Diabetes Care Volume 43, Supplement 1, January 2020 S135

11. Microvascular Complications American Diabetes Association and Foot Care: Standards of Medical Care in Diabetes22020

Diabetes Care 2020;43(Suppl. 1):S135–S151 | https://doi.org/10.2337/dc20-s011 1 IRVSUA OPIAIN N OTCARE FOOT AND COMPLICATIONS MICROVASCULAR 11.

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/dc20- 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/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

For prevention and management of diabetes complications in children and adoles- cents, please refer to Section 13 “Children and Adolescents” (https://doi.org/10.2337/ dc20-S013).

CHRONIC KIDNEY DISEASE Screening

Recommendations 11.1 At least once a year, assess urinary albumin (e.g., spot urinary albumin-to- creatinine ratio) and estimated glomerular filtration rate (eGFR) in patients with type 1 diabetes with duration of $5 years and in all patients with type 2 diabetes regardless of treatment. B Patients with urinary albumin .30 mg/g creatinine and/or an eGFR ,60 mL/min/1.73 m2 should be monitored twice annually to guide therapy. C

Treatment

Recommendations 11.2 Optimize glucose control to reduce the risk or slow the progression of chronic kidney disease. A 11.3 For patients with type 2 diabetes and diabetic kidney disease, consider use Suggested citation: American Diabetes Associa- of a sodium–glucose cotransporter 2 inhibitor in patients with an estimated tion. 11. Microvascular complications and glomerular filtration rate $30 mL/min/1.73 m2 and urinary albumin .30 foot care: Standards of Medical Care in d . Diabetes 2020. Diabetes Care 2020;43(Suppl. mg/g creatinine, particularly in those with urinary albumin 300 mg/g 1):S135–S151 creatinine, to reduce risk of chronic kidney disease (CKD) progression, © 2019 by the American Diabetes Association. cardiovascular events, or both. A In patients with CKD who are at increased Readers may use this article as long as the work risk for cardiovascular events, use of a glucagon-like peptide 1 receptor is properly cited, the use is educational and agonist may reduce risk of progression of albuminuria, cardiovascular not for profit, and the work is not altered. events, or both (Table 9.1). C More information is available at http://www .diabetesjournals.org/content/license. S136 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

or very high albuminuria (1,2,10,11). 11.4 Optimize blood pressure con- about the etiology of kidney Exercise within 24 h, infection, fever, trol to reduce the risk or slow disease, difficult management congestive heart failure, marked hyper- the progression of chronic kid- issues, and rapidly progressing glycemia, menstruation, and marked ney disease. A kidney disease. A hypertension may elevate UACR inde- 11.5 Do not discontinue renin-an- pendently of kidney damage (12). giotensin system blockade for eGFR should be calculated from serum minor increases in serum cre- Epidemiology of Diabetes and Chronic creatinine using a validated formula. The atinine (,30%) in the absence Kidney Disease Chronic kidney disease (CKD) is diag- Chronic Kidney Disease Epidemiology of volume depletion. B nosed by the persistent presence of Collaboration (CKD-EPI) equation is 11.6 For people with nondialysis- elevated urinary albumin excretion (al- generally preferred (2). eGFR is routinely dependent chronic kidney dis- buminuria), low estimated glomerular reported by laboratories with serum ease, dietary protein intake should filtration rate (eGFR), or other manifes- creatinine, and eGFR calculators are be approximately 0.8 g/kg body tations of kidney damage (1,2). In this available online at nkdep.nih.gov. An weight per day (the recommen- section, the focus will be on CKD eGFR persistently ,60 mL/min/1.73 m2 ded daily allowance). A For pa- attributed to diabetes (diabetic kidney is considered abnormal, though optimal tients on dialysis, higher levels of disease), which occurs in 20–40% of thresholds for clinical diagnosis are de- dietary protein intake should be patients with diabetes (1,3–5). CKD typ- bated in older adults (2,13). considered, since malnutrition ically develops after diabetes duration is a major problem in some of 10 years in type 1 diabetes but may Diagnosis of Diabetic Kidney Disease dialysis patients. B be present at diagnosis of type 2 di- Diabetic kidney disease is usually a clin- 11.7 In nonpregnant patients with abetes. CKD can progress to end-stage ical diagnosis made based on the pres- diabetes and hypertension, ei- renal disease (ESRD) requiring dialysis ence of albuminuria and/or reduced ther an ACE inhibitor or an or kidney transplantation and is the eGFRintheabsenceofsignsorsymptoms angiotensin receptor blocker leading cause of ESRD in the U.S. (6). of other primary causes of kidney dam- is recommended for those In addition, among people with type 1 or age. The typical presentation of diabetic with modestly elevated urinary 2 diabetes, the presence of CKD mark- kidney disease is considered to include a albumin-to-creatinine ratio edly increases cardiovascular risk and long-standing duration of diabetes, ret- (30–299 mg/g creatinine) B and health care costs (7). inopathy, albuminuria without gross is strongly recommended for hematuria, and gradually progressive those with urinary albumin-to- loss of eGFR. However, signs of CKD $ Assessment of Albuminuria and creatinine ratio 300 mg/g may be present at diagnosis or without creatinine and/or estimated Estimated Glomerular Filtration Rate Screening for albuminuria can be most retinopathy in type 2 diabetes, and re- glomerular filtration rate ,60 easily performed by urinary albumin-to- duced eGFR without albuminuria has mL/min/1.73 m2. A creatinine ratio (UACR) in a random spot been frequently reported in type 1 11.8 Periodically monitor serum urine collection (1,2). Timed or 24-h and type 2 diabetes and is becoming creatinine and potassium lev- collections are more burdensome and more common over time as the prev- els for the development of add little to prediction or accuracy. Mea- alence of diabetes increases in the U.S. increased creatinineor changes surement of a spot urine sample for (3,4,14,15). in potassium when ACE inhibi- albuminalone(whetherbyimmunoassay An active urinary sediment (containing tors, angiotensin receptor block- or by using a sensitive dipstick test red or white blood cells or cellular ers, or diuretics are used. B specific for albuminuria) without simul- casts), rapidly increasing albuminuria or 11.9 An ACE inhibitor or an angio- taneously measuring urine creatinine nephrotic syndrome, rapidly decreasing tensin receptor blocker is not (Cr) is less expensive but susceptible eGFR, or the absence of retinopathy (in recommended for the primary to false-negative and false-positive de- type 1 diabetes) suggests alternative or prevention of chronic kidney terminations as a result of variation in additional causes of kidney disease. For disease in patients with diabetes urine concentration due to hydration. patients with these features, referral to a who have normal blood pres- Normal UACR is defined as ,30 mg/g nephrologist for further diagnosis, in- sure, normal urinary albumin- Cr, and high urinary albumin excretion is cluding the possibility of kidney biopsy, to-creatinine ratio (,30 mg/g defined as $30 mg/g Cr. However, UACR should be considered. It is rare for pa- creatinine), and normal estimated is a continuous measurement, and differ- tients with type 1 diabetes to develop glomerular filtration rate. A ences within the normal and abnormal kidney disease without retinopathy. In 11.10 Patients should be referred for ranges are associated with renal and type 2 diabetes, retinopathy is only mod- evaluation by a nephrologist if cardiovascular outcomes (7–9). Further- erately sensitive and specific for CKD they have an estimated glo- more, because of high biological variabil- caused by diabetes, as confirmed by merular filtration rate ,30 ity of .20% between measurements in kidney biopsy (16). mL/min/1.73 m2. A urinary albumin excretion, two of three 11.11 Promptly refer to a physician specimens of UACR collected within a 3- experienced in the care of Staging of Chronic Kidney Disease to 6-month period should be abnormal Stages 1–2 CKD have been defined by kidney disease for uncertainty before considering a patient to have high evidence of high albuminuria with care.diabetesjournals.org Microvascular Complications and Foot Care S137

Figure 11.1—Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular filtration rate (GFR)andalbuminuria.TheGFRandalbuminuriagriddepictsthe riskofprogression,morbidity,andmortality bycolor,frombesttoworst(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 biopsyabnormalities,with follow-upmeasurements annually; yellow requirescaution and measurements at least once per year;orangerequires 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 cliniciansmaywishtodiscusswiththeirnephrologyservice,dependingonlocalarrangements regardingtreating orreferring.Reprintedwith permission from Vassalotti et al. (188). eGFR $60 mL/min/1.73 m2, while stages progression and other adverse health particularly when combined with diu- 3–5 CKD have been defined by progres- outcomes) and cause of kidney damage retics or other medications that reduce sively lower ranges of eGFR (17) (Fig. (including possible causes other than glomerular filtration; however, this 11.1). At any eGFR, the degree of albu- diabetes) may also affect these decisions has not been found to be true in ran- minuria is associated with risk of cardio- (20). domized clinical outcome trials of ad- vascular disease (CVD), CKD progression, vanced kidney disease (24) or high and mortality (7). Therefore, Kidney Acute Kidney Injury cardiovascular disease risk with normal Disease: Improving Global Outcomes Acute kidney injury (AKI) is diagnosed kidney function (25–27). Timely iden- (KDIGO) recommends a more compre- by a 50% or greater sustained increase tification and treatment of AKI is im- hensive CKD staging that incorporates in serum creatinine over a short period portant because AKI is associated with albuminuria at all stages of eGFR; this of time, which is also reflected as a rapid increased risks of progressive CKD and system is more closely associated with decrease in eGFR (21,22). People with other poor health outcomes (28). risk but is also more complex and does diabetes are at higher risk of AKI than Small elevations in serum creatinine not translate directly to treatment deci- those without diabetes (23). Other risk (upto30%frombaseline)withrenin- sions (2). Thus, based on the current factors for AKI include preexisting CKD, angiotensin system blockers (such as classification system, both eGFR and the use of medications that cause ACE inhibitors and ARBs) must not be albuminuria must be quantified to guide kidney injury (e.g., nonsteroidal anti- confused with AKI (29). An analysis treatment decisions. This is also impor- inflammatory drugs), and the use of oftheActiontoControlCardiovascu- tant since eGFR levels are essential to medications that alter renal blood flow lar Risk in Diabetes Blood Pressure modify drug dosage or restrictions of use and intrarenal hemodynamics. In partic- (ACCORD BP) trial demonstrates that those (Fig. 11.1) (18,19). The degree of albu- ular, many antihypertensive medications randomized to intensive blood pressure minuria may influence choice of antihy- (e.g., diuretics, ACE inhibitors, and an- lowering with up to a 30% increase in pertensive (see Section 10 “Cardiovascular giotensin receptor blockers [ARBs]) can serum creatinine did not have any in- Disease and Risk Management,” https:// reduce intravascular volume, renal blood crease in mortality or progressive kidney doi.org.10.2337/dc20-S010) or glucose- flow, and/or glomerular filtration. There disease (30–32). Moreover, a measure of lowering medications (see below). Ob- was concern that sodium–glucose co- markers for AKI showed no significant served history of eGFR loss (which transporter 2 (SGLT2) inhibitors may increase of any markers with increased is also associated with risk of CKD promote AKI through volume depletion, creatinine (32). Accordingly, ACE inhibitors S138 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

Table 11.1—Selected complications of chronic kidney disease recommended because it does not alter Complication Medical and laboratory evaluation glycemic measures, cardiovascular risk measures, or the course of GFR decline (39). . Elevated blood pressure 140/90 mmHg Blood pressure, weight Restriction of dietary sodium (to ,2,300 Volume overload History, physical examination, weight mg/day) may be useful to control blood Electrolyte abnormalities Serum electrolytes pressure and reduce cardiovascular risk Metabolic acidosis Serum electrolytes (40,41), and restriction of dietary potas- Anemia Hemoglobin; iron testing if indicated sium may be necessary to control se- Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D rum potassium concentration (23,33–35). Complications of chronic kidney disease (CKD) generally become prevalent when estimated These interventions may be most important glomerular filtration rate falls below 60 mL/min/1.73 m2 (stage 3 CKD or greater) and become more for patients with reduced eGFR, for whom common and severe as CKD progresses. Evaluation of elevated blood pressure and volume urinary excretion of sodium and potassium 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– may be impaired. For patients on dialysis, 3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in therapy. PTH, higher levels of dietary protein intake should parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D. be considered, since malnutrition is a major problem in some dialysis patients (42). Recommendations for dietary sodium and and ARBs should not be discontinued for 2 diabetes, reducing albuminuria from potassium intake should be individualized , $ minor increases in serum creatinine ( 30%), levels 300 mg/g Cr has been associated on the basis of comorbid conditions, med- in the absense of volume depletion. with improved renal and cardiovascular ication use, blood pressure, and labora- outcomes, leading some to suggest that tory data. Surveillance medications should be titrated to min- Albuminuria and eGFR should be mon- imize UACR. However, this approach has Glycemic Targets itored regularly to enable timely diagno- not been formally evaluated in prospec- Intensive glycemic control with the goal sis of CKD, monitor progression of CKD, tive trials. In type 1 diabetes, remission of achieving near-normoglycemia has detect superimposed kidney diseases of albuminuria may occur spontane- beenshowninlargeprospective random- including AKI, assess risk of CKD compli- ously and cohort studies evaluating ized studies to delay the onset and pro- cations, dose drugs appropriately, and associations of change in albuminuria gression of albuminuria and reduced determine whether nephrology referral with clinical outcomes have reported eGFR in patients with type 1 diabetes is needed. Among people with existing inconsistent results (36,37). (43,44) and type 2 diabetes (1,45–51). kidney disease, albuminuria and eGFR The prevalence of CKD complications Insulin alone was used to lower blood may change due to progression of CKD, correlates with eGFR (38). When eGFR glucose in the Diabetes Control and , 2 development of a separate superim- is 60 mL/min/1.73 m , screening for Complications Trial (DCCT)/Epidemiol- posed cause of kidney disease, AKI, or complications of CKD is indicated (Table ogy of Diabetes Interventions and Com- other effects of medications, as noted 11.1). Early vaccination against hepatitis plications (EDIC) study of type 1 diabetes, above. Serum potassium should also B virus is indicated in patients likely to while a variety of agents were used in “ be monitored for patients treated with progress to ESRD (see Section 4 Com- clinical trials of type 2 diabetes, support- ACE inhibitors, ARBs, and diuretics be- prehensive Medical Evaluation and As- ing the conclusion that glycemic control ” cause these medications can cause hy- sessment of Comorbidities, https://doi itself helps prevent CKD and its progres- perkalemia or hypokalemia, which are .org/10.2337/dc20-S004, for further in- sion. The effects of glucose-lowering associated with cardiovascular risk and formation on immunization). therapies on CKD have helped define mortality (33–35). For patients with A1C targets (see Table 6.2). eGFR ,60 mL/min/1.73 m2, appropriate Interventions The presence of CKD affects the risks medication dosing should be verified, Nutrition and benefits of intensive glycemic con- exposure to nephrotoxins (e.g., nonste- For people with nondialysis-dependent trol and a number of specific glucose- roidal anti-inflammatory drugs and io- CKD, dietary protein intake should be lowering medications. In the Action to dinated contrast) should be minimized, ;0.8 g/kg body weight per day (the Control Cardiovascular Risk in Diabetes and potential CKD complications should recommended daily allowance) (1). (ACCORD) trial of type 2 diabetes, ad- be evaluated (Table 11.1). Compared with higher levels of dietary verse effects of intensive glycemic con- The need for annual quantitative as- protein intake, this level slowed GFR trol (hypoglycemia and mortality) were sessment of albumin excretion after di- decline with evidence of a greater effect increased among patients with kidney agnosis of albuminuria, institution of ACE over time. Higher levels of dietary pro- disease at baseline (52,53). Moreover, inhibitors or ARB therapy, and achiev- tein intake (.20% of daily calories from there is a lag time of at least 2 years in ing blood pressure control is a subject protein or .1.3 g/kg/day) have been type 2 diabetes to over 10 years in type 1 of debate. Continued surveillance can associated with increased albuminuria, diabetes for the effects of intensive glu- assess both response to therapy and more rapid kidney function loss, and cose control to manifest as improved disease progression and may aid in as- CVD mortality and therefore should be eGFR outcomes (49,54,55). Therefore, in sessing adherence to ACE inhibitor or avoided. Reducing the amount of di- some patients with prevalent CKD and ARB therapy. In addition, in clinical trials etary protein below the recommended substantial comorbidity, target A1C levels of ACE inhibitors or ARB therapy in type daily allowance of 0.8 g/kg/day is not maybelessintensive(1,56). care.diabetesjournals.org Microvascular Complications and Foot Care S139

Direct Renal Effects of Glucose-Lowering constraints, metformin should be con- In addition, subgroup analyses of CANVAS Medications sidered the first-line treatment for all and LEADER suggested that the renal Some glucose-lowering medications also patients with type 2 diabetes, including benefits of canagliflozin and liraglutide have effects on the kidney that are direct, those with CKD. were as great or greater for participants i.e., not mediated through glycemia. For SGLT2 inhibitors and GLP-1 RAs should withCKD at baseline(27,66) andinCANVAS example, SGLT2 inhibitors reduce renal be considered for patients with type 2 were similar for participants with or with- tubular glucose reabsorption, weight, diabetes and CKD who require another out atherosclerotic cardiovascular disease systemic blood pressure, intraglomerular drug added to metformin to attain target (ASCVD) at baseline (72). pressure, and albuminuria and slow GFR A1C or cannot use or tolerate metformin. Several large clinical trials of SGLT2 loss through mechanisms that appear SGLT2 inhibitors reduce risks of CKD inhibitors focused on patients with ad- independent of glycemia (26,57–60). progression, CVD events, and hypogly- vanced CKD, and assessment of primary Moreover, recent data support the cemia. GLP-1 RAs are suggested because renal outcomes are completed or ongo- notion that SGLT2 inhibitors reduce ox- they reduce risks of CVD events and ing. Canagliflozin and Renal End points in idative stress in the kidney by .50% and hypoglycemia and appear to possibly Diabetes with Established Nephropa- blunt increases in angiotensinogen as slow CKD progression. thy Clinical Evaluation (CREDENCE), a well as reduce NLRP3 inflammasome A number of large cardiovascular out- placebo-controlled trial of canagliflozin activity (61–63). Glucagon-like peptide comes trials in patients with type 2 di- among 4,401 adults with type 2 diabetes, 1 receptor agonists (GLP-1 RAs) also have abetes at high risk for CVD or with UACR $300 mg/g Cr, and mean eGFR direct effects on the kidney and have existing CVD examined kidney effects 56 mL/min/1.73 m2 with a mean albu- been reported to improve renal out- as secondary outcomes. These trials minuria level of over 900 mg/day, has a comes compared with placebo (64–67). include EMPA-REG OUTCOME [BI primary composite end point of ESRD, Renal effects should be considered when 10773 (Empagliflozin) Cardiovascular doubling of serum creatinine, or renal or selecting antihyperglycemia agents (see Outcome Event Trial in Type 2 Diabetes cardiovascular death (24,73). It was stop- Section 9 “Pharmacologic Approaches to Mellitus Patients], CANVAS (Canagliflozin ped early due to positive efficacy and Glycemic Treatment,” https://doi.org/10 Cardiovascular Assessment Study), showed a 32% risk reduction for devel- .2337/dc20-S009). LEADER (Liraglutide Effect and Action opment of ESRD over control (24). in Diabetes: Evaluation of Cardiovascular Additionally, the development of the Selection of Glucose-Lowering Medications Outcome Results), and SUSTAIN-6 (Trial primary end point, which included for Patients With Chronic Kidney Disease to Evaluate Cardiovascular and Other chronic dialysis for $30 days, kidney For patients with type 2 diabetes and Long-term Outcomes With Semaglutide transplantation or eGFR ,15 mL/min/ established CKD, special considerations in Subjects With Type 2 Diabetes) 1.73 m2 sustained for $30 days by forthe selectionofglucose-lowering med- (59,64,67,71). Specifically, compared central laboratory assessment, doubling ications include limitations to available with placebo, empagliflozin reduced from the baseline serum creatinine av- medications when eGFR is diminished the risk of incident or worsening ne- erage sustained for $30 days by central and a desire to mitigate high risks of phropathy (a composite of progression laboratory assessment, or renal death or CKD progression, CVD, and hypoglycemia to UACR .300 mg/g Cr, doubling of cardiovascular death, was reduced by (68,69). Drug dosing may require modifi- serum creatinine, ESRD, or death from 30%. This benefit was on background cation with eGFR ,60 mL/min/1.73 m2 (1). ESRD) by 39% and the risk of doubling ACE inhibitor or ARB therapy in .99% of The U.S. Food and Drug Administration of serum creatinine accompanied by the patients (24). Moreover, in this ad- (FDA) revised its guidance for the use of eGFR #45 mL/min/1.73 m2 by 44%; vanced CKD group, there were clear metformin in CKD in 2016 (70), recom- canagliflozin reduced the risk of progres- benefits on cardiovascular outcomes mending use of eGFR instead of serum sion of albuminuria by 27% and the risk demonstrating a 31% reduction in car- creatinine to guide treatment and ex- of reductionin eGFR,ESRD, or death from diovascular death or heart failure hos- panding the pool of patients with kidney ESRD by 40%; liraglutide reduced the risk pitalization and a 20% reduction in disease for whom metformin treatment of new or worsening nephropathy (a cardiovascular death, nonfatal myocar- should be considered. The revised FDA composite of persistent macroalbumin- dial infarction, or nonfatal stroke (24,74). guidance states that metformin is uria, doubling of serum creatinine, ESRD, In addition to renal effects, some contraindicated inpatientswithan or death from ESRD) by 22%; and sema- SGLT2 inhibitors and GLP-1 RAs have eGFR ,30 mL/min/1.73 m2; eGFR should glutide reduced the risk of new or wors- demonstrated cardiovascular benefits. be monitored while taking metformin; ening nephropathy (a composite of Namely, in EMPA-REG OUTCOME, CANVAS, the benefits and risks of continuing persistent UACR .300 mg/g Cr, doubling and LEADER, empagliflozin, canagliflozin, treatment should be reassessed when of serum creatinine, or ESRD) by 36% and liraglutide, respectively, each reduced eGFR falls ,45 mL/min/1.73 m2;met- (each P , 0.01). cardiovascular events,evaluatedas primary formin should not be initiated for These analyses were limited by eval- outcomes, compared with placebo (see patients with an eGFR ,45 mL/min/ uation of study populations not selected Section 10 “Cardiovascular Disease and 1.73 m2; and metformin should be primarily for CKD and examination of Risk Management,” https://doi.org/10 temporarily discontinued at the time renal effects as secondary outcomes. .2337/dc20-S010 for further discussion). of or before iodinated contrast imag- However, all of these trials included large While the glucose-lowering effects ing procedures in patients with eGFR numbers of people with stage 3a (eGFR of SGLT2 inhibitors are blunted with 30–60 mL/min/1.73 m2. Within these 45–59 mL/min/1.73 m2) kidney disease. eGFR ,45 mL/min/1.73 m2,therenal S140 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

and cardiovascular benefits were still Cardiovascular Disease and Blood Pressure blockers (92). In a trial of people with seen down to eGFR levels of 30 mL/ Hypertension is a strong risk factor for type 2 diabetes and normal urine albu- min/1.73 m2 with no significant change the development and progression of CKD min excretion, an ARB reduced or sup- in glucose (24,26,43,45,52,56,71). Most (78). Antihypertensive therapy reduces pressed the development of albuminuria participants with CKD in these trials the risk of albuminuria (79–82), and but increased the rate of cardiovascular also had diagnosed ASCVD at baseline, among patients with type 1 or 2 diabetes events (93).Ina trial of people with type 1 though ;28% of CANVAS participants with established CKD (eGFR ,60 mL/ diabetes exhibiting neither albuminuria with CKD did not have diagnosed min/1.73 m2 and UACR $300 mg/g Cr), nor hypertension, ACE inhibitors or ARBs ASCVD (27). ACE inhibitor or ARB therapy reduces the did not prevent the development of Based on evidence from the CREDENCE risk of progression to ESRD (83–85). diabetic glomerulopathy assessed by kid- trial and secondary analyses of cardio- Moreover, antihypertensive therapy re- ney biopsy (90) This was further sup- vascular outcomes trials with SGLT2 duces risks of cardiovascular events (79). ported by a similar trial in patients with inhibitors, cardiovascular and renal Blood pressure levels ,140/90 mmHg type 2 diabetes (91). Therefore, ACE events are reduced with SGLT2 inhibitor are generally recommended to reduce inhibitors or ARBs are not recommended useinpatientsdowntoaneGFRof CVD mortality and slow CKD progres- for patients without hypertension to pre- 30 mL/min/1.73 m2 even independent sion among all people with diabetes vent the development of CKD. of glucose-lowering effects (75). (82). Lower blood pressure targets Two clinical trials studied the combi- While there is clear cardiovascular risk (e.g., ,130/80 mmHg) should be con- nations of ACE inhibitors and ARBs and reduction associated with GLP-1 RA use sidered for patients based on individual found no benefits on CVD or CKD, and the in patients with type 2 diabetes and CKD, anticipated benefits and risks. Patients drug combination had higher adverse the proof of benefit on renal outcome with CKD are at increased risk of CKD event rates (hyperkalemia and/or AKI) will come with the results of the ongoing progression (particularly those with al- (94,95). Therefore, the combined useof ACE FLOW (A Research Study to See How buminuria) and CVD and therefore may inhibitors and ARBs should be avoided. Semaglutide Works Compared to Pla- be suitable in some cases for lower blood Mineralocorticoid receptor antago- cebo in People With Type 2 Diabetes pressure targets, especially in those nists (spironolactone, eplerenone, and and Chronic Kidney Disease) trial with with $300 mg/day albuminuria. finerenone) in combination with ACE injectable semaglutide (76). As noted ACE inhibitors or ARBs are the pre- inhibitors or ARBs remain an area of above, published data address a limited ferred first-line agent for blood pressure great interest. Mineralocorticoid recep- group of CKD patients, mostly with coex- treatment among patients with diabe- tor antagonists are effective for man- isting ASCVD. Renal events have been tes, hypertension, eGFR ,60 mL/min/ agementofresistanthypertension,have 2 examined, however, as both primary and 1.73 m , and UACR $300 mg/g Cr be- been shown to reduce albuminuria in secondary outcomes in published large cause of their proven benefits for pre- short-term studies of CKD, and may trials. Also, adverse event profiles of vention of CKD progression (83–86). In have additional cardiovascular benefits these agents must be considered. Please general, ACE inhibitors and ARBs are (96–98). There has been, however, an fi refer to Table 9.1 for drug-specific considered to have similar bene ts increase in hyperkalemic episodes in factors, including adverse event infor- (87,88) and risks. In the setting of lower those on dual therapy, and larger, longer – mation, for these agents. Additional levels of albuminuria (30 299 mg/g Cr), trials with clinical outcomes are needed clinical trials focusing on CKD and car- ACE inhibitor or ARB therapy has been before recommending such therapy. diovascular outcomes in CKD patients demonstrated to reduce progression to are ongoing and will be reported in the more advanced albuminuria ($300 mg/g Referral to a Nephrologist next few years. Cr) and cardiovascular events but not Consider referral to a physician experi- For patients with type 2 diabetes and progression to ESRD (86,89). While ACE enced in the care of kidney disease when CKD, the selection of specific agents may inhibitors or ARBs are often prescribed there is uncertainty about the etiology fi depend on comorbidity and CKD stage. for high albuminuria without hyperten- of kidney disease, for dif cult manage- SGLT2 inhibitors may be more useful for sion, outcome trials have not been per- ment issues (anemia, secondary hyper- patients at high risk of CKD progression formed in this setting to determine parathyroidism, metabolic bone disease, (i.e., with albuminuria or a history of whether this improves renal outcomes. resistant hypertension, or electrolyte dis- documented eGFR loss) (Fig. 9.1) be- Moreover, two long-term, double-blind turbances), or when there is advanced cause they appear to have large bene- studies demonstrate no renoprotective kidney disease (eGFR ,30 mL/min/ 2 ficial effects on CKD incidence. The SGLT2 effect of either ACE inhibitors or ARBs in 1.73 m ) requiring discussion of renal inhibitors canagliflozin, empagliflozin, type 1 and type 2 diabetes among those replacement therapy for ESRD (2). The and dapagliflozin are approved by the who were normotensive with or without threshold for referral may vary depending FDA for use with eGFR $45 mL/min/ high albuminuria (formerly microalbu- on the frequency with which a provider 1.73 m2 (though pivotal trials for each minuria) (90,91). encounters patients with diabetes and included participants with eGFR $30 Absent kidney disease, ACE inhibitors kidney disease. Consultation with a ne- mL/min/1.73 m2 and demonstrated or ARBs are useful to control blood phrologist when stage 4 CKD develops benefit in subgroups with low eGFR) pressure but have not proven superior (eGFR ,30 mL/min/1.73 m2) has been (26,27,77). Some GLP-1 RAs may be used to alternative classes of antihypertensive found to reduce cost, improve quality of with lower eGFR, but most require dose therapy, including thiazide-like diuretics care, and delay dialysis (99). However, adjustment. and dihydropyridine calcium channel other specialists and providers should care.diabetesjournals.org Microvascular Complications and Foot Care S141

also educate their patients about the Diabetic retinopathy is a highly specific 11.18 Women with preexisting type progressive nature of CKD, the kidney vascular complication of both type 1 and 1ortype2diabeteswhoare preservation benefits of proactive treat- type 2 diabetes, with prevalence strongly planning pregnancy or who are mentofbloodpressureandbloodglucose, related to both the duration of diabetes pregnant should be counseled and the potential need for renal replace- and the level of glycemic control (100). on the risk of development and/ ment therapy. Diabetic retinopathy is the most frequent or progression of diabetic reti- cause of new cases of blindness among nopathy. B adults aged 20–74 years in developed DIABETIC RETINOPATHY 11.19 Eye examinations should occur countries. Glaucoma, cataracts, and other before pregnancy or in the first Recommendations disorders of the eye occur earlier and trimester in patients with pre- 11.12 Optimize glycemic control to more frequently in people with diabetes. existing type 1 or type 2 di- reduce the risk or slow the In addition to diabetes duration, fac- abetes, and then patients progression of diabetic reti- tors that increase the risk of, or are should be monitored every tri- nopathy. A associated with, retinopathy include mester and for 1 year postpar- 11.13 Optimize blood pressure and chronic hyperglycemia (101), nephropa- tum as indicated by the degree serum lipid control to reduce thy (102), hypertension (103), and of retinopathy. B the risk or slow the progression dyslipidemia (104). Intensive diabetes of diabetic retinopathy. A management with the goal of achieving Treatment near-normoglycemia has been shown in Screening large prospective randomized studies to Recommendations prevent and/or delay the onset and pro- Recommendations 11.20 Promptly refer patients with gression of diabetic retinopathy and po- 11.14 Adults with type 1 diabetes any level of macular edema, tentially improve patient reported visual should have an initial dilated severe nonproliferative dia- function (46,105–107). and comprehensive eye exam- betic retinopathy (a precursor Several case series and a controlled ination by an ophthalmologist of proliferative diabetic reti- prospective study suggest that preg- or optometrist within 5 years nopathy), or any proliferative nancy in patients with type 1 diabe- after the onset of diabetes. B diabetic retinopathy to an oph- tes may aggravate retinopathy and 11.15 Patients with type 2 diabetes thalmologist who is knowl- threaten vision, especially when gly- should have an initial dilated edgeable and experienced in cemic control is poor at the time of and comprehensive eye exam- the management of diabetic conception (108,109). Laser photocoagu- ination by an ophthalmologist retinopathy. A lation surgery can minimize the risk of or optometrist at the time of 11.21 The traditional standard treat- vision loss (109). the diabetes diagnosis. B ment, panretinal laser photo- 11.16 If there is no evidence of ret- coagulation therapy, is indicated inopathy for one or more an- to reduce the risk of vision loss Screening The preventive effects of therapy and nual eye exams and glycemia is in patients with high-risk prolif- the fact that patients with proliferative well controlled, then screening erative diabetic retinopathy and, diabetic retinopathy (PDR) or macular every 1–2 years may be con- in some cases, severe nonproli- edema may be asymptomatic provide sidered. If any level of diabetic ferative diabetic retinopathy. A strong support for screening to detect retinopathy is present, subse- 11.22 Intravitreousinjectionsofanti– diabetic retinopathy. quent dilated retinal examina- vascular endothelial growth fac- Diabetic retinopathy screening should tions should be repeated at least tor ranibizumab are not inferior be performed using validated ap- annually by an ophthalmologist to traditional panretinal laser proaches and methodologies. Youth or optometrist. If retinopathy is photocoagulation and are also with type 1 or type 2 diabetes are progressing or sight-threatening, indicatedtoreducetheriskof also at risk for complications and need then examinations will be re- vision loss in patients with pro- to be screened for diabetic retinopathy quired more frequently. B liferative diabetic retinopathy. A (110). If diabetic retinopathy is evident 11.17 Programs that use retinal pho- 11.23 Intravitreousinjectionsofanti– on screening, prompt referral to an oph- tography (with remote reading vascular endothelial growth thalmologist is recommended. Subse- or use of a validated assess- factor are indicated for central quent examinations for patients with ment tool) to improve access involveddiabeticmacularedema, type 1 or type 2 diabetes are generally to diabetic retinopathy screen- which occurs beneath the foveal repeated annually for patients with min- ing can be appropriate screen- center and may threaten reading imal to no retinopathy. Exams every 1–2 ing strategies for diabetic vision. A years may be cost effective after one or retinopathy. Such programs 11.24 The presence of retinopathy is more normal eye exams, and in a pop- need to provide pathways not a contraindication to aspirin ulation with well controlled type 2 di- for timely referral for a com- therapy for cardioprotection, as abetes, there was essentially no risk of prehensive eye examination aspirin does not increase the risk development of significant retinopathy when indicated. B of retinal hemorrhage. A with a 3-year interval after a normal S142 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

examination (111). Less frequent intervals comprehensive eye examination at the growth factor (anti-VEGF) agent, specif- have been found in simulated modeling time of diagnosis. ically ranibizumab, resulted in visual acu- to be potentially effective in screening for ity outcomes that were not inferior to Pregnancy diabetic retinopathy in patients without Pregnancy is associated with a rapid those observed in patients treated with diabetic retinopathy(112).Morefrequent progression of diabetic retinopathy panretinal laser at 2 years of followup examinations by the ophthalmologist will (117,118). Women with preexisting (121). In addition, it was observed that be required if retinopathy is progressing. type 1 or type 2 diabetes who are plan- patients treated with ranibizumab Retinal photography with remote ning pregnancy or who have become tended to have less peripheral visual fi reading by experts has great potential pregnant should be counseled on the eld loss, fewer vitrectomy surgeries to provide screening services in areas risk of development and/or progression for secondary complications from their fi where quali ed eye care professionals of diabetic retinopathy. In addition, rapid proliferative disease, and a lower risk of are not readily available (105,106). High implementation of intensive glycemic developing diabetic macular edema. quality fundus photographs can detect management in the setting of retinopa- However, a potential drawback in using fi most clinically signi cant diabetic reti- thy is associated with early worsening anti-VEGF therapy to manage prolifer- nopathy. Interpretation of the images of retinopathy (109). Women who de- ative disease is that patients were re- should be performed by a trained eye velop gestational diabetes mellitus do quired to have a greater number of visits care provider. Retinal photography may not require eye examinations during and received a greater number of fi also enhance ef ciency and reduce pregnancy and do not appear to be treatments than is typically required costs when the expertise of ophthalmol- at increased risk of developing diabetic for management with panretinal laser, ogistscanbeusedformorecomplex retinopathy during pregnancy (119). which may not be optimal for some pa- examinations and for therapy (113,114). tients. Other emerging therapies for In-person exams are still necessary Treatment retinopathy that may use sustained intra- when the retinal photos are of unaccept- Two of the main motivations for screen- vitreal delivery of pharmacologic agents able quality and for follow-up if abnor- ing for diabetic retinopathy are to pre- are currently under investigation. The FDA malities are detected. Retinal photos are vent loss of vision and to intervene with approved ranibizumab for the treatment not a substitute for comprehensive eye treatment when vision loss can be pre- of diabetic retinopathy in 2017. exams, which should be performed at vented or reversed. While the ETDRS (122) established the least initially and at intervals thereafter benefit of focal laser photocoagulation as recommended by an eye care pro- Photocoagulation Surgery surgery in eyes with clinically significant Two large trials, the Diabetic Retinop- fessional. Artificial intelligence systems macularedema (definedasretinaledema athy Study (DRS) in patients with PDR that detect more than mild diabetic located at or within 500 mm of the center and the Early Treatment Diabetic Ret- retinopathy and diabetic macular edema of the macula), current data from well- inopathy Study (ETDRS) in patients with authorized for use by the FDA represent designed clinical trials demonstrate that macular edema, provide the strongest an alternative to traditional screening intravitreal anti-VEGF agents provide a support for the therapeutic benefits approaches (115). However, the bene- more effective treatment regimen for of photocoagulation surgery. The DRS fits and optimal utilization of this type central-involved diabetic macular edema (120) showed in 1978 that panretinal of screening have yet to be fully de- than monotherapy or even combination photocoagulation surgery reduced the termined. Artificial intelligence systems therapy with laser (123,124). There risk of severe vision loss from PDR from should not be used for patients with are currently three anti-VEGF agents 15.9% in untreated eyes to 6.4% in known retinopathy, prior retinopathy commonlyusedtotreateyeswith treated eyes with the greatest benefit treatment, or symptoms of vision central-involved diabetic macular ratio in those with more advanced base- impairment. Results of eye examina- edemadbevacizumab, ranibizumab, line disease (disc neovascularization tions should be documented and trans- and aflibercept (100). or vitreous hemorrhage). In 1985, the mitted to the referring health care In both the DRS and the ETDRS, laser ETDRS also verified the benefits of professional. photocoagulation surgery was beneficial panretinal photocoagulation for high- in reducing the risk of further visual loss Type 1 Diabetes risk PDR and in older-onset patients in affected patients but generally not Because retinopathy is estimated to with severe nonproliferative diabetic beneficial in reversing already dimin- take at least 5 years to develop after retinopathy or less-than-high-risk PDR. ished acuity. Anti-VEGF therapy im- the onset of hyperglycemia, patients Panretinal laser photocoagulation is still proves vision and has replaced the with type 1 diabetes should have an commonly used to manage compli- need for laser photocoagulation in initial dilated and comprehensive eye ex- cations of diabetic retinopathy that in- the vast majority of patients with di- amination within 5 years after the diagnosis volve retinal neovascularization and its abetic macular edema (125). Most of diabetes (116). complications. patients require near-monthly admin- Type 2 Diabetes Anti–Vascular Endothelial Growth Factor istration of intravitreal therapy with Patients with type 2 diabetes who may Treatment anti-VEGF agents during the first 12 have had years of undiagnosed diabetes Recent data from the Diabetic Retinop- months of treatment, with fewer injec- and have a significant risk of prevalent athy Clinical Research Network and tions needed in subsequent years to diabetic retinopathy at the time of di- others demonstrate that intravitreal in- maintain remission from central-involved agnosis should have an initial dilated and jections of anti–vascular endothelial diabetic macular edema. care.diabetesjournals.org Microvascular Complications and Foot Care S143

Adjunctive Therapy loss of protective sensation (LOPS). 11.30 Pregabalin, duloxetine, or ga- Lowering blood pressure has been shown LOPS indicates the presence of distal bapentin are recommended as to decrease retinopathy progression, al- sensorimotor polyneuropathy and is a initial pharmacologic treat- though tight targets (systolic blood risk factor for diabetic foot ulceration. ments for neuropathic pain pressure ,120 mmHg) do not impart The following clinical tests may be used in diabetes. A additional benefit (106). ACE inhibitors to assess small- and large-fiber function and ARBs are both effective treatments and protective sensation: The diabetic neuropathies are a hetero- in diabetic retinopathy (126). In patients geneous group of disorders with diverse with dyslipidemia, retinopathy progres- 1. Small-fiber function: pinprick and tem- clinical manifestations. The early recog- perature sensation sion may be slowed by the addition of nition and appropriate management of fi 2. Large-fiber function: vibration percep- feno brate, particularly with very mild neuropathy in the patient with diabetes tion and 10-g monofilament nonproliferative diabetic retinopathy at is important. baseline (104,127). 3. Protective sensation: 10-g monofilament 1. Diabetic neuropathy is a diagnosis of These tests not only screen for the pres- exclusion. Nondiabetic neuropathies NEUROPATHY ence of dysfunction but also predict future may be present in patients with di- Screening risk of complications. Electrophysiological abetes and may be treatable. testing or referral to a neurologist is rarely Recommendations 2. Numerous treatment options exist for needed, except in situations where the 11.25 All patients should be assessed symptomatic diabetic neuropathy. clinical features are atypical or the di- for diabetic peripheral neurop- 3. Up to 50% of diabetic peripheral neu- agnosis is unclear. athy starting at diagnosis of ropathy (DPN) may be a symptomatic. In all patients with diabetes and DPN, type 2 diabetes and 5 years If not recognized and if preventive foot causes of neuropathy other than diabetes after the diagnosis of type 1 care is not implemented, patients are should be considered, including toxins diabetes and at least annually at risk for injuries to their insensate (e.g., alcohol), neurotoxic medications thereafter. B feet. (e.g., chemotherapy), vitamin B12 defi- 11.26 Assessment for distal symmet- 4. Recognition and treatment of auto- ciency, hypothyroidism, renal disease, ric polyneuropathy should nomic neuropathy may improve malignancies (e.g., multiple myeloma, bron- include a careful history and symptoms, reduce sequelae, and im- assessment of either temper- chogenic carcinoma), infections (e.g., prove quality of life. fl ature or pinprick sensation HIV), chronic in ammatory demyelinat- ing neuropathy, inherited neuropathies, (small fiber function) and vi- Specific treatment for the underlying and vasculitis (131). See the American bration sensation using a nerve damage, other than improved Diabetes Association (ADA) position 128-Hz tuning fork (for large- glycemic control, is currently not avail- statement “Diabetic Neuropathy” for fiber function). All patients should able. Glycemic control can effectively more details (130). have annual 10-g monofila- prevent DPN and cardiac autonomic ment testing to identify feet neuropathy (CAN) in type 1 diabetes Diabetic Autonomic Neuropathy at risk for ulceration and am- (128,129) and may modestly slow their The symptoms and signs of autonomic putation. B progression in type 2 diabetes (48), but it neuropathy should be elicited carefully 11.27 Symptoms and signs of auto- does not reverse neuronal loss. Thera- during the history and physical exami- nomic neuropathy should be peutic strategies (pharmacologic and nation. Major clinical manifestations assessed in patients with mi- nonpharmacologic) for the relief of pain- of diabetic autonomic neuropathy in- crovascular complications. E ful DPN and symptoms of autonomic clude hypoglycemia unawareness, rest- neuropathy can potentially reduce pain ing tachycardia, orthostatic hypotension, (130) and improve quality of life. gastroparesis, constipation, diarrhea, fe- Treatment cal incontinence, erectile dysfunction, Recommendations Diagnosis neurogenic bladder, and sudomotor dys- 11.28 Optimize glucose control to function with either increased or de- Diabetic Peripheral Neuropathy prevent or delay the develop- Patients with type 1 diabetes for 5 or more creased sweating. mentof neuropathy in patients years and all patients with type 2 diabetes Cardiac Autonomic Neuropathy. CAN is with type 1 diabetes A and to should be assessed annually for DPN associated with mortality independently slow the progression of neu- using the medical history and simple of other cardiovascular risk factors ropathy in patients with type 2 clinical tests (130). Symptoms vary ac- (132,133). In its early stages, CAN may diabetes. B cording to the class of sensory fibers be completely asymptomatic and de- 11.29 Assess and treat patients to involved. The most common early symp- tected only by decreased heart rate var- reduce pain related to diabetic toms are induced by the involvement of iability with deep breathing. Advanced peripheral neuropathy B and small fibers and include pain and dys- disease may be associated with resting symptoms of autonomic neu- esthesia(unpleasantsensations ofburn- tachycardia (.100 bpm) and orthostatic ropathy and to improve quality ing and tingling). The involvement of hypotension (a fall in systolic or dia- of life. E large fibers may cause numbness and stolic blood pressure by .20 mmHg or S144 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

.10 mmHg, respectively, upon standing a modest slowing of progression without expensive, although it is not FDA ap- without an appropriate increase in heart reversal of neuronal loss (48,139). Specific proved for this indication (154). rate). CAN treatment is generally focused glucose-lowering strategies may have dif- Duloxetine is a selective norepineph- on alleviating symptoms. ferent effects. In a post hoc analysis, par- rine and serotonin reuptake inhibitor. Gastrointestinal Neuropathies. Gastroin- ticipants, particularly men, in the Bypass Doses of 60 and 120 mg/day showed testinal neuropathies may involve any Angioplasty Revascularization Investigation efficacy in the treatment of pain associ- portion of the gastrointestinal tract with in Type 2 Diabetes (BARI 2D) trial treated ated with DPN in multicenter randomized manifestations including esophageal with insulin sensitizers had a lower inci- trials, although some of these had dysmotility, gastroparesis, constipation, dence of distal symmetric polyneuropathy high drop-out rates (143,145,150,152). diarrhea, and fecal incontinence. Gastro- over4yearsthanthosetreatedwithinsulin/ Duloxetine also appeared to improve paresis should be suspected in individ- sulfonylurea (140). neuropathy-related quality of life (155). uals with erratic glycemic control or with In longer-term studies, a small increase in upper gastrointestinal symptoms with- Neuropathic Pain A1C was reported in people with diabetes out another identified cause. Exclusion of Neuropathic pain can be severe and can treated with duloxetine compared with organic causes of gastric outlet obstruc- impact quality of life, limit mobility, and placebo (156). Adverse events may be tion or peptic ulcer disease (with esoph- contribute to depression and social dys- more severe in older people but may be agogastroduodenoscopy or a barium function (141). No compelling evidence attenuated with lower doses and slower study of the stomach) is needed before exists in support of glycemic control or titrations of duloxetine. considering a diagnosis of or specialized lifestyle management as therapies for Tapentadol is a centrally acting opioid testing for gastroparesis. The diagnostic neuropathic pain in diabetes or predia- analgesic that exerts its analgesic effects gold standard for gastroparesis is the betes, which leaves only pharmaceutical through both m-opioid receptor agonism measurement of gastric emptying with interventions (142). and noradrenaline reuptake inhibition. scintigraphy of digestible solids at Pregabalin and duloxetine have re- Extended-release tapentadol was ap- 15-min intervals for 4 h after food intake. ceived regulatory approval by the FDA, proved by the FDA for the treatment The use of 13C octanoic acid breath test Health Canada, and the European Med- of neuropathic pain associated with is emerging as a viable alternative. icines Agency for the treatment of neu- diabetes based on data from two mul- ropathic pain in diabetes. The opioid ticenter clinical trials in which partici- Genitourinary Disturbances. Diabetic auto- tapentadol has regulatory approval in pants titrated to an optimal dose of nomic neuropathy may also cause gen- the U.S. and Canada, but the evidence tapentadol were randomly assigned to itourinary disturbances, including sexual of its use is weaker (143). Comparative continue that dose or switch to placebo dysfunction and bladder dysfunction. In effectiveness studies and trials that in- (157,158). However, both used a design men, diabetic autonomic neuropathy clude quality-of-life outcomes are rare, enriched for patients who responded to may cause erectile dysfunction and/or so treatment decisions must consider tapentadol and therefore their results are retrograde ejaculation (130). Female each patient’s presentation and comor- not generalizable. A recent systematic sexual dysfunction occurs more frequently bidities and often follow a trial-and-error review and meta-analysis by the Special in those with diabetes and presents as approach. Given the range of partially Interest Group on Neuropathic Pain of the decreased sexual desire, increased pain effective treatment options, a tailored International Association for the Study of during intercourse, decreased sexual and stepwise pharmacologic strategy Pain found the evidence supporting the arousal, and inadequate lubrication with careful attention to relative symp- effectiveness of tapentadol in reducing (134). Lower urinary tract symptoms tom improvement, medication adher- neuropathic pain to be inconclusive (143). manifest as urinary incontinence and ence, and medication side effects is Therefore, given the high risk for addiction bladder dysfunction (nocturia, frequent recommended to achieve pain reduction and safety concerns compared with the urination, urination urgency, and weak – and improve quality of life (144 146). relatively modest pain reduction, the use urinary stream). Evaluation of bladder a d Pregabalin, a calcium channel 2- of extended release tapentadol is not function should be performed for indi- subunit ligand, is the most extensively generally recommended as a first- or viduals with diabetes who have recurrent studied drug for DPN. The majority of second-line therapy. The use of any urinary tract infections, pyelonephritis, studies testing pregabalin have reported opioids for management of chronic neu- incontinence, or a palpable bladder. favorable effects on the proportion of ropathic pain carries the risk of addiction participants with at least 30–50% im- and should be avoided. Treatment provement in pain (143,145,147–150). Tricyclic antidepressants, venlafaxine, Glycemic Control However, not all trials with pregabalin carbamazepine, and topical capsaicin, Near-normal glycemic control, imple- have been positive (143,145,151,152), although not approved for the treatment mented early in the course of diabetes, especially when treating patients with has been shown to effectively delay or advanced refractory DPN (149). Adverse of painful DPN, may be effective and prevent the development of DPN and effects may be more severe in older considered for the treatment of painful CAN in patients with type 1 diabetes patients (153) and may be attenuated DPN (130,143,145). (135–138). Although the evidence for by lower starting doses and more gradual Orthostatic Hypotension the benefit of near-normal glycemic titration. The related drug, gabapentin, Treating orthostatic hypotension is chal- control is not as strong for type 2 di- has also shown efficacy for pain control lenging. The therapeutic goal is to min- abetes, some studies have demonstrated in diabetic neuropathy and may be less imize postural symptoms rather than care.diabetesjournals.org Microvascular Complications and Foot Care S145

to restore normotension. Most patients Medicines Agency. It should be reserved be referred for ankle-brachial require both nonpharmacologic mea- for severe cases that are unresponsive to index and for further vascular sures (e.g., ensuring adequate salt intake, other therapies (166). Other treatment assessment as appropriate. C avoiding medications that aggravate hy- options include domperidone (available 11.36 A multidisciplinary approach is potension,orusingcompressivegarments outside of the U.S.) and erythromycin, recommended for individuals over the legs and abdomen) and phar- which is only effective for short-term use with foot ulcers and high-risk macologic measures. Physical activity and due to tachyphylaxis (167,168). Gastric feet (e.g., dialysis patients and exercise should be encouraged to avoid electrical stimulation using a surgically those with Charcot foot or deconditioning, which is known to exac- implantable device has received approval prior ulcers or amputation). B from the FDA, although its efficacy is erbate orthostatic intolerance, and vol- 11.37 Refer patients who smoke or who fl variable and use is limited to patients ume repletion with uids and salt is have histories of prior lower- with severe symptoms that are refractory critical. There have been clinical studies extremity complications, loss of to other treatments (169). that assessed the impact of an approach protective sensation, structural incorporating the aforementioned non- Erectile Dysfunction abnormalities, or peripheral arte- pharmacologic measures. Additionally, rial disease to foot care special- supine blood pressure tends to be In addition to treatment of hypogonad- ism if present, treatments for erectile ists for ongoing preventive care much higher in these patients, often re- and lifelong surveillance. C quiring treatment of blood pressure at dysfunction may include phosphodies- terase type 5 inhibitors, intracorporeal 11.38 Provide general preventive bedtime with shorter-acting drugs that foot self-care education to also affect baroreceptor activity such as or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with all patients with diabetes. B guanfacine or clonidine, shorter-acting DPN treatments, these interventions do 11.39 The use of specialized therapeu- calcium blockers (e.g., isradipine), or not change the underlying pathology tic footwear is recommended for shorter-acting b-blockers such as atenolol and natural history of the disease pro- high-risk patients with diabetes or metoprolol tartrate. Alternatives can cess but may improve the patient’s including those with severe neu- include enalapril if patients are unable ropathy, foot deformities, ulcers, – quality of life. to tolerate preferred agents (159 161). callousformation,poorperipheral Midodrine and droxidopa are approved circulation, or history of amputa- by the FDA for the treatment of ortho- FOOT CARE tion. B static hypotension. Recommendations Foot ulcers and amputation, which are Gastroparesis 11.31 Perform a comprehensive foot Treatment for diabetic gastroparesis evaluation at least annually to consequences of diabetic neuropathy may be very challenging. A low-fiber, identify risk factors for ulcers and/or peripheral arterial disease low-fat eating plan provided in small and amputations. B (PAD), are common and represent major frequent meals with a greater propor- 11.32 Patients with evidence of sen- causes of morbidity and mortality in tion of liquid calories may be useful sory loss or prior ulceration or people with diabetes. (162–164). In addition, foods with amputation should have their Early recognition and treatment of smallparticlesizemayimprovekey feet inspected at every visit. B patients with diabetes and feet at risk symptoms (165). Withdrawing drugs 11.33 Obtain a prior history of ulcer- for ulcers and amputations can delay or with adverse effects on gastrointestinal ation, amputation, Charcot foot, prevent adverse outcomes. motility including opioids, anticholiner- angioplasty or vascular surgery, The risk of ulcers or amputations is gics, tricyclic antidepressants, GLP-1 RAs, cigarette smoking, retinopathy, increased in people who have the fol- pramlintide, and possibly dipeptidyl and renal disease and assess lowing risk factors: peptidase 4 inhibitors may also im- current symptoms of neuropa- prove intestinal motility (162,166). In thy (pain, burning, numbness) c Poor glycemic control cases of severe gastroparesis, pharma- andvasculardisease(legfatigue, c Peripheral neuropathy with LOPS cologic interventions are needed. Only claudication). B c Cigarette smoking metoclopramide, a prokinetic agent, is 11.34 The examination should include c Foot deformities approved by the FDA for the treatment inspection of the skin, assess- c Preulcerative callus or corn of gastroparesis. However, the level of ment of foot deformities, neu- c PAD rological assessment (10-g evidence regarding the benefits of me- c History of foot ulcer monofilament testing with at toclopramide for the management of c Amputation least one other assessment: gastroparesis is weak, and given the risk c Visual impairment pinprick, temperature, vibra- for serious adverse effects (extrapyra- c CKD (especially patients on dialysis) tion), and vascular assess- midal signs such as acute dystonic ment including pulses in the fi reactions, drug-induced parkinsonism, Moreover, there is suf cient good- legs and feet. B akathisia, and tardive dyskinesia), its quality evidence to support use of ap- 11.35 Patients with symptoms of use in the treatment of gastroparesis propriate therapeutic footwear with claudication or decreased or beyond 12 weeks is no longer recomm- demonstrated pressure relief that is absent pedal pulses should ended by the FDA or the European worn by the patient to prevent plantar S146 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

foot ulcer recurrence or worsening. How- ulcer and peripheral arterial disease consideration and a thorough workup ever, there is very little evidence for the should be performed: skin perfusion should be performed when patients with use of interventions to prevent a first foot pressure ($40 mmHg), toe pressure neuropathy present with the acute onset ulcer or heal ischemic, infected, non- ($30 mmHG), or transcutaneous oxygen of a red, hot, swollen foot or ankle, and plantar, or proximal foot ulcers (170). pressure (TcPO2 $25 mmHg). Urgent Charcot neuroarthropathy should be ex- Studies on specific types of footwear vascular imaging and revascularization cluded. Early diagnosis and treatment of demonstrated that shape and barefoot should be considered in a patient with Charcot neuroarthropathy is the best plantar pressure–based orthoses were a diabetic foot ulcer and an ankle pres- way to prevent deformities that increase more effective in reducing submeta- sure (ankle-brachial index) ,50 mmHg, the risk of ulceration and amputation. tarsal head plantar ulcer recurrence toe pressure ,30 mmHg, or a TcPO2 The routine prescription of therapeutic than current standard-of-care orthoses ,25 mmHg (130,175). footwear is not generally recommended. (171). However, patients should be provided Clinicians are encouraged to review Patient Education adequate information to aid in selection ADA screening recommendations for fur- All patients with diabetes and partic- of appropriate footwear. General foot- ther details and practical descriptions of ularly those with high-risk foot condi- wear recommendations include a broad how to perform components of the com- tions (history of ulcer or amputation, and square toe box, laces with three or prehensive foot examination (172). deformity, LOPS, or PAD) and their four eyes per side, padded tongue, qual- families should be provided general ity lightweight materials, and sufficient Evaluation for Loss of Protective education about risk factors and ap- size to accommodate a cushioned insole. Sensation propriate management (176). Patients Use of custom therapeutic footwear can All adults with diabetes should undergo a at risk should understand the implica- help reduce the risk of future foot ulcers comprehensive foot evaluation at least tions of foot deformities, LOPS, and in high-risk patients (173,176). annually. Detailed foot assessments may Most diabetic foot infections are poly- occur more frequently in patients with PAD; the proper care of the foot, in- microbial, with aerobic gram-positive histories of ulcers or amputations, foot cluding nail and skin care; and the cocci. Staphylococci and streptococci deformities, insensate feet, and PAD importance of foot monitoring on a are the most common causative organ- (173,174).Toassessrisk, clinicians should daily basis. Patients with LOPS should isms. Wounds without evidence of soft ask about history of foot ulcers or am- be educated on ways to substitute tissue or bone infection do not require putation, neuropathic and peripheral other sensory modalities (palpation or visual inspection using an unbreak- antibiotic therapy. Empiric antibiotic vascular symptoms, impaired vision, re- able mirror) for surveillance of early therapy can be narrowly targeted at nal disease, tobacco use, and foot care foot problems. gram-positive cocci in many patients practices. A general inspection of skin The selection of appropriate footwear with acute infections, but those at risk integrity and musculoskeletal deform- and footwear behaviors at home should for infection with antibiotic-resistant ities should be performed. Vascular as- ’ organisms or with chronic, previously sessment should include inspection and also be discussed. Patients understand- treated, or severe infections require palpation of pedal pulses. ing of these issues and their physical broader-spectrum regimens and should The neurological exam performed as ability to conduct proper foot surveil- be referred to specialized care centers part of the foot examination is designed lance and care should be assessed. Pa- fi (177). Foot ulcers and wound care may to identify LOPS rather than early neu- tients with visual dif culties, physical require care by a podiatrist, orthopedic ropathy. The 10-g monofilament is the constraints preventing movement, or cognitive problems that impair their abil- or vascular surgeon, or rehabilitation most useful test to diagnose LOPS. ity to assess the condition of the foot and specialist experienced in the manage- Ideally, the 10-g monofilament test to institute appropriate responses will ment of individuals with diabetes (177). should be performed with at least need other people, such as family mem- Hyperbaric oxygen therapy (HBOT) in one other assessment (pinprick, tem- bers, to assist with their care. patients with diabetic foot ulcers has perature or vibration sensation using a mixed evidence supporting its use as 128-Hz tuning fork, or ankle reflexes). an adjunctive treatment to enhance Absent monofilament sensation sug- Treatment People with neuropathy or evidence of wound healing and prevent amputation gests LOPS, while at least two normal increased plantar pressures (e.g., ery- (178–181). A well-conducted random- tests (and no abnormal test) rules out thema, warmth, or calluses) may be ized controlled study performed in LOPS. adequately managed with well-fitted 103 patients found that HBOT did not Evaluation for Peripheral Arterial walking shoes or athletic shoes that reduce the indication for amputation or Disease cushion the feet and redistribute pres- facilitate wound healing compared with Initial screening for PAD should include a sure. People with bony deformities comprehensive wound care in patients history of decreased walking speed, leg (e.g., hammertoes, prominent metatar- with chronic diabetic foot ulcers (182). fatigue, claudication, and an assessment sal heads, bunions) may need extra Moreover, a systematic review by the of the pedal pulses. Ankle-brachial index wide or deep shoes. People with bony International Working Group on the Di- testing should be performed in patients deformities, including Charcot foot, who abetic Foot of interventions to improve with symptoms or signs of PAD. Addi- cannot be accommodated with com- the healing of chronic diabetic foot ulcers tionally, at least one of the following mercial therapeutic footwear, will re- concluded that analysis of the evidence tests in a patient with a diabetic foot quire custom-molded shoes. Special continues to present methodological care.diabetesjournals.org Microvascular Complications and Foot Care S147

challenges as randomized controlled type 2 diabetes. J Am Soc Nephrol 2013;24:302– 24. Perkovic V, Jardine MJ, Neal B, et al. Canagli- studies remain few, with a majority being 308 flozin and renal outcomes in type 2 diabetes and – of poor quality (179). Thus, HBOT does 9. Groop P-H, Thomas MC, Moran JL, et al.; nephropathy. N Engl J Med 2019;380:2295 2306 FinnDiane Study Group. The presence and se- 25. Nadkarni GN, Ferrandino R, Chang A, et al. not have a significant effect on health- verity of chronic kidney disease predicts all-cause Acute kidney injury in patients on SGLT2 inhib- related quality of life in patients with mortality in type 1 diabetes. Diabetes 2009;58: itors: a propensity-matched analysis. Diabetes diabetic foot ulcers (183,184). A recent 1651–1658 Care 2017;40:1479–1485 review concluded that the evidence to 10. Gomes MB, Gonçalves MF. Is there a phys- 26. Wanner C, Inzucchi SE, Lachin JM, et al.; iological variability for albumin excretion rate? EMPA-REG OUTCOME Investigators. Empagli- date remains inconclusive regarding the Study in patients with diabetes type 1 and non- flozin and progression of kidney disease in clinical and cost-effectiveness of HBOT as diabetic individuals. Clin Chim Acta 2001;304: type 2 diabetes. N Engl J Med 2016;375:323– an adjunctive treatment to standard 117–123 334 wound care for diabetic foot ulcers 11. Naresh CN, Hayen A, Weening A, Craig JC, 27. Neuen BL, Ohkuma T, Neal B, et al. Cardio- fl (185). Results from the Dutch DAMOCLES Chadban SJ. Day-to-day variability in spot urine vascular and renal outcomes with canagli ozin albumin-creatinine ratio. Am J Kidney Dis 2013; according to baseline kidney function: data from (Does Applying More Oxygen Cure 62:1095–1101 the CANVAS Program. Circulation 2018;138: Lower Extremity Sores?) trial demon- 12. Tankeu AT, Kaze FF, Noubiap JJ, Chelo D, 1537–1550 strated that HBOT in patients with di- Dehayem MY, Sobngwi E. Exercise-induced albu- 28. Thakar CV, Christianson A, Himmelfarb J, abetes and ischemic wounds did not minuria and circadian blood pressure abnormalities Leonard AC. Acute kidney injury episodes and – significantly improve complete wound intype 2diabetes.WorldJNephrol2017;6:209 216 chronic kidney disease risk in diabetes mellitus. 13. Delanaye P, Glassock RJ, Pottel H, Rule AD. Clin J Am Soc Nephrol 2011;6:2567–2572 healing and limb salvage (186). While An age-calibrated definition of chronic kidney 29. Bakris GL, Weir MR. Angiotensin-converting the Centers for Medicare & Medicaid disease: rationale and benefits. Clin Biochem Rev enzyme inhibitor-associated elevations in serum Services currently covers HBOT for di- 2016;37:17–26 creatinine: is this a cause for concern? Arch abetic foot ulcers that have failed a 14. Kramer HJ, Nguyen QD, Curhan G, Hsu C-Y. Intern Med 2000;160:685–693 fi standard course of wound therapy Renal insuf ciency in the absence of albuminuria 30. Beddhu S, Greene T, Boucher R, et al. In- and retinopathy among adults with type 2 di- tensive systolic blood pressure control and in- when there are no measurable signs abetes mellitus. JAMA 2003;289:3273–3277 cident chronic kidney disease in people with and of healing for at least 30 consecutive 15. Molitch ME, Steffes M, Sun W, et al.; Epide- without diabetes mellitus: secondary analyses of days (187), given the data not support- miology of Diabetes Interventions and Com- two randomised controlled trials. Lancet Diabe- inganeffect,suchanapproachisnot plications Study Group. Development and progression tes Endocrinol 2018;6:555–563 of renal insufficiency with and without albu- 31. Collard D, Brouwer TF, Peters RJG, Vogt L, currently warranted. HBOT should be a minuria in adults with type 1 diabetes in the van den Born BH. Creatinine rise during blood topic of shared decision-making before Diabetes Control and Complications Trial and pressure therapy and the risk of adverse clinical treatment is considered for selected the Epidemiology of Diabetes Interventions and outcomes in patients with type 2 diabetes mel- patients with diabetic foot ulcers (187). Complications study. Diabetes Care 2010;33: litus. Hypertension 2018;72:1337–1344 1536–1543 32. Malhotra R, Craven T, Ambrosius WT, et al.; 16. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic SPRINT Research Group. Effects of intensive References retinopathy in predicting diabetic nephropathy blood pressure lowering on kidney tubule injury 1. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic in patients with type 2 diabetes and renal in CKD: a longitudinal subgroup analysis in kidney disease: a report from an ADA Consensus disease: a meta-analysis. Diabetologia 2013; SPRINT. Am J Kidney Dis 2019;73:21–30 – Conference. Diabetes Care 2014;37:2864 2883 56:457–466 33. Hughes-Austin JM, Rifkin DE, Beben T, et al. 2. National Kidney Foundation. KDIGO 2012 clin- 17. Levey AS, Coresh J, Balk E, et al.; National The relation of serum potassium concentration ical practice guideline for the evaluation and Kidney Foundation. National Kidney Foundation with cardiovascular events and mortality in management of chronic kidney disease. Kidney practice guidelines for chronic kidney disease: community-living individuals. Clin J Am Soc Int Suppl 2013;3:1–150 evaluation, classification, and stratification. Ann Nephrol 2017;12:245–252 3. Afkarian M, Zelnick LR, Hall YN, et al. Clinical Intern Med 2003;139:137–147 34. Bandak G, Sang Y, Gasparini A, et al. Hyper- manifestations of kidney disease among US 18. Flynn C, Bakris GL. Noninsulin glucose- kalemia after initiating renin-angiotensin system Adults with diabetes, 1988-2014. 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De- 36. de Boer IH, Gao X, Cleary PA, et al.; Diabetes Control and Complications Trial/Epidemiology of cline in estimated glomerular filtration rate and Control and Complications Trial/Epidemiology Diabetes Interventions and Complications study. subsequent risk of end-stage renal disease and of Diabetes Interventions and Complications Diabetes Care 2014;37:24–30 mortality. JAMA 2014;311:2518–2531 (DCCT/EDIC) Research Group. Albuminuria 6. United States Renal Data System. Annual Data 21. Zhou J, Liu Y, Tang Y, et al. A comparison of changes and cardiovascular and renal outcomes Report: Epidemiology of Kidney Disease in the RIFLE, AKIN, KDIGO, and Cys-C criteria for the intype1diabetes:theDCCT/EDICstudy.ClinJAm United STates. Bethesda, MD, National Institutes definition of acute kidney injury in critically ill Soc Nephrol 2016;11:1969–1977 of Health, National Institute of Diabetes and patients. Int Urol Nephrol 2016;48:125–132 37. Sumida K, Molnar MZ, Potukuchi PK, et al. Digestive and Kidney Diseases, 2016 22. Hoste EAJ, Kellum JA, Selby NM, et al. Global Changes in albuminuria and subsequent risk of 7. Fox CS, Matsushita K, Woodward M, et al.; epidemiology and outcomes of acute kidney incident kidney disease. Clin J Am Soc Nephrol Chronic Kidney Disease Prognosis Consortium. injury. Nat Rev Nephrol 2018;14:607–625 2017;12:1941–1949 Associations of kidney disease measures with 23. James MT, Grams ME, Woodward M, et al.; 38. Inker LA, Grams ME, Levey AS, et al.; CKD mortality and end-stage renal disease in indi- CKD Prognosis Consortium. A meta-analysis of Prognosis Consortium. Relationship of estimated viduals with and without diabetes: a meta- the association of estimatedGFR, albuminuria, GFR and albuminuria to concurrent laboratory analysis. Lancet 2012;380:1662–1673 diabetes mellitus, and hypertension with abnormalities: an individual participant data 8. Afkarian M, Sachs MC, Kestenbaum B, et al. acute kidney injury. 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