals with type 1 or type 2 diabetes are agnostics). These services are covered
ams and glycemic indicators are within
generally repeated annually for individuals by most insurance plans. Prospective
the goal range, then screening every
without or with mild retinopathy. Exams multicenter clinical trials on diagnostic
1–2 years may be considered. If any
every 1–2 years may be cost-effective af- accuracy have been published for each
level of diabetic retinopathy is present,
ter one or more normal eye exams. In a platform (26). However, the benefits
subsequent dilated retinal examinations
population with well-managed type 2 dia- and optimal utilization of this type of
should be repeated at least annually by
betes, there was little risk of development screening have yet to be fully determined.
an ophthalmologist or optometrist. If
of significant retinopathy within a 3-year Results of all screening eye examinations
retinopathy is progressing or sight-
interval after a normal examination (18), should be documented and transmitted
threatening, then examinations by an
and less frequent intervals have been to the referring health care professional.
ophthalmologist will be required more
found in simulated modeling to be poten-
frequently. B
tially effective in screening for diabetic ret- Type 1 Diabetes
12.6 Programs that use retinal photog-
inopathy in individuals without diabetic Because retinopathy is estimated to take
raphy with remote reading or the use
retinopathy (19). However, it is important at least 5 years to develop after the on-
of U.S. Food and Drug Administration–
to adjust screening intervals based on the set of hyperglycemia, people with type 1
approved artificial intelligence algo-
presence of specific risk factors for reti- diabetes should have an initial dilated
rithms to improve access to diabetic
nopathy onset and worsening retinopathy. and comprehensive eye examination
retinopathy screening are appropri-
More frequent examinations by the oph- within 5 years after the diagnosis of di-
ate screening strategies for diabetic
thalmologist will be required if retinopathy abetes (19).
retinopathy. Such programs need to
is progressing or risk factors such as not
provide pathways for timely referral
meeting glycemic goals, advanced retinopa- Type 2 Diabetes
for a comprehensive eye examination
thy, or diabetic macular edema are present. People with type 2 diabetes who may
when indicated. B
Retinal photography with remote read- have had undiagnosed diabetes for years
12.7 Counsel individuals of childbear-
ing by experts has great potential to pro- and have a significant risk of prevalent
ing potential with preexisting type 1 or
vide screening services in areas where diabetic retinopathy at the time of diag-
type 2 diabetes who are planning preg-
qualified eye care professionals are not nosis should have an initial dilated and
nancy or who are pregnant on the risk
readily available (20–22). High-quality comprehensive eye examination at the
of development and/or progression of
fundus photographs can detect most clin- time of diagnosis.
diabetic retinopathy. B
ically significant diabetic retinopathy. In-
12.8 Individuals with preexisting type 1
terpretation of the images should be Pregnancy
or type 2 diabetes should receive an
performed by a trained eye care profes- Individuals who develop gestational diabe-
eye exam before pregnancy as well as
sional or reading center technician or by tes mellitus do not require eye examinations
S254 Retinopathy, Neuropathy, and Foot Care Diabetes Care Volume 48, Supplement 1, January 2025

during pregnancy, since they do not appear Treatment untreated eyes to 6.4% in treated eyes
to be at increased risk of developing diabetic Recommendations with the greatest benefit ratio in those
retinopathy during pregnancy (27). How- 12.9 Promptly refer individuals with with more advanced baseline disease
ever, individuals of childbearing potential any level of diabetic macular edema, (disc neovascularization or vitreous hem-
with preexisting type 1 or type 2 diabetes moderate or worse nonproliferative orrhage). Later, the ETDRS verified the
who are planning pregnancy or who have diabetic retinopathy (a precursor of benefits of panretinal photocoagulation
become pregnant should be counseled on proliferative diabetic retinopathy [PDR]), for high-risk PDR and in older-onset indi-
the baseline prevalence and risk of devel- or any PDR to an ophthalmologist who viduals with severe nonproliferative dia-
opment and/or progression of diabetic is knowledgeable and experienced in betic retinopathy or less-than-high-risk
retinopathy. In a systematic review and the management of diabetic retinop- PDR (31). Panretinal laser photocoagula-
meta-analysis of 18 observational studies athy. A tion is still commonly used to manage
of pregnant individuals with preexisting 12.10 Panretinal laser photocoagula- proliferative diabetic retinopathy. A mac-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

type 1 or type 2 diabetes, the prevalence tion therapy is indicated to reduce the ular focal/grid laser photocoagulation
of any diabetic retinopathy and proliferative risk of vision loss in individuals with technique was shown in the ETDRS to be
diabetic retinopathy (PDR) in early preg- high-risk PDR and, in some cases, se- effective in treating eyes with clinically
nancy was 52.3% and 6.1%, respectively. vere nonproliferative diabetic retinop- significant macular edema from diabetes
The pooled progression rate per 100 (31), but this is now largely considered a
athy. A
pregnancies for new diabetic retinopa- second-line treatment for diabetic macular
12.11 Intravitreous injections of anti–
thy development was 15.0 (95% CI edema.
vascular endothelial growth factor
9.9–20.8), worsened nonproliferative
(anti-VEGF) are a reasonable alter-
diabetic retinopathy was 31.0 (95% CI Anti-VEGF Treatment
native to traditional panretinal laser
23.2–39.2), pooled sight-threatening Data from the DRCR Retina Network (for-
photocoagulation for some individu-
progression rate from nonproliferative merly the Diabetic Retinopathy Clinical
als with PDR and also reduce the risk
diabetic retinopathy to PDR was 6.3 (95% Research Network) and others demon-
of vision loss in these individuals. A
CI 3.3–10.0), and worsened PDR was 37.0 strate that intravitreal injections of anti-
12.12 Intravitreous injections of anti-
(95% CI 21.2–54.0), demonstrating that VEGF agents are effective at regressing
VEGF are indicated as first-line treat-
close follow-up should be maintained proliferative disease and lead to noninfe-
ment for most eyes with diabetic mac-
during pregnancy to prevent vision loss rior or superior visual acuity outcomes
ular edema that involves the foveal
(28). In addition, rapid implementation compared with panretinal laser over 2 years
center and impairs vision acuity. A
of intensive glycemic management in of follow-up (32,33). In addition, it was
12.13 Macular focal/grid photocoagu-
the setting of retinopathy is associated observed that individuals treated with
lation and intravitreal injections of cor-
with early worsening of retinopathy, and ranibizumab tended to have less periph-
ticosteroid are reasonable treatments
these individuals may also benefit from eral visual field loss, fewer vitrectomy
in eyes with persistent diabetic macu-
more frequent follow-up initially (29). surgeries for secondary complications
lar edema despite previous anti-VEGF
A systematic review and meta-analysis from their proliferative disease, and a
therapy or eyes that are not candi-
and a controlled prospective study dem- lower risk of developing diabetic macular
onstrate that pregnancy in individuals dates for this first-line approach. A edema (32). However, a potential draw-
with type 1 diabetes may aggravate reti- 12.14 The presence of retinopathy is back in using anti-VEGF therapy to man-
nopathy and threaten vision, especially not a contraindication to aspirin ther- age proliferative disease is that individuals
when glycemic management is subopti- apy for cardioprotection, as aspirin were required to have a greater number
mal or retinopathy severity is advanced does not increase the risk of retinal of visits and received a greater number of
at the time of conception (28,29). Laser hemorrhage. A treatments than is typically required for
photocoagulation surgery can minimize management by panretinal laser, which
the risk of vision loss during pregnancy Two of the main motivations for screen- may not be optimal for some individuals.
for individuals with high-risk PDR or ing for diabetic retinopathy are to pre- Additionally, unlike panretinal laser, anti-
center-involved diabetic macular edema vent loss of vision and to intervene with VEGF therapy requires participation in
(29). The use of anti–vascular endothe- treatment when vision loss can be pre- scheduled follow-up. Individuals with non-
lial growth factor (anti-VEGF) injections vented or reversed. intentional lapses in treatment are at risk
in pregnant individuals may be justified for worse visual acuity and anatomic out-
only if the potential benefit outweighs Photocoagulation Surgery comes (34). The FDA has approved afliber-
the potential risk to the fetus and only if Two large trials, the Diabetic Retinopathy cept and ranibizumab for the treatment
clearly indicated. Current anti-VEGF medi- Study (DRS) in individuals with PDR and of eyes with diabetic retinopathy. Other
cations have been assigned to pregnancy the Early Treatment Diabetic Retinopa- emerging therapies for retinopathy that
category C by the FDA (animal studies thy Study (ETDRS) in individuals with may use sustained intravitreal delivery
have revealed evidence of embryo-fetal macular edema, provide the strongest of pharmacologic agents are currently
toxicity, but there are no controlled data support for the therapeutic benefits of under investigation. Anti-VEGF treatment
in human pregnancy), and caution should laser photocoagulation surgery. The DRS of eyes with nonproliferative diabetic reti-
be used in pregnant individuals with dia- (30) showed that panretinal photocoag- nopathy has been demonstrated to reduce
betes because of theoretical risks to the ulation surgery reduced the risk of se- subsequent development of retinal neovas-
vasculature of the developing fetus. vere vision loss from PDR from 15.9% in cularization and diabetic macular edema
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S255

but has not been shown to improve visual RA and lower intraocular pressure (44) careful history and assessment of ei-
outcomes over 2 years of therapy and as well as a reduced risk of glaucoma ther temperature or pinprick sensation
therefore has not been widely adopted for (45–47). (small-fiber function) and vibration sen-
this indication (35). sation using a 128-Hz tuning fork (for
While the ETDRS (31) established the Visual Rehabilitation large-fiber function). All people with di-
benefit of focal laser photocoagulation Recommendations abetes should have annual 10-g mono-
surgery in eyes with clinically significant 12.15 People who experience vision filament testing to identify feet at risk
macular edema (defined as retinal edema
loss from diabetes should be counseled for ulceration and amputation. B
located at or threatening the macular
on the availability and scope of vision 12.19 Symptoms and signs of auto-
center), current data from well-designed
rehabilitation care and provided, or re- nomic neuropathy should be assessed
clinical trials demonstrate that intravitreal
ferred for, a comprehensive evaluation in people with diabetes starting at diag-
anti-VEGF agents provide more effective
of their visual impairment by a practi- nosis of type 2 diabetes and 5 years

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

treatment for center-involved diabetic
tioner experienced in vision rehabilita- after the diagnosis of type 1 diabetes,
macular edema than monotherapy with
tion. E and at least annually thereafter, and
laser (36,37). With ranibizumab and afli-
12.16 People with vision loss from dia- with evidence of other microvascular
bercept, most individuals require admin-
betes should receive educational mate- complications, particularly kidney dis-
istration of intravitreal therapy with anti-
rials and resources for eye care support ease and diabetic peripheral neuropa-
VEGF agents every 4–8 weeks during the
in addition to self-management educa- thy. Screening can include asking about
first 12 months of treatment, with fewer
tion (e.g., glycemic management and orthostatic dizziness, syncope, early sa-
injections needed in subsequent years to
hypoglycemia awareness). E tiety, erectile dysfunction, changes in
maintain remission from center-involved
diabetic macular edema. Five anti-VEGF sweating patterns, or dry cracked skin
agents currently are used to treat eyes In the U.S., 12% of adults with diabetes in the extremities. Signs of autonomic
with center-involved diabetic macular have some level of vision impairment neuropathy include orthostatic hypo-
edema, namely, bevacizumab, ranibizumab, (48). They may have difficulty reaching tension, a resting tachycardia, or
aflibercept (2 mg and 8 mg), brolucizumab, their diabetes treatment goals and per- evidence of peripheral dryness or
and faricimab (1), and a comparative effec- forming many other activities of daily liv- cracking of skin. E
tiveness study demonstrated that afliber- ing, which can lead to depression, anxiety,
cept provides vision outcomes superior to social isolation, and difficulties at home,
in the workplace, or at school (49). Diabetic neuropathies are a heteroge-
those of bevacizumab when eyes have
People with diabetes are at increased neous group of disorders with diverse
moderate visual impairment (vision of
risk of chronic vision loss, subsequent clinical manifestations. The early recog-
20/50 or worse) from diabetic macular
functional decline, and resulting disability. nition and appropriate management of
edema (38). For eyes that have good vi-
sion (20/25 or better) despite diabetic Vision impairment has physical, psycho- neuropathy in people with diabetes is
macular edema, close monitoring with logical, behavioral, and social consequen- important. Points to be aware of include
initiation of anti-VEGF therapy if vision ces that affect people with diabetes, their the following:
worsens provides 2-year vision outcomes families, friends, and caregivers. Health
similar to those of immediate initiation of care professionals and stakeholders may 1. Diabetic neuropathy is a diagnosis
anti-VEGF therapy (39). not be aware of the overall impact of vi- of exclusion. Non–diabetic neuropa-
Eyes that have persistent diabetic mac- sion loss on an individual’s health and thies may be present in people with
ular edema despite anti-VEGF treatment well-being. People with diabetic vision diabetes and may be treatable.
may benefit from macular laser photoco- loss should be evaluated to determine 2. Up to 50% of diabetic peripheral neu-
agulation or intravitreal therapy with cor- their potential to benefit from compre- ropathy may be asymptomatic. If not
ticosteroids (40). Both of these therapies hensive vision restoration. Vision rehabil- recognized and if preventive foot care is
are also reasonable first-line approaches itation can help people with vision loss not implemented, people with diabetes
for individuals who are not candidates achieve maximum function, indepen- are at risk for injuries as well as diabetic
for anti-VEGF treatment due to systemic dence, and quality of life. foot ulcers (DFUs) and amputations.
considerations such as pregnancy. 3. Recognition and treatment of auto-
NEUROPATHY nomic neuropathy may improve symp-
Adjunctive Therapy Screening toms, reduce sequelae, and improve
Lowering blood pressure has been shown quality of life.
Recommendations
to decrease retinopathy progression, al- 12.17 All people with diabetes should
though strict goals (systolic blood pressure be assessed for diabetic peripheral Specific treatment to reverse the under-
<120 mmHg) do not impart additional neuropathy starting at diagnosis of lying nerve damage is currently not avail-
benefit (6). In individuals with dyslipide- able. Glycemic management can effectively
type 2 diabetes and 5 years after the
mia, retinopathy progression may be prevent diabetic peripheral neuropathy
diagnosis of type 1 diabetes and at
slowed by the addition of fenofibrate, (DPN) and cardiovascular autonomic neu-
least annually thereafter. B
particularly with early diabetic retinopa- ropathy (CAN) in type 1 diabetes (50,51)
12.18 Assessment for distal symmetric
thy at baseline (41–43). Several studies and may modestly slow their progression
polyneuropathy should include a
have shown an association with GLP-1 in type 2 diabetes (52), but it does not
S256 Retinopathy, Neuropathy, and Foot Care Diabetes Care Volume 48, Supplement 1, January 2025

reverse neuronal loss. Treatments of other neuropathy, inherited neuropathies, and with manifestations including esopha-
modifiable risk factors (including obesity, vasculitis (58). See the American Diabetes geal dysmotility, gastroparesis, constipa-
lipids, and blood pressure) can aid in pre- Association position statement “Diabetic tion, diarrhea, and fecal incontinence.
vention of DPN progression in type 2 dia- Neuropathy” for more details (57). Gastroparesis should be suspected in
betes and may reduce disease progression individuals with erratic glycemic man-
in type 1 diabetes (53–56). Therapeutic Diabetic Autonomic Neuropathy agement or with upper gastrointestinal
strategies (pharmacologic and nonpharma- Individuals who have had type 1 diabetes symptoms without another identified
cologic) for the relief of painful DPN and for $5 years and all individuals with type 2 cause. Exclusion of reversible/iatrogenic
symptoms of autonomic neuropathy can diabetes should be assessed annually for causes such as medications or organic
potentially reduce pain (57) and improve autonomic neuropathy (57). The symptoms causes of gastric outlet obstruction or
quality of life. and signs of autonomic neuropathy should peptic ulcer disease (with esophagogas-
be elicited carefully during the history and troduodenoscopy or a barium study of

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

Diagnosis physical examination. Major clinical mani- the stomach) is needed before consider-
Diabetic Peripheral Neuropathy festations of diabetic autonomic neuropa- ing a diagnosis of or specialized testing for
Individuals with a type 1 diabetes dura- gastroparesis. The diagnostic gold stan-
thy include resting tachycardia, orthostatic
tion $5 years and all individuals with dard for gastroparesis is the measurement
hypotension, gastroparesis, constipation,
type 2 diabetes should be assessed an- of gastric emptying with scintigraphy
diarrhea, fecal incontinence, erectile dys-
nually for DPN using medical history and of digestible solids at 15-min intervals
function, neurogenic bladder, and sudo- for 4 h after food intake. The use of 13C
simple clinical tests (57). Symptoms vary motor dysfunction with either increased or
according to the class of sensory fibers octanoic acid breath test is an approved
decreased sweating. Screening for symp- alternative.
involved. The most common early symp- toms of autonomic neuropathy includes
toms are induced by the involvement of asking about symptoms of orthostatic intol- Genitourinary Disturbances
small fibers and include pain and dyses- erance (dizziness, lightheadedness, or Diabetic autonomic neuropathy may also
thesia (unpleasant sensations of burning weakness with standing), syncope, exer- cause genitourinary disturbances, includ-
and tingling). The involvement of large fi-
cise intolerance, constipation, diarrhea, ing sexual dysfunction and bladder dys-
bers may cause balance issues, numb-
urinary retention, urinary incontinence, function. In men, diabetic autonomic
ness, and loss of protective sensation
or changes in sweat function. Further neuropathy may cause erectile dysfunc-
(LOPS). LOPS indicates the presence of
testing can be considered if symptoms tion and/or retrograde ejaculation (57).
distal sensory polyneuropathy and is a
are present and will depend on the end Female sexual dysfunction occurs more
risk factor for diabetic foot ulceration. frequently in those with diabetes and pre-
organ involved but might include cardio-
The following clinical tests may be used sents as decreased sexual desire, increased
vascular autonomic testing, sweat testing,
to assess small- and large-fiber function pain during intercourse, decreased sexual
and protective sensation: urodynamic studies, gastric emptying, or
endoscopy or colonoscopy. Impaired coun- arousal, and inadequate lubrication (61).
terregulatory responses to hypoglycemia Lower urinary tract symptoms manifest as
1. Small-fiber function: pinprick and tem- urinary incontinence and bladder dysfunc-
perature sensation. in type 1 and type 2 diabetes can lead to
tion (nocturia, frequent urination, urina-
2. Large-fiber function: lower-extremity impaired hypoglycemia awareness but
tion urgency, and weak urinary stream).
reflexes, vibration perception, and are not directly linked to autonomic
Evaluation of bladder function should be
10-g monofilament. neuropathy.
performed for individuals with diabetes
3. Protective sensation: 10-g monofilament. who have recurrent urinary tract infec-
Cardiovascular Autonomic Neuropathy
tions, pyelonephritis, incontinence, or a
These tests not only screen for the pres- CAN is associated with mortality inde-
palpable bladder.
ence of dysfunction but also predict future pendent of other cardiovascular risk fac-
risk of complications. Electrophysiological tors (59,60). In its early stages, CAN may Treatment
testing or referral to a neurologist is rarely be completely asymptomatic and de-
tected only by decreased heart rate vari- Recommendations
needed, except in situations where the
ability with deep breathing. Advanced 12.20 Optimize glucose management
clinical features are atypical (acute or sub-
disease may be associated with resting to prevent or delay the development
acute presentation, non–length dependent,
tachycardia (>100 bpm) and orthostatic of neuropathy in people with type 1
asymmetric, and/or motor involvement) or
diabetes A and to slow the progression
the diagnosis is unclear. hypotension (a fall in systolic or dia-
of neuropathy in people with type 2 di-
In all people with diabetes and DPN, stolic blood pressure by >20 mmHg or
abetes. C Optimize weight, blood pres-
causes of neuropathy other than diabetes >10 mmHg, respectively, upon standing
sure, and serum lipid management to
should be considered, including toxins without an appropriate increase in heart
reduce the risk or slow the progression
(e.g., alcohol), neurotoxic medications rate). CAN treatment is generally fo-
of diabetic neuropathy. B
(e.g., chemotherapy), vitamin B12 defi- cused on alleviating symptoms.
12.21 Assess and treat pain related to
ciency, hypothyroidism, kidney disease,
diabetic peripheral neuropathy B and
malignancies (e.g., multiple myeloma, Gastrointestinal Neuropathies
symptoms of autonomic neuropathy to
bronchogenic carcinoma), infections (e.g., Gastrointestinal neuropathies may involve
improve quality of life. E
HIV), chronic inflammatory demyelinating any portion of the gastrointestinal tract,
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S257

12.22 Gabapentinoids, serotonin- the impacts of exenatide and topiramate interventions (79). A recent guideline by
norepinephrine reuptake inhibitors, on DPN and CAN measurements led to the American Academy of Neurology rec-
tricyclic antidepressants, and sodium no substantial weight loss (70,71). Exer- ommends that the initial treatment of pain
channel blockers are recommended cise often leads to a small reduction in should also focus on the concurrent treat-
as initial pharmacologic treatments weight and may also have positive ef- ment of both sleep and mood disorders
fects on diabetic neuropathy through because of increased frequency of these
for neuropathic pain in diabetes. A
other mechanisms. Two systematic reviews problems in individuals with DPN (80).
Opioids, including tramadol and ta-
have shown that exercise interventions im- Several pharmacologic therapies exist
pentadol, should not be used for
prove diabetic neuropathy outcomes, in- for treatment of pain in diabetes. The
neuropathic pain treatment in diabe-
cluding symptoms, examination findings, American Academy of Neurology (AAN)
tes given the potential for adverse
balance, and functional assessments, but update suggested that gabapentinoids,
events. B
the strength of the evidence is low (72,73). serotonin-norepinephrine reuptake in-

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

hibitors (SNRIs), sodium channel block-
Glycemic Management Lipid Management ers, and tricyclic antidepressants (TCAs)
Near-normal glycemic management, im- Dyslipidemia is a key factor in the devel- all could be considered in the treatment
plemented early in the course of diabetes, opment of neuropathy in people with of pain in DPN (80). These AAN recom-
has been shown to effectively delay or pre- type 2 diabetes and may contribute to mendations offer a supplement to a re-
vent the development of DPN and CAN in neuropathy risk in people with type 1 di- cent American Diabetes Association pain
people with type 1 diabetes (62–65). Al- abetes (74,75). Although the evidence monograph (81). A head-to-head trial
though the evidence for the benefit of for a relationship between lipids and suggested therapeutic equivalency for
near-normal glycemic management is not neuropathy development has become TCAs, SNRIs, and gabapentinoids in the
as strong for type 2 diabetes, some studies increasingly clear in type 2 diabetes, the treatment of pain in DPN (82). The trial
have demonstrated a modest slowing of optimal therapeutic intervention has not also supported the role of combination
progression without reversal of neuronal been identified. Positive effects of physi- therapy over monotherapy for the treat-
loss (52,66). Specific glucose-lowering cal activity, weight loss, and metabolic ment of pain in DPN.
strategies may have different effects. In a surgery have been reported in individu-
post hoc analysis, participants, particularly als with DPN, but use of conventional Gabapentinoids. Gabapentinoids include
men, in the Bypass Angioplasty Revascu- lipid-lowering pharmacotherapy (such as several calcium channel a2-d subunit
larization Investigation in Type 2 Diabetes statins or fenofibrates) does not appear ligands. Several high-quality and medium-
(BARI 2D) trial treated with insulin sensi- to be effective in treating or preventing quality studies support the role of prega-
tizers had a lower incidence of distal sym- DPN development (76). balin in treatment of pain in DPN. One
metric polyneuropathy over 4 years than high-quality study and many small studies
those treated with insulin or sulfonylurea Blood Pressure Management support the role of gabapentin in the
(67). Additionally, recent evidence from There are multiple reasons for blood treatment of pain in DPN. Medium-quality
the Action to Control Cardiovascular Risk pressure management in people with studies suggest that mirogabalin has a
in Diabetes (ACCORD) trial showed benefit diabetes, and neuropathy progression small effect on pain in DPN (80). Ad-
of intensive glucose and blood pressure (especially in type 2 diabetes) has now verse effects may be more severe in
management on the prevention of CAN in been added to this list. Although data older individuals (83) and may be at-
type 2 diabetes (68). from many studies have supported the tenuated by lower starting doses and
role of hypertension in the risk of neu- more gradual titration.
Weight Management ropathy development, a meta-analysis of
Obesity is consistently associated with data from 14 countries in the Interna- SNRIs. SNRIs include duloxetine, venla-
neuropathy in cross-sectional and longi- tional Prevalence and Treatment of Dia- faxine, and desvenlafaxine, all selective
tudinal studies (69). While obesity has betes and Depression (INTERPRET-DD) SNRIs. Two high-quality studies and five
been established as a risk factor for neu- study revealed hypertension as an inde- medium-quality studies support the role
ropathy, including in those with diabetes, pendent risk factor for DPN develop- of duloxetine in the treatment of pain in
treatments of obesity are less well stud- ment with an odds ratio of 1.58 (95% CI DPN. A high-quality study supports the
ied. The Look AHEAD (Action for Health 1.18–2.12) (77). In the ACCORD trial, in- role of venlafaxine in the treatment of
in Diabetes) randomized trial found that tensive blood pressure intervention also pain in DPN. Only one medium-quality study
a lifestyle intervention primarily focused decreased CAN risk by 25% (68). supports a possible role for desvenlafaxine
on dietary weight loss led to improve- for treatment of pain in DPN (80). Adverse
ments in neuropathy symptoms but not Neuropathic Pain events may be more severe in older people
neuropathy examination scores (53). Neuropathic pain can be severe and can but may be attenuated with lower doses
Observational studies of metabolic sur- impact quality of life, affect sleep, limit and slower titration of duloxetine.
gery have also revealed improvements mobility, and contribute to depression
in neuropathy outcomes, but random- and anxiety (78). No compelling evi- Tricyclic Antidepressants. TCAs have been
ized trials are lacking (55,56). Weight loss dence exists in support of glycemic or studied for treatment of pain. Most of
medications have not been well studied lifestyle management as therapies for the relevant data were acquired from tri-
to date with two negative trials (topira- neuropathic pain in diabetes or predia- als of amitriptyline and include two high-
mate and exenatide). Trials investigating betes, which leaves only pharmaceutical quality studies and two medium-quality
S258 Retinopathy, Neuropathy, and Foot Care Diabetes Care Volume 48, Supplement 1, January 2025

studies supporting the effectiveness of is not surprising that these SNRI and opioid approved by the FDA for the treatment of
amitryiptylinein in the treatment of pain- agents are effective in the treatment of gastroparesis (96). However, the level of
ful DPN (80,82). Anticholinergic side ef- pain in DPN too (80). However, the effect evidence regarding the benefits of meto-
fects may be dose limiting and restrict size is similar to that of other effective clopramide for the management of gas-
use in individuals $65 years of age. therapies, such as SNRIs, and these medi- troparesis is weak, and given the risk for
cations have the same risks as other serious adverse effects (extrapyramidal
Sodium Channel Blockers. Sodium chan- opioids listed above. In fact, tramadol signs such as acute dystonic reactions,
nel blockers include lamotrigine, lacosa- has been shown to be associated with drug-induced parkinsonism, akathisia, and
mide, carbamazepine, oxcarbazepine, and all-cause mortality with an effect size simi- tardive dyskinesia), its use in the treat-
valproic acid. Five medium-quality studies lar to that of codeine (87). Similar to other ment of gastroparesis beyond 12 weeks is
support the role of sodium channel block- opioids, risks likely outweigh benefits, and no longer recommended by the FDA. It
ers in treating pain in DPN (80). the AAN guidelines also recommend should be reserved for severe cases that

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

against their use for painful DPN (80). are unresponsive to other therapies (95).
Capsaicin. Capsaicin has received FDA ap- Other treatment options include domperi-
proval for treatment of pain in DPN using Orthostatic Hypotension done (available outside the U.S.) and
an 8% patch, with one high-quality study Treating orthostatic hypotension is chal- erythromycin, which is only effective for
reported. One medium-quality study of lenging. The therapeutic goal is to mini- short-term use due to tachyphylaxis (96).
0.075% capsaicin cream has been re- mize postural symptoms rather than to Gastric electrical stimulation using a surgi-
ported. In individuals with contraindica- restore normotension. Most individuals cally implantable device has received ap-
tions to oral pharmacotherapy or who require both nonpharmacologic measures proval from the FDA, although there are
(e.g., ensuring adequate salt intake, avoid- very limited data on DPN and the results
prefer topical treatments, the use of top-
ing medications that aggravate hypoten- do not support gastric stimulation as an
ical capsaicin can be considered.
sion, or using compressive garments over effective therapy in diabetic gastroparesis
the legs and abdomen) and pharmacologic (97).
Lidocaine 5% Plaster/Patch. Lidocaine
patches have limited data supporting measures. Physical activity and exercise
their use in DPN and are not effective should be encouraged to avoid decondi- Erectile Dysfunction
tioning, which is known to exacerbate In addition to treatment of hypogonad-
in more widespread distribution of pain
orthostatic intolerance, and volume re- ism if present, treatments for erectile dys-
(although they may be of use in individu-
pletion with fluids and salt is critical. Ad- function may include phosphodiesterase
als with nocturnal neuropathic foot pain).
ditionally, supine blood pressure tends type 5 inhibitors, intracorporeal or intra-
Lidocaine patches cannot be used for urethral prostaglandins, vacuum devices,
to be much higher in these individuals,
more than 12 h in a 24-h period (84). or penile prostheses. As with DPN treat-
often requiring treatment of blood pres-
sure at bedtime with shorter-acting drugs ments, these interventions do not change
Opioids. Several randomized controlled the underlying pathology and natural his-
that also affect baroreceptor activity
trials (RCTs) have demonstrated that tory of the disease process but may im-
such as guanfacine or clonidine, shorter-
opioids (dextromethorphan, oxycodone, prove a person’s quality of life.
acting calcium blockers (e.g., isradipine),
morphine sulfate) can reduce pain in indi-
or shorter-acting b-blockers such as aten-
viduals with DPN (84). However, evidence olol or metoprolol tartrate. Alternatives FOOT CARE
for the long-term efficacy of opioids in can include enalapril if an individual Recommendations
neuropathic pain is lacking. In fact, the Cen- is unable to tolerate preferred agents
ters for Disease Control and Prevention 12.23 Perform a comprehensive foot
(88–90). Midodrine and droxidopa are ap- evaluation at least annually to iden-
(CDC) performed a systematic review that proved by the FDA for the treatment of
found no studies of opioids for chronic tify risk factors for ulcers and ampu-
orthostatic hypotension. tations. A
pain have evaluated long-term outcomes,
including pain, function, and quality of life 12.24 The examination should include
Gastroparesis
(85). Moreover, CDC and AAN reviews have inspection of the skin, assessment of
Treatment of diabetic gastroparesis may foot deformities, neurological assess-
documented the long-term harms from be very challenging. A small-particle diet ment (10-g monofilament testing or
opioids, including abuse, addiction, fractures, may provide some symptom relief Ipswich touch test with at least one
heart attacks, motor vehicle accidents, over- (91–93). In addition, foods with small additional assessment: pinprick, tem-
dose, and mortality (85,86). The current evi- particle size may improve key symptoms perature, or vibration), and vascular
dence balancing risks and benefits has led (94). Withdrawing drugs with adverse ef- assessment, including pulses in the
the AAN to recommend against opioids for fects on gastrointestinal motility, includ-
legs and feet. B
the treatment of painful DPN (80). ing opioids, anticholinergics, TCAs, GLP-1
12.25 Individuals with evidence of
RAs, and pramlintide, may also improve
sensory loss or prior ulceration or
Tapentadol and Tramadol. Tapentadol intestinal motility (91,95). However, the
amputation should have their feet
and tramadol exert their analgesic effects risk of removal of GLP-1 RAs should be
inspected at every visit. A
through both m-opioid receptor agonism balanced against their potential benefits.
12.26 Obtain a prior history of ulcera-
(opioid) and norepinephrine and serotonin In cases of severe gastroparesis, pharma-
tion, amputation, Charcot foot, angio-
reuptake inhibition. Given that opioids and cologic interventions are needed. Only
plasty or vascular surgery, cigarette
SNRIs are both effective for painful DPN, it metoclopramide, a prokinetic agent, is
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S259

smoking, retinopathy, and renal dis- substitutes, several acellular matrices, care and surveillance. The physical exami-
ease and assess current symptoms of autologous fibrin and leukocyte platelet nation can stratify people with diabetes
neuropathy (pain, burning, numbness) patches, and topical oxygen therapy. A into different categories and determine the
and vascular disease (leg fatigue, clau- frequency of these visits (99) (Table 12.1).
dication). B
12.27 Initial screening for peripheral Foot ulcerations and amputations are Evaluation for Loss of Protective
arterial disease (PAD) should include common complications associated with Sensation
assessment of lower-extremity pulses, diabetes. These may be the consequences The presence of peripheral sensory neu-
capillary refill time, rubor on depen- of several factors, including peripheral ropathy is the single most common com-
dency, pallor on elevation, and venous neuropathy, PAD, and foot deformities. ponent cause for foot ulceration. In a
filling time. Individuals with a history They represent major causes of morbidity multicenter trial, peripheral neuropathy
of leg fatigue, claudication, and rest and mortality in people with diabetes. was found to be a component cause in

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

pain relieved with dependency or de- Early recognition of at-risk feet, preulcer- 78% of people with diabetes with ulcera-
creased or absent pedal pulses should ative lesions, and prompt treatment of tions and that the triad of peripheral
be referred for ankle-brachial index ulcerations and other lower-extremity sensory neuropathy, minor trauma, and
with toe pressures and for further complications can delay or prevent ad- foot deformity was present in >63% of
vascular assessment as appropriate. B verse outcomes. participants (100). All people with diabe-
12.28 An interprofessional approach Early recognition requires an under- tes should undergo a comprehensive
facilitated by a podiatrist in conjunction standing of those factors that put peo- foot examination at least annually or
with other appropriate team members ple with diabetes at increased risk for more frequently for those in higher-risk
is recommended for individuals with ulcerations and amputations. Factors that categories (98,99).
foot ulcers and high-risk feet (e.g., those are associated with the at-risk foot in- LOPS is vital to risk assessment. One
on dialysis, those with Charcot foot, clude the following: of the most useful tests to determine
those with a history of prior ulcers or LOPS is the 10-g monofilament test.
Studies have shown that clinical exami-
amputation, and those with PAD). B • Poor glycemic management
nation and the 10-g monofilament test
12.29 Refer individuals who smoke and • Peripheral neuropathy/LOPS
are the two most sensitive tests in iden-
have a history of prior lower-extremity • PAD
tifying the foot at risk for ulceration
complications, loss of protective sensa- • Foot deformities (bunions, hammer-
tion, structural abnormalities, or PAD to (101). The monofilament test should be
toes, Charcot joint, etc.)
performed with at least one other neu-
foot care specialists for ongoing preven- • Preulcerative corns or calluses
rologic assessment tool (e.g., pinprick,
tive care and lifelong surveillance. B • Prior ulceration
temperature perception, ankle reflexes,
These individuals should also be pro- • Prior amputation
or vibratory perception with a 128-Hz
vided with information on the impor- • Smoking
tuning fork or similar device). Absent
tance of smoke cessation and referred • Retinopathy
monofilament sensation and one other
for counseling on smoke cessation. A • Nephropathy (particularly individuals
12.30 Provide general preventive abnormal test confirms the presence of
on dialysis or posttransplant)
foot self-care education to all people LOPS. Further neurological testing, such
with diabetes, including those with as nerve conduction, electromyography,
Identifying the at-risk foot begins with
loss of protective sensation, on ap- nerve biopsy, or intraepidermal nerve fi-
a detailed history documenting diabetes
propriate ways to examine their feet ber density biopsies, are rarely indicated
management, smoking history, exercise
(palpation or visual inspection with for the diagnosis of peripheral sensory
tolerance, history of claudication or rest
an unbreakable mirror) for daily sur- neuropathy (57).
pain, and prior ulcerations or amputa-
veillance of early foot problems. B tions. A thorough examination of the feet
12.31 The use of specialized thera- Evaluation for Peripheral Arterial
should be performed annually in all peo- Disease
peutic footwear is recommended for ple with diabetes and more frequently in Initial screening for PAD should include a
people with diabetes at high risk for at-risk individuals (98). The examination history of leg fatigue, claudication, and
ulceration, including those with loss should include assessment of skin integ- rest pain relieved with dependency. Phys-
of protective sensation, foot deformi- rity, assessment for LOPS using the 10-g ical examination for PAD should include
ties, ulcers, callous formation, poor monofilament along with at least one assessment of lower-extremity pulses,
peripheral circulation, or history of other neurological assessment tool, pulse capillary refill time, rubor on dependency,
amputation. B examination of the dorsalis pedis and pallor on elevation, and venous filling
12.32 For chronic diabetic foot ulcers posterior tibial arteries, and assessment time (98,102). Any individual exhibiting
that have failed to heal with optimal for foot deformities such as bunions, signs and symptoms of PAD should be re-
standard care alone, adjunctive treat-
hammertoes, and prominent metatarsals, ferred for noninvasive arterial studies in
ment with randomized controlled trial–
which increase plantar foot pressures and the form of Doppler ultrasound with
proven advanced agents should be con-
increase risk for ulcerations. At-risk in- pulse volume recordings. While ankle-
sidered. Considerations might include
dividuals should be assessed at each brachial indices will be calculated, they
negative-pressure wound therapy, pla-
visit and should be referred to foot should be interpreted carefully, as they
cental membranes, bioengineered skin
care specialists for ongoing preventive are known to be inaccurate in people
S260 Retinopathy, Neuropathy, and Foot Care Diabetes Care Volume 48, Supplement 1, January 2025

Table 12.1—International Working Group on 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

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

Adapted with permission from Schaper et al. (99). LOPS, loss of protective sensation; PAD, peripheral artery disease. *Examination frequency
suggestions are based on expert opinion and person-centered requirements.

with diabetes due to noncompressible Individuals considered at risk should peak plantar pressures more significantly
vessels. Toe systolic blood pressure tends understand the implications of foot de- than insoles alone. A systematic review,
to be more accurate. Toe systolic blood formities, LOPS, and PAD; the proper however, showed there was no signifi-
pressure <30 mmHg is suggestive of PAD care of the foot, including nail and skin cant reduction in ulcer incidence after
and an inability to heal foot ulcerations care; and the importance of daily foot in- 18 months compared with standard in-
(103). Individuals with abnormal pulse spections. Individuals with LOPS should soles and extra-depth shoes. Further, it
volume recording tracings and toe pres- be educated on appropriate ways to ex- was also noted that evidence to prevent
sures <30 mmHg with foot ulcers should amine their feet (palpation or visual in- first ulcerations was nonexistent (111).
be referred for immediate vascular evalu- spection with an unbreakable mirror) for
ation. Due to the high prevalence of PAD daily surveillance of early foot problems. Treatment
in people with diabetes, the Society for People with diabetes should also be edu- Treatment recommendations for people
Vascular Surgery and the American Podi- cated on the importance of referrals with diabetes will be determined by their
atric Medical Association guidelines rec- to foot care specialists. A recent study risk category. No-risk or low-risk individu-
ommend that all people with diabetes showed that people with diabetes and foot als often can be managed with education
>50 years of age should undergo screen- disease lacked awareness of their risk sta- and self-care. People in the moderate- to
ing via noninvasive arterial studies (102, tus and why they were being referred to high-risk category should be referred to
104). If normal, these should be repeated an interprofessional team of foot care spe- foot care specialists for further evaluation
every 5 years (102). cialists. Further, they exhibited a variable and regular surveillance as outlined in
degree of interest in learning further about Table 12.1. This category includes individ-
Education for People With Diabetes foot complications (110). uals with LOPS, PAD, and/or structural
All people with diabetes (and their care- Individuals’ understanding of these is- foot deformities, such as Charcot foot,
givers), particularly those with the afore- sues and their physical ability to conduct bunions, or hammertoes. Individuals with
mentioned high-risk conditions, should proper foot surveillance and care should any open ulceration or unexplained swell-
receive general foot care education, in- be assessed. Those with visual difficulties, ing, erythema, or increased skin tempera-
cluding appropriate management strate- physical constraints preventing movement, ture should be referred urgently to a foot
gies (105–107). This education should be or cognitive problems that impair their care specialist or interprofessional team.
provided to all newly diagnosed people ability to assess the condition of the foot Initial treatment recommendations
with diabetes as part of an annual com- and to institute appropriate responses will should include daily foot inspection, use
prehensive examination and to individu- need other people, such as family mem- of moisturizers for dry, scaly skin, and
als with high-risk conditions at every bers, to assist with their care. avoidance of self-care of ingrown nails
visit. Recent studies have shown that The selection of appropriate footwear and calluses. Well-fitted athletic or walk-
while education improves knowledge of and footwear behaviors at home should ing shoes with customized pressure-
diabetic foot problems and self-care of also be discussed (e.g., no walking bare- relieving orthoses should be part of initial
the foot, it does not improve behaviors foot, avoiding open-toed shoes). Thera- recommendations for people with in-
associated with active participation in their peutic footwear with custom-made creased plantar pressures (as demonstrated
overall diabetes care and the achievement orthotic devices have been shown to re- by plantar calluses). Individuals with defor-
of personal health goals (108). Evidence duce peak plantar pressures (107). Most mities such as bunions or hammertoes
also suggests that while education for studies use reduction in peak plantar may require specialized footwear such as
people with diabetes and their families is pressures as an outcome as opposed to extra-depth shoes. Those with even more
important, the knowledge is quickly for- ulcer prevention. Certain design features significant deformities, as in Charcot joint
gotten and needs to be reinforced regu- of the orthoses, such as rocker soles and disease, may require custom-made foot-
larly (109). metatarsal accommodations, can reduce wear. For recalcitrant deformities or for
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S261

recurrent ulcerations not amenable to is necessary to determine if there are as- preparation for skin grafts and flaps and
conservative footwear therapy alone, ap- sociated deformities predisposing to high assists in the closure of deep, large
propriate surgical reconstruction by an ex- plantar pressures that need to be ad- wounds (125,126). A variety of types exist
perienced diabetic foot surgeon should be dressed with surgical offloading proce- in the marketplace and range from elec-
considered (112,113). dures to expedite healing (112,122,123). trically powered to mechanically powered
Special consideration should be given Additionally, underlying osteomyelitis in different sizes depending upon the spe-
to individuals with neuropathy who pre- must be ruled out as a cause for the non- cific wound requirements.
sent with a warm, swollen, red foot with healing ulcer and treated as necessary. Electrical stimulation, pulsed radiofre-
or without a history of trauma and with- Once these complicating factors have quency energy, and extracorporeal shock-
out an open ulceration. These individuals been addressed, adjunctive advanced wave therapy are biophysical modalities
require a thorough workup for possible wound therapy can play an important role. that are believed to upregulate growth
Charcot neuroarthropathy (114,115). Foot When to use advanced wound therapy has factors or cytokines to stimulate wound

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

and ankle X-rays should be performed in been the subject of much discussion, as healing, while low-frequency noncontact
all individuals presenting with the above the therapy is often quite expensive. It has ultrasound is used to debride wounds.
clinical findings. Early diagnosis and treat- been determined that if a wound fails to However, most of the studies advocating
ment of this condition is of paramount im- show a reduction of 50% or more after 4 the use of these modalities have been
portance in preventing deformities and weeks of appropriate wound management retrospective observational studies or
instability that can lead to ulceration and (i.e., the five basic principles above), con- poor-quality RCTs.
amputation. These individuals require to- sideration should be given to the use of ad- Hyperbaric oxygen therapy is the deliv-
tal non–weight-bearing and urgent refer- vanced wound therapy (124). Treatment of ery of oxygen through a chamber, either in-
ral to a foot care specialist for further these chronic wounds is best managed in dividual or multiperson, with the intention
management. Surgical reconstruction of an interprofessional setting. of increasing tissue oxygenation to increase
these complex limb-threatening deformi- Evidence to support advanced wound tissue perfusion and neovascularization,
therapy is challenging to produce and combat resistant bacteria, and stimulate
ties has assumed an important role in re-
to assess. Randomization of trial partici- wound healing. While there had been great
cent years, with many surgeries yielding
pants is difficult, as there are many vari- interest in this modality being able to expe-
high levels of success and limb salvage
ables that can affect wound healing. In dite healing of chronic diabetic foot ulcers
(113,116,117). Nonetheless, such proce-
addition, many RCTs exclude certain co- (DFUs), there is one RCT with positive re-
dures need to be approached by experi-
horts of people, e.g., individuals with sults that reported increased healing rates
enced surgeons with an appreciation not
chronic renal disease or those on dialy- at 9 and 12 months compared with control
only for the complexities of the deformity
sis. Finally, blinding of participants and participants (127). More recent studies
but also for the complexities of the indi-
clinicians is not always possible. Meta- with significant design deficiencies and par-
viduals themselves.
analyses and systematic reviews of ob- ticipant dropouts have failed to provide cor-
There have been a number of develop-
servational studies are used to deter- roborating evidence that hyperbaric oxygen
ments in the treatment of ulcerations mine the clinical effectiveness of these therapy should be widely used for managing
over the years (118). These include nega- modalities. Such studies can augment nonhealing DFUs (128,129). While there
tive-pressure therapy, growth factors, bio- formal RCTs by including a greater vari- may be some benefit in prevention of am-
engineered tissue, acellular matrix tissue, ety of participants in various clinical set- putation in selected chronic neuroischemic
stem cell therapy, hyperbaric oxygen ther- tings who are typically excluded from ulcers, recent studies have shown no bene-
apy, and, most recently, topical oxygen the more rigidly structured clinical trials. fit in healing DFUs in the absence of ische-
therapy (119–121). While there is literature Advanced wound therapy can be clas- mia and/or infection (120,130).
to support many modalities currently used sified into nine broad categories (118) Topical oxygen therapy has been stud-
to treat diabetic foot wounds, robust RCTs (Table 12.2). Topical growth factors, acel- ied rather vigorously in recent years, with
are often lacking. However, it is agreed lular matrix tissues, and bioengineered several high-quality RCTs and at least five
that the initial treatment and evaluation of cellular therapies are commonly used in systematic reviews and meta-analyses all
ulcerations include the following five basic offices and wound care centers to expe- supporting its efficacy in healing chronic
principles of ulcer treatment: dite healing of chronic, more superficial DFUs at 12 weeks (119,121,131–135).
ulcerations. Numerous clinical reports Three types of topical oxygen devices are
• Offloading of plantar ulcerations and retrospective studies have demon- available, including continuous-delivery,
• Debridement of necrotic, nonviable strated the clinical effectiveness of each low-constant-pressure, and cyclical-pressure
tissue of these modalities. Over the years, there modalities. Importantly, topical oxygen
• Revascularization of ischemic wounds has been increased evidence to support therapy devices provide for home-based
when necessary the use of these modalities. Nonetheless, therapy and replace the need for daily vis-
• Management of infection: soft tissue use of those products or agents with ro- its to specialized centers. Very high partic-
or bone bust RCTs or systematic reviews should ipation with very few reported adverse
• Use of physiologic, topical dressings generally be preferred over those without events combined with improved healing
level 1 evidence (Table 12.2). rates makes this therapy another attrac-
However, despite following the above Negative-pressure wound therapy was tive option for advanced wound care.
principles, some ulcerations will become first introduced in the early to mid-1990s. If DFUs fail to heal despite appropriate
chronic and fail to heal. Careful evaluation It has become especially useful in wound standard or surgical wound care, adjunctive
S262 Retinopathy, Neuropathy, and Foot Care Diabetes Care Volume 48, Supplement 1, January 2025

5. Yau JW, Rogers SL, Kawasaki R, et al.; Meta-

Table 12.2—Categories of advanced wound therapies Analysis for Eye Disease (META-EYE) Study
Negative-pressure wound therapy Group. Global prevalence and major risk factors
of diabetic retinopathy. Diabetes Care 2012;35:
Standard electrically powered
556–564
Mechanically powered
6. Chew EY, Ambrosius WT, Davis MD, et al.;
Oxygen therapies ACCORD Eye Study Group. Effects of medical
Hyperbaric oxygen therapy therapies on retinopathy progression in type 2
Topical oxygen therapy diabetes. N Engl J Med 2010;363:233–244
Oxygen-releasing sprays, dressings 7. Sacks FM, Hermans MP, Fioretto P, et al.
Association between plasma triglycerides and
Biophysical high-density lipoprotein cholesterol and microvascular
Electrical stimulation, diathermy kidney disease and retinopathy in type 2 diabetes
Pulsed electromagnetic fields, pulsed radiofrequency energy mellitus: a global case-control study in 13 countries.
Low-frequency noncontact ultrasound Circulation 2014;129:999–1008

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

Extracorporeal shock wave therapy 8. Yin L, Zhang D, Ren Q, Su X, Sun Z. Prevalence
Growth factors and risk factors of diabetic retinopathy in diabetic
patients: a community based cross-sectional
Becaplermin: platelet-derived growth factor
study. Medicine (Baltimore) 2020;99:e19236
Fibroblast growth factor 9. UK Prospective Diabetes Study (UKPDS)
Epidermal growth factor Group. Intensive blood-glucose control with
Autologous blood products sulphonylureas or insulin compared with con-
Platelet-rich plasma ventional treatment and risk of complications in
Leukocyte, platelet, fibrin multilayered patches patients with type 2 diabetes (UKPDS 33). Lancet
Whole blood clot 1998;352:837–853
10. Gubitosi-Klug RA, Sun W, Cleary PA, et al.;
Acellular matrix tissues Writing Team for the DCCT/EDIC Research Group.
Xenograft dermis Effects of prior intensive insulin therapy and risk
Bovine dermis factors on patient-reported visual function outcomes
Xenograft acellular matrices in the Diabetes Control and Complications
Small intestine submucosa Trial/Epidemiology of Diabetes Interventions
Porcine urinary bladder matrix and Complications (DCCT/EDIC) cohort. JAMA
Ovine forestomach Ophthalmol 2016;134:137–145
Equine pericardium 11. Aiello LP, Sun W, Das A, et al.; DCCT/EDIC
Fish skin graft Research Group. Intensive diabetes therapy and
Bovine collagen ocular surgery in type 1 diabetes. N Engl J Med
Bilayered dermal regeneration matrix 2015;372:1722–1733
Human dermis products 12. Yoshida Y, Joshi P, Barri S, et al. Progression
Human pericardium of retinopathy with glucagon-like peptide-1
receptor agonists with cardiovascular benefits in
Placental tissues
type 2 diabetes—a systematic review and meta-
Amniotic tissues/amniotic fluid
analysis. J Diabetes Complications 2022;36:108255
Umbilical cord
13. Ntentakis DP, Correa VSMC, Ntentaki AM,
Bioengineered allogeneic cellular therapies et al. Effects of newer-generation anti-diabetics
Bilayered skin equivalent (human keratinocytes and fibroblasts) on diabetic retinopathy: a critical review. Graefes
Dermal replacement therapy (human fibroblasts) Arch Clin Exp Ophthalmol 2024;262:717–752
14. Bethel MA, Diaz R, Castellana N, Bhattacharya
Stem cell therapies I, Gerstein HC, Lakshmanan MC. HbA1c change
Autogenous: bone marrow–derived stem cells and diabetic retinopathy during GLP-1 receptor
Allogeneic: amniotic matrix with mesenchymal stem cells agonist cardiovascular outcome trials: a meta-
Miscellaneous active dressings analysis and meta-regression. Diabetes Care 2021;
44:290–296
Hyaluronic acid, honey dressings, etc.
15. Dabelea D, Stafford JM, Mayer-Davis EJ,
Sucrose octasulfate dressing
et al.; SEARCH for Diabetes in Youth Research
Adapted with permission from Frykberg and Banks (118). Group. Association of type 1 diabetes vs type 2
diabetes diagnosed during childhood and
adolescence with complications during teenage
advanced therapies should be instituted 2. Nathan DM, Genuth S, Lachin J, et al.; Diabetes years and young adulthood. JAMA 2017;317:
and are best managed in an interprofes- Control and Complications Trial Research Group. 825–835
The effect of intensive treatment of diabetes on 16. TODAY Study Group. Development and
sional manner. Once healed, all individuals the development and progression of long-term progression of diabetic retinopathy in adolescents
should be enrolled in a formal comprehen- complications in insulin-dependent diabetes mellitus. and young adults with type 2 diabetes: results
sive prevention program focused on reduc- N Engl J Med 1993;329:977–986 from the TODAY study. Diabetes Care 2021;45:
ing the incidence of recurrent ulcerations 3. Stratton IM, Kohner EM, Aldington SJ, et al. 1049–1055
UKPDS 50: risk factors for incidence and 17. Jensen ET, Rigdon J, Rezaei KA, et al.
and subsequent amputations (98,136,137). progression of retinopathy in type II diabetes Prevalence, progression, and modifiable risk
over 6 years from diagnosis. Diabetologia 2001; factors for diabetic retinopathy in youth and
References 44:156–163 young adults with youth-onset type 1 and type 2
1. Solomon SD, Chew E, Duh EJ, et al. Diabetic 4. Estacio RO, McFarling E, Biggerstaff S, Jeffers diabetes: the SEARCH for Diabetes in Youth
retinopathy: a position statement by the American BW, Johnson D, Schrier RW. Overt albuminuria Study. Diabetes Care 2023;46:1252–1260
Diabetes Association. Diabetes Care 2017;40: predicts diabetic retinopathy in Hispanics with 18. Agardh E, Tababat-Khani P. Adopting 3-year
412–418 NIDDM. Am J Kidney Dis 1998;31:947–953 screening intervals for sight-threatening retinal
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S263

vascular lesions in type 2 diabetic subjects without patients with proliferative diabetic retinopathy at agonist use is associated with reduced risk for
retinopathy. Diabetes Care 2011;34:1318–1319 52 weeks (CLARITY): a multicentre, single-blinded, glaucoma. Br J Ophthalmol 2023;107:215–220
19. Nathan DM, Bebu I, Hainsworth D, et al.; randomised, controlled, phase 2b, non-inferiority 47. Niazi S, Gnesin F, Thein A-S, et al. Association
DCCT/EDIC Research Group. Frequency of trial. Lancet 2017;389:2193–2203 between glucagon-like peptide-1 receptor agonists
evidence-based screening for retinopathy in type 1 34. Obeid A, Su D, Patel SN, et al. Outcomes of and the risk of glaucoma in individuals with type 2
diabetes. N Engl J Med 2017;376:1507–1516 eyes lost to follow-up with proliferative diabetic diabetes. Ophthalmology 2024;131:1056–1063
20. Silva PS, Horton MB, Clary D, et al. retinopathy that received panretinal photo- 48. Centers for Disease Control and Prevention.
Identification of diabetic retinopathy and coagulation versus intravitreal anti-vascular National Diabetes Statistics Report: Coexisting
ungradable image rate with ultrawide field endothelial growth factor. Ophthalmology 2019; Conditions and Complications, 2024. Accessed 1
imaging in a national teleophthalmology program. 126:407–413 June 2024. Available from https://www.cdc.gov/
Ophthalmology 2016;123:1360–1367 35. Maturi RK, Glassman AR, Josic K, et al.; DRCR diabetes/php/data-research/index.html#cdc_report_
21. Bragge P, Gruen RL, Chau M, Forbes A, Retina Network. Effect of intravitreous anti- pub_study_section_8-coexisting-conditions-and-
Taylor HR. Screening for presence or absence vascular endothelial growth factor vs sham complications
of diabetic retinopathy: a meta-analysis. Arch treatment for prevention of vision-threatening 49. Rees G, Xie J, Fenwick EK, et al. Association
Ophthalmol 2011;129:435–444 complications of diabetic retinopathy: the Protocol between diabetes-related eye complications and

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

22. Walton OB, Garoon RB, Weng CY, et al. W Randomized Clinical Trial. JAMA Ophthalmol symptoms of anxiety and depression. JAMA
Evaluation of automated teleretinal screening 2021;139:701–712 Ophthalmol 2016;134:1007–1014
program for diabetic retinopathy. JAMA Ophthalmol 36. Elman MJ, Bressler NM, Qin H, et al.; 50. Ang L, Jaiswal M, Martin C, Pop-Busui R.
2016;134:204–209 Diabetic Retinopathy Clinical Research Network. Glucose control and diabetic neuropathy: lessons
23. Daskivich LP, Vasquez C, Martinez C, Jr., Expanded 2-year follow-up of ranibizumab plus from recent large clinical trials. Curr Diab Rep
Tseng C-H, Mangione CM. Implementation and prompt or deferred laser or triamcinolone plus 2014;14:528
evaluation of a large-scale teleretinal diabetic prompt laser for diabetic macular edema. Ophth- 51. Martin CL, Albers JW, Pop-Busui R, DCCT/
retinopathy screening program in the Los Angeles almology 2011;118:609–614 EDIC Research Group. Neuropathy and related
County Department of Health Services. JAMA 37. Mitchell P, Bandello F, Schmidt-Erfurth U, findings in the diabetes control and complications
Intern Med 2017;177:642–649 et al.; RESTORE Study Group. The RESTORE study: trial/epidemiology of diabetes interventions and
24. Sim DA, Mitry D, Alexander P, et al. The ranibizumab monotherapy or combined with complications study. Diabetes Care 2014;37:
evolution of teleophthalmology programs in the laser versus laser monotherapy for diabetic 31–38
United Kingdom: beyond diabetic retinopathy macular edema. Ophthalmology 2011;118:615– 52. Ismail-Beigi F, Craven T, Banerji MA, et al.;
screening. J Diabetes Sci Technol 2016;10:308–317 625 ACCORD Trial Group. Effect of intensive
25. Abr
amoff MD, Lavin PT, Birch M, Shah N, 38. Wells JA, Glassman AR, Ayala AR, et al.; treatment of hyperglycaemia on microvascular
Folk JC. Pivotal trial of an autonomous AI-based Diabetic Retinopathy Clinical Research Network. outcomes in type 2 diabetes: an analysis of the
diagnostic system for detection of diabetic Aflibercept, bevacizumab, or ranibizumab for ACCORD randomised trial. Lancet 2010;376:
retinopathy in primary care offices. NPJ Digit Med diabetic macular edema. N Engl J Med 2015; 419–430
2018;1:39 372:1193–1203 53. Look AHEAD Research Group. Effects of a
26. Nakayama LF, Zago Ribeiro L, Novaes F, et al. 39. Baker CW, Glassman AR, Beaulieu WT, et al.; long-term lifestyle modification programme on
Artificial intelligence for telemedicine diabetic DRCR Retina Network. Effect of initial management peripheral neuropathy in overweight or obese
retinopathy screening: a review. Ann Med 2023; with aflibercept vs laser photocoagulation vs adults with type 2 diabetes: the Look AHEAD
55:2258149 observation on vision loss among patients with study. Diabetologia 2017;60:980–988
27. Gunderson EP, Lewis CE, Tsai A-L, et al. A diabetic macular edema involving the center of 54. Callaghan BC, Reynolds EL, Banerjee M,
20-year prospective study of childbearing and the macula and good visual acuity: a randomized et al. Dietary weight loss in people with severe
incidence of diabetes in young women, controlling clinical trial. JAMA 2019;321:1880–1894 obesity stabilizes neuropathy and improves
for glycemia before conception: the Coronary 40. Rittiphairoj T, Mir TA, Li T, Virgili G. symptomatology. Obesity (Silver Spring) 2021;29:
Artery Risk Development in Young Adults (CARDIA) Intravitreal steroids for macular edema in diabetes. 2108–2118
study. Diabetes 2007;56:2990–2996 Cochrane Database Syst Rev 2020;11:Cd005656 55. Aghili R, Malek M, Tanha K, Mottaghi A.
28. Widyaputri F, Rogers SL, Kandasamy R, Shub 41. Chew EY, Davis MD, Danis RP, et al.; Action The effect of bariatric surgery on peripheral
A, Symons RCA, Lim LL. Global estimates of to Control Cardiovascular Risk in Diabetes Eye polyneuropathy: a systematic review and meta-
diabetic retinopathy prevalence and progression Study Research Group. The effects of medical analysis. Obes Surg 2019;29:3010–3020
in pregnant women with preexisting diabetes: a management on the progression of diabetic 56. Reynolds EL, Watanabe M, Banerjee M, et al.
systematic review and meta-analysis. JAMA retinopathy in persons with type 2 diabetes: the The effect of surgical weight loss on diabetes
Ophthalmol 2022;140:486–494 Action to Control Cardiovascular Risk in Diabetes complications in individuals with class II/III
29. Diabetes Control and Complications Trial (ACCORD) Eye Study. Ophthalmology 2014;121: obesity. Diabetologia 2023;66:1192–1207
Research Group. Effect of pregnancy on 2443–2451 57. Pop-Busui R, Boulton AJM, Feldman EL, et al.
microvascular complications in the diabetes control 42. Kataoka SY, Lois N, Kawano S, Kataoka Y, Diabetic neuropathy: a position statement by the
and complications trial. Diabetes Care 2000;23: Inoue K, Watanabe N. Fenofibrate for diabetic American Diabetes Association. Diabetes Care
1084–1091 retinopathy. Cochrane Database Syst Rev 2023; 2017;40:136–154
30. Diabetic Retinopathy Study Research Group. 6:Cd013318 58. Freeman R. Not all neuropathy in diabetes
Preliminary report on effects of photocoagulation 43. Preiss D, Logue J, Sammons E, et al. Effect of is of diabetic etiology: differential diagnosis of
therapy. Am J Ophthalmol 1976;81:383–396 fenofibrate on progression of diabetic retinopathy. diabetic neuropathy. Curr Diab Rep 2009;9:
31. Early Treatment Diabetic Retinopathy Study NEJM Evid 2024;3:EVIDoa2400179 423–431
Research Group. Photocoagulation for diabetic 44. Hallaj S, Halfpenny W, Chuter BG, Weinreb 59. Pop-Busui R, Cleary PA, Braffett BH, et al.;
macular edema. Arch Ophthalmol 1985;103:1796– RN, Baxter SL, Cui QN. Association between DCCT/EDIC Research Group. Association between
1806 glucagon-like peptide 1 (GLP-1) receptor agonists cardiovascular autonomic neuropathy and left
32. Gross JG, Glassman AR, Jampol LM, et al.; exposure and intraocular pressure change: GLP-1 ventricular dysfunction: DCCT/EDIC study (Diabetes
Writing Committee for the Diabetic Retinopathy receptor agonists and intraocular pressure change. Control and Complications Trial/Epidemiology of
Clinical Research Network. Panretinal photo- Am J Ophthalmol 2025;269:255–265 Diabetes Interventions and Complications). J Am
coagulation vs intravitreous ranibizumab for 45. Shao S-C, Su Y-C, Lai EC-C, et al. Association Coll Cardiol 2013;61:447–454
proliferative diabetic retinopathy: a randomized between sodium glucose co-transporter 2 60. Pop-Busui R, Evans GW, Gerstein HC, et al.;
clinical trial. JAMA 2015;314:2137–2146 inhibitors and incident glaucoma in patients with Action to Control Cardiovascular Risk in Diabetes
33. Sivaprasad S, Prevost AT, Vasconcelos JC, type 2 diabetes: a multi-institutional cohort study Study Group. Effects of cardiac autonomic
et al.; CLARITY Study Group. Clinical efficacy of in Taiwan. Diabetes Metab 2022;48:101318 dysfunction on mortality risk in the Action to
intravitreal aflibercept versus panretinal photo- 46. Sterling J, Hua P, Dunaief JL, Cui QN, Control Cardiovascular Risk in Diabetes (ACCORD)
coagulation for best corrected visual acuity in VanderBeek BL. Glucagon-like peptide 1 receptor trial. Diabetes Care 2010;33:1578–1584
S264 Retinopathy, Neuropathy, and Foot Care Diabetes Care Volume 48, Supplement 1, January 2025

61. Pontiroli AE, Cortelazzi D, Morabito A. 74. Callaghan BC, Xia R, Banerjee M, et al.; 88. Briasoulis A, Silver A, Yano Y, Bakris GL.
Female sexual dysfunction and diabetes: a Health ABC Study. Metabolic syndrome components Orthostatic hypotension associated with
systematic review and meta-analysis. J Sex Med are associated with symptomatic polyneuropathy baroreceptor dysfunction: treatment approaches.
2013;10:1044–1051 independent of glycemic status. Diabetes Care J Clin Hypertens (Greenwich) 2014;16:141–148
62. Diabetes Control and Complications Trial 2016;39:801–807 89. Figueroa JJ, Basford JR, Low PA. Preventing
(DCCT) Research Group. Effect of intensive 75. Andersen ST, Witte DR, Dalsgaard E-M, et al. and treating orthostatic hypotension: as easy as
diabetes treatment on nerve conduction in the Risk factors for incident diabetic polyneuropathy A, B, C. Cleve Clin J Med 2010;77:298–306
Diabetes Control and Complications Trial. Ann in a cohort with screen-detected type 2 diabetes 90. Jordan J, Fanciulli A, Tank J, et al.
Neurol 1995;38:869–880 followed for 13 years: ADDITION-Denmark. Management of supine hypertension in patients
63. Diabetes Control and Complications Trial Diabetes Care 2018;41:1068–1075 with neurogenic orthostatic hypotension: scientific
(DCCT) Research Group. The effect of intensive 76. Afshinnia F, Reynolds EL, Rajendiran TM, statement of the American Autonomic Society,
diabetes therapy on measures of autonomic et al. Serum lipidomic determinants of human European Federation of Autonomic Societies, and
nervous system function in the Diabetes Control diabetic neuropathy in type 2 diabetes. Ann Clin the European Society of Hypertension. J Hypertens
and Complications Trial (DCCT). Diabetologia Transl Neurol 2022;9:1392–1404 2019;37:1541–1546
1998;41:416–423 77. Lu Y, Xing P, Cai X, et al. Prevalence and risk 91. Camilleri M, Kuo B, Nguyen L, et al. ACG

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

64. Albers JW, Herman WH, Pop-Busui R, et al.; factors for diabetic peripheral neuropathy in type 2 clinical guideline: gastroparesis. Am J Gastroenterol
Diabetes Control and Complications Trial/ diabetic patients from 14 countries: estimates of 2022;117:1197–1220
Epidemiology of Diabetes Interventions and the INTERPRET-DD study. Front Public Health 2020; 92. Parrish CR, Pastors JG. Nutritional management
Complications Research Group. Effect of prior 8:534372 of gastroparesis in people with diabetes. Diabetes
intensive insulin treatment during the Diabetes 78. Gylfadottir SS, Christensen DH, Nicolaisen Spectrum 2007;20:231–234
Control and Complications Trial (DCCT) on SK, et al. Diabetic polyneuropathy and pain, 93. Parkman HP, Yates KP, Hasler WL, et al.;
peripheral neuropathy in type 1 diabetes during prevalence, and patient characteristics: a cross- NIDDK Gastroparesis Clinical Research Consortium.
the Epidemiology of Diabetes Interventions and sectional questionnaire study of 5,514 patients Dietary intake and nutritional deficiencies in
Complications (EDIC) study. Diabetes Care 2010; with recently diagnosed type 2 diabetes. Pain 2020; patients with diabetic or idiopathic gastroparesis.
33:1090–1096 161:574–583 Gastroenterology 2011;141:486–498
65. Pop-Busui R, Low PA, Waberski BH, et al.; 79. Waldfogel JM, Nesbit SA, Dy SM, et al. 94. Olausson EA, St€ orsrud S, Grundin H, Isaksson
DCCT/EDIC Research Group. Effects of prior Pharmacotherapy for diabetic peripheral M, Attvall S, Simr en M. A small particle size diet
intensive insulin therapy on cardiac autonomic neuropathy pain and quality of life: a systematic reduces upper gastrointestinal symptoms in
nervous system function in type 1 diabetes review. Neurology 2017;88:1958–1967 patients with diabetic gastroparesis: a randomized
mellitus: the Diabetes Control and Complications 80. Price R, Smith D, Franklin G, et al. Oral and controlled trial. Am J Gastroenterol 2014;109:
Trial/Epidemiology of Diabetes Interventions and topical treatment of painful diabetic poly- 375–385
Complications study (DCCT/EDIC). Circulation 2009; 95. Umpierrez GE. Therapy for Diabetes Mellitus
neuropathy: practice guideline update summary:
119:2886–2893 and Related Disorders. Alexandria, VA, American
report of the AAN Guideline Subcommittee.
66. Callaghan BC, Little AA, Feldman EL, Hughes Diabetes Association, 2014
Neurology 2022;98:31–43
RAC. Enhanced glucose control for preventing and 96. Asha MZ, Khalil SFH. Pharmacological
81. Pop-Busui R, Ang L, Boulton AJM, et al.
treating diabetic neuropathy. Cochrane Database approaches to diabetic gastroparesis: a systematic
Diagnosis and Treatment of Painful Diabetic
Syst Rev 2012;6:Cd007543 review of randomised clinical trials. Sultan Qaboos
Peripheral Neuropathy. Arlington, VA, American
67. Pop-Busui R, Lu J, Brooks MM, et al.; BARI Univ Med J 2019;19:e291–e304
Diabetes Association, 2022
2D Study Group. Impact of glycemic control 97. McCallum RW, Snape W, Brody F, Wo J,
82. Tesfaye S, Sloan G, Petrie J, et al.; OPTION-
strategies on the progression of diabetic Parkman HP, Nowak T. Gastric electrical stimulation
DM Trial Group. Comparison of amitriptyline
peripheral neuropathy in the Bypass Angioplasty with Enterra therapy improves symptoms from
supplemented with pregabalin, pregabalin
Revascularization Investigation 2 Diabetes (BARI diabetic gastroparesis in a prospective study. Clin
supplemented with amitriptyline, and duloxetine
2D) cohort. Diabetes Care 2013;36:3208–3215 Gastroenterol Hepatol 2010;8:947–954
68. Tang Y, Shah H, Bueno Junior CR, et al. supplemented with pregabalin for the treatment 98. Boulton AJM, Armstrong DG, Albert SF, et al.;
Intensive risk factor management and cardio- of diabetic peripheral neuropathic pain (OPTION- American Association of Clinical Endocrinologists.
vascular autonomic neuropathy in type 2 DM): a multicentre, double-blind, randomised Comprehensive foot examination and risk
diabetes: the ACCORD trial. Diabetes Care 2021; crossover trial. Lancet 2022;400:680–690 assessment: a report of the task force of the foot
44:164–173 83. Dworkin RH, Jensen MP, Gammaitoni AR, care interest group of the American Diabetes
69. O’Brien PD, Hinder LM, Callaghan BC, Olaleye DO, Galer BS. Symptom profiles differ in Association, with endorsement by the American
Feldman EL. Neurological consequences of obesity. patients with neuropathic versus non-neuropathic Association of Clinical Endocrinologists. Diabetes
Lancet Neurol 2017;16:465–477 pain. J Pain 2007;8:118–126 Care 2008;31:1679–1685
70. Smith AG, Singleton JR, Aperghis A, et al.; 84. Bril V, England J, Franklin GM, et al.; 99. Schaper NC, van Netten JJ, Apelqvist J, Bus
NeuroNEXT NN108 TopCSPN Study Team. Safety American Academy of Physical Medicine and SA, Hinchliffe RJ, Lipsky BA; IWGDF Editorial
and efficacy of topiramate in individuals with Rehabilitation. Evidence-based guideline: treatment Board. Practical guidelines on the prevention and
cryptogenic sensory peripheral neuropathy with of painful diabetic neuropathy: report of the management of diabetic foot disease (IWGDF
metabolic syndrome: the TopCSPN randomized American Academy of Neurology, the American 2019 update). Diabetes Metab Res Rev 2020;
clinical trial. JAMA Neurol 2023;80:1334–1343 Association of Neuromuscular and Electrodiagnostic 36(Suppl 1):e3266
71. Jaiswal M, Martin CL, Brown MB, et al. Medicine, and the American Academy of Physical 100. Reiber GE, Vileikyte L, Boyko EJ, et al.
Effects of exenatide on measures of diabetic Medicine and Rehabilitation. Neurology 2011;76: Causal pathways for incident lower-extremity
neuropathy in subjects with type 2 diabetes: 1758–1765 ulcers in patients with diabetes from two settings.
results from an 18-month proof-of-concept open- 85. Dowell D, Haegerich TM, Chou R. CDC Diabetes Care 1999;22:157–162
label randomized study. J Diabetes Complications guideline for prescribing opioids for chronic 101. Pham H, Armstrong DG, Harvey C, Harkless
2015;29:1287–1294 pain–United States, 2016. JAMA 2016;315:1624– LB, Giurini JM, Veves A. Screening techniques to
72. Hernando-Garijo I, Medrano-de-la-Fuente R, 1645 identify people at high risk for diabetic foot
Mingo-G omez MT, Lahuerta Martın S, Ceballos- 86. Franklin GM; American Academy of ulceration: a prospective multicenter trial. Diabetes
Laita L, Jim enez-Del-Barrio S. Effects of exercise Neurology. Opioids for chronic noncancer pain: a Care 2000;23:606–611
therapy on diabetic neuropathy: a systematic position paper of the American Academy of 102. Hingorani A, LaMuraglia GM, Henke P, et al.
review and meta-analysis. Physiother Theory Pract Neurology. Neurology 2014;83:1277–1284 The management of diabetic foot: a clinical
2024;40:2116–2129 87. Zeng C, Dubreuil M, LaRochelle MR, et al. practice guideline by the Society for Vascular
73. Streckmann F, Balke M, Cavaletti G, et al. Association of tramadol with all-cause mortality Surgery in collaboration with the American
Exercise and neuropathy: systematic review with among patients with osteoarthritis. JAMA 2019; Podiatric Medical Association and the Society for
meta-analysis. Sports Med 2022;52:1043–1065 321:969–982 Vascular Medicine. J Vasc Surg 2016;63:3s–21s
diabetesjournals.org/care Retinopathy, Neuropathy, and Foot Care S265

103. Conte MS, Bradbury AW, Kolh P, et al.; GVG foot: a key component of care. Diabetes Metab 126. Argenta LC, Morykwas MJ, Marks MW,
Writing Group for the Joint Guidelines of the Res Rev 2020;36(Suppl 1):e3251 DeFranzo AJ, Molnar JA, David LR. Vacuum-
Society for Vascular Surgery (SVS), European 114. Rogers LC, Frykberg RG, Armstrong DG, assisted closure: state of clinic art. Plast Reconstr
Society for Vascular Surgery (ESVS), and World et al. The Charcot foot in diabetes. Diabetes Care Surg 2006;117:127s–142s
Federation of Vascular Societies (WFVS). Global 2011;34:2123–2129 127. L€ ondahl M, Katzman P, Nilsson A,
vascular guidelines on the management of chronic 115. Raspovic KM, Schaper NC, Gooday C, et al. Hammarlund C. Hyperbaric oxygen therapy
limb-threatening ischemia. Eur J Vasc Endovasc Diagnosis and treatment of active Charcot neuro- facilitates healing of chronic foot ulcers in patients
Surg 2019;58:S1–S109.e133 osteoarthropathy in persons with diabetes with diabetes. Diabetes Care 2010;33:998–1003
104. American Diabetes Association. Peripheral mellitus: a systematic review. Diabetes Metab 128. Santema KTB, Stoekenbroek RM, Koelemay
arterial disease in people with diabetes. Diabetes Res Rev 2024;40:e3653 MJW, et al.; DAMO2CLES Study Group. Hyperbaric
Care 2003;26:3333–3341 116. Pinzur MS. The modern treatment of oxygen therapy in the treatment of ischemic
105. Reaney M, Gladwin T, Churchill S. Charcot foot arthropathy. J Am Acad Orthop Surg lower-extremity ulcers in patients with diabetes:
Information about foot care provided to people 2023;31:71–79 results of the DAMO2CLES multicenter randomized
with diabetes with or without their partners: 117. Ha J, Hester T, Foley R, et al. Charcot foot clinical trial. Diabetes Care 2018;41:112–119
impact on recommended foot care behavior. Appl reconstruction outcomes: a systematic review. J 129. Fedorko L, Bowen JM, Jones W, et al.

Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S252/791472/dc25s012.pdf by guest on 14 December 2024

Psychol Health Well Being 2022;14:465–482 Clin Orthop Trauma 2020;11:357–368 Hyperbaric oxygen therapy does not reduce
106. Heng ML, Kwan YH, Ilya N, et al. A 118. Frykberg RG, Banks J. Challenges in the indications for amputation in patients with
collaborative approach in patient education for treatment of chronic wounds. Adv Wound Care diabetes with nonhealing ulcers of the lower
diabetes foot and wound care: a pragmatic (New Rochelle) 2015;4:560–582 limb: a prospective, double-blind, randomized
randomised controlled trial. Int Wound J 2020; 119. Frykberg RG, Franks PJ, Edmonds M, et al.; controlled clinical trial. Diabetes Care 2016;39:
17:1678–1686 TWO2 Study Group. A multinational, multicenter, 392–399
107. Bus SA, Lavery LA, Monteiro-Soares M, randomized, double-blinded, placebo-controlled 130. Lalieu RC, Brouwer RJ, Ubbink DT,
et al.; International Working Group on the trial to evaluate the efficacy of cyclical topical Hoencamp R, Bol Raap R, van Hulst RA.
Diabetic Foot. Guidelines on the prevention of wound oxygen (TWO2) therapy in the treatment Hyperbaric oxygen therapy for nonischemic
foot ulcers in persons with diabetes (IWGDF 2019 of chronic diabetic foot ulcers: the TWO2 study. diabetic ulcers: a systematic review. Wound
update). Diabetes Metab Res Rev 2020;36(Suppl 1): Diabetes Care 2020;43:616–624 Repair Regen 2020;28:266–275
e3269 120. Boulton AJM, Armstrong DG, L€ ondahl M, 131. Niederauer MQ, Michalek JE, Liu Q, Papas
108. Goodall RJ, Ellauzi J, Tan MKH, Onida S, et al. New Evidence-Based Therapies for Complex KK, Lavery LA, Armstrong DG. Continuous
Davies AH, Shalhoub J. A systematic review of the Diabetic Foot Wounds. Arlington, VA, American diffusion of oxygen improves diabetic foot ulcer
impact of foot care education on self efficacy and Diabetes Association, 2022 healing when compared with a placebo control: a
self care in patients with diabetes. Eur J Vasc 121. Carter MJ, Frykberg RG, Oropallo A, et al. randomised, double-blind, multicentre study. J
Endovasc Surg 2020;60:282–292 Efficacy of topical wound oxygen therapy in Wound Care 2018;27:S30–S45
109. Yuncken J, Williams CM, Stolwyk RJ, Haines healing chronic diabetic foot ulcers: systematic 132. Serena TE, Bullock NM, Cole W, et al.
TP. Correction to: People with diabetes do not review and meta-analysis. Adv Wound Care (New Topical oxygen therapy in the treatment of
learn and recall their diabetes foot education: a Rochelle) 2023;12:177–186 diabetic foot ulcers: a multicentre, open,
cohort study. Endocrine 2018;63:660–258 122. Yammine K, Assi C. Surgical offloading randomised controlled clinical trial. J Wound Care
110. Walton DV, Edmonds ME, Bates M, Vas PRJ, techniques should be used more often and 2021;30:S7–S14
Petrova NL, Manu CA. People living with diabetes earlier in treating forefoot diabetic ulcers: an 133. Sun X-K, Li R, Yang X-L, Yuan L. Efficacy and
are unaware of their foot risk status or why they evidence-based review. Int J Low Extrem Wounds safety of topical oxygen therapy for diabetic foot
are referred to a multidisciplinary foot team. J 2020;19:112–119 ulcers: an updated systematic review and meta-
Wound Care 2021;30:598–603 123. La Fontaine J, Lavery LA, Hunt NA, analysis. Int Wound J 2022;19:2200–2209
111. Bus SA, van Deursen RW, Armstrong DG, Murdoch DP. The role of surgical off-loading to 134. Frykberg RG. Topical wound oxygen
Lewis JEA, Caravaggi CF, Cavanagh PR, prevent recurrent ulcerations. Int J Low Extrem therapy in the treatment of chronic diabetic foot
International Working Group on the Diabetic Wounds 2014;13:320–334 ulcers. Medicina (Kaunas) 2021;57:917
Foot. Footwear and offloading interventions to 124. Sheehan P, Jones P, Caselli A, Giurini JM, 135. Sethi A, Khambhayta Y, Vas P. Topical
prevent and heal foot ulcers and reduce plantar Veves A. Percent change in wound area of oxygen therapy for healing diabetic foot ulcers: a
pressure in patients with diabetes: a systematic diabetic foot ulcers over a 4-week period is a systematic review and meta-analysis of randomised
review. Diabetes Metab Res Rev 2016;32(Suppl robust predictor of complete healing in a 12- control trials. Health Sci Rev 2022;3:100028
1):99–118 week prospective trial. Diabetes Care 2003;26: 136. van Netten JJ, Price PE, Lavery LA, et al.;
112. Bus SA, Armstrong DG, Crews RT, et al. 1879–1882 International Working Group on the Diabetic
Guidelines on offloading foot ulcers in persons 125. Blume PA, Walters J, Payne W, Ayala J, Foot. Prevention of foot ulcers in the at-risk patient
with diabetes (IWGDF 2023 update). Diabetes Lantis J. Comparison of negative pressure wound with diabetes: a systematic review. Diabetes Metab
Metab Res Rev 2024;40:e3647 therapy using vacuum-assisted closure with Res Rev 2016;32(Suppl 1):84–98
113. Frykberg RG, Wukich DK, Kavarthapu V, advanced moist wound therapy in the treatment 137. Frykberg RG, Vileikyte L, Boulton AJM,
Zgonis T, Dalla Paola L; Board of the Association of diabetic foot ulcers: a multicenter randomized Armstrong DG. The at-risk diabetic foot: time to focus
of Diabetic Foot Surgeons. Surgery for the diabetic controlled trial. Diabetes Care 2008;31:631–636 on prevention. Diabetes Care 2022;45:e144–e145