AGP Report: Continuous Glucose Monitoring
12. Retinopathy, Neuropathy, and Foot Care: Standards of Medical
Care in Diabetes—2022
Diabetes Care 2022;45(Suppl. 1):S185–S194 | https://doi.org/10.2337/dc22-S012
American Diabetes Association Professional Practice Committee*
The American Diabetes Association (ADA) “Standards of Medical Care in Dia-betes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Profes-sional Practice Committee, a multidisciplinary expert committee (https://doi .org/10.2337/dc22-SPPC), 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, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). 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” (https://doi.org/
10.2337/dc22-S014).
DIABETIC RETINOPATHY Recommendations
12.1 Optimize glycemic control to reduce the risk or slow the progression of diabetic retinopathy.A
12.2 Optimize blood pressure and serum lipid control to reduce the risk or slow the progression of diabetic retinopathy.A
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 disorders of the eye 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
*A complete list of members of the American Diabetes Association Professional Practice Committee can be found at https://doi.org/
10.2337/dc22-SPPC.
Suggested citation: American Diabetes Association Professional Practice Committee. 12. Retinopathy, neuropathy, and foot care: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022;
45(Suppl. 1):S185–S194
© 2021 by the American Diabetes Association.
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12.RETINOPATHY,NEUROPATHY,ANDFOOTCARE
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agonist (GLP-1 RA) treatment and reti-nopathy per se, except through the asso-ciation between retinopathy and average A1C reduction at the 3-month and 1-year follow-up. Long-term impact of improved glycemic control on retinopathy was not studied in these trials. Retinopathy status should be assessed when intensifying glu-cose-lowering therapies such as those using GLP-1 RAs (11).
Several case series and a controlled prospective study suggest that pregnancy in patients with type 1 diabetes may agg-ravate retinopathy and threaten vision, especially when glycemic control is poor or retinopathy severity is advanced at the time of conception (12,13). Laser photo-coagulation surgery can minimize the risk of vision loss during pregnancy for patients with high-risk proliferative dia-betic retinopathy (PDR) or center-involved diabetic macular edema (13). Anti –vascu-lar endothelial growth factor (anti-VEGF) medications should not be used in preg-nant patients with diabetes because of theoretical risks to the vasculature of the developing fetus.
Screening
Recommendations
12.3 Adults with type 1 diabetes should have an initial dilated and comprehensive eye exam-ination by an ophthalmologist or optometrist within 5 years after the onset of diabetes.B 12.4 Patients with type 2 diabetes
should have an initial dilated and comprehensive eye exam-ination by an ophthalmologist or optometrist at the time of the diabetes diagnosis.B 12.5 If there is no evidence of
reti-nopathy for one or more annual eye exams and glycemia is well controlled, then screening every 1–2 years may be considered. If any level of diabetic retinopathy is present, subsequent dilated retinal examinations should be repeated at least annually by an ophthalmologist or optometrist.
If retinopathy is progressing or sight-threatening, then examina-tions will be required more fre-quently.B
12.6 Programs that use retinal pho-tography (with remote reading
or use of a validated assessment tool) to improve access to dia-betic retinopathy screening can be appropriate screening strate-gies for diabetic retinopathy.
Such programs need to provide pathways for timely referral for a comprehensive eye examina-tion when indicated.B
12.7 Women with preexisting type 1 or type 2 diabetes who are plan-ning pregnancy or who are pregnant should be counseled on the risk of development and/
or progression of diabetic reti-nopathy.B
12.8 Eye examinations should occur before pregnancy or in the first trimester in patients with preexisting type 1 or type 2 diabetes, and then patients should be monitored every tri-mester and for 1 year postpar-tum as indicated by the degree of retinopathy.B
The preventive effects of therapy and the fact that patients with PDR or macu-lar edema may be asymptomatic pro-vide strong support for screening to detect diabetic retinopathy. Prompt diagnosis allows triage of patients and timely intervention that may prevent vision loss in patients who are asymp-tomatic 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 (14) (see Section 14,
“Children and Adolescents,” https://doi .org/10.2337/dc22-S014). If diabetic reti-nopathy is evident on screening, prompt referral to an ophthalmologist is recom-mended. Subsequent examinations for patients with type 1 or type 2 diabetes are generally repeated annually for patients with minimal to no retinopathy.
Exams every 1–2 years may be cost-effec-tive after one or more normal eye exams.
In a population with well-controlled type 2 diabetes, there was little risk of develop-ment of significant retinopathy with a 3-year interval after a normal examination (15), and less frequent intervals have been found in simulated modeling to be
potentially effective in screening for betic retinopathy in patients without dia-betic retinopathy (16). However, it is important to adjust screening intervals based on the presence of specific risk fac-tors for retinopathy onset and worsening retinopathy. More frequent examinations by the ophthalmologist will be required if retinopathy is progressing or risk factors such as uncontrolled hyperglycemia or 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 (17–19). High-quality fun-dus photographs can detect most clini-cally significant diabetic retinopathy.
Interpretation of the images should be performed by a trained eye care provider.
Retinal photography may also enhance efficiency and reduce costs when the expertise of ophthalmologists can be used for more complex examinations and for therapy (17,20,21). In-person exams are still necessary when the retinal pho-tos are of unacceptable quality and for follow-up if abnormalities are detected.
Retinal photos are not a substitute for dilated comprehensive eye exams, which should be performed at least initially and at intervals thereafter as recommended by an eye care professional. Artificial intelligence systems that detect more than mild diabetic retinopathy and dia-betic macular edema, authorized for use by the U.S. Food and Drug Administration (FDA), represent an alternative to tradi-tional screening approaches (22). How-ever, 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 referring health care professional.
Type 1 Diabetes
Because retinopathy is estimated to take at least 5 years to develop after the onset of hyperglycemia, patients with type 1 diabetes should have an initial dilated and comprehensive eye examination within 5 years after the diagnosis of dia-betes (23).
Type 2 Diabetes
Patients with type 2 diabetes who may have had years of undiagnosed diabetes and have a significant risk of prevalent
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diabetic retinopathy at the time of diag-nosis should have an initial dilated and comprehensive eye examination at the time of diagnosis.
Pregnancy
Pregnancy is associated with a rapid pro-gression of diabetic retinopathy (24,25).
Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic retinopa-thy. In addition, rapid implementation of intensive glycemic management in the setting of retinopathy is associated with early worsening of retinopathy (13).
Women who develop gestational diabe-tes mellitus do not require eye examina-tions during pregnancy and do not appear to be at increased risk of devel-oping diabetic retinopathy during preg-nancy (26).
Treatment
Recommendations
12.9 Promptly refer patients with any level of diabetic macular edema, moderate or worse nonproliferative diabetic reti-nopathy (a precursor of prolif-erative diabetic retinopathy), or any proliferative diabetic retinopathy to an ophthalmol-ogist who is knowledgeable and experienced in the man-agement of diabetic retinopa-thy.A
12.10 Panretinal laser photocoagu-lation therapy is indicated to reduce the risk of vision loss in patients with high-risk proliferative diabetic retinop-athy and, in some cases, severe nonproliferative dia-betic retinopathy.A
12.11 Intravitreous injections of anti–
vascular endothelial growth fac-tor are a reasonable alternative to traditional panretinal laser photocoagulation for some patients with proliferative dia-betic retinopathy and also reduce the risk of vision loss in these patients.A
12.12 Intravitreous injections of anti–vascular endothelial growth factor are indicated asfirst-line treatment for most eyes with
diabetic macular edema that involves the foveal center and impairs vision acuity.A
12.13 Macular focal/grid photocoagula-tion and intravitreal injecphotocoagula-tions of corticosteroid are reasonable treatments in eyes with persis-tent diabetic macular edema despite previous anti–vascular endothelial growth factor ther-apy or eyes that are not candi-dates for this first-line appro-ach.A
12.14 The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as aspirin does not increase the risk of retinal hemorrhage.A
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 patients with PDR and the Early Treatment Diabetic Reti-nopathy Study (ETDRS) in patients with macular edema, provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRS (27) 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 vit-reous hemorrhage). In 1985, the ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR and in older-onset patients with severe nonproliferative diabetic retinopathy or less-than-high-risk PDR.
Panretinal laser photocoagulation is still commonly used to manage com-plications of diabetic retinopathy that involve retinal neovascularization and its complications. A more gentle, mac-ular focal/grid laser photocoagulation technique was shown in the ETDRS to be effective in treating eyes with clini-cally significant macular edema from diabetes (28), but this is now largely considered to be second-line treat-ment for diabetic macular edema.
Anti–Vascular Endothelial Growth Factor Treatment
Data from the DRCR Retina Network (for-merly the Diabetic Retinopathy Clinical Research Network) and others demon-strate that intravitreal injections of anti-VEGF agents are effective at regressing proliferative disease and lead to noninfe-rior or supenoninfe-rior visual acuity outcomes compared with panretinal laser over 2 years of follow-up (29,30). In addition, it was observed that patients treated with ranibizumab tended to have less periph-eral visual field loss, fewer vitrectomy surgeries for secondary complications from their proliferative disease, 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 vis-its and received a greater number of treatments than is typically required for management with panretinal laser, which may not be optimal for some patients.
Other emerging therapies for retinopathy that may use sustained intravitreal deliv-ery of pharmacologic agents are currently under investigation. The FDA has approved aflibercept and ranibizumab for the treatment of eyes with diabetic reti-nopathy. Anti-VEGF treatment of eyes with nonproliferative 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 (31).
While the ETDRS (28) 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 intravitreal anti-VEGF agents provide a more effective treatment regimen for center-involved diabetic macular edema than monotherapy with laser (32,33).
Most patients require near-monthly administration of intravitreal therapy with anti-VEGF agents during the first 12 months of treatment, with fewer injec-tions needed in subsequent years to maintain remission from central-involved diabetic macular edema. There are cur-rently three anti-VEGF agents commonly used to treat eyes with central-involved
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diabetic macular edema—bevacizumab, ranibizumab, and aflibercept (1)—and a comparative effectiveness study demon-strated that aflibercept provides vision outcomes superior to those of bevacizu-mab when eyes have moderate visual impairment (vision of 20/50 or worse) from diabetic macular edema (34). For eyes that have good vision (20/25 or bet-ter) despite diabetic macular edema, close monitoring with initiation of anti-VEGF therapy if vision worsens provides similar 2-year vision outcomes compared with immediate initiaion of anti-VEGF therapy (35).
Eyes that have persistent diabetic mac-ular edema despite anti-VEGF treatment may benefit from macular laser photoco-agulation or intravitreal therapy with cor-ticosteroids. Both of these therapies are also reasonable first-line approaches for patients who are not candidates for anti-VEGF treatment due to systemic consider-ations 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 patients with dyslipidemia, retinopathy progression may be slowed by the addition of feno fi-brate, particularly with very mild nonpro-liferative diabetic retinopathy at baseline (36,37).
NEUROPATHY Screening
Recommendations
12.15 All patients should be assessed for diabetic peripheral neurop-athy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter.B
12.16 Assessment for distal symmetric polyneuropathy should include a careful history and assess-ment of either temperature or pinprick sensation (small fiber function) and vibration sensa-tion using a 128-Hz tuning fork (for large-fiber function).
All patients should have annual 10-g monofilament testing to identify feet at risk
for ulceration and amputa-tion.B
12.17 Symptoms and signs of auto-nomic neuropathy should be assessed in patients with microvascular complications.E
The diabetic neuropathies are a hetero-geneous group of disorders with diverse clinical manifestations. The early recog-nition and appropriate management of neuropathy in the patient with diabetes is important.
1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with dia-betes and may be treatable.
2. Up to 50% of diabetic peripheral neuropathy may be asymptomatic.
If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet.
3. Recognition and treatment of auto-nomic neuropathy may improve symp-toms, reduce sequelae, and improve quality of life.
Specific treatment for the underlying nerve damage, other than improved gly-cemic control, is currently not available.
Glycemic control can effectively prevent diabetic peripheral neuropathy (DPN) and cardiac autonomic neuropathy (CAN) in type 1 diabetes (38,39) and may modestly slow their progression in type 2 diabetes (40), but it does not reverse neuronal loss. Therapeutic strategies (pharmaco-logic and nonpharmaco(pharmaco-logic) for the relief of painful DPN and symptoms of auto-nomic neuropathy can potentially reduce pain (41) and improve quality of life.
Diagnosis
Diabetic Peripheral Neuropathy
Patients with type 1 diabetes for 5 or more years and all patients with type 2 diabetes should be assessed annually for DPN using the medical history and simple clinical tests (41). Symptoms vary accord-ing to the class of sensoryfibers involved.
The most common early symptoms are induced by the involvement of small fibers and include pain and dysesthesia (unpleasant sensations of burning and tingling). The involvement of largefibers may cause numbness and loss of
protective sensation (LOPS). LOPS indi-cates 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 function and protective sensation:
1. Small-fiber function: pinprick and temperature sensation.
2. Large-fiber function: vibration per-ception and 10-g monofilament.
3. Protective sensation: 10-g mono-filament.
These tests not only screen for the presence of dysfunction but also predict future risk of complications. Electro-physiological testing or referral to a neurologist is rarely needed, except in situations where the clinical features are atypical or the diagnosis is unclear.
In all patients with diabetes and DPN, causes of neuropathy other than diabetes should be considered, including toxins (e.g., alcohol), neurotoxic medications (e.g., chemotherapy), vitamin B12 de fi-ciency, hypothyroidism, renal disease, malignancies (e.g., multiple myeloma, bronchogenic carcinoma), infections (e.g., HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (42). See the American Diabetes Association position statement “Diabetic Neuropathy” for more details (41).
Diabetic Autonomic Neuropathy
The symptoms and signs of autonomic neuropathy should be elicited carefully dur-ing the history and physical examination.
Major clinical manifestations of diabetic autonomic neuropathy include hypoglyce-mia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, con-stipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating.
Cardiac Autonomic Neuropathy. CAN is associated with mortality independently of other cardiovascular risk factors (43,44). 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 tachy-cardia (>100 bpm) and orthostatic hypotension (a fall in systolic or diastolic
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blood pressure by >20 mmHg or >10 mmHg, respectively, upon standing without an appropriate increase in heart rate). CAN treatment is generally focused on alleviating symptoms.
Gastrointestinal Neuropathies. Gastro-intestinal neuropathies may involve any portion 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 without another identified cause. Exclusion of organic causes of gastric outlet obstruc-tion or peptic ulcer disease (with esopha-gogastroduodenoscopy 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 emerging as a viable alternative.
Genitourinary Disturbances. Diabetic autonomic neuropathy may also cause genitourinary disturbances, including sex-ual dysfunction and bladder dysfunction.
In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation (41). 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 (45).
Lower urinary tract symptoms manifest as urinary incontinence and bladder dys-function (nocturia, frequent urination, urination urgency, and weak urinary stream). Evaluation of bladder function should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, inconti-nence, or a palpable bladder.
Treatment
Recommendations
12.18 Optimize glucose control to prevent or delay the develop-ment of neuropathy in patients with type 1 diabetes Aand to slow the progression
of neuropathy in patients with type 2 diabetes.B 12.19 Assess and treat patients to
reduce pain related to dia-betic peripheral neuropathyB and symptoms of autonomic neuropathy and to improve quality of life.E
12.20 Pregabalin, duloxetine, or gaba-pentin are recommended as initial pharmacologic treat-ments for neuropathic pain in diabetes.A
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 patients with type 1 diabetes (46–49). Although the evidence for the benefit of near-normal glycemic control is not as strong for type 2 diabetes, some studies have demonstrated a mod-est slowing of progression without rever-sal of neuronal loss (40,50). Specific glucose-lowering strategies may have dif-ferent effects. In a post hoc analysis, par-ticipants, particularly men, in the Bypass Angioplasty Revascularization Investiga-tion in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower incidence of distal symmetric poly-neuropathy over 4 years than those treated with insulin/sulfonylurea (51).
Neuropathic Pain
Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dys-function (52). 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 (53).
Pregabalin and duloxetine have received regulatory approval by the FDA, Health Canada, and the European Medi-cines Agency for the treatment of neuro-pathic pain in diabetes. The opioid tapentadol has regulatory approval in the U.S. and Canada, but the evidence of its use is weaker (54). Comparative effective-ness studies and trials that include qual-ity-of-life outcomes are rare, so treatment decisions must consider each patient’s presentation and comorbidities and often
follow a trial-and-error approach. Given the range of partially effective treatment options, a tailored and stepwise pharmaco-logic strategy with careful attention to rela-tive symptom improvement, medication adherence, and medication side effects is recommended to achieve pain reduction and improve quality of life (55–57).
Pregabalin, a calcium channel a2-d subunit ligand, is the most extensively studied drug for DPN. The majority of studies testing pregabalin have reported favorable effects on the pro-portion of participants with at least 30–50% improvement in pain (54,56, 58–61). However, not all trials with pre-gabalin have been positive (54,56,62,63), especially when treating patients with advanced refractory DPN (60). Adverse effects may be more severe in older patients (64) and may be attenuated by lower starting doses and more gradual titration. The related drug, gabapentin, has also shown efficacy for pain control in diabetic neuropathy and may be less expensive, although it is not FDA approved for this indication (65).
Duloxetine is a selective norepineph-rine and serotonin reuptake inhibitor.
Doses of 60 and 120 mg/day showed efficacy in the treatment of pain associ-ated with DPN in multicenter random-ized trials, although some of these had high drop-out rates (54,56,61,63).
Duloxetine also appeared to improve neuropathy-related quality of life (66).
In longer-term studies, a small increase in A1C was reported in people with dia-betes treated with duloxetine compared with placebo (67). Adverse events may be more severe in older people but may be attenuated with lower doses and slower titration of duloxetine.
Tapentadol is a centrally acting opioid analgesic that exerts its analgesic effects through both m-opioid receptor agonism and noradrenaline reuptake inhibition.
Extended-release tapentadol was approved by the FDA for the treatment of neuro-pathic pain associated with diabetes based on data from two multicenter clini-cal trials in which participants titrated to an optimal dose of tapentadol were ran-domly assigned to continue that dose or switch to placebo (68,69). However, both used a design enriched for patients who responded to tapentadol, and therefore their results are not generalizable. A recent systematic review and meta-analy-sis by the Special Interest Group on
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