Reprinted from


12. Retinopathy, Neuropathy, and Foot Care:

Standards of Care in Diabetes 2023

Nuha A. ElSayed, Grazia Aleppo, Vanita R. Aroda,

Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer Billy S. Collins, Christopher H. Gibbons, John M. Giurini,

Marisa E. Hilliard, Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry,

Priya Prahalad, Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on hehalf of the American Diabetes Association

Diabetes Care 2023;46(Suppl. 1):S203-S215 |

ISSN 0149-5992

12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2023

Diabetes Care 2023;46(Suppl. 1):5203-5215 I

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, a multidisciplinary expert committee, are responsible for up­ dating the Standards of Care annually, or more frequently as warranted. For a de­ tailed 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

For prevention and management of diabetes complications in children and adoles­ cents, please refer to Section 14, “Children and Adolescents.”


Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, with prevalence strongly related to both the duration of diabetes and the level of glycemic control (1). Diabetic retinopathy is the most frequent 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 frequently in people with diabetes.

In addition to diabetes duration, factors that increase the risk of, or are associ­ ated with, retinopathy include chronic hyperglycemia (2,3), nephropathy (4), hyper­ tension (5), and dyslipidemia (6). Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy, reduce the need for future ocular surgical procedures, and potentially improve patient-reported visual function (2,7-10). A meta-analysis of data from cardiovascular outcomes studies showed no association between glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment and retinopathy per se, except through the association between retinopathy and average AlC reduction at the 3-month and 1-year follow­ up. Long-term impact of improved glycemic control on retinopathy was not studied

Nuha A. EISayed, Grazia Aleppo,

Vanita R. Aroda, Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer, Billy 5. Collins, Christopher H. Gibbons, John M. Giurini, Marisa E. Hilliard,

Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry, Priya Prahalad,

Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on behalf of the American Diabetes Association

Disclosure information for each author is available at

Suggested citation: EISayed NA, Aleppo G, Aroda VR, et al., American Diabetes Association. 12. Retinopathy, neuropathy, and foot care: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46(Suppl. 1}:5203-5215

© 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.

in these trials. Retinopathy status should be assessed when intensifying glucose­ lowering therapies such as those using GLP-1 RAs, since rapid reductions in AlC can be associated with initial worsening of retinopathy (11).


The preventive effects of therapy and the fact that individuals with prolifera­ tive diabetic retinopathy (PDR) or macu­ lar edema may be asymptomatic provide strong support for screening to detect diabetic retinopathy. Prompt diagnosis allows triage of patients and timely in­ tervention that may prevent vision loss in individuals who are asymptomatic despite advanced diabetic eye disease.

Diabetic retinopathy screening should be performed using validated approaches and methodologies. Youth with type 1 or type 2 diabetes are also at risk for compli­ cations and need to be screened for dia­ betic retinopathy (12) (see Section 14, “Children and Adolescents). If diabetic retinopathy is evident on screening, prompt referral to an ophthalmologist is recom­ mended. Subsequent examinations for individuals with type 1 or type 2 diabe­ tes are generally repeated annually for individuals with minimal to no retinop­ athy. Exams every 1-2 years may be cost-effective after one or more normal eye exams. In a population with well­ controlled type 2 diabetes, there was little risk of development of significant retinopathy within a 3-year interval af­ ter a normal examination (13), and less frequent intervals have been found in simulated modeling to be potentially ef­ fective in screening for diabetic retinop­ athy in individuals without diabetic retinopathy (14). However, it is impor­ tant to adjust screening intervals based on the presence of specific risk factors for retinopathy onset and worsening retinopathy. More frequent examina­ tions by the ophthalmologist will be re­ quired if retinopathy is progressing or risk factors such as uncontrolled hyperglyce­ mia, advanced baseline retinopathy, or diabetic macular edema are present.

Retinal photography with remote read­ ing by experts has great potential to pro­ vide screening services in areas where qualified eye care professionals are not readily available (15-17). High-quality fun­ dus photographs can detect most clinically significant diabetic retinopathy. Interpreta­ tion of the images should be performed by a trained eye care professional. Retinal

photography may also enhance efficiency and reduce costs when the expertise of ophthalmologists can be used for more complex examinations and for therapy (15,18,19). In-person exams are still nec­ essary when the retinal photos are of unacceptable quality and for follow-up if abnormalities are detected. Retinal pho­ tos are not a substitute for dilated com­ prehensive eye exams, which should be performed at least initially and at yearly intervals thereafter or more frequently as recommended by an eye care profes­ sional. Artificial intelligence systems that detect more than mild diabetic retinopa­ thy and diabetic macular edema, autho­ rized for use by the U.S. Food and Drug Administration (FDA), represent an alter­ native to traditional screening approaches

(20). However, the benefits and optimal utilization of this type of screening have yet to be fully determined. Results of all screening eye examinations should be documented and transmitted to the refer­ ring health care professional.

Type 1 Diabetes

Because retinopathy is estimated to take at least 5 years to develop after the on­ set of hyperglycemia, people with type 1 diabetes should have an initial dilated and comprehensive eye exami­ nation within 5 years after the diagnosis of diabetes (21).

Type 2 Diabetes

People with type 2 diabetes who may have had years of undiagnosed diabetes and have a significant risk of prevalent diabetic retinopathy at the time of diag­ nosis should have an initial dilated and comprehensive eye examination at the time of diagnosis.


Individuals who develop gestational dia­ betes mellitus do not require eye ex­ aminations during pregnancy since they do not appear to be at increased risk of developing diabetic retinopathy during pregnancy (22). However, individuals of childbearing potential with preexisting type 1 or type 2 diabetes who are plan­ ning pregnancy or who have become pregnant should be counseled on the baseline prevalence and risk of devel­ opment and/or progression of diabetic retinopathy. In a systematic review and meta-analysis of 18 observational studies of pregnant individuals with preexisting

type 1 or type 2 diabetes, the prevalence of any diabetic retinopathy and PDR in early pregnancy was 52.3% and 6.1%, re­ spectively. The pooled progression rate per 100 pregnancies for new diabetic reti­ nopathy development was 15.0 (95% Cl

9.9-20.8), worsened nonproliferative

diabetic retinopathy was 31.0 (95% Cl 23.2-39.2), pooled sight-threatening pro­ gression rate from nonproliferative dia­ betic retinopathy to PDR was 6.3 (95% Cl 3.3-10.0), and worsened PDR was 37.0

(95% Cl 21.2-54.0), demonstrating that close follow-up should be maintained during pregnancy to prevent vision loss

(23). In addition, rapid implementation of intensive glycemic management in the setting of retinopathy is associ­ ated with early worsening of retinop­ athy (24).

A systematic review and meta-analysis and a controlled prospective study dem­ onstrate that pregnancy in individuals with type 1 diabetes may aggravate reti­ nopathy and threaten vision, especially when glycemic control is poor or retinop­ athy severity is advanced at the time of conception (23,24). Laser photocoagu­ lation surgery can minimize the risk of vision loss during pregnancy for individ­ uals with high-risk PDR or center-involved diabetic macular edema (24). Anti-vascular endothelial growth factor (anti-VEGF) med­ ications should not be used in pregnant individuals with diabetes because of the­ oretical risks to the vasculature of the developing fetus.


Two of the main motivations for screen­ ing for diabetic retinopathy are to pre­ vent loss of vision and to intervene with treatment when vision loss can be pre­ vented or reversed.

Photocoagulation Surgery

Two large trials, the Diabetic Retinopa­ thy Study (DRS) in individuals with PDR and the Early Treatment Diabetic Reti­ nopathy Study (ETDRS) in individuals with macular edema, provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRS (25) showed in 1978 that panretinal photo­ coagulation surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes with the greatest benefit ratio in those with more advanced baseline disease (disc neovascularization or vitre­ ous hemorrhage). In 1985, the ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR and in older-onset individuals with severe

nonproliferative diabetic retinopathy or less-than-high-risk PDR. Panretinal laser photocoagulation is still commonly used to manage complications of dia­ betic retinopathy that involve retinal neovascularization and its complications. A more gentle, macular focal/grid laser photocoagulation technique was shown in the ETDRS to be effective in treating eyes with clinically significant macular edema from diabetes (26), but this is now largely considered to be second-line treatment for diabetic macular edema.

Anti-Vascular Endothelial Growth Factor Treatment

Data from the DRCR Retina Network

(formerly the Diabetic Retinopathy Clini­ cal Research Network) and others dem­ onstrate that intravitreal injections of antiVEGF agents are effective at re­ gressing proliferative disease and lead to noninferior or superior visual acuity outcomes compared with panretinal la­ ser over 2 years of follow-up (27,28). In addition, it was observed that individuals treated with ranibizumab tended to have less peripheral visual field loss, fewer vitrectomy surgeries for secondary com­ plications from their proliferative dis­ ease, and a lower risk of developing diabetic macular edema. However, a potential drawback in using anti-VEGF therapy to manage proliferative disease is that patients were required to have a greater number of visits and received a greater number of treatments than is typically required for management with panretinal laser, which may not be opti­ mal for some individuals. The FDA has approved aflibercept and ranibizumab for the treatment of eyes with diabetic retinopathy. Other emerging therapies for retinopathy that may use sustained intravitreal delivery of pharmacologic agents are currently under investigation. Anti-VEGF treatment of eyes with non­ proliferative diabetic retinopathy has been demonstrated to reduce subse­ quent development of retinal neovascu­ larization and diabetic macular edema but has not been shown to improve visual outcomes over 2 years of therapy and therefore is not routinely recom­ mended for this indication (29).

While the ETDRS (26) established the

benefit of focal laser photocoagulation surgery in eyes with clinically significant macular edema (defined as retinal edema

located at or threatening the macular center), current data from well-designed clinical trials demonstrate that intravi­ treal anti-VEGF agents provide a more effective treatment plan for center­ involved diabetic macular edema than monotherapy with laser (30,31). Most patients require near-monthly adminis­ tration of intravitreal therapy with anti­ VEGF agents during the first 12 months of treatment, with fewer injections needed in subsequent years to maintain remission from central-involved diabetic macular edema. There are currently three anti­ VEGF agents commonly used to treat eyes with central-involved diabetic macular edema-bevacizumab, ranibizumab, and atlibercept (1)-and a comparative effec­ tiveness study demonstrated that atliber­ cept provides vision outcomes superior to those of bevacizumab when eyes have moderate visual impairment (vision of 20/50 or worse) from diabetic macular edema (32). For eyes that have good vision (20/25 or better) despite diabetic macular edema, close monitoring with initiation of anti-VEGF therapy if vision worsens provides similar 2-year vision outcomes compared with immediate initi­ ation of anti-VEGF therapy (33).

Eyes that have persistent diabetic macu­ lar edema despite anti-VEGF treatment may benefit from macular laser photo­ coagulation or intravitreal therapy with corticosteroids. Both of these therapies are also reasonable first-line approaches for individuals who are not candidates for anti-VEGF treatment due to systemic considerations such as pregnancy.

Adjunctive Therapy

Lowering blood pressure has been shown to decrease retinopathy progression, although tight targets (systolic blood pressure <120 mmHg) do not impart additional benefit (8). In individuals with dyslipidemia, retinopathy progression may be slowed by the addition of feno­ fibrate, particularly with very mild non­ proliferative diabetic retinopathy at baseline (34,35).



Diabetic neuropathies are a heteroge­ neous group of disorders with diverse clinical manifestations. The early rec­ ognition and appropriate management of neuropathy in people with diabetes is important. Points to be aware of in­ clude the following:

  1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropa­ thies may be present in people with diabetes and may be treatable.
  2. Up to 50% of diabetic peripheral neu­ ropathy may be asymptomatic. If not recognized and if preventive foot care is not implemented, people with dia­ betes are at risk for injuries as well as diabetic foot ulcers and amputations.
  3. Recognition and treatment of au-

symptoms, reduce sequelae, and im­ prove quality of life.

Specific treatment to reverse the un­ derlying nerve damage is currently not available. Glycemic control can effec­ tively prevent diabetic peripheral neu­ ropathy (DPN) and cardiac autonomic neuropathy (CAN) in type 1 diabetes (36,37) and may modestly slow their progression in type 2 diabetes (38), but it does not reverse neuronal loss. Treat­ ments of other modifiable risk factors (including lipids and blood pressure) can aid in prevention of DPN progression in type 2 diabetes and may reduce disease progression in type 1 diabetes (39-41). Therapeutic strategies (pharmacologic and nonpharmacologic) for the relief of painful DPN and symptoms of autonomic neurop­ athy can potentially reduce pain (42) and improve quality of life.


Diabetic Peripheral Neuropathy

Individuals with a type 1 diabetes dura­ tion 2′.5 years and all individuals with type 2 diabetes should be assessed an­ nually for DPN using the medical history and simple clinical tests (42). Symptoms vary according to the class of sensory fi­ bers involved. The most common early symptoms are induced by the involve­ ment of small fibers and include pain and dysesthesia (unpleasant sensations of burning and tingling). The involve­ ment of large fibers may cause numb­ ness and loss of protective sensation (LOPS). LOPS indicates the presence of distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration. The following clinical tests may be used to assess small- and large-fiber func­ tion and protective sensation:

  1. Small-fiber function: pinprick and temperature sensation.
  2. Large-fiber function: lower-extremity

reflexes, vibration perception, and 10-g monofilament.

  1. Protective sensation: 10-g mono­ filament.

These tests not only screen for the presence of dysfunction but also predict future risk of complications. Electrophysi­ ological testing or referral to a neurolo-

tonomic neuropathy may improve gist is rarely needed, except in situations

where the clinical features are atypical or the diagnosis is unclear.

In all people with diabetes and DPN, causes of neuropathy other than diabetes should be considered, including toxins (e.g., alcohol), neurotoxic medica­ tions (e.g., chemotherapy), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies (e.g., multiple myeloma, bronchogenic carcinoma), infections (e.g., HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (43). See the American Diabetes Association position statement “Diabetic Neuropathy” for more details (42).

Diabetic Autonomic Neuropathy

Individuals who have had type 1 diabe­ tes for 2:5 years and all individuals with type 2 diabetes should be assessed an­ nually for autonomic neuropathy (42). The symptoms and signs of autonomic neuropathy should be elicited carefully during the history and physical examina­ tion. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, orthostatic hypoten­ sion, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating. Screening for symp­ toms of autonomic neuropathy includes asking about symptoms of orthostatic in­ tolerance (dizziness, lightheadedness, or weakness with standing), syncope, exer­ cise intolerance, constipation, diarrhea, urinary retention, urinary incontinence, or changes in sweat function. Further testing can be considered if symptoms are present and will depend on the end organ involved but might include cardio­ vascular autonomic testing, sweat testing, urodynamic studies, gastric emptying, or endoscopy/colonoscopy. Impaired coun­ terregulatory responses to hypoglycemia in type 1 and type 2 diabetes can lead to hypoglycemia unawareness but are not directly linked to autonomic neuropathy.

Cardiovascular Autonomic Neuropathy. CAN is associated with mortality independently of other cardiovascular risk factors (44,45). In its early stages, CAN may be completely asymptomatic and detected only by decreased heart rate variability with deep breathing. Advanced disease may be associated with resting tachycardia (>100 bpm) and orthostatic hypoten­ sion (a fall in systolic or diastolic blood

pressure by >20 mmHg or >10 mmHg, respectively, upon standing without an appropriate increase in heart rate). CAN treatment is generally focused on allevi­ ating symptoms.

Gastrointestinal Neuropathies. Gastrointes­ tinal neuropathies may involve any por­ tion of the gastrointestinal tract, with manifestations including esophageal dysmotility, gastroparesis, constipation, diarrhea, and fecal incontinence. Gastro­ paresis should be suspected in individu­ als with erratic glycemic control or with upper gastrointestinal symptoms with­ out another identified cause. Exclusion of reversible/iatrogenic causes such as medi­ cations or organic causes of gastric outlet obstruction or peptic ulcer disease (with esophagogastroduodenoscopy or a barium study of the stomach) is needed before considering a diagnosis of or specialized testing for gastroparesis. The diagnostic gold standard for gastroparesis is the measurement of gastric emptying with scintigraphy of digestible solids at 15-min intervals for 4 h after food intake. The use of 13C octanoic acid breath test is an ap­ proved alternative.

Genitourinary Disturbances. Diabetic auto­ nomic neuropathy may also cause geni­ tourinary disturbances, including sexual dysfunction and bladder dysfunction. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation (42). Female sex­ ual dysfunction occurs more frequently in those with diabetes and presents as decreased sexual desire, increased pain during intercourse, decreased sexual arousal, and inadequate lubrication (46). Lower urinary tract symptoms manifest as urinary incontinence and bladder dys­ function (nocturia, frequent urination, urination urgency, and weak urinary stream). Evaluation of bladder func­ tion should be performed for individuals with diabetes who have recurrent uri­ nary tract infections, pyelonephritis, in­ continence, or a palpable bladder.


Glycemic Control

Near-normal glycemic control, imple­ mented early in the course of diabetes, has been shown to effectively delay or prevent the development of DPN and CAN in people with type 1 diabetes (47-50). Although the evidence for the benefit of near-normal glycemic control is not as strong that for type 2 diabetes, some studies have demonstrated a mod­ est slowing of progression without rever­ sal of neuronal loss (38,51). Specific glucose-lowering strategies may have dif­ ferent effects. In a post hoc analysis, par­ ticipants, particularly men, in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower inci­ dence of distal symmetric polyneuropathy over 4 years than those treated with insu­ lin/sulfonylurea (52). Additionally, recent evidence from the Action to Control Car­ diovascular Risk in Diabetes (ACCORD) trial showed clear benefit of intensive glucose and blood pressure control on the preven­ tion of CAN in type 2 diabetes (53).

Lipid Control

Dyslipidemia is a key factor in the development of neuropathy in people with type 2 diabetes and may contrib­ ute to neuropathy risk in people with type 1 diabetes (54,55). Although the ev­ idence for a relationship between lipids

and neuropathy development has be­ come increasingly clear in type 2 diabe­ tes, the optimal therapeutic intervention has not been identified. Positive effects of physical activity, weight loss, and bar­ iatric surgery have been reported in indi­ viduals with DPN, but use of conventional lipid-lowering pharmacotherapy (such as statins or fenofibrates) does not appear to be effective in treating or preventing DPN development (56).

Blood Pressure Control

There are multiple reasons for blood pressure control in people with diabetes, but neuropathy progression (especially in type 2 diabetes) has now been added to this list. Although data from many studies have supported the role of hy­ pertension in risk of neuropathy devel­ opment, a recent meta-analysis of data from 14 countries in the International Prevalence and Treatment of Diabetes and Depression (INTERPRET-DD) study re­ vealed hypertension as an independent risk of DPN development with an odds ratio of 1.58 (57). In the ACCORD trial, intensive blood pressure intervention decreased CAN risk by 25% (53).

Neuropathic Pain

Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dys­ function (58). No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or predia­ betes, which leaves only pharmaceutical interventions (59). A recent guideline by the American Academy of Neurology rec­ ommends that the initial treatment of pain should also focus on the concurrent treatment of both sleep and mood dis­ orders because of increased frequency of these problems in individuals with DPN (60).

A number of pharmacologic therapies exist for treatment of pain in diabetes. The American Academy of Neurology update suggested that gabapentinoids, serotonin-norepinephrine reuptake inhibi­ tors (SNRls), sodium channel blockers, tricyclic antidepressants (TCAs), and SNRI/ opioid dual-mechanism agents could all be considered in the treatment of pain in DPN (60). These American Academy of Neurology recommendations offer a sup­ plement to a recent American Diabetes Association pain monograph, although

some areas of disagreement exist, particu­ larly around SNRl/opioid dual-mechanism agents (61). A recent head-to-head trial suggested therapeutic equivalency for TCAs, SNRls, and gabapentinoids in the treatment of pain in DPN (62). The trial also supported the role of combination therapy over monotherapy for the treat­ ment of pain in DPN.

Gabapentinoids. Gabapentinoids include

several calcium channel a2-o subunit li­ gands. Eight high-quality studies and seven medium-quality studies support the role of pregabalin in treatment of pain in DPN. One high-quality study and many small studies support the role of gabapentin in the treatment of pain in DPN. Two medium-quality studies suggest that micro­ gabalin has a small effect on pain in DPN

(60). Adverse effects may be more severe in older individuals (63) and may be at­ tenuated by lower starting doses and more gradual titration.

SNRls. SNRls include duloxetine, venla­

faxine, and desvenlafaxine, all selective SNRls. Two high-quality studies and five medium-quality studies support the role of duloxetine in the treatment of pain in DPN. A high-quality study supports the role of venlafaxine in the treatment of pain in DPN. Only one medium-quality study sup­ ports a possible role for desvenlafaxine for treatment of pain in DPN (60). Adverse events may be more severe in older peo­ ple but may be attenuated with lower doses and slower titration of duloxetine. Tapentadol and Tramadol. Tapentadol and tramadol are centrally acting opioid anal­ gesics that exert their analgesic effects through both µ-opioid receptor agonism and norepinephrine and serotonin reuptake inhibition. SNRl/opioid agents are probably effective in the treatment of pain in DPN. However, the use of any opioids for man­ agement of chronic neuropathic pain carries the risk of addiction and should be avoided. Tricyclic Antidepressants. Tricyclic anti­ depressants have been studied for treat­ ment of pain, and most of the relevant data was acquired from trials of ami­ triptyline and include two high-quality studies and two medium-quality stud­ ies supporting the treatment of pain in DPN (60,62). Anticholinergic side effects may be dose limiting and restrict use in individuals 2′.65 years of age.

Sodium Channel Blockers. Sodium channel blockers include lamotrigine, lacosamide, oxcarbazepine, and valproic acid. Five medium-quality studies support the role

of sodium channel blockers in treating pain in DPN (60).

Capsaicin. Capsaicin has received FDA ap­ proval for treatment of pain in DPN using an 8% patch, with one high-quality study reported. One medium-quality study of 0.075% capsaicin cream has been re­ ported. In patients with contraindica­ tions to oral pharmacotherapy or who prefer topical treatments, the use of topical capsaicin can be considered.

Carbamazepine and a-Lipoic Acid. Carba­

mazepine and a-lipoic acid, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN (41,54,56).

Orthostatic Hypotension

Treating orthostatic hypotension is chal­ lenging. The therapeutic goal is to mini­ mize postural symptoms rather than to restore normotension. Most patients re­ quire both nonpharmacologic measures (e.g., ensuring adequate salt intake, avoid­ ing medications that aggravate hypoten­ sion, or using compressive garments over the legs and abdomen) and pharmaco­ logic measures. Physical activity and ex­ ercise should be encouraged to avoid deconditioning, which is known to ex­ acerbate orthostatic intolerance, and volume repletion with fluids and salt is critical. There have been clinical studies that assessed the impact of an approach incorporating the aforementioned non­ pharmacologic measures. Additionally, supine blood pressure tends to be much higher in these individuals, often requir­ ing treatment of blood pressure at bed­ time with shorter-acting drugs that also affect baroreceptor activity such as guan­ facine or clonidine, shorter-acting calcium blockers (e.g., isradipine), or shorter­ acting [3-blockers such as atenolol or metoprolol tartrate. Alternatives can in­ clude enalapril if an individual is unable to tolerate preferred agents (64-66). Midodrine and droxidopa are approved by the FDA for the treatment of ortho­ static hypotension.


Treatment for diabetic gastroparesis may be very challenging. A low-fiber, low-fat eating plan provided in small frequent meals with a greater proportion of liquid calories may be useful (67-69). In addi­ tion, foods with small particle size may improve key symptoms (70). With­ drawing drugs with adverse effects on

gastrointestinal motility, including opioids, anticholinergics, tricyclic antidepressants, GLP-1 RAs, and pramlintide, may also improve intestinal motility (67,71). How­ ever, the risk of removal of GLP-1 RAs should be balanced against their potential benefits. In cases of severe gastroparesis, pharmacologic interventions are needed. Only metoclopramide, a prokinetic agent, is approved by the FDA for the treatment of gastroparesis. However, the level of evidence regarding the benefits of meto­ clopramide for the management of gas­ troparesis is weak, and given the risk for serious adverse effects (extrapyramidal signs such as acute dystonic reactions, drug-induced parkinsonism, akathisia, and tardive dyskinesia), its use in the treat­ ment of gastroparesis beyond 12 weeks is no longer recommended by the FDA. It should be reserved for severe cases that are unresponsive to other thera­ pies (71). Other treatment options in­ clude domperidone (available outside the U.S.) and erythromycin, which is only effective for short-term use due to tachy­ phylaxis (72,73). Gastric electrical stimula­ tion using a surgically implantable device has received approval from the FDA, although its efficacy is variable and use is limited to individuals with severe symp­ toms that are refractory to other treat­ ments (74).

Erectile Dysfunction

In addition to treatment of hypogonadism if present, treatments for erectile dys­ function may include phosphodiester­ ase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with DPN treatments, these interventions do not change the underlying pathol­ ogy and natural history of the disease process but may improve a person’s qual­ ity of life.


Foot ulcerations and amputations are common complications associated with diabetes. These may be the consequences of several factors, including peripheral neuropathy, peripheral arterial disease (PAD), and foot deformities. They rep­ resent major causes of morbidity and mortality in people with diabetes. Early recognition of at-risk feet, preulcerative lesions, and prompt treatment of ulcer­ ations and other lower-extremity com­ plications can delay or prevent adverse outcomes.

Early recognition requires an under­

standing of those factors that put peo­ ple with diabetes at increased risk for ulcerations and amputations. Factors that are associated with the at-risk foot include the following:

    • Poor glycemic control
    • Peripheral neuropathy/LOPS
    • PAD
    • Foot deformities (bunions, hammer- toes, Charcot joint, etc.)
    • Preulcerative corns or calluses
    • Prior ulceration
    • Prior amputation
    • Smoking
    • Retinopathy
    • Nephropathy (particularly individuals on dialysis or posttransplant)

Identifying the at-risk foot begins with a detailed history documenting diabetes control, smoking history, exercise toler­ ance, history of claudication or rest pain, and prior ulcerations or amputations. A thorough examination of the feet should be performed annually in all people with diabetes and more frequently in at-risk individuals (75). The examination should include assessment of skin integrity, as­ sessment for LOPS using the 10-g mono­ filament along with at least one other neurological assessment tool, pulse ex­ amination of the dorsalis pedis and pos­ terior tibial arteries, and assessment for foot deformities such as bunions, ham­ mertoes, and prominent metatarsals, which increase plantar foot pressures and increase risk for ulcerations. At-risk individuals should be assessed at each visit and should be referred to foot care specialists for ongoing preventive care and surveillance. The physical examina­ tion can stratify patients into different categories and determine the frequency of these visits (76) (Table 12.1).

Evaluation for Loss of Protective Sensation

The presence of peripheral sensory neu­ ropathy is the single most common com­ ponent cause for foot ulceration. In a multicenter trial, peripheral neuropathy was found to be a component cause in 78% of people with diabetes with ulcer­ ations and that the triad of peripheral sensory neuropathy, minor trauma, and foot deformity was present in >63% of participants (77). All people with dia­ betes should undergo a comprehensive foot examination at least annually, or

more frequently for those in higher-risk categories (75,76).

LOPS is vital to risk assessment. One of the most useful tests to determine LOPS is the 10-g monofilament test. Studies have shown that clinical exami­ nation and the 10-g monofilament test are the two most sensitive tests in iden­ tifying the foot at risk for ulceration

(78). The monofilament test should be performed with at least one other neu­ rologic assessment tool (e.g., pinprick, temperature perception, ankle reflexes, or vibratory perception with a 128-Hz tuning fork or similar device). Absent monofilament sensation and one other abnormal test confirms the presence of LOPS. Further neurological testing, such as nerve conduction, electromyography, nerve biopsy, or intraepidermal nerve fi­ ber density biopsies, are rarely indicated for the diagnosis of peripheral sensory neuropathy (42).

Evaluation for Peripheral Arterial Disease

Initial screening for PAD should include a history of leg fatigue, claudication, and rest pain relieved with dependency. Physical examination for PAD should include assessment of lower-extremity pulses, capillary refill time, rubor on dependency, pallor on elevation, and ve­ nous filling time (75,79). Any patient ex­ hibiting signs and symptoms of PAD should be referred for noninvasive arte­ rial studies in the form of Doppler ultra­ sound with pulse volume recordings. While ankle-brachia! indices will be calculated, they should be interpreted carefully, as they are known to be inac­ curate in people with diabetes due to

noncompressible vessels. Toe systolic blood pressure tends to be more accurate. Toe systolic blood pressures <30 mmHg are suggestive of PAD and an inability to heal foot ulcerations (80). Individuals with abnormal pulse volume recording tracings and toe pressures <30 mmHg with foot ulcers should be referred for immediate vascular evaluation. Due to the high prevalence of PAD in people with dia­ betes, it has been recommended by the Society for Vascular Surgery and the American Pediatric Medical Associa­ tion in their 2016 guidelines that all people with diabetes >50 years of age should undergo screening via noninva­ sive arterial studies (79,81). If nor­ mal, these should be repeated every 5 years (79).

Patient Education

All people with diabetes (and their families), particularly those with the aforementioned high-risk conditions, should receive general foot care edu­ cation, including appropriate manage­ ment strategies (82-84). This education should be provided to all newly diag­ nosed people with diabetes as part of an annual comprehensive examination and to individuals with high-risk conditions at every visit. Recent studies have shown that while education improves knowl­ edge of diabetic foot problems and self­ care of the foot, it does not improve behaviors associated with active participa­ tion in their overall diabetes care and to achieve personal health goals (85). Evi­ dence also suggests that while patient and family education are important, the knowledge is quickly forgotten and needs to be reinforced regularly (86).

Table 12.1-lnternational Working Group on the Diabetic Foot risk stratification system and corresponding foot screening frequency

Category Ulcer risk Characteristics Examination frequency*

0 Very low No LOPS and No PAD Annually




Every 6-12 months



LOPS + PAD, or

LOPS + foot deformity, or PAD + foot deformity

Every 3-6 months

3 High LOPS or PAD and one or more of the following: Every 1-3 months

  • History of foot ulcer
  • Amputation (minor or major)
  • End-stage renal disease

Adapted with permission from Schaper et al. (76). LOPS, loss of protective sensation; PAD, peripheral artery disease. *Examination frequency suggestions are based on expert opinion and patient-centered requirements.

Individuals considered at risk should understand the implications of foot de­ formities, LOPS, and PAD; the proper care of the foot, including nail and skin care; and the importance of foot inspec­ tions on a daily basis. Individuals with LOPS should be educated on appropriate ways to examine their feet (palpation or visual inspection with an unbreakable mirror) for daily surveillance of early foot problems. Patients should also be educated on the importance of refer­ rals to foot care specialists. A recent study showed that people with diabetes and foot disease lacked awareness of their risk status and why they were be­ ing referred to a multidisciplinary team of foot care specialists. Further, they ex­ hibited a variable degree of interest in learning further about foot complica­ tions (87).

Patients’ understanding of these issues

and their physical ability to conduct proper foot suNeillance and care should be as­ sessed. Those with visual difficulties, physi­ cal constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist with their care.

The selection of appropriate footwear and footwear behaviors at home should also be discussed (e.g., no walking barefoot, avoiding open-toed shoes). Therapeutic footwear with custom-made orthotic devices have been shown to re­ duce peak plantar pressures (84). Most studies use reduction in peak plantar pressures as an outcome as opposed to ulcer prevention. Certain design features of the orthoses, such as rocker soles and metatarsal accommodations, can reduce peak plantar pressures more significantly than insoles alone. A systematic review, however, showed there was no signifi­ cant reduction in ulcer incidence after

18 months compared with standard insoles and extra-depth shoes. Fur­ ther, it was also noted that evidence to prevent first ulcerations was non­ existent (88).


Treatment recommendations for people with diabetes will be determined by their risk category. No-risk or low-risk individuals can often be managed with

education and self-care. People in the moderate- to high-risk category should be referred to foot care specialists for further evaluation and regular surveil­ lance as outlined in Table 12.1. This in­ cludes individuals with LOPS, PAD, and/ or structural foot deformities, such as Charcot foot, bunions, or hammertoes. Individuals with any open ulceration or unexplained swelling, erythema, or in­ creased skin temperature should be re­ ferred urgently to a foot care specialist or multidisciplinary team.

Initial treatment recommendations should include daily foot inspection, use of moisturizers for dry, scaly skin, and avoidance of self-care of ingrown nails and calluses. Well-fitted athletic or walking shoes with customized pressure­ relieving orthoses should be part of ini­ tial recommendations for people with increased plantar pressures (as demon­ strated by plantar calluses). Individuals with deformities such as bunions or hammertoes may require specialized footwear such as extra-depth shoes. Those with even more significant de­ formities, as in Charcot joint disease, may require custom-made footwear.

Special consideration should be given to individuals with neuropathy who pre­ sent with a warm, swollen, red foot with or without a history of trauma and without an open ulceration. These indi­ viduals require a thorough workup for possible Charcot neuroarthropathy (89). Early diagnosis and treatment of this condition is of paramount importance in preventing deformities and instability that can lead to ulceration and amputa­ tion. These individuals require total non­ weight-bearing and urgent referral to a foot care specialist for further manage­ ment. Foot and ankle X-rays should be performed in all individuals presenting with the above clinical findings.

There have been a number of devel­

opments in the treatment of ulcerations over the years (90). These include negative-pressure therapy, growth fac­ tors, bioengineered tissue, acellular ma­ trix tissue, stem cell therapy, hyperbaric oxygen therapy, and, most recently, topi­ cal oxygen therapy (91-93). While there is literature to support many modalities currently used to treat diabetic foot wounds, robust randomized controlled trials (RCTs) are often lacking. How­ ever, it is agreed that the initial treat­ ment and evaluation of ulcerations

include the following five basic prin­ ciples of ulcer treatment:

  • Offloading of plantar ulcerations
  • Debridementofnecrotic,nonviable tissue
  • Revascularization of ischemic wounds when necessary
  • Management of infection: soft tissue or bone
  • Use of physiologic, topical dressings

However, despite following the above principles, some ulcerations will become chronic and fail to heal. In those situa­ tions, advanced wound therapy can play a role. When to employ advanced wound therapy has been the subject of much discussion, as the therapy is often quite expensive. It has been determined that if a wound fails to show a reduc­ tion of 50% or more after 4 weeks of appropriate wound management (i.e., the five basic principles above), consid­ eration should be given to the use of advanced wound therapy (94). Treat­ ment of these chronic wounds is best managed in a multidisciplinary setting.

Evidence to support advanced wound

therapy is challenging to produce and to assess. Randomization of trial partici­ pants is difficult, as there are many variables that can affect wound heal­ ing. In addition, many RCTs exclude certain cohorts of people, e.g., individu­ als with chronic renal disease or those on dialysis. Finally, blinding of participants and clinicians is not always possible. Meta-analyses and systematic reviews of obseNational studies are used to deter­ mine the clinical effectiveness of these modalities. Such studies can augment for­ mal RCTs by including a greater variety of participants in various clinical settings who are typically excluded from the more rigidly structured clinical trials.

Advanced wound therapy can be cat­

egorized into nine broad categories (90) (Table 12.2). Topical growth factors, acel­ lular matrix tissues, and bioengineered cellular therapies are commonly em­ ployed in offices and wound care cen­ ters to expedite healing of chronic, more superficial ulcerations. Numerous clinical reports and retrospective studies have demonstrated the clinical effectiveness of each of these modalities. Over the years, there has been increased evidence to support the use of these modalities.

Nonetheless, use of those products or agents with robust RCTs or system­ atic reviews should generally be pre­ ferred over those without level 1 evidence (Table 12.2).

Negative-pressure wound therapy was

first introduced in the early to mid- 1990s. It has become especially useful in wound preparation for skin grafts and flaps and assists in the closure of deep, large wounds (95,96). A variety of types exist in the marketplace and range from electrically powered to mechanically

powered in different sizes depending upon the specific wound requirements.

Electrical stimulation, pulsed radio­ frequency energy, and extracorporeal shockwave therapy are biophysical mo­ dalities that are believed to upregulate growth factors or cytokines to stimulate wound healing, while low-frequency non­ contact ultrasound is used to debride wounds. However, most of the studies advocating the use of these modalities have been retrospective observational or poor-quality RCTs.

Hyperbaric oxygen therapy is the de­ livery of oxygen through a chamber, ei­ ther individual or multiperson, with the intention of increasing tissue oxygena­ tion to increase tissue perfusion and neovascularization, combat resistant bac­ teria, and stimulate wound healing. While there had been great interest in this modality being able to expedite healing of chronic diabetic foot ulcers (DFUs), there has only been one positive RCT published in the last decade that re­ ported increased healing rates at 9 and 12 months compared with control subjects (97). More recent studies with significant design deficiencies and par­ ticipant dropouts have failed to provide corroborating evidence that hyperbaric oxygen therapy should be widely used for managing nonhealing DFUs (98,99). While there may be some benefit in prevention of amputation in selected chronic neuroischemic ulcers, recent stud­ ies have shown no benefit in healing DFUs in the absence of ischemia and/ or infection (93,100).

Topical oxygen therapy has been studied rather vigorously in recent years, with several high-quality RCTs and at least five systematic reviews and meta­ analyses all supporting its efficacy in healing chronic DFUs at 12 weeks (19,20,30-34,91,92,101-105). Three

types of topical oxygen devices are available, including continuous-delivery, low-constant-pressure, and cyclical­ pressure modalities. Importantly, topical oxygen therapy devices provide for home-based therapy rather than the need for daily visits to specialized cen­ ters. Very high participation with very few reported adverse events combined with improved healing rates makes this therapy another attractive option for ad­ vanced wound care.

If DFUs fail to heal despite appropriate wound care, adjunctive advanced thera­ pies should be instituted and are best managed in a multidisciplinary manner. Once healed, all individuals should be enrolled in a formal comprehensive prevention program focused on reducing the incidence of recurrent ulcerations and subsequent amputations (75,106,107).


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