The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” 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 Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-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/dc21-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 adolescents, please refer to Section 13 “Children and Adolescents” (https://doi.org/10.2337/dc21-S013).

Screening

Recommendations

  • 11.1a At least annually, urinary albumin (e.g., spot urinary albumin-to-creatinine ratio) and estimated glomerular filtration rate should be assessed in patients with type 1 diabetes with duration of ≥5 years and in all patients with type 2 diabetes regardless of treatment. B

  • 11.1b Patients with diabetes and urinary albumin >300 mg/g creatinine and/or an estimated glomerular filtration rate 30–60 mL/min/1.73 m2 should be monitored twice annually to guide therapy. B

Treatment

Recommendations

  • 11.2 Optimize glucose control to reduce the risk or slow the progression of chronic kidney disease. A

  • 11.3a For patients with type 2 diabetes and diabetic kidney disease, consider use of a sodiumglucose cotransporter 2 inhibitor in patients with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 and urinary albumin >300 mg/g creatinine. A

  • 11.3b In patients with type 2 diabetes and diabetic kidney disease, consider use of sodium–glucose cotransporter 2 inhibitors additionally for cardiovascular risk reduction when estimated glomerular filtration rate and urinary albumin creatinine are ≥30 mL/min/1.73 m2 or >300 mg/g, respectively. A

  • 11.3c In patients with chronic kidney disease who are at increased risk for cardiovascular events, use of a glucagon-like peptide 1 receptor agonist reduces renal end point, primarily albuminuria, progression of albuminuria, and cardiovascular events (Table 9.1). A

  • 11.4 Optimize blood pressure control to reduce the risk or slow the progression of chronic kidney disease. A

  • 11.5 Do not discontinue renin-angiotensin system blockade for minor increases in serum creatinine (<30%) in the absence of volume depletion. A

  • 11.6 For people with nondialysis-dependent chronic kidney disease, dietary protein intake should be approximately 0.8 g/kg body weight per day (the recommended daily allowance). A For patients on dialysis, higher levels of dietary protein intake should be considered, since malnutrition is a major problem in some dialysis patients. B

  • 11.7 In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an angiotensin receptor blocker is recommended for those with modestly elevated urinary albumin-to-creatinine ratio (30299 mg/g creatinine) B and is strongly recommended for those with urinary albumin-to-creatinine ratio ≥300 mg/g creatinine and/or estimated glomerular filtration rate <60 mL/min/1.73 m2. A

  • 11.8 Periodically monitor serum creatinine and potassium levels for the development of increased creatinine or changes in potassium when ACE inhibitors, angiotensin receptor blockers, or diuretics are used. B

  • 11.9 An ACE inhibitor or an angiotensin receptor blocker is not recommended for the primary prevention of chronic kidney disease in patients with diabetes who have normal blood pressure, normal urinary albumin-to-creatinine ratio (<30 mg/g creatinine), and normal estimated glomerular filtration rate. A

  • 11.10 Patients should be referred for evaluation by a nephrologist if they have an estimated glomerular filtration rate <30 mL/min/1.73 m2. A

  • 11.11 Promptly refer to a physician experienced in the care of kidney disease for uncertainty about the etiology of kidney disease, difficult management issues, and rapidly progressing kidney disease. A

Epidemiology of Diabetes and Chronic Kidney Disease

Chronic kidney disease (CKD) is diagnosed by the persistent presence of elevated urinary albumin excretion (albuminuria), low estimated glomerular filtration rate (eGFR), or other manifestations of kidney damage (1,2). In this section, the focus is on CKD attributed to diabetes (diabetic kidney disease), which occurs in 20–40% of patients with diabetes (1,35). CKD typically develops after diabetes duration of 10 years in type 1 diabetes but may be present at diagnosis of type 2 diabetes. CKD can progress to end-stage renal disease (ESRD) requiring dialysis or kidney transplantation and is the leading cause of ESRD in the U.S. (6). In addition, among people with type 1 or 2 diabetes, the presence of CKD markedly increases cardiovascular risk and health care costs (7).

Assessment of Albuminuria and Estimated Glomerular Filtration Rate

Screening for albuminuria can be most easily performed by urinary albumin-to-creatinine ratio (UACR) in a random spot urine collection (1,2). Timed or 24-h collections are more burdensome and add little to prediction or accuracy. Measurement of a spot urine sample for albumin alone (whether by immunoassay or by using a sensitive dipstick test specific for albuminuria) without simultaneously measuring urine creatinine (Cr) is less expensive but susceptible to false-negative and false-positive determinations as a result of variation in urine concentration due to hydration (8).

Normal UACR is defined as <30 mg/g Cr, and high urinary albumin excretion is defined as ≥30 mg/g Cr. However, UACR is a continuous measurement, and differences within the normal and abnormal ranges are associated with renal and cardiovascular outcomes (7,9,10). Furthermore, because of high biological variability of >20% between measurements in urinary albumin excretion, two of three specimens of UACR collected within a 3- to 6-month period should be abnormal before considering a patient to have high or very high albuminuria (1,2,11,12). Exercise within 24 h, infection, fever, congestive heart failure, marked hyperglycemia, menstruation, and marked hypertension may elevate UACR independently of kidney damage (13).

eGFR should be calculated from serum creatinine using a validated formula. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is generally preferred (2). eGFR is routinely reported by laboratories with serum creatinine, and eGFR calculators are available online at nkdep.nih.gov. An eGFR persistently <60 mL/min/1.73 m2 is considered abnormal, though optimal thresholds for clinical diagnosis are debated in older adults (2,14).

Diagnosis of Diabetic Kidney Disease

Diabetic kidney disease is usually a clinical diagnosis made based on the presence of albuminuria and/or reduced eGFR in the absence of signs or symptoms of other primary causes of kidney damage. The typical presentation of diabetic kidney disease is considered to include a long-standing duration of diabetes, retinopathy, albuminuria without gross hematuria, and gradually progressive loss of eGFR. However, signs of CKD may be present at diagnosis or without retinopathy in type 2 diabetes, and reduced eGFR without albuminuria has been frequently reported in type 1 and type 2 diabetes and is becoming more common over time as the prevalence of diabetes increases in the U.S. (3,4,15,16).

An active urinary sediment (containing red or white blood cells or cellular casts), rapidly increasing albuminuria or nephrotic syndrome, rapidly decreasing eGFR, or the absence of retinopathy (in type 1 diabetes) suggests alternative or additional causes of kidney disease. For patients with these features, referral to a nephrologist for further diagnosis, including the possibility of kidney biopsy, should be considered. It is rare for patients with type 1 diabetes to develop kidney disease without retinopathy. In type 2 diabetes, retinopathy is only moderately sensitive and specific for CKD caused by diabetes, as confirmed by kidney biopsy (17).

Staging of Chronic Kidney Disease

Stages 1–2 CKD have been defined by evidence of high albuminuria with eGFR ≥60 mL/min/1.73 m2, while stages 3–5 CKD have been defined by progressively lower ranges of eGFR (18) (Fig. 11.1). At any eGFR, the degree of albuminuria is associated with risk of cardiovascular disease (CVD), CKD progression, and mortality (7). Therefore, Kidney Disease: Improving Global Outcomes (KDIGO) recommends a more comprehensive CKD staging that incorporates albuminuria at all stages of eGFR; this system is more closely associated with risk but is also more complex and does not translate directly to treatment decisions (2). Thus, based on the current classification system, both eGFR and albuminuria must be quantified to guide treatment decisions. This is also important since eGFR levels are essential to modify drug dosage or restrictions of use (Fig. 11.1) (19,20). The degree of albuminuria may influence choice of antihypertensive (see Section 10 “Cardiovascular Disease and Risk Management,” https://doi.org/10.2337/dc21-S010) or glucose-lowering medications (see below). Observed history of eGFR loss (which is also associated with risk of CKD progression and other adverse health outcomes) and cause of kidney damage (including possible causes other than diabetes) may also affect these decisions (21).

Figure 11.1

Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular filtration rate (GFR) and albuminuria. The GFR and albuminuria grid depicts the risk of progression, morbidity, and mortality by color, from best to worst (green, yellow, orange, red, dark red). The numbers in the boxes are a guide to the frequency of visits (number of times per year). Green can reflect CKD with normal eGFR and albumin-to-creatinine ratio only in the presence of other markers of kidney damage, such as imaging showing polycystic kidney disease or kidney biopsy abnormalities, with follow-up measurements annually; yellow requires caution and measurements at least once per year; orange requires measurements twice per year; red requires measurements three times per year; and dark red requires measurements four times per year. These are general parameters only, based on expert opinion, and underlying comorbid conditions and disease state as well as the likelihood of impacting a change in management for any individual patient must be taken into account. “Refer” indicates that nephrology services are recommended. *Referring clinicians may wish to discuss with their nephrology service, depending on local arrangements regarding treating or referring. Reprinted with permission from Vassalotti et al. (22).

Figure 11.1

Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular filtration rate (GFR) and albuminuria. The GFR and albuminuria grid depicts the risk of progression, morbidity, and mortality by color, from best to worst (green, yellow, orange, red, dark red). The numbers in the boxes are a guide to the frequency of visits (number of times per year). Green can reflect CKD with normal eGFR and albumin-to-creatinine ratio only in the presence of other markers of kidney damage, such as imaging showing polycystic kidney disease or kidney biopsy abnormalities, with follow-up measurements annually; yellow requires caution and measurements at least once per year; orange requires measurements twice per year; red requires measurements three times per year; and dark red requires measurements four times per year. These are general parameters only, based on expert opinion, and underlying comorbid conditions and disease state as well as the likelihood of impacting a change in management for any individual patient must be taken into account. “Refer” indicates that nephrology services are recommended. *Referring clinicians may wish to discuss with their nephrology service, depending on local arrangements regarding treating or referring. Reprinted with permission from Vassalotti et al. (22).

Acute Kidney Injury

Acute kidney injury (AKI) is diagnosed by a 50% or greater sustained increase in serum creatinine over a short period of time, which is also reflected as a rapid decrease in eGFR (23,24). People with diabetes are at higher risk of AKI than those without diabetes (25). Other risk factors for AKI include preexisting CKD, the use of medications that cause kidney injury (e.g., nonsteroidal anti-inflammatory drugs), and the use of medications that alter renal blood flow and intrarenal hemodynamics. In particular, many antihypertensive medications (e.g., diuretics, ACE inhibitors, and angiotensin receptor blockers [ARBs]) can reduce intravascular volume, renal blood flow, and/or glomerular filtration. There was concern that sodium–glucose cotransporter 2 (SGLT2) inhibitors may promote AKI through volume depletion, particularly when combined with diuretics or other medications that reduce glomerular filtration; however, this has not been found to be true in randomized clinical outcome trials of advanced kidney disease (26) or high cardiovascular disease risk with normal kidney function (2729). Timely identification and treatment of AKI is important because AKI is associated with increased risks of progressive CKD and other poor health outcomes (30).

Small elevations in serum creatinine (up to 30% from baseline) with renin-angiotensin system blockers (such as ACE inhibitors and ARBs) must not be confused with AKI (31). An analysis of the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) trial demonstrates that those randomized to intensive blood pressure lowering with up to a 30% increase in serum creatinine did not have any increase in mortality or progressive kidney disease (3236). Moreover, a measure of markers for AKI showed no significant increase of any markers with increased creatinine (34). Accordingly, ACE inhibitors and ARBs should not be discontinued for minor increases in serum creatinine (<30%), in the absence of volume depletion.

Surveillance

Albuminuria and eGFR should be monitored regularly to enable timely diagnosis of CKD, monitor progression of CKD, detect superimposed kidney diseases including AKI, assess risk of CKD complications, dose drugs appropriately, and determine whether nephrology referral is needed. Among people with existing kidney disease, albuminuria and eGFR may change due to progression of CKD, development of a separate superimposed cause of kidney disease, AKI, or other effects of medications, as noted above. Serum potassium should also be monitored for patients treated with ACE inhibitors, ARBs, and diuretics because these medications can cause hyperkalemia or hypokalemia, which are associated with cardiovascular risk and mortality (3739). For patients with eGFR <60 mL/min/1.73 m2, appropriate medication dosing should be verified, exposure to nephrotoxins (e.g., nonsteroidal anti-inflammatory drugs and iodinated contrast) should be minimized, and potential CKD complications should be evaluated (Table 11.1).

Table 11.1

Selected complications of chronic kidney disease

ComplicationMedical and laboratory evaluation
Elevated blood pressure >140/90 mmHg Blood pressure, weight 
Volume overload History, physical examination, weight 
Electrolyte abnormalities Serum electrolyte 
Metabolic acidosis Serum electrolytes 
Anemia Hemoglobin; iron testing if indicated 
Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D 
ComplicationMedical and laboratory evaluation
Elevated blood pressure >140/90 mmHg Blood pressure, weight 
Volume overload History, physical examination, weight 
Electrolyte abnormalities Serum electrolyte 
Metabolic acidosis Serum electrolytes 
Anemia Hemoglobin; iron testing if indicated 
Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D 

Complications of chronic kidney disease (CKD) generally become prevalent when estimated glomerular filtration rate falls below 60 mL/min/1.73 m2 (stage 3 CKD or greater) and become more common and severe as CKD progresses. Evaluation of elevated blood pressure and volume overload should occur at every clinical contact possible; laboratory evaluations are generally indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage 4 CKD, and every 1–3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in therapy. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.

The need for annual quantitative assessment of albumin excretion after diagnosis of albuminuria, institution of ACE inhibitors or ARB therapy, and achievement of blood pressure control is a subject of debate. Continued surveillance can assess both response to therapy and disease progression and may aid in assessing adherence to ACE inhibitor or ARB therapy. In addition, in clinical trials of ACE inhibitors or ARB therapy in type 2 diabetes, reducing albuminuria from levels ≥300 mg/g Cr has been associated with improved renal and cardiovascular outcomes, leading some to suggest that medications should be titrated to minimize UACR. However, this approach has not been formally evaluated in prospective trials. In type 1 diabetes, remission of albuminuria may occur spontaneously, and cohort studies evaluating associations of change in albuminuria with clinical outcomes have reported inconsistent results (40,41).

The prevalence of CKD complications correlates with eGFR (42). When eGFR is <60 mL/min/1.73 m2, screening for complications of CKD is indicated (Table 11.1). Early vaccination against hepatitis B virus is indicated in patients likely to progress to ESRD (see Section 4 “Comprehensive Medical Evaluation and Assessment of Comorbidities,” https://doi.org/10.2337/dc21-S004, for further information on immunization).

Interventions

Nutrition

For people with nondialysis-dependent CKD, dietary protein intake should be ∼0.8 g/kg body weight per day (the recommended daily allowance) (1). Compared with higher levels of dietary protein intake, this level slowed GFR decline with evidence of a greater effect over time. Higher levels of dietary protein intake (>20% of daily calories from protein or >1.3 g/kg/day) have been associated with increased albuminuria, more rapid kidney function loss, and CVD mortality and therefore should be avoided. Reducing the amount of dietary protein below the recommended daily allowance of 0.8 g/kg/day is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline (43).

Restriction of dietary sodium (to <2,300 mg/day) may be useful to control blood pressure and reduce cardiovascular risk (44,45), and restriction of dietary potassium may be necessary to control serum potassium concentration (25,3739). These interventions may be most important for patients with reduced eGFR, for whom urinary excretion of sodium and potassium may be impaired. For patients on dialysis, higher levels of dietary protein intake should be considered, since malnutrition is a major problem in some dialysis patients (46). Recommendations for dietary sodium and potassium intake should be individualized on the basis of comorbid conditions, medication use, blood pressure, and laboratory data.

Glycemic Targets

Intensive glycemic control with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to delay the onset and progression of albuminuria and reduced eGFR in patients with type 1 diabetes (47,48) and type 2 diabetes (1,4955). Insulin alone was used to lower blood glucose in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study of type 1 diabetes, while a variety of agents were used in clinical trials of type 2 diabetes, supporting the conclusion that glycemic control itself helps prevent CKD and its progression. The effects of glucose-lowering therapies on CKD have helped define A1C targets (see Table 6.2).

The presence of CKD affects the risks and benefits of intensive glycemic control and a number of specific glucose-lowering medications. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of type 2 diabetes, adverse effects of intensive glycemic control (hypoglycemia and mortality) were increased among patients with kidney disease at baseline (56,57). Moreover, there is a lag time of at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes for the effects of intensive glucose control to manifest as improved eGFR outcomes (53,58,59). Therefore, in some patients with prevalent CKD and substantial comorbidity, target A1C levels may be less intensive (1,60).

Direct Renal Effects of Glucose-Lowering Medications

Some glucose-lowering medications also have effects on the kidney that are direct, i.e., not mediated through glycemia. For example, SGLT2 inhibitors reduce renal tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, and albuminuria and slow GFR loss through mechanisms that appear independent of glycemia (28,6164). Moreover, recent data support the notion that SGLT2 inhibitors reduce oxidative stress in the kidney by >50% and blunt increases in angiotensinogen as well as reduce NLRP3 inflammasome activity (6567). Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) also have direct effects on the kidney and have been reported to improve renal outcomes compared with placebo (6871). Renal effects should be considered when selecting antihyperglycemia agents (see Section 9 “Pharmacologic Approaches to Glycemic Treatment,” https://doi.org/10.2337/dc21-S009).

Selection of Glucose-Lowering Medications for Patients With Chronic Kidney Disease

For patients with type 2 diabetes and established CKD, special considerations for the selection of glucose-lowering medications include limitations to available medications when eGFR is diminished and a desire to mitigate high risks of CKD progression, CVD, and hypoglycemia (72,73). Drug dosing may require modification with eGFR <60 mL/min/1.73 m2 (1).

The U.S. Food and Drug Administration (FDA) revised its guidance for the use of metformin in CKD in 2016 (74), recommending use of eGFR instead of serum creatinine to guide treatment and expanding the pool of patients with kidney disease for whom metformin treatment should be considered. The revised FDA guidance states that metformin is contraindicated in patients with an eGFR <30 mL/min/1.73 m2; eGFR should be monitored while taking metformin; the benefits and risks of continuing treatment should be reassessed when eGFR falls to <45 mL/min/1.73 m2 (75,76); metformin should not be initiated for patients with an eGFR <45 mL/min/1.73 m2; and metformin should be temporarily discontinued at the time of or before iodinated contrast imaging procedures in patients with eGFR 30–60 mL/min/1.73 m2. Within these constraints, metformin should be considered the first-line treatment for all patients with type 2 diabetes, including those with CKD.

SGLT2 inhibitors and GLP-1 RAs should be considered for patients with type 2 diabetes and CKD who require another drug added to metformin to attain target A1C or cannot use or tolerate metformin. SGLT2 inhibitors reduce risks of CKD progression, CVD events, and hypoglycemia. GLP-1 RAs are suggested because they reduce risks of CVD events and hypoglycemia and appear to possibly slow CKD progression (77).

A number of large cardiovascular outcomes trials in patients with type 2 diabetes at high risk for CVD or with existing CVD examined kidney effects as secondary outcomes. These trials include EMPA-REG OUTCOME [BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients], CANVAS (Canagliflozin Cardiovascular Assessment Study), LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) (63,68,71,78). Specifically, compared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g Cr, doubling of serum creatinine, ESRD, or death from ESRD) by 39% and the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/min/1.73 m2 by 44%; canagliflozin reduced the risk of progression of albuminuria by 27% and the risk of reduction in eGFR, ESRD, or death from ESRD by 40%; liraglutide reduced the risk of new or worsening nephropathy (a composite of persistent macroalbuminuria, doubling of serum creatinine, ESRD, or death from ESRD) by 22%; and semaglutide reduced the risk of new or worsening nephropathy (a composite of persistent UACR >300 mg/g Cr, doubling of serum creatinine, or ESRD) by 36% (each P < 0.01).

These analyses were limited by evaluation of study populations not selected primarily for CKD and examination of renal effects as secondary outcomes. However, all of these trials included large numbers of people with stage 3a (eGFR 45–59 mL/min/1.73 m2) kidney disease. In addition, subgroup analyses of CANVAS and LEADER suggested that the renal benefits of canagliflozin and liraglutide were as great or greater for participants with CKD at baseline (29,70) and in CANVAS were similar for participants with or without atherosclerotic cardiovascular disease (ASCVD) at baseline (79).

Several large clinical trials of SGLT2 inhibitors focused on patients with advanced CKD, and assessment of primary renal outcomes are completed or ongoing. Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), a placebo-controlled trial of canagliflozin among 4,401 adults with type 2 diabetes, UACR ≥300 mg/g Cr, and mean eGFR 56 mL/min/1.73 m2 with a mean albuminuria level of over 900 mg/day, had a primary composite end point of ESRD, doubling of serum creatinine, or renal or cardiovascular death (26,80). It was stopped early due to positive efficacy and showed a 32% risk reduction for development of ESRD over control (26). Additionally, the development of the primary end point, which included chronic dialysis for ≥30 days, kidney transplantation or eGFR <15 mL/min/1.73 m2 sustained for ≥30 days by central laboratory assessment, doubling from the baseline serum creatinine average sustained for ≥30 days by central laboratory assessment, or renal death or cardiovascular death, was reduced by 30%. This benefit was on background ACE inhibitor or ARB therapy in >99% of the patients (26). Moreover, in this advanced CKD group, there were clear benefits on cardiovascular outcomes demonstrating a 31% reduction in cardiovascular death or heart failure hospitalization and a 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (26,81,82).

In addition to renal effects, some SGLT2 inhibitors and GLP-1 RAs have demonstrated cardiovascular benefits. Namely, in EMPA-REG OUTCOME, CANVAS, LEADER, and SUSTAIN-6, empagliflozin, canagliflozin, liraglutide, and semaglutide, respectively, each reduced cardiovascular events, evaluated as primary outcomes, compared with placebo (see Section 10 “Cardiovascular Disease and Risk Management,” https://doi.org/10.2337/dc21-S010 for further discussion). While the glucose-lowering effects of SGLT2 inhibitors are blunted with eGFR <45 mL/min/1.73 m2, the renal and cardiovascular benefits were still seen down to eGFR levels of 30 mL/min/1.73 m2 with no significant change in glucose (26,28,47,49,56,60,71,78). Most participants with CKD in these trials also had diagnosed ASCVD at baseline, though ∼28% of CANVAS participants with CKD did not have diagnosed ASCVD (29).

Based on evidence from the CREDENCE trial and secondary analyses of cardiovascular outcomes trials with SGLT2 inhibitors, cardiovascular and renal events are reduced with SGLT2 inhibitor use in patients down to an eGFR of 30 mL/min/1.73 m2, independent of glucose-lowering effects (81,82).

While there is clear cardiovascular risk reduction associated with GLP-1 RA use in patients with type 2 diabetes and CKD, the proof of benefit on renal outcome will come with the results of the ongoing FLOW (A Research Study to See How Semaglutide Works Compared with Placebo in People With Type 2 Diabetes and Chronic Kidney Disease) trial with injectable semaglutide (83). As noted above, published data address a limited group of CKD patients, mostly with coexisting ASCVD. Renal events have been examined, however, as both primary and secondary outcomes in published large trials. Also, adverse event profiles of these agents must be considered. Please refer to Table 9.1 for drug-specific factors, including adverse event information, for these agents. Additional clinical trials focusing on CKD and cardiovascular outcomes in CKD patients are ongoing and will be reported in the next few years.

For patients with type 2 diabetes and CKD, the selection of specific agents may depend on comorbidity and CKD stage. SGLT2 inhibitors may be more useful for patients at high risk of CKD progression (i.e., with albuminuria or a history of documented eGFR loss) (Fig. 9.1) because they appear to have large beneficial effects on CKD incidence. The SGLT2 inhibitors empagliflozin and dapagliflozin are approved by the FDA for use with eGFR ≥45 mL/min/1.73 m2 (though pivotal trials for each included participants with eGFR ≥30 mL/min/1.73 m2 and demonstrated benefit in subgroups with low eGFR) (28,29,84). Canagliflozin was recently approved to be started down to eGFR levels of 30 mL/min/1.73 m2. Some GLP-1 RAs may be used with lower eGFR, but most require dose adjustment.

Cardiovascular Disease and Blood Pressure

Hypertension is a strong risk factor for the development and progression of CKD (85). Antihypertensive therapy reduces the risk of albuminuria (8689), and among patients with type 1 or 2 diabetes with established CKD (eGFR <60 mL/min/1.73 m2 and UACR ≥300 mg/g Cr), ACE inhibitor or ARB therapy reduces the risk of progression to ESRD (9092). Moreover, antihypertensive therapy reduces risks of cardiovascular events (86).

Blood pressure levels <140/90 mmHg are generally recommended to reduce CVD mortality and slow CKD progression among all people with diabetes (89). Lower blood pressure targets (e.g., <130/80 mmHg) should be considered for patients based on individual anticipated benefits and risks. Patients with CKD are at increased risk of CKD progression (particularly those with albuminuria) and CVD and therefore may be suitable in some cases for lower blood pressure targets, especially in those with ≥300 mg/g Cr albuminuria.

ACE inhibitors or ARBs are the preferred first-line agent for blood pressure treatment among patients with diabetes, hypertension, eGFR <60 mL/min/1.73 m2, and UACR ≥300 mg/g Cr because of their proven benefits for prevention of CKD progression (9093). In general, ACE inhibitors and ARBs are considered to have similar benefits (94,95) and risks. In the setting of lower levels of albuminuria (30299 mg/g Cr), ACE inhibitor or ARB therapy has been demonstrated to reduce progression to more advanced albuminuria (≥300 mg/g Cr) and cardiovascular events but not progression to ESRD (93,96). While ACE inhibitors or ARBs are often prescribed for high albuminuria without hypertension, outcome trials have not been performed in this setting to determine whether this improves renal outcomes. Moreover, two long-term, double-blind studies demonstrate no renoprotective effect of either ACE inhibitors or ARBs in type 1 and type 2 diabetes among those who were normotensive with or without high albuminuria (formerly microalbuminuria) (97,98).

Absent kidney disease, ACE inhibitors or ARBs are useful to control blood pressure but have not proven superior to alternative classes of antihypertensive therapy, including thiazide-like diuretics and dihydropyridine calcium channel blockers (99). In a trial of people with type 2 diabetes and normal urine albumin excretion, an ARB reduced or suppressed the development of albuminuria but increased the rate of cardiovascular events (100). In a trial of people with type 1 diabetes exhibiting neither albuminuria nor hypertension, ACE inhibitors or ARBs did not prevent the development of diabetic glomerulopathy assessed by kidney biopsy (97). This was further supported by a similar trial in patients with type 2 diabetes (98). Therefore, ACE inhibitors or ARBs are not recommended for patients without hypertension to prevent the development of CKD.

Two clinical trials studied the combinations of ACE inhibitors and ARBs and found no benefits on CVD or CKD, and the drug combination had higher adverse event rates (hyperkalemia and/or AKI) (101,102). Therefore, the combined use of ACE inhibitors and ARBs should be avoided.

Mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) in combination with ACE inhibitors or ARBs remain an area of great interest. Mineralocorticoid receptor antagonists are effective for management of resistant hypertension, have been shown to reduce albuminuria in short-term studies of CKD, and may have additional cardiovascular benefits (103105). There has been, however, an increase in hyperkalemic episodes in those on dual therapy, and larger, longer trials with clinical outcomes are needed before recommending such therapy.

Referral to a Nephrologist

Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease, for difficult management issues (anemia, secondary hyperparathyroidism, metabolic bone disease, resistant hypertension, or electrolyte disturbances), or when there is advanced kidney disease (eGFR <30 mL/min/1.73 m2) requiring discussion of renal replacement therapy for ESRD (2). The threshold for referral may vary depending on the frequency with which a provider encounters patients with diabetes and kidney disease. Consultation with a nephrologist when stage 4 CKD develops (eGFR <30 mL/min/1.73 m2) has been found to reduce cost, improve quality of care, and delay dialysis (106). However, other specialists and providers should also educate their patients about the progressive nature of CKD, the kidney preservation benefits of proactive treatment of blood pressure and blood glucose, and the potential need for renal replacement therapy.

Recommendations

  • 11.12 Optimize glycemic control to reduce the risk or slow the progression of diabetic retinopathy. A

  • 11.13 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 (107). 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 associated with, retinopathy include chronic hyperglycemia (108), nephropathy (109), hypertension (110), and dyslipidemia (111). 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 and potentially improve patient reported visual function (50,112114).

Several case series and a controlled prospective study suggest that pregnancy in patients with type 1 diabetes may aggravate retinopathy and threaten vision, especially when glycemic control is poor at the time of conception (115,116). Laser photocoagulation surgery can minimize the risk of vision loss (116). However, intervention is not appropriate during pregnancy. This problem often resolves after pregnancy and so does not require treatment.

Screening

Recommendations

  • 11.14 Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes. B

  • 11.15 Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis. B

  • 11.16 If there is no evidence of retinopathy 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 examinations will be required more frequently. B

  • 11.17 Programs that use retinal photography (with remote reading or use of a validated assessment tool) to improve access to diabetic retinopathy screening can be appropriate screening strategies for diabetic retinopathy. Such programs need to provide pathways for timely referral for a comprehensive eye examination when indicated. B

  • 11.18 Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who are pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy. B

  • 11.19 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 trimester and for 1 year postpartum as indicated by the degree of retinopathy. B

The preventive effects of therapy and the fact that patients with proliferative diabetic retinopathy (PDR) or macular edema may be asymptomatic provide strong support for screening to detect diabetic retinopathy.

Diabetic retinopathy screening should be performed using validated approaches and methodologies. Youth with type 1 or type 2 diabetes are also at risk for complications and need to be screened for diabetic retinopathy (117). If diabetic retinopathy is evident on screening, prompt referral to an ophthalmologist is recommended. 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-effective after one or more normal eye exams, and in a population with well controlled type 2 diabetes, there was essentially no risk of development of significant retinopathy with a 3-year interval after a normal examination (118). Less frequent intervals have been found in simulated modeling to be potentially effective in screening for diabetic retinopathy in patients without diabetic retinopathy (119). More frequent examinations by the ophthalmologist will be required if retinopathy is progressing.

Retinal photography with remote reading by experts has great potential to provide screening services in areas where qualified eye care professionals are not readily available (112,113). High-quality fundus photographs can detect most clinically 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 (120,121). In-person exams are still necessary when the retinal photos are of unacceptable quality and for follow-up if abnormalities are detected. Retinal photos are not a substitute for 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 diabetic macular edema authorized for use by the FDA represent an alternative to traditional screening approaches (122). However, the benefits and optimal utilization of this type of screening have yet to be fully determined. Artificial intelligence systems should not be used for patients with known retinopathy, prior retinopathy treatment, or symptoms of vision impairment. Results of 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 diabetes (123).

Type 2 Diabetes

Patients 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 diagnosis should have an initial dilated and comprehensive eye examination at the time of diagnosis.

Pregnancy

Pregnancy is associated with a rapid progression of diabetic retinopathy (124,125). 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 retinopathy. In addition, rapid implementation of intensive glycemic management in the setting of retinopathy is associated with early worsening of retinopathy (116). Women who develop gestational diabetes mellitus do not require eye examinations during pregnancy and do not appear to be at increased risk of developing diabetic retinopathy during pregnancy (126).

Treatment

Recommendations

  • 11.20 Promptly refer patients with any level of macular edema, severe nonproliferative diabetic retinopathy (a precursor of proliferative diabetic retinopathy), or any proliferative diabetic retinopathy to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. A

  • 11.21 The traditional standard treatment, panretinal laser photocoagulation therapy, is indicated to reduce the risk of vision loss in patients with high-risk proliferative diabetic retinopathy and, in some cases, severe nonproliferative diabetic retinopathy. A

  • 11.22 Intravitreous injections of anti–vascular endothelial growth factor are not inferior to traditional panretinal laser photocoagulation and are also indicated to reduce the risk of vision loss in patients with proliferative diabetic retinopathy. A

  • 11.23 Intravitreous injections of anti–vascular endothelial growth factor are indicated for central involved diabetic macular edema, which occurs beneath the foveal center and may threaten reading vision. A

  • 11.24 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 screening for diabetic retinopathy are to prevent loss of vision and to intervene with treatment when vision loss can be prevented or reversed.

Photocoagulation Surgery

Two large trials, the Diabetic Retinopathy Study (DRS) in patients with PDR and the Early Treatment Diabetic Retinopathy Study (ETDRS) in patients with macular edema, provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRS (127) showed in 1978 that panretinal photocoagulation 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 vitreous 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 complications of diabetic retinopathy that involve retinal neovascularization and its complications.

Anti–Vascular Endothelial Growth Factor Treatment

Recent data from the Diabetic Retinopathy Clinical Research Network and others demonstrate that intravitreal injections of anti–vascular endothelial growth factor (anti-VEGF) agent, specifically ranibizumab, resulted in visual acuity outcomes that were not inferior to those observed in patients treated with panretinal laser at 2 years of follow-up (128). In addition, it was observed that patients treated with ranibizumab tended to have less peripheral 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 visits 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 delivery of pharmacologic agents are currently under investigation. The FDA approved ranibizumab for the treatment of diabetic retinopathy in 2017.

While the ETDRS (129) established the benefit of focal laser photocoagulation surgery in eyes with clinically significant macular edema (defined as retinal edema located at or within 500 µm of the center of the macula), current data from well-designed clinical trials demonstrate that intravitreal anti-VEGF agents provide a more effective treatment regimen for central-involved diabetic macular edema than monotherapy or even combination therapy with a laser (130,131). There are currently three anti-VEGF agents commonly used to treat eyes with central-involved diabetic macular edema—bevacizumab, ranibizumab, and aflibercept (107).

In both the DRS and the ETDRS, laser photocoagulation surgery was beneficial in reducing the risk of further visual loss in affected patients but generally not beneficial in reversing already diminished acuity. Anti-VEGF therapy improves vision and has replaced the need for laser photocoagulation in the vast majority of patients with diabetic macular edema (132). Most patients require near-monthly administration 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.

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 (113). ACE inhibitors and ARBs are both effective treatments in diabetic retinopathy (133). In patients with dyslipidemia, retinopathy progression may be slowed by the addition of fenofibrate, particularly with very mild nonproliferative diabetic retinopathy at baseline (111,134).

Screening

Recommendations

  • 11.25 All patients should be assessed for diabetic peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter. B

  • 11.26 Assessment for distal symmetric polyneuropathy should include a careful history and assessment of either temperature or pinprick sensation (small fiber function) and vibration sensation 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 amputation. B

  • 11.27 Symptoms and signs of autonomic neuropathy should be assessed in patients with microvascular complications. E

The diabetic neuropathies are a heterogeneous group of disorders with diverse clinical manifestations. The early recognition 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 diabetes and may be treatable.

  • 2. Up to 50% of diabetic peripheral neuropathy may be a symptomatic. 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 autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life.

Specific treatment for the underlying nerve damage, other than improved glycemic control, is currently not available. Glycemic control can effectively prevent diabetic peripheral neuropathy (DPN) and cardiac autonomic neuropathy (CAN) in type 1 diabetes (135,136) and may modestly slow their progression in type 2 diabetes (52), but it does not reverse neuronal loss. Therapeutic strategies (pharmacologic and nonpharmacologic) for the relief of painful DPN and symptoms of autonomic neuropathy can potentially reduce pain (137) 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 (137). Symptoms vary according to the class of sensory fibers 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 large fibers may cause numbness 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 function and protective sensation:

  1. Small-fiber function: pinprick and temperature sensation

  2. Large-fiber function: vibration perception and 10-g monofilament

  3. Protective sensation: 10-g monofilament

These tests not only screen for the presence of dysfunction but also predict future risk of complications. Electrophysiological 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 deficiency, hypothyroidism, renal disease, malignancies (e.g., multiple myeloma, bronchogenic carcinoma), infections (e.g., HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (138). See the American Diabetes Association (ADA) position statement “Diabetic Neuropathy” for more details (137).

Diabetic Autonomic Neuropathy

The symptoms and signs of autonomic neuropathy should be elicited carefully during the history and physical examination. Major clinical manifestations of diabetic autonomic neuropathy include hypoglycemia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, constipation, 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 (139,140). 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 hypotension (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 alleviating symptoms.

Gastrointestinal Neuropathies.

Gastrointestinal neuropathies may involve any portion of the gastrointestinal tract with manifestations including esophageal dysmotility, gastroparesis, constipation, diarrhea, and fecal incontinence. Gastroparesis should be suspected in individuals with erratic glycemic control or with upper gastrointestinal symptoms without another identified cause. Exclusion of 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 emerging as a viable alternative.

Genitourinary Disturbances.

Diabetic autonomic neuropathy may also cause genitourinary disturbances, including sexual dysfunction and bladder dysfunction. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation (137). Female sexual dysfunction occurs more frequently in those with diabetes and presents as decreased sexual desire, increased pain during intercourse, decreased sexual arousal, and inadequate lubrication (141). Lower urinary tract symptoms manifest as urinary incontinence and bladder dysfunction (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, incontinence, or a palpable bladder.

Treatment

Recommendations

  • 11.28 Optimize glucose control to prevent or delay the development of neuropathy in patients with type 1 diabetes A and to slow the progression of neuropathy in patients with type 2 diabetes. B

  • 11.29 Assess and treat patients to reduce pain related to diabetic peripheral neuropathy B and symptoms of autonomic neuropathy and to improve quality of life. E

  • 11.30 Pregabalin, duloxetine, or gabapentin are recommended as initial pharmacologic treatments for neuropathic pain in diabetes. A

Glycemic Control

Near-normal glycemic control, implemented 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 (142145). Although the evidence for the benefit of near-normal glycemic control is not as strong for type 2 diabetes, some studies have demonstrated a modest slowing of progression without reversal of neuronal loss (52,146). Specific glucose-lowering strategies may have different effects. In a post hoc analysis, participants, particularly men, in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower incidence of distal symmetric polyneuropathy over 4 years than those treated with insulin/sulfonylurea (147).

Neuropathic Pain

Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dysfunction (148). No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or prediabetes, which leaves only pharmaceutical interventions (149).

Pregabalin and duloxetine have received regulatory approval by the FDA, Health Canada, and the European Medicines Agency for the treatment of neuropathic pain in diabetes. The opioid tapentadol has regulatory approval in the U.S. and Canada, but the evidence of its use is weaker (150). Comparative effectiveness studies and trials that include quality-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 pharmacologic strategy with careful attention to relative symptom improvement, medication adherence, and medication side effects is recommended to achieve pain reduction and improve quality of life (151153).

Pregabalin, a calcium channel α2-δ subunit ligand, is the most extensively studied drug for DPN. The majority of studies testing pregabalin have reported favorable effects on the proportion of participants with at least 30–50% improvement in pain (150,152,154157). However, not all trials with pregabalin have been positive (150,152,158,159), especially when treating patients with advanced refractory DPN (156). Adverse effects may be more severe in older patients (160) 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 (161).

Duloxetine is a selective norepinephrine and serotonin reuptake inhibitor. Doses of 60 and 120 mg/day showed efficacy in the treatment of pain associated with DPN in multicenter randomized trials, although some of these had high drop-out rates (150,152,157,159). Duloxetine also appeared to improve neuropathy-related quality of life (162). In longer-term studies, a small increase in A1C was reported in people with diabetes treated with duloxetine compared with placebo (163). 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 µ-opioid receptor agonism and noradrenaline reuptake inhibition. Extended-release tapentadol was approved by the FDA for the treatment of neuropathic pain associated with diabetes based on data from two multicenter clinical trials in which participants titrated to an optimal dose of tapentadol were randomly assigned to continue that dose or switch to placebo (164,165). 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-analysis by the Special Interest Group on Neuropathic Pain of the International Association for the Study of Pain found the evidence supporting the effectiveness of tapentadol in reducing neuropathic pain to be inconclusive (150). Therefore, given the high risk for addiction and safety concerns compared with the relatively modest pain reduction, the use of extended-release tapentadol is not generally recommended as a first-or second-line therapy. The use of any opioids for management of chronic neuropathic pain carries the risk of addiction and should be avoided.

Tricyclic antidepressants, venlafaxine, carbamazepine, and topical capsaicin, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN (137,150,152).

Orthostatic Hypotension

Treating orthostatic hypotension is challenging. The therapeutic goal is to minimize postural symptoms rather than to restore normotension. Most patients require both nonpharmacologic measures (e.g., ensuring adequate salt intake, avoiding medications that aggravate hypotension, or using compressive garments over the legs and abdomen) and pharmacologic measures. Physical activity and exercise should be encouraged to avoid deconditioning, which is known to exacerbate 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 nonpharmacologic measures. Additionally, supine blood pressure tends to be much higher in these patients, often requiring treatment of blood pressure at bedtime with shorter-acting drugs that also affect baroreceptor activity such as guanfacine or clonidine, shorter-acting calcium blockers (e.g., isradipine), or shorter-acting β-blockers such as atenolol or metoprolol tartrate. Alternatives can include enalapril if patients are unable to tolerate preferred agents (166168). Midodrine and droxidopa are approved by the FDA for the treatment of orthostatic hypotension.

Gastroparesis

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 (169171). In addition, foods with small particle size may improve key symptoms (172). Withdrawing drugs with adverse effects on gastrointestinal motility, including opioids, anticholinergics, tricyclic antidepressants, GLP-1 RAs, pramlintide, and possibly dipeptidyl peptidase 4 inhibitors, may also improve intestinal motility (169,173). 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 metoclopramide for the management of gastroparesis 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 treatment of gastroparesis beyond 12 weeks is no longer recommended by the FDA or the European Medicines Agency. It should be reserved for severe cases that are unresponsive to other therapies (173). Other treatment options include domperidone (available outside of the U.S.) and erythromycin, which is only effective for short-term use due to tachyphylaxis (174,175). Gastric electrical stimulation using a surgically implantable device has received approval from the FDA, although its efficacy is variable and use is limited to patients with severe symptoms that are refractory to other treatments (176).

Erectile Dysfunction

In addition to treatment of hypogonadism if present, treatments for erectile dysfunction may include phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with DPN treatments, these interventions do not change the underlying pathology and natural history of the disease process but may improve the patient's quality of life.

Recommendations

  • 11.31 Perform a comprehensive foot evaluation at least annually to identify risk factors for ulcers and amputations. B

  • 11.32 Patients with evidence of sensory loss or prior ulceration or amputation should have their feet inspected at every visit. B

  • 11.33 Obtain a prior history of ulceration, amputation, Charcot foot, angioplasty or vascular surgery, cigarette smoking, retinopathy, and renal disease and assess current symptoms of neuropathy (pain, burning, numbness) and vascular disease (leg fatigue, claudication). B

  • 11.34 The examination should include inspection of the skin, assessment of foot deformities, neurological assessment (10-g monofilament testing with at least one other assessment: pinprick, temperature, vibration), and vascular assessment including pulses in the legs and feet. B

  • 11.35 Patients with symptoms of claudication or decreased or absent pedal pulses should be referred for ankle-brachial index and for further vascular assessment as appropriate. C

  • 11.36 A multidisciplinary approach is recommended for individuals with foot ulcers and high-risk feet (e.g., dialysis patients and those with Charcot foot or prior ulcers or amputation). B

  • 11.37 Refer patients who smoke or who have histories of prior lower-extremity complications, loss of protective sensation, structural abnormalities, or peripheral arterial disease to foot care specialists for ongoing preventive care and lifelong surveillance. C

  • 11.38 Provide general preventive foot self-care education to all patients with diabetes. B

  • 11.39 The use of specialized therapeutic footwear is recommended for high-risk patients with diabetes including those with severe neuropathy, foot deformities, ulcers, callous formation, poor peripheral circulation, or history of amputation. B

Foot ulcers and amputation, which are consequences of diabetic neuropathy and/or peripheral arterial disease (PAD), are common and represent major causes of morbidity and mortality in people with diabetes.

Early recognition and treatment of patients with diabetes and feet at risk for ulcers and amputations can delay or prevent adverse outcomes.

The risk of ulcers or amputations is increased in people who have the following risk factors:

  • Poor glycemic control

  • Peripheral neuropathy with LOPS

  • Cigarette smoking

  • Foot deformities

  • Preulcerative callus or corn

  • PAD

  • History of foot ulcer

  • Amputation

  • Visual impairment

  • CKD (especially patients on dialysis)

Moreover, there is good-quality evidence to support use of appropriate therapeutic footwear with demonstrated pressure relief that is worn by the patient to prevent plantar foot ulcer recurrence or worsening. However, there is very little evidence for the use of interventions to prevent a first foot ulcer or heal ischemic, infected, nonplantar, or proximal foot ulcers (177). Studies on specific types of footwear demonstrated that shape and barefoot plantar pressure–based orthoses were more effective in reducing submetatarsal head plantar ulcer recurrence than current standard-of-care orthoses (178).

Clinicians are encouraged to review ADA screening recommendations for further details and practical descriptions of how to perform components of the comprehensive foot examination (179).

Evaluation for Loss of Protective Sensation

All adults with diabetes should undergo a comprehensive foot evaluation at least annually. Detailed foot assessments may occur more frequently in patients with histories of ulcers or amputations, foot deformities, insensate feet, and PAD (180,181). To assess risk, clinicians should ask about history of foot ulcers or amputation, neuropathic and peripheral vascular symptoms, impaired vision, renal disease, tobacco use, and foot care practices. A general inspection of skin integrity and musculoskeletal deformities should be performed. Vascular assessment should include inspection and palpation of pedal pulses.

The neurological exam performed as part of the foot examination is designed to identify LOPS rather than early neuropathy. The 10-g monofilament is the most useful test to diagnose LOPS. Ideally, the 10-g monofilament test should be performed with at least one other assessment (pinprick, temperature or vibration sensation using a 128-Hz tuning fork, or ankle reflexes). Absent monofilament sensation suggests LOPS, while at least two normal tests (and no abnormal test) rules out LOPS.

Evaluation for Peripheral Arterial Disease

Initial screening for PAD should include a history of decreased walking speed, leg fatigue, claudication, and an assessment of the pedal pulses. Ankle-brachial index testing should be performed in patients with symptoms or signs of PAD. Additionally, at least one of the following tests in a patient with a diabetic foot ulcer and PAD should be performed: skin perfusion pressure (≥40 mmHg), toe pressure (≥30 mmHg), or transcutaneous oxygen pressure (TcPO2 ≥25 mmHg). Urgent vascular imaging and revascularization should be considered in a patient with a diabetic foot ulcer and an ankle pressure (ankle-brachial index) <50 mmHg, toe pressure <30 mmHg, or a TcPO2 <25 mmHg (137,182).

Patient Education

All patients with diabetes and particularly those with high-risk foot conditions (history of ulcer or amputation, deformity, LOPS, or PAD) and their families should be provided general education about risk factors and appropriate management (183). Patients at risk should understand the implications of foot deformities, LOPS, and PAD; the proper care of the foot, including nail and skin care; and the importance of foot monitoring on a daily basis. Patients with LOPS should be educated on ways to substitute other sensory modalities (palpation or visual inspection using an unbreakable mirror) for surveillance of early foot problems.

The selection of appropriate footwear and footwear behaviors at home should also be discussed. Patientsʼ understanding of these issues and their physical ability to conduct proper foot surveillance and care should be assessed. Patients with visual difficulties, physical 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.

Treatment

People with neuropathy or evidence of increased plantar pressures (e.g., erythema, warmth, or calluses) may be adequately managed with well-fitted walking shoes or athletic shoes that cushion the feet and redistribute pressure. People with bony deformities (e.g., hammertoes, prominent metatarsal heads, bunions) may need extra wide or deep shoes. People with bony deformities, including Charcot foot, who cannot be accommodated with commercial therapeutic footwear, will require custom-molded shoes. Special consideration and a thorough workup should be performed when patients with neuropathy present with the acute onset of a red, hot, swollen foot or ankle, and Charcot neuroarthropathy should be excluded. Early diagnosis and treatment of Charcot neuroarthropathy is the best way to prevent deformities that increase the risk of ulceration and amputation. The routine prescription of therapeutic footwear is not generally recommended. However, patients should be provided adequate information to aid in selection of appropriate footwear. General footwear recommendations include a broad and square toe box, laces with three or four eyes per side, padded tongue, quality lightweight materials, and sufficient size to accommodate a cushioned insole. Use of custom therapeutic footwear can help reduce the risk of future foot ulcers in high-risk patients (180,183).

Most diabetic foot infections are polymicrobial, with aerobic gram-positive cocci. Staphylococci and streptococci are the most common causative organisms. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. Empiric antibiotic therapy can be narrowly targeted at gram-positive cocci in many patients with acute infections, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections require broader-spectrum regimens and should be referred to specialized care centers (184). Foot ulcers and wound care may require care by a podiatrist, orthopedic or vascular surgeon, or rehabilitation specialist experienced in the management of individuals with diabetes (184).

Hyperbaric oxygen therapy (HBOT) in patients with diabetic foot ulcers has mixed evidence supporting its use as an adjunctive treatment to enhance wound healing and prevent amputation (185188). A well-conducted randomized controlled study performed in 103 patients found that HBOT did not reduce the indication for amputation or facilitate wound healing compared with comprehensive wound care in patients with chronic diabetic foot ulcers (189). Moreover, a systematic review by the International Working Group on the Diabetic Foot of interventions to improve the healing of chronic diabetic foot ulcers concluded that analysis of the evidence continues to present methodological challenges as randomized controlled studies remain few, with a majority being of poor quality (186). Thus, HBOT does not have a significant effect on health-related quality of life in patients with diabetic foot ulcers (190,191). A recent review concluded that the evidence to date remains inconclusive regarding the clinical and cost-effectiveness of HBOT as an adjunctive treatment to standard wound care for diabetic foot ulcers (192). Results from the Dutch DAMOCLES (Does Applying More Oxygen Cure Lower Extremity Sores?) trial demonstrated that HBOT in patients with diabetes and ischemic wounds did not significantly improve complete wound healing and limb salvage (193). While the Centers for Medicare & Medicaid Services currently covers HBOT for diabetic foot ulcers that have failed a standard course of wound therapy when there are no measurable signs of healing for at least 30 consecutive days (194), given the data not supporting an effect, such an approach is not currently warranted. HBOT should be a topic of shared decision-making before treatment is considered for selected patients with diabetic foot ulcers (194).

Suggested citation: American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes—2021. Diabetes Care 2021;44(Suppl. 1):S151–S167

1.
Tuttle
KR
,
Bakris
GL
,
Bilous
RW
, et al
.
Diabetic kidney disease: a report from an ADA Consensus Conference
.
Diabetes Care
2014
;
37
:
2864
2883
2.
National Kidney Foundation
.
KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease
.
Kidney Int suppl
2013
;
3
:
1
150
3.
Afkarian
M
,
Zelnick
LR
,
Hall
YN
, et al
.
Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014
.
JAMA
2016
;
316
:
602
610
4.
de Boer
IH
,
Rue
TC
,
Hall
YN
,
Heagerty
PJ
,
Weiss
NS
,
Himmelfarb
J
.
Temporal trends in the prevalence of diabetic kidney disease in the United States
.
JAMA
2011
;
305
:
2532
2539
5.
de Boer
IH
;
DCCT/EDIC Research Group
.
Kidney disease and related findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study
.
Diabetes Care
2014
;
37
:
24
30
6.
United States Renal Data System
.
Annual Data Report: Epidemiology of Kidney Disease in the United States
.
Bethesda, MD
,
National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases
,
2016
7.
Fox
CS
,
Matsushita
K
,
Woodward
M
, et al.;
Chronic Kidney Disease Prognosis Consortium
.
Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis
.
Lancet
2012
;
380
:
1662
1673
8.
Yarnoff
BO
,
Hoerger
TJ
,
Simpson
SK
, et al.;
Centers for Disease Control and Prevention CKD Initiative
.
The cost-effectiveness of using chronic kidney disease risk scores to screen for early-stage chronic kidney disease
.
BMC Nephrol
2017
;
18
:
85
9.
Afkarian
M
,
Sachs
MC
,
Kestenbaum
B
, et al
.
Kidney disease and increased mortality risk in type 2 diabetes
.
J Am Soc Nephrol
2013
;
24
:
302
308
10.
Groop
P-H
,
Thomas
MC
,
Moran
JL
, et al.;
FinnDiane Study Group
.
The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes
.
Diabetes
2009
;
58
:
1651
1658
11.
Gomes
MB
,
Gonçalves
MF
.
Is there a physiological variability for albumin excretion rate? Study in patients with diabetes type 1 and non-diabetic individuals
.
Clin Chim Acta
2001
;
304
:
117
123
12.
Naresh
CN
,
Hayen
A
,
Weening
A
,
Craig
JC
,
Chadban
SJ
.
Day-to-day variability in spot urine albumin-creatinine ratio
.
Am J Kidney Dis
2013
;
62
:
1095
1101
13.
Tankeu
AT
,
Kaze
FF
,
Noubiap
JJ
,
Chelo
D
,
Dehayem
MY
,
Sobngwi
E
.
Exercise-induced albuminuria and circadian blood pressure abnormalities in type 2 diabetes
.
World J Nephrol
2017
;
6
:
209
216
14.
Delanaye
P
,
Glassock
RJ
,
Pottel
H
,
Rule
AD
.
An age-calibrated definition of chronic kidney disease: rationale and benefits
.
Clin Biochem Rev
2016
;
37
:
17
26
15.
Kramer
HJ
,
Nguyen
QD
,
Curhan
G
,
Hsu
C-Y
.
Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus
.
JAMA
2003
;
289
:
3273
3277
16.
Molitch
ME
,
Steffes
M
,
Sun
W
, et al.;
Epidemiology of Diabetes Interventions and Complications Study Group
.
Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study
.
Diabetes Care
2010
;
33
:
1536
1543
17.
He
F
,
Xia
X
,
Wu
XF
,
Yu
XQ
,
Huang
FX
.
Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis
.
Diabetologia
2013
;
56
:
457
466
18.
Levey
AS
,
Coresh
J
,
Balk
E
, et al.;
National Kidney Foundation
.
National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification
.
Ann Intern Med
2003
;
139
:
137
147
19.
Flynn
C
,
Bakris
GL
.
Noninsulin glucose-lowering agents for the treatment of patients on dialysis
.
Nat Rev Nephrol
2013
;
9
:
147
153
20.
Matzke
GR
,
Aronoff
GR
,
Atkinson
AJ
 Jr
, et al
.
Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)
.
Kidney Int
2011
;
80
:
1122
1137
21.
Coresh
J
,
Turin
TC
,
Matsushita
K
, et al
.
Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality
.
JAMA
2014
;
311
:
2518
2531
22.
Vassalotti
JA
,
Centor
R
,
Turner
BJ
,
Greer
RC
,
Choi
M
,
Sequist
TD
;
National Kidney Foundation Kidney Disease Outcomes Quality Initiative
.
Practical approach to detection and management of chronic kidney disease for the primary care clinician
.
Am J Med
2016
;
129
:
153
162.e7
23.
Zhou
J
,
Liu
Y
,
Tang
Y
, et al
.
A comparison of RIFLE, AKIN, KDIGO, and Cys-C criteria for the definition of acute kidney injury in critically ill patients
.
Int Urol Nephrol
2016
;
48
:
125
132
24.
Hoste
EAJ
,
Kellum
JA
,
Selby
NM
, et al
.
Global epidemiology and outcomes of acute kidney injury
.
Nat Rev Nephrol
2018
;
14
:
607
625
25.
James
MT
,
Grams
ME
,
Woodward
M
, et al.;
CKD Prognosis Consortium
.
A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury
.
Am J Kidney Dis
2015
;
66
:
602
612
26.
Perkovic
V
,
Jardine
MJ
,
Neal
B
, et al
.
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy
.
N Engl J Med
2019
;
380
:
2295
2306
27.
Nadkarni
GN
,
Ferrandino
R
,
Chang
A
, et al
.
Acute kidney injury in patients on SGLT2 inhibitors: a propensity-matched analysis
.
Diabetes Care
2017
;
40
:
1479
1485
28.
Wanner
C
,
Inzucchi
SE
,
Lachin
JM
, et al.;
EMPA-REG OUTCOME Investigators
.
Empagliflozin and progression of kidney disease in type 2 diabetes
.
N Engl J Med
2016
;
375
:
323
334
29.
Neuen
BL
,
Ohkuma
T
,
Neal
B
, et al
.
Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS Program
.
Circulation
2018
;
138
:
1537
1550
30.
Thakar
CV
,
Christianson
A
,
Himmelfarb
J
,
Leonard
AC
.
Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus
.
Clin J Am Soc Nephrol
2011
;
6
:
2567
2572
31.
Bakris
GL
,
Weir
MR
.
Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?
Arch Intern Med
2000
;
160
:
685
693
32.
Beddhu
S
,
Greene
T
,
Boucher
R
, et al
.
Intensive systolic blood pressure control and incident chronic kidney disease in people with and without diabetes mellitus: secondary analyses of two randomised controlled trials
.
Lancet Diabetes Endocrinol
2018
;
6
:
555
563
33.
Collard
D
,
Brouwer
TF
,
Peters
RJG
,
Vogt
L
,
van den Born
BH
.
Creatinine rise during blood pressure therapy and the risk of adverse clinical outcomes in patients with type 2 diabetes mellitus
.
Hypertension
2018
;
72
:
1337
1344
34.
Malhotra
R
,
Craven
T
,
Ambrosius
WT
, et al.;
SPRINT Research Group
.
Effects of intensive blood pressure lowering on kidney tubule injury in CKD: a longitudinal subgroup analysis in SPRINT
.
Am J Kidney Dis
2019
;
73
:
21
30
35.
Qiao
Y
,
Shin
J-I
,
Chen
TK
, et al
.
Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate
.
JAMA Intern Med
2020
;
180
:
718
726
36.
Collard
D
,
Brouwer
TF
,
Olde Engberink
RHG
,
Zwinderman
AH
,
Vogt
L
,
van den Born
BH
.
Initial estimated glomerular filtration rate decline and long-term renal function during intensive antihypertensive therapy: a post hoc analysis of the SPRINT and ACCORD-BP randomized controlled trials
.
Hypertension
2020
;
75
:
1205
1212
37.
Hughes-Austin
JM
,
Rifkin
DE
,
Beben
T
, et al
.
The relation of serum potassium concentration with cardiovascular events and mortality in community-living individuals
.
Clin J Am Soc Nephrol
2017
;
12
:
245
252
38.
Bandak
G
,
Sang
Y
,
Gasparini
A
, et al
.
Hyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) project
.
J Am Heart Assoc
2017
;
6
:
e005428
39.
Nilsson
E
,
Gasparini
A
,
Ärnlöv
J
, et al
.
Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system
.
Int J Cardiol
2017
;
245
:
277
284
40.
de Boer
IH
,
Gao
X
,
Cleary
PA
, et al
.;
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group. Albuminuria changes and cardiovascular and renal outcomes in type 1 diabetes: the DCCT/EDIC study
.
Clin J Am Soc Nephrol
2016
;
11
:
1969
1977
41.
Sumida
K
,
Molnar
MZ
,
Potukuchi
PK
, et al
.
Changes in albuminuria and subsequent risk of incident kidney disease
.
Clin J Am Soc Nephrol
2017
;
12
:
1941
1949
42.
Inker
LA
,
Grams
ME
,
Levey
AS
, et al.;
CKD Prognosis Consortium
.
Relationship of estimated GFR and albuminuria to concurrent laboratory abnormalities: an individual participant data meta-analysis in a global consortium
.
Am J Kidney Dis
2019
;
73
:
206
217
43.
Klahr
S
,
Levey
AS
,
Beck
GJ
, et al.;
Modification of Diet in Renal Disease Study Group
.
The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease
.
N Engl J Med
1994
;
330
:
877
884
44.
Mills
KT
,
Chen
J
,
Yang
W
, et al.;
Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
.
Sodium excretion and the risk of cardiovascular disease in patients with chronic kidney disease
.
JAMA
2016
;
315
:
2200
2210
45.
Whelton
PK
,
Carey
RM
,
Aronow
WS
, et al
.
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines
.
Hypertension
2018
;
71
:
1269
1324
46.
Murray
DP
,
Young
L
,
Waller
J
, et al
.
Is dietary protein intake predictive of 1-year mortality in dialysis patients?
Am J Med Sci
2018
;
356
:
234
243
47.
DCCT/EDIC research group
.
Effect of intensive diabetes treatment on albuminuria in type 1 diabetes: long-term follow-up of the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study
.
Lancet Diabetes Endocrinol
2014
;
2
:
793
800
48.
de Boer
IH
,
Sun
W
,
Cleary
PA
, et al.;
DCCT/EDIC Research Group
.
Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes
.
N Engl J Med
2011
;
365
:
2366
2376
49.
UK Prospective Diabetes Study (UKPDS) Group
.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
.
Lancet
1998
;
352
:
854
865
50.
UK Prospective Diabetes Study (UKPDS) Group
.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
.
Lancet
1998
;
352
:
837
853
51.
Patel
A
,
MacMahon
S
,
Chalmers
J
, et al.;
ADVANCE Collaborative Group
.
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes
.
N Engl J Med
2008
;
358
:
2560
2572
52.
Ismail-Beigi
F
,
Craven
T
,
Banerji
MA
, et al.;
ACCORD trial group
.
Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial
.
Lancet
2010
;
376
:
419
430
53.
Zoungas
S
,
Chalmers
J
,
Neal
B
, et al.;
ADVANCE-ON Collaborative Group
.
Follow-up of blood-pressure lowering and glucose control in type 2 diabetes
.
N Engl J Med
2014
;
371
:
1392
1406
54.
Zoungas
S
,
Arima
H
,
Gerstein
HC
, et al.;
Collaborators on Trials of Lowering Glucose (CONTROL) group
.
Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials
.
Lancet Diabetes Endocrinol
2017
;
5
:
431
437
55.
Agrawal
L
,
Azad
N
,
Bahn
GD
, et al.;
VADT Study Group
.
Long-term follow-up of intensive glycaemic control on renal outcomes in the Veterans Affairs Diabetes Trial (VADT)
.
Diabetologia
2018
;
61
:
295
299
56.
Miller
ME
,
Bonds
DE
,
Gerstein
HC
, et al
.;
ACCORD Investigators. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study
.
BMJ
2010
;
340
:
b5444
57.
Papademetriou
V
,
Lovato
L
,
Doumas
M
, et al.;
ACCORD Study Group
.
Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes
.
Kidney Int
2015
;
87
:
649
659
58.
Perkovic
V
,
Heerspink
HL
,
Chalmers
J
, et al.;
ADVANCE Collaborative Group
.
Intensive glucose control improves kidney outcomes in patients with type 2 diabetes
.
Kidney Int
2013
;
83
:
517
523
59.
Wong
MG
,
Perkovic
V
,
Chalmers
J
, et al.;
ADVANCE-ON Collaborative Group
.
Long-term benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON
.
Diabetes Care
2016
;
39
:
694
700
60.
National Kidney Foundation
.
KDOQI clinical practice guideline for diabetes and CKD: 2012 update
.
Am J Kidney Dis
2012
;
60
:
850
886
61.
Cherney
DZI
,
Perkins
BA
,
Soleymanlou
N
, et al
.
Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus
.
Circulation
2014
;
129
:
587
597
62.
Heerspink
HJL
,
Desai
M
,
Jardine
M
,
Balis
D
,
Meininger
G
,
Perkovic
V
.
Canagliflozin slows progression of renal function decline independently of glycemic effects
.
J Am Soc Nephrol
2017
;
28
:
368
375
https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=27539604&dopt=Abstract
63.
Neal
B
,
Perkovic
V
,
Mahaffey
KW
, et al.;
CANVAS Program Collaborative Group
.
Canagliflozin and cardiovascular and renal events in type 2 diabetes
.
N Engl J Med
2017
;
377
:
644
657
64.
Zelniker
TA
,
Braunwald
E
.
Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review
.
J Am Coll Cardiol
2018
;
72
:
1845
1855
65.
Woods
TC
,
Satou
R
,
Miyata
K
, et al
.
Canagliflozin prevents intrarenal angiotensinogen augmentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes mellitus
.
Am J Nephrol
2019
;
49
:
331
342
66.
Heerspink
HJL
,
Perco
P
,
Mulder
S
, et al
.
Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease
.
Diabetologia
2019
;
62
:
1154
1166
67.
Yaribeygi
H
,
Butler
AE
,
Atkin
SL
,
Katsiki
N
,
Sahebkar
A
.
Sodium-glucose cotransporter 2 inhibitors and inflammation in chronic kidney disease: possible molecular pathways
.
J Cell Physiol
2018
;
234
:
223
230
68.
Marso
SP
,
Daniels
GH
,
Brown-Frandsen
K
, et al.;
LEADER Steering Committee; LEADER Trial Investigators
.
Liraglutide and cardiovascular outcomes in type 2 diabetes
.
N Engl J Med
2016
;
375
:
311
322
69.
Cooper
ME
,
Perkovic
V
,
McGill
JB
, et al
.
Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of the dipeptidyl peptidase 4 inhibitor linagliptin in type 2 diabetes
.
Am J Kidney Dis
2015
;
66
:
441
449
70.
Mann
JFE
,
Ørsted
DD
,
Brown-Frandsen
K
, et al
.;
LEADER Steering Committee and Investigators. Liraglutide and renal outcomes in type 2 diabetes
.
N Engl J Med
2017
;
377
:
839
848
71.
Marso
SP
,
Bain
SC
,
Consoli
A
, et al.;
SUSTAIN-6 Investigators
.
Semaglutide and cardiovascular outcomes in patients with type 2 diabetes
.
N Engl J Med
2016
;
375
:
1834
1844
72.
Karter
AJ
,
Warton
EM
,
Lipska
KJ
, et al
.
Development and validation of a tool to identify patients with type 2 diabetes at high risk of hypoglycemia-related emergency department or hospital use
.
JAMA Intern Med
2017
;
177
:
1461
1470
73.
Moen
MF
,
Zhan
M
,
Hsu
VD
, et al
.
Frequency of hypoglycemia and its significance in chronic kidney disease
.
Clin J Am Soc Nephrol
2009
;
4
:
1121
1127
74.
U.S. Food and Drug Administration
.
FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function, 2016. Accessed 11 August 2020. Available from http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm
75.
Lalau
J-D
,
Kajbaf
F
,
Bennis
Y
,
Hurtel-Lemaire
A-S
,
Belpaire
F
,
De Broe
ME
.
Metformin treatment in patients with type 2 diabetes and chronic kidney disease stages 3A, 3B, or 4
.
Diabetes Care
2018
;
41
:
547
553
76.
Chu
PY
,
Hackstadt
AJ
,
Chipman
J
, et al
.
Hospitalization for lactic acidosis among patients with reduced kidney function treated with metformin or sulfonylureas
.
Diabetes Care
2020
;
43
:
1462
1470
77.
Zelniker
TA
,
Wiviott
SD
,
Raz
I
, et al
.
Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus
.
Circulation
2019
;
139
:
2022
2031
78.
Zinman
B
,
Wanner
C
,
Lachin
JM
, et al.;
EMPA-REG OUTCOME Investigators
.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes
.
N Engl J Med
2015
;
373
:
2117
2128
79.
Mahaffey
KW
,
Neal
B
,
Perkovic
V
, et al.;
CANVAS Program Collaborative Group
.
Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)
.
Circulation
2018
;
137
:
323
334
80.
Jardine
MJ
,
Mahaffey
KW
,
Neal
B
, et al.;
CREDENCE study investigators
.
The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics
.
Am J Nephrol
2017
;
46
:
462
472
81.
Mahaffey
KW
,
Jardine
MJ
,
Bompoint
S
, et al
.
Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups
.
Circulation
2019
;
140
:
739
750
82.
Bakris
GL
.
Major advancements in slowing diabetic kidney disease progression: focus on SGLT2 inhibitors
.
Am J Kidney Dis
2019
;
74
:
573
575
83.
Novo Nordisk A/S
.
A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease (FLOW). In: ClinicalTrials.gov. Bethesda, MD, National Library of Medicine, 2019. Accessed 11 August 2020. Available from https://clinicaltrials.gov/ct2/show/NCT03819153
84.
Franki
,
L
.
FDA approves label extension for dapagliflozin. Accessed 11 August 2020. Available from https://www.mdedge.com/endocrinology/article/195314/diabetes/fda-approves-label-extension-dapagliflozin
85.
Leehey
DJ
,
Zhang
JH
,
Emanuele
NV
, et al.;
VA NEPHRON-D Study Group
.
BP and renal outcomes in diabetic kidney disease: the Veterans Affairs Nephropathy in Diabetes Trial
.
Clin J Am Soc Nephrol
2015
;
10
:
2159
2169
86.
Emdin
CA
,
Rahimi
K
,
Neal
B
,
Callender
T
,
Perkovic
V
,
Patel
A
.
Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis
.
JAMA
2015
;
313
:
603
615
87.
Cushman
WC
,
Evans
GW
,
Byington
RP
, et al.;
ACCORD Study Group
.
Effects of intensive blood-pressure control in type 2 diabetes mellitus
.
N Engl J Med
2010
;
362
:
1575
1585
88.
UK Prospective Diabetes Study Group
.
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38
.
BMJ
1998
;
317
:
703
713
89.
de Boer
IH
,
Bangalore
S
,
Benetos
A
, et al
.
Diabetes and hypertension: a position statement by the American Diabetes Association
.
Diabetes Care
2017
;
40
:
1273
1284
90.
Brenner
BM
,
Cooper
ME
,
de Zeeuw
D
, et al.;
RENAAL Study Investigators
.
Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy
.
N Engl J Med
2001
;
345
:
861
869
91.
Lewis
EJ
,
Hunsicker
LG
,
Bain
RP
,
Rohde
RD
;
The Collaborative Study Group
.
The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy
.
N Engl J Med
1993
;
329
:
1456
1462
92.
Lewis
EJ
,
Hunsicker
LG
,
Clarke
WR
, et al.;
Collaborative Study Group
.
Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes
.
N Engl J Med
2001
;
345
:
851
860
93.
Heart Outcomes Prevention Evaluation Study Investigators
.
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy
.
Lancet
2000
;
355
:
253
259
94.
Barnett
AH
,
Bain
SC
,
Bouter
P
, et al.;
Diabetics Exposed to Telmisartan and Enalapril Study Group
.
Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy
.
N Engl J Med
2004
;
351
:
1952
1961
95.
Wu
H-Y
,
Peng
C-L
,
Chen
P-C
, et al
.
Comparative effectiveness of angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers for major renal outcomes in patients with diabetes: a 15-year cohort study
.
PLoS One
2017
;
12
:
e0177654
96.
Parving
HH
,
Lehnert
H
,
Bröchner-Mortensen
J
,
Gomis
R
,
Andersen
S
,
Arner
P
;
Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group
.
The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes
.
N Engl J Med
2001
;
345
:
870
878
97.
Mauer
M
,
Zinman
B
,
Gardiner
R
, et al
.
Renal and retinal effects of enalapril and losartan in type 1 diabetes
.
N Engl J Med
2009
;
361
:
40
51
98.
Weil
EJ
,
Fufaa
G
,
Jones
LI
, et al
.
Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes
.
Diabetes
2013
;
62
:
3224
3231
99.
Bangalore
S
,
Fakheri
R
,
Toklu
B
,
Messerli
FH
.
Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials
.
BMJ
2016
;
352
:
i438
100.
Haller
H
,
Ito
S
,
Izzo
JL
 Jr
, et al.;
ROADMAP Trial Investigators
.
Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes
.
N Engl J Med
2011
;
364
:
907
917
101.
Yusuf
S
,
Teo
KK
,
Pogue
J
, et al.;
ONTARGET Investigators
.
Telmisartan, ramipril, or both in patients at high risk for vascular events
.
N Engl J Med
2008
;
358
:
1547
1559
102.
Fried
LF
,
Emanuele
N
,
Zhang
JH
, et al.;
VA NEPHRON-D Investigators
.
Combined angiotensin inhibition for the treatment of diabetic nephropathy
.
N Engl J Med
2013
;
369
:
1892
1903
103.
Bakris
GL
,
Agarwal
R
,
Chan
JC
, et al.;
Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group
.
Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial
.
JAMA
2015
;
314
:
884
894
104.
Williams
B
,
MacDonald
TM
,
Morant
S
, et al.;
British Hypertension Society’s PATHWAY Studies Group
.
Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial
.
Lancet
2015
;
386
:
2059
2068
105.
Filippatos
G
,
Anker
SD
,
Böhm
M
, et al
.
A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease
.
Eur Heart J
2016
;
37
:
2105
2114
106.
Smart
NA
,
Dieberg
G
,
Ladhani
M
,
Titus
T
.
Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease
.
Cochrane Database Syst Rev
2014
;
6
:
CD007333
107.
Solomon
SD
,
Chew
E
,
Duh
EJ
, et al
.
Diabetic retinopathy: a position statement by the American Diabetes Association
.
Diabetes Care
2017
;
40
:
412
418
108.
Klein
R
.
Hyperglycemia and microvascular and macrovascular disease in diabetes
.
Diabetes Care
1995
;
18
:
258
268
109.
Estacio
RO
,
McFarling
E
,
Biggerstaff
S
,
Jeffers
BW
,
Johnson
D
,
Schrier
RW
.
Overt albuminuria predicts diabetic retinopathy in Hispanics with NIDDM
.
Am J Kidney Dis
1998
;
31
:
947
953
110.
Leske
MC
,
Wu
S-Y
,
Hennis
A
, et al.;
Barbados Eye Study Group
.
Hyperglycemia, blood pressure, and the 9-year incidence of diabetic retinopathy: the Barbados Eye Studies
.
Ophthalmology
2005
;
112
:
799
805
111.
Chew
EY
,
Davis
MD
,
Danis
RP
, et al.;
Action to Control Cardiovascular Risk in Diabetes Eye Study Research Group
.
The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study
.
Ophthalmology
2014
;
121
:
2443
2451
112.
Nathan
DM
,
Genuth
S
,
Lachin
J
, et al
.;
Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus
.
N Engl J Med
1993
;
329
:
977
986
113.
Chew
EY
,
Ambrosius
WT
,
Davis
MD
, et al.;
ACCORD Study Group
;
ACCORD Eye Study Group
.
Effects of medical therapies on retinopathy progression in type 2 diabetes
.
N Engl J Med
2010
;
363
:
233
244
114.
Gubitosi-Klug
RA
,
Sun
W
,
Cleary
PA
, et al
.;
Writing Team for the DCCT/EDIC Research Group. Effects of prior intensive insulin therapy and risk factors on patient-reported visual function outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort
.
JAMA Ophthalmol
2016
;
134
:
137
145
115.
Fong
DS
,
Aiello
LP
,
Ferris
FL
 3rd
,
Klein
R
.
Diabetic retinopathy
.
Diabetes Care
2004
;
27
:
2540
2553
116.
Diabetes Control and Complications Trial Research Group
.
Effect of pregnancy on microvascular complications in the diabetes control and complications trial
.
Diabetes Care
2000
;
23
:
1084
1091
117.
Dabelea
D
,
Stafford
JM
,
Mayer-Davis
EJ
, et al
.;
SEARCH for Diabetes in Youth Research Group. Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood
.
JAMA
2017
;
317
:
825
835
118.
Agardh
E
,
Tababat-Khani
P
.
Adopting 3-year screening intervals for sight-threatening retinal vascular lesions in type 2 diabetic subjects without retinopathy
.
Diabetes Care
2011
;
34
:
1318
1319
119.
Nathan
DM
,
Bebu
I
,
Hainsworth
D
, et al.;
DCCT/EDIC Research Group
.
Frequency of evidence-based screening for retinopathy in type 1 diabetes
.
N Engl J Med
2017
;
376
:
1507
1516
120.
Daskivich
LP
,
Vasquez
C
,
Martinez
C
 Jr
,
Tseng
C-H
,
Mangione
CM
.
Implementation and evaluation of a large-scale teleretinal diabetic retinopathy screening program in the Los Angeles County Department of Health Services
.
JAMA Intern Med
2017
;
177
:
642
649
121.
Sim
DA
,
Mitry
D
,
Alexander
P
, et al
.
The evolution of teleophthalmology programs in the United Kingdom: beyond diabetic retinopathy screening
.
J Diabetes Sci Technol
2016
;
10
:
308
317
122.
Abràmoff
MD
,
Lavin
PT
,
Birch
M
,
Shah
N
,
Folk
JC
.
Pivotal trial of an autonomous AI-based diagnostic system for detection of diabetic retinopathy in primary care offices
.
npj Digital Med
2018
;
1
:
39
123.
Hooper
P
,
Boucher
MC
,
Cruess
A
, et al
.
Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy
.
Can J Ophthalmol
2012
;
47
(
Suppl. 1
):
S1
S30
124.
Axer-Siegel
R
,
Hod
M
,
Fink-Cohen
S
, et al
.
Diabetic retinopathy during pregnancy
.
Ophthalmology
1996
;
103
:
1815
1819
125.
Best
RM
,
Chakravarthy
U
.
Diabetic retinopathy in pregnancy
.
Br J Ophthalmol
1997
;
81
:
249
251
126.
Gunderson
EP
,
Lewis
CE
,
Tsai
A-L
, et al
.
A 20-year prospective study of childbearing and incidence of diabetes in young women, controlling for glycemia before conception: the Coronary Artery Risk Development in Young Adults (CARDIA) Study
.
Diabetes
2007
;
56
:
2990
2996
127.
The Diabetic Retinopathy Study Research Group
.
Preliminary report on effects of photocoagulation therapy
.
Am J Ophthalmol
1976
;
81
:
383
396
128.
Gross
JG
,
Glassman
AR
,
Jampol
LM
, et al.;
Writing Committee for the Diabetic Retinopathy Clinical Research Network
.
Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial
.
JAMA
2015
;
314
:
2137
2146
129.
Early Treatment Diabetic Retinopathy Study research group
.
Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1
.
Arch Ophthalmol
1985
;
103
:
1796
1806
130.
Elman
MJ
,
Bressler
NM
,
Qin
H
, et al.;
Diabetic Retinopathy Clinical Research Network
.
Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema
.
Ophthalmology
2011
;
118
:
609
614
131.
Mitchell
P
,
Bandello
F
,
Schmidt-Erfurth
U
, et al.;
RESTORE study group
.
The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema
.
Ophthalmology
2011
;
118
:
615
625
132.
Nguyen
QD
,
Brown
DM
,
Marcus
DM
, et al.;
RISE and RIDE Research Group
.
Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE
.
Ophthalmology
2012
;
119
:
789
801
133.
Shih
C-J
,
Chen
H-T
,
Kuo
S-C
, et al
.
Comparative effectiveness of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy
.
CMAJ
2016
;
188
:
E148
E157
134.
Shi
R
,
Zhao
L
,
Wang
F
, et al
.
Effects of lipid-lowering agents on diabetic retinopathy: a meta-analysis and systematic review
.
Int J Ophthalmol
2018
;
11
:
287
295
135.
Ang
L
,
Jaiswal
M
,
Martin
C
,
Pop-Busui
R
.
Glucose control and diabetic neuropathy: lessons from recent large clinical trials
.
Curr Diab Rep
2014
;
14
:
528
136.
Martin
CL
,
Albers
JW
,
Pop-Busui
R
;
DCCT/EDIC Research Group
.
Neuropathy and related findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study
.
Diabetes Care
2014
;
37
:
31
38
137.
Pop-Busui
R
,
Boulton
AJM
,
Feldman
EL
, et al
.
Diabetic neuropathy: a position statement by the American Diabetes Association
.
Diabetes Care
2017
;
40
:
136
154
138.
Freeman
R
.
Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of diabetic neuropathy
.
Curr Diab Rep
2009
;
9
:
423
431
139.
Pop-Busui
R
,
Evans
GW
,
Gerstein
HC
, et al.;
Action to Control Cardiovascular Risk in Diabetes Study Group
.
Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial
.
Diabetes Care
2010
;
33
:
1578
1584
140.
Pop-Busui
R
,
Cleary
PA
,
Braffett
BH
, et al.;
DCCT/EDIC Research Group
.
Association between cardiovascular autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications)
.
J Am Coll Cardiol
2013
;
61
:
447
454
141.
Smith
AG
,
Lessard
M
,
Reyna
S
,
Doudova
M
,
Singleton
JR
.
The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy
.
J Diabetes Complications
2014
;
28
:
511
516
142.
Diabetes Control and Complications Trial (DCCT) Research Group
.
Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial
.
Ann Neurol
1995
;
38
:
869
880
143.
CDC Study Group
.
The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT)
.
Diabetologia
1998
;
41
:
416
423
144.
Albers
JW
,
Herman
WH
,
Pop-Busui
R
, et al.;
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group
.
Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study
.
Diabetes Care
2010
;
33
:
1090
1096
145.
Pop-Busui
R
,
Low
PA
,
Waberski
BH
, et al.;
DCCT/EDIC Research Group
.
Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC)
.
Circulation
2009
;
119
:
2886
2893
146.
Callaghan
BC
,
Little
AA
,
Feldman
EL
,
Hughes
RAC
.
Enhanced glucose control for preventing and treating diabetic neuropathy
.
Cochrane Database Syst Rev
2012
;
6
:
CD007543
147.
Pop-Busui
R
,
Lu
J
,
Brooks
MM
, et al.;
BARI 2D Study Group
.
Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort
.
Diabetes Care
2013
;
36
:
3208
3215
148.
Sadosky
A
,
Schaefer
C
,
Mann
R
, et al
.
Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the US: results from a retrospective chart review and cross-sectional survey
.
Diabetes Metab Syndr Obes
2013
;
6
:
79
92
149.
Waldfogel
JM
,
Nesbit
SA
,
Dy
SM
, et al
.
Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review
.
Neurology
2017
;
88
:
1958
1967
150.
Finnerup
NB
,
Attal
N
,
Haroutounian
S
, et al
.
Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis
.
Lancet Neurol
2015
;
14
:
162
173
151.
Bril
V
,
England
J
,
Franklin
GM
, et al
.;
American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation [published correction appears in Neurology 2011;77:603]
.
Neurology
2011
;
76
:
1758
1765
152.
Griebeler
ML
,
Morey-Vargas
OL
,
Brito
JP
, et al
.
Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis
.
Ann Intern Med
2014
;
161
:
639
649
153.
Ziegler
D
,
Fonseca
V
.
From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy
.
J Diabetes Complications
2015
;
29
:
146
156
154.
Freeman
R
,
Durso-Decruz
E
,
Emir
B
.
Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses
.
Diabetes Care
2008
;
31
:
1448
1454
155.
Moore
RA
,
Straube
S
,
Wiffen
PJ
,
Derry
S
,
McQuay
HJ
.
Pregabalin for acute and chronic pain in adults
.
Cochrane Database Syst Rev
2009
;
3
:
CD007076
156.
Raskin
P
,
Huffman
C
,
Toth
C
, et al
.
Pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy: a randomized withdrawal trial
.
Clin J Pain
2014
;
30
:
379
390
157.
Tesfaye
S
,
Wilhelm
S
,
Lledo
A
, et al
.
Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain
.
Pain
2013
;
154
:
2616
2625
158.
Ziegler
D
,
Duan
WR
,
An
G
,
Thomas
JW
,
Nothaft
W
.
A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain
.
Pain
2015
;
156
:
2013
2020
159.
Quilici
S
,
Chancellor
J
,
Löthgren
M
, et al
.
Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain
.
BMC Neurol
2009
;
9
:
6
160.
Dworkin
RH
,
Jensen
MP
,
Gammaitoni
AR
,
Olaleye
DO
,
Galer
BS
.
Symptom profiles differ in patients with neuropathic versus non-neuropathic pain
.
J Pain
2007
;
8
:
118
126
161.
Wiffen
PJ
,
Derry
S
,
Bell
RF
, et al
.
Gabapentin for chronic neuropathic pain in adults
.
Cochrane Database Syst Rev
2017
;
6
:
CD007938
162.
Wernicke
JF
,
Pritchett
YL
,
D’Souza
DN
, et al
.
A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain
.
Neurology
2006
;
67
:
1411
1420
163.
Hardy
T
,
Sachson
R
,
Shen
S
,
Armbruster
M
,
Boulton
AJM
.
Does treatment with duloxetine for neuropathic pain impact glycemic control?
Diabetes Care
2007
;
30
:
21
26
164.
Schwartz
S
,
Etropolski
M
,
Shapiro
DY
, et al
.
Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial
.
Curr Med Res Opin
2011
;
27
:
151
162
165.
Vinik
AI
,
Shapiro
DY
,
Rauschkolb
C
, et al
.
A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy
.
Diabetes Care
2014
;
37
:
2302
2309
166.
Briasoulis
A
,
Silver
A
,
Yano
Y
,
Bakris
GL
.
Orthostatic hypotension associated with baroreceptor dysfunction: treatment approaches
.
J Clin Hypertens (Greenwich)
2014
;
16
:
141
148
167.
Figueroa
JJ
,
Basford
JR
,
Low
PA
.
Preventing and treating orthostatic hypotension: as easy as A, B, C
.
Cleve Clin J Med
2010
;
77
:
298
306
168.
Jordan
J
,
Fanciulli
A
,
Tank
J
, et al
.
Management of supine hypertension in patients with neurogenic orthostatic hypotension: scientific statement of the American Autonomic Society, European Federation of Autonomic Societies, and the European Society of Hypertension
.
J Hypertens
2019
;
37
:
1541
1546
169.
Camilleri
M
,
Parkman
HP
,
Shafi
MA
,
Abell
TL
,
Gerson
L
;
American College of Gastroenterology
.
Clinical guideline: management of gastroparesis
.
Am J Gastroenterol
2013
;
108
:
18
37; quiz 38
170.
Parrish
CR
,
Pastors
JG
.
Nutritional management of gastroparesis in people with diabetes
.
Diabetes Spectr
2007
;
20
:
231
234
171.
Parkman
HP
,
Yates
KP
,
Hasler
WL
, et al.;
NIDDK Gastroparesis Clinical Research Consortium
.
Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis
.
Gastroenterology
2011
;
141
:
486
498, 498.e1–498.e7
172.
Olausson
EA
,
Störsrud
S
,
Grundin
H
,
Isaksson
M
,
Attvall
S
,
Simrén
M
.
A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: a randomized controlled trial
.
Am J Gastroenterol
2014
;
109
:
375
385
173.
Umpierrez
GE
, Ed.
Therapy for Diabetes Mellitus and Related Disorders.
6th ed.
Alexandria, VA
,
American Diabetes Association
,
2014
174.
Sugumar
A
,
Singh
A
,
Pasricha
PJ
.
A systematic review of the efficacy of domperidone for the treatment of diabetic gastroparesis
.
Clin Gastroenterol Hepatol
2008
;
6
:
726
733
175.
Maganti
K
,
Onyemere
K
,
Jones
MP
.
Oral erythromycin and symptomatic relief of gastroparesis: a systematic review
.
Am J Gastroenterol
2003
;
98
:
259
263
176.
McCallum
RW
,
Snape
W
,
Brody
F
,
Wo
J
,
Parkman
HP
,
Nowak
T
.
Gastric electrical stimulation with Enterra therapy improves symptoms from diabetic gastroparesis in a prospective study
.
Clin Gastroenterol Hepatol
2010
;
8
:
947
954; quiz e116
177.
Bus
SA
,
van Deursen
RW
,
Armstrong
DG
,
Lewis
JE
,
Caravaggi
CF
,
Cavanagh
PR
;
International Working Group on the Diabetic Foot
.
Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review
.
Diabetes Metab Res Rev
2016
;
32
(
Suppl. 1
):
99
118
178.
Ulbrecht
JS
,
Hurley
T
,
Mauger
DT
,
Cavanaugh
PR
.
Prevention of recurrent foot ulcers with plantar pressure–based in-shoe orthoses: the CareFUL Prevention multicenter randomized controlled trial
.
Diabetes Care
2014
;
37
:
1982
1989
179.
Boulton
AJM
,
Armstrong
DG
,
Albert
SF
, et al.;
American Diabetes Association; American Association of Clinical Endocrinologists
.
Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists
.
Diabetes Care
2008
;
31
:
1679
1685
180.
Hingorani
A
,
LaMuraglia
GM
,
Henke
P
, et al
.
The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine
.
J Vasc Surg
2016
;
63
(
Suppl.
):
3S
21S
181.
Litzelman
DK
,
Slemenda
CW
,
Langefeld
CD
, et al
.
Reduction of lower extremity clinical abnormalities in patients with non-insulin-dependent diabetes mellitus. A randomized, controlled trial
.
Ann Intern Med
1993
;
119
:
36
41
182.
IWGDF
. I
WGDF Guidelines on the prevention and management of diabetic foot disease. Accessed 11 August 2020. Available from https://iwgdfguidelines.org/wp-content/uploads/2019/05/IWGDF-Guidelines-2019.pdf
183.
Bonner
T
,
Foster
M
,
Spears-Lanoix
E
.
Type 2 diabetes-related foot care knowledge and foot self-care practice interventions in the United States: a systematic review of the literature
.
Diabet Foot Ankle
2016
;
7
:
29758
184.
Lipsky
BA
,
Berendt
AR
,
Cornia
PB
, et al.;
Infectious Diseases Society of America
.
2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections
.
Clin Infect Dis
2012
;
54
:
e132
e173
185.
Elraiyah
T
,
Tsapas
A
,
Prutsky
G
, et al
.
A systematic review and meta-analysis of adjunctive therapies in diabetic foot ulcers
.
J Vasc Surg
2016
;
63
(
2 Suppl.
)
:46S
58S
.e1–e2
186.
Game
FL
,
Apelqvist
J
,
Attinger
C
, et al.;
International Working Group on the Diabetic Foot
.
Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review
.
Diabetes Metab Res Rev
2016
;
32
(
Suppl. 1
):
154
168
187.
Kranke
P
,
Bennett
MH
,
Martyn-St James
M
,
Schnabel
A
,
Debus
SE
,
Weibel
S
.
Hyperbaric oxygen therapy for chronic wounds
.
Cochrane Database Syst Rev
2015
(
6
):
CD004123
188.
Löndahl
M
,
Katzman
P
,
Nilsson
A
,
Hammarlund
C
.
Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes
.
Diabetes Care
2010
;
33
:
998
1003
189.
Fedorko
L
,
Bowen
JM
,
Jones
W
, et al
.
Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a prospective, double-blind, randomized controlled clinical trial
.
Diabetes Care
2016
;
39
:
392
399
190.
Li
G
,
Hopkins
RB
,
Levine
MAH
, et al
.
Relationship between hyperbaric oxygen therapy and quality of life in participants with chronic diabetic foot ulcers: data from a randomized controlled trial
.
Acta Diabetol
2017
;
54
:
823
831
191.
Boulton
AJM
.
The Diabetic Foot, 2000. South Dartmouth, MA, MDText.com, Inc. Accessed 11 August 2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK409609/
192.
Health Quality Ontario
.
Hyperbaric oxygen therapy for the treatment of diabetic foot ulcers: a health technology assessment
.
Ont Health Technol Assess Ser
2017
;
17
:
1
142
193.
Stoekenbroek
RM
,
Santema
TB
,
Koelemay
MJ
, et al
.
Is additional hyperbaric oxygen therapy cost-effective for treating ischemic diabetic ulcers? Study protocol for the Dutch DAMOCLES multicenter randomized clinical trial?
J Diabetes
2015
;
7
:
125
132
194.
Huang
ET
,
Mansouri
J
,
Murad
MH
, et al.;
UHMS CPG Oversight Committee
.
A clinical practice guideline for the use of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers
.
Undersea Hyperb Med
2015
;
42
:
205
247
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.diabetesjournals.org/content/license.