11. Microvascular Complicationsand Foot Care: Standards ofMedical Care in Diabetesd2019Diabetes Care 2019;42(Suppl. 1):S124–S138 | https://doi.org/10.2337/dc19-S011

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includesADA’s current clinicalpractice recommendationsand is intendedtoprovidethe components of diabetes care, general treatment goals and guidelines, and toolsto evaluate quality of care.Members of theADAProfessional Practice Committee, amultidisciplinary expert committee, are responsible for updating the Standardsof Care annually, or more frequently as warranted. For a detailed description ofADA standards, statements, and reports, aswell as the evidence-grading system forADA’s clinical practice recommendations, please refer to the Standards of CareIntroduction. Readers who wish to comment on the Standards of Care are invitedto 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.”

CHRONIC KIDNEY DISEASE

Recommendations

Screening11.1 At least once a year, assess urinary albumin (e.g., spot urinary albumin-to-

creatinine ratio) and estimated glomerular filtration rate in patients withtype1diabeteswithdurationof$5years, in all patientswith type2diabetes,and in all patients with comorbid hypertension. B

Treatment11.2 Optimize glucose control to reduce the risk or slow theprogressionof chronic

kidney disease. A11.3 For patients with type 2 diabetes and chronic kidney disease, consider use of a

sodium–glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptoragonist shown to reduce risk of chronic kidney disease progression, cardio-vascular events, or both (Table 9.1). C

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

11.5 For people with nondialysis-dependent chronic kidney disease, dietaryprotein intake should be approximately 0.8 g/kg body weight per day(the recommended daily allowance). For patients on dialysis, higher levels ofdietary protein intake should be considered. B

11.6 In nonpregnant patients with diabetes and hypertension, either an ACEinhibitor or an angiotensin receptor blocker is recommended for those withmodestly elevatedurinary albumin-to-creatinine ratio (30–299mg/g creatinine)B and is strongly recommended for those with urinary albumin-to-creatinine

Suggested citation: American Diabetes Association.11. Microvascular complications and foot care:Standards of Medical Care in Diabetesd2019.Diabetes Care 2019;42(Suppl. 1):S124–S138

© 2018 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

American Diabetes Association

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11.MICROVASCULA

RCOMPLICATIONSANDFO

OTCARE

ratio $300 mg/g creatinineand/or estimated glomerularfiltration rate ,60 mL/min/1.73 m2. A

11.7 Periodically monitor serum cre-atinine and potassium levels forthe development of increasedcreatinine or changes in potas-sium when ACE inhibitors, an-giotensin receptor blockers, ordiuretics are used. B

11.8 Continuedmonitoring of urinaryalbumin-to-creatinine ratio in pa-tients with albuminuria treatedwith an ACE inhibitor or an an-giotensin receptor blocker isreasonable to assess the re-sponsetotreatmentandprogres-sion of chronic kidney disease. E

11.9 An ACE inhibitor or an angioten-sin receptor blocker is not rec-ommended for the primaryprevention of chronic kidneydisease in patients with diabeteswho have normal blood pres-sure, normal urinary albumin-to-creatinine ratio (,30 mg/gcreatinine), and normal estimatedglomerular filtration rate. B

11.10 When estimated glomerular fil-tration rate is ,60 mL/min/1.73 m2, evaluate and managepotential complicationsofchronickidney disease. E

11.11 Patients should be referred forevaluation for renal replace-ment treatment if they havean estimated glomerular filtra-tion rate,30 mL/min/1.73 m2. A

11.12 Promptly refer to a physicianexperienced in the care of kid-neydisease foruncertaintyaboutthe etiology of kidney disease,difficult management issues, andrapidly progressing kidney dis-ease. B

Epidemiology of Diabetes and ChronicKidney DiseaseChronic kidney disease (CKD) is diag-nosed by the persistent presence ofelevated urinary albumin excretion (al-buminuria), low estimated glomerularfiltration rate (eGFR), or othermanifesta-tions of kidney damage (1,2). In thissection, the focus will be on CKD attrib-uted to diabetes (diabetic kidney dis-ease), which occurs in 20–40% of patientswith diabetes (1,3–5). CKD typically

develops after diabetes duration of 10years in type1diabetesbutmaybepresentat diagnosis of type 2 diabetes. CKDcan progress to end-stage renal disease(ESRD) requiring dialysis or kidney trans-plantation and is the leading cause ofESRD in the U.S. (6). In addition, amongpeople with type 1 or 2 diabetes, thepresence of CKD markedly increases car-diovascular risk and health care costs (7).

Assessment of Albuminuria andEstimated Glomerular Filtration RateScreening for albuminuria can be mosteasily performed by urinary albumin-to-creatinine ratio (UACR) in a randomspot urine collection (1,2). Timed or 24-hcollections are more burdensome andadd little to prediction or accuracy. Mea-surement of a spot urine sample for al-bumin alone (whether by immunoassay orbyusinga sensitivedipstick test specific foralbuminuria)without simultaneouslymea-suring urine creatinine (Cr) is less expen-sive but susceptible to false-negative andfalse-positive determinations as a resultof variation in urine concentration due tohydration.

Normal UACR is generally definedas ,30 mg/g Cr, and increased urinaryalbumin excretion is defined as$30 mg/gCr. However, UACR is a continuousmeasurement, and differences within thenormal andabnormal ranges are associatedwith renal and cardiovascular outcomes(7–9). Furthermore, because of biologicalvariability in urinary albumin excretion, twoof three specimens of UACR collectedwithin a 3- to 6-month period should beabnormal before considering a patient tohave albuminuria. Exercise within 24 h,infection, fever, congestive heart failure,marked hyperglycemia, menstruation,and marked hypertension may elevateUACR independently of kidney damage.

eGFR should be calculated from se-rum Cr using a validated formula. TheChronic Kidney Disease EpidemiologyCollaboration (CKD-EPI) equation is gener-ally preferred (2). eGFR is routinely re-ported by laboratories with serum Cr,and eGFR calculators are available fromwww.nkdep.nih.gov. An eGFR ,60 mL/min/1.73 m2 is generally consideredabnormal, though optimal thresholdsfor clinical diagnosis are debated (10).

Urinary albumin excretion and eGFReach vary within people over time, andabnormal results should be confirmed tostage CKD (1,2).

Diagnosis of Diabetic Kidney DiseaseDiabetic kidney disease is usually a clin-ical diagnosis made based on the pres-ence of albuminuria and/or reducedeGFR in theabsenceof signsor symptomsof other primary causes of kidney dam-age. The typical presentation of diabetickidney disease is considered to includea long-standing duration of diabetes,retinopathy, albuminuria without hema-turia, and gradually progressive loss ofeGFR. However, signs of CKD maybe present at diagnosis or without ret-inopathy in type 2 diabetes, and reducedeGFR without albuminuria has been fre-quently reported in type 1 and type 2diabetes and is becoming more commonover time as the prevalence of diabetesincreases in the U.S. (3,4,11,12).

Anactive urinary sediment (containingred or white blood cells or cellular casts),rapidly increasing albuminuria or ne-phrotic syndrome, rapidly decreasingeGFR, or the absence of retinopathy(in type 1 diabetes) may suggest alter-native or additional causes of kidneydisease. For patients with these features,referral to a nephrologist for furtherdiagnosis, including the possibility ofkidney biopsy, should be considered. It israre for patients with type 1 diabetesto develop kidney disease without ret-inopathy. In type 2 diabetes, retinopathyis only moderately sensitive and specificfor CKD caused by diabetes, as confirmedby kidney biopsy (13).

Staging of Chronic Kidney DiseaseStages 1–2 CKD have been defined byevidence of kidney damage (usually al-buminuria) with eGFR $60 mL/min/1.73 m2, while stages 3–5 CKD havebeen defined by progressively lowerranges of eGFR (14) (Table 11.1). Atany eGFR, the degree of albuminuriais associated with risk of CKD progres-sion, cardiovascular disease (CVD), andmortality (7). Therefore, Kidney Disease:Improving Global Outcomes (KDIGO)recommends a more comprehensiveCKD staging that incorporates albumin-uria at all stages of eGFR; this system ismore closely associated with risk but isalso more complex and does not trans-late directly to treatment decisions (2).Regardless of classification scheme, botheGFR and albuminuria should be quanti-fied to guide treatment decisions: CKDcomplications (Table 11.2) correlatewith eGFR, many drugs are limited to

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acceptable eGFR ranges, and the de-gree of albuminuria may influencechoice of antihypertensive (see Section10 “Cardiovascular Disease and RiskManagement”) or glucose-loweringmedications (see below). Observed his-toryof eGFR loss (which is also associatedwith risk of CKD progression and otheradverse health outcomes) and cause ofkidney damage (including possible causesother than diabetes) may also affectthese decisions (15).

Acute Kidney InjuryAcute kidney injury (AKI) is usually di-agnosed by a rapid increase in serum Cr,which is also reflected as a rapid decreasein eGFR, over a relatively short period oftime. People with diabetes are at higherrisk of AKI than those without diabetes(16). Other risk factors for AKI includepreexisting CKD, the use of medica-tions that cause kidney injury (e.g.,

nonsteroidal anti-inflammatory drugs),and the use of medications that alterrenal blood flow and intrarenal hemo-dynamics. In particular, many antihyper-tensive medications (e.g., diuretics, ACEinhibitors, and angiotensin receptorblockers [ARBs]) can reduce intravascu-lar volume, renal blood flow, and/orglomerular filtration. There is a con-cern that sodium–glucose cotransporter2 (SGLT2) inhibitors may promote AKIthrough volume depletion, particu-larly when combined with diureticsor other medications that reduce glo-merular filtration. However, existingevidence from clinical trials and obser-vational studies suggests that SGLT2inhibitors do not significantly increaseAKI (17–19). Timely identification andtreatment of AKI are important becauseAKI is associated with increased risks ofprogressive CKD and other poor healthoutcomes (20).

SurveillanceAlbuminuria and eGFR should be mon-itored regularly to enable timely diagno-sis of CKD, monitor progression of CKD,detect superimposed kidney diseasesincluding AKI, assess risk of CKD compli-cations, dose drugs appropriately, anddetermine whether nephrology referralis needed. Among people with existingkidney disease, albuminuria and eGFRmay change due to progression of CKD,development of a separate superim-posed cause of kidney disease, AKI, orother effects of medications, as notedabove. Serum potassium should also bemonitored for patients treated with ACEinhibitors, ARBs, and diuretics becausethese medications can cause hyperkale-mia or hypokalemia, which are associatedwith cardiovascular risk and mortality(21–23). For patients with eGFR ,60mL/min/1.73 m2, appropriate medica-tion dosing should be verified, expo-sure to nephrotoxins (e.g., nonsteroidalanti-inflammatory drugs and iodinatedcontrast) should be minimized, andpotential CKD complications shouldbe evaluated (Table 11.2).

The need for annual quantitative as-sessment of albumin excretion after di-agnosis of albuminuria, institution of ACEinhibitors or ARB therapy, and achievingblood pressure control is a subject ofdebate. Continued surveillance can as-sess both response to therapy and dis-easeprogressionandmayaid inassessingadherence to ACE inhibitor or ARB ther-apy. In addition, in clinical trials of ACEinhibitors or ARB therapy in type 2diabetes, reducing albuminuria from

Table 11.1—CKD stages and corresponding focus of kidney-related care

CKD stage† Focus of kidney-related care

StageeGFR

(mL/min/1.73 m2)

Evidence ofkidney

damage*Diagnose causeof kidney injury

Evaluate and treat riskfactors for CKDprogression**

Evaluate and treat CKDcomplications***

Prepare for renalreplacementtherapy

No clinicalevidence of CKD $60 2

1 $90 1 U U

2 60–89 1 U U

3 30–59 1/2 U U U

4 15–29 1/2 U U U

5 ,15 1/2 U U

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. †CKD stages 1 and 2 are defined by evidence of kidney damage (1), whileCKD stages 3–5 are defined by reduced eGFR with or without evidence of kidney damage (1/2). At any stage of CKD, the degree of albuminuria,observed history of eGFR loss, and cause of kidney damage (including possible causes other than diabetes) may also be used to characterizeCKD, gauge prognosis, and guide treatment decisions. *Kidney damage ismost oftenmanifest as albuminuria (UACR$30mg/g Cr) but can also includeglomerular hematuria, other abnormalities of the urinary sediment, radiographic abnormalities, and other presentations. **Risk factors for CKDprogression include elevated blood pressure, hyperglycemia, and albuminuria. ***See Table 11.2.

Table 11.2—Selected complications of CKD

Complication Medical and laboratory evaluation

Elevated blood pressure Blood pressure, weight

Volume overload History, physical examination, weight

Electrolyte abnormalities Serum electrolytes

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 estimatedglomerularfiltration rate falls below60mL/min/1.73m2 (stage3CKDorgreater) andbecomemorecommon and severe as CKD progresses. Evaluation of elevated blood pressure and volumeoverload should occur at every clinical contact possible; laboratory evaluations aregenerally 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 intherapy. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.

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levels$300mg/g Cr has been associatedwith improved renal and cardiovascularoutcomes, leading some to suggest thatmedications should be titrated to min-imize UACR. However, this approach hasnot been formally evaluated in prospec-tive trials. In type1diabetes, remissionofalbuminuria may occur spontaneouslyand cohort studies evaluating associa-tions of change in albuminuria withclinical outcomes have reported incon-sistent results (24,25).The prevalence of CKD complications

correlates with eGFR (25a). When eGFRis ,60 mL/min/1.73 m2, screening forcomplications of CKD is indicated (Table11.2). Early vaccination against hepati-tis B virus is indicated in patients likelyto progress to ESRD (see Section 4“Comprehensive Medical Evaluation andAssessment of Comorbidities” for furtherinformation on immunization).

Interventions

Nutrition

For people with nondialysis-dependentCKD, dietary protein intake should beapproximately 0.8 g/kg body weight perday (the recommended daily allowance)(1). Compared with higher levels of di-etary protein intake, this level slowedGFR decline with evidence of a greatereffect over time. Higher levels of dietaryprotein intake (.20% of daily caloriesfrom protein or .1.3 g/kg/day) havebeen associated with increased albumin-uria, more rapid kidney function loss, andCVD mortality and therefore should beavoided. Reducing the amount of dietaryprotein below the recommended dailyallowance of 0.8 g/kg/day is not recom-mended because it does not alter glycemicmeasures, cardiovascular risk measures,or the course of GFR decline.Restriction of dietary sodium (to

,2,300 mg/day) may be useful to controlblood pressure and reduce cardiovascu-lar risk (26), and restriction of dietarypotassium may be necessary to controlserum potassium concentration (16,21–23).These interventions may be most impor-tant for patients with reduced eGFR, forwhom urinary excretion of sodium andpotassium may be impaired. Recom-mendations for dietary sodium andpotassium intake should be individual-ized on the basis of comorbid condi-tions, medication use, blood pressure,and laboratory data.

Glycemic Targets

Intensive glycemic control with the goalof achieving near-normoglycemia hasbeen shown in large prospective random-ized studies to delay the onset and pro-gression of albuminuria and reducedeGFR in patients with type 1 diabetes(27,28) and type 2 diabetes (1,29–34).Insulin alone was used to lower bloodglucose in the Diabetes Control andComplications Trial (DCCT)/Epidemiol-ogy of Diabetes Interventions and Com-plications (EDIC) study of type 1diabetes, while a variety of agentswere used in clinical trials of type 2diabetes, supporting the conclusionthat glycemic control itself helps pre-vent CKD and its progression. The ef-fects of glucose-lowering therapies onCKD have helped define A1C targets(see Table 6.2).

The presence of CKD affects the risksand benefits of intensive glycemic con-trol and a number of specific glucose-lowering medications. In the Action toControl Cardiovascular Risk in Diabetes(ACCORD) trial of type 2 diabetes, ad-verse effects of intensive glycemic con-trol (hypoglycemia and mortality) wereincreased among patients with kidneydisease at baseline (35,36). Moreover,there is a lag time of at least 2 years intype 2 diabetes to over 10 years in type 1diabetes for the effects of intensiveglucose control to manifest as improvedeGFR outcomes (33,37,38). Therefore, insome patients with prevalent CKD andsubstantial comorbidity, target A1C lev-els may be less intensive (1,39).

Direct Renal Effects of Glucose-Lowering

Medications

Some glucose-lowering medications alsohave effects on the kidney that are direct,i.e., not mediated through glycemia. Forexample, SGLT2 inhibitors reduce renaltubular glucose reabsorption, weight,systemicbloodpressure, intraglomerularpressure, and albuminuria and slow GFRloss through mechanisms that appearindependent of glycemia (18,40–43).Glucagon-like peptide 1 receptor ago-nists (GLP-1 RA) also have direct effectson the kidney and have been reportedto improve renal outcomes comparedwith placebo (44–47). Renal effectsshould be considered when selectingantihyperglycemia agents (see Section 9“Pharmacologic Approaches to GlycemicTreatment”).

Selection of Glucose-Lowering Medications

for Patients With Chronic Kidney Disease

For patients with type 2 diabetes andestablished CKD, special considerationsfor the selection of glucose-lowering med-ications include limitations to availablemedications when eGFR is diminishedand a desire to mitigate high risks of CKDprogression, CVD, and hypoglycemia(48,49). Drug dosing may require modifi-cationwitheGFR,60mL/min/1.73m2 (1).

TheU.S. FoodandDrugAdministration(FDA) revised its guidance for the usemetformin in CKD in 2016 (50), recom-mending use of eGFR instead of serumCrto guide treatment and expanding thepool of patients with kidney disease forwhom metformin treatment should beconsidered. The revised FDA guidancestates that metformin is contraindicatedin patients with an eGFR ,30 mL/min/1.73m2, eGFRshouldbemonitoredwhiletaking metformin, the benefits and risksof continuing treatment should be re-assessed when eGFR falls ,45 mL/min/1.73 m2, metformin should not be initi-ated for patients with an eGFR,45 mL/min/1.73 m2, and metformin should betemporarily discontinued at the time ofor before iodinated contrast imagingprocedures in patients with eGFR 30–60 mL/min/1.73 m2. Within these con-straints, metformin should be consideredthe first-line treatment for all patientswithtype 2 diabetes, including those with CKD.

SGLT2 inhibitors and GLP-1 RA shouldbe considered for patients with type 2diabetes and CKD who require anotherdrug added tometformin to attain targetA1C or cannot use or tolerate metfor-min. SGLT2 inhibitors and GLP-1 RA aresuggested because they appear to reducerisks of CKD progression, CVD events,and hypoglycemia.

A number of large cardiovascularoutcomes trials in patients with type 2diabetes at high risk for CVD or withexisting CVD examined kidney effectsas secondary outcomes. These trials in-clude EMPA-REG OUTCOME [BI 10773(Empagliflozin) Cardiovascular OutcomeEvent Trial in Type 2 Diabetes MellitusPatients], CANVAS (Canagliflozin Car-diovascular Assessment Study), LEADER(Liraglutide Effect and Action in Diabetes:Evaluation of Cardiovascular OutcomeResults), and SUSTAIN-6 (Trial to EvaluateCardiovascular and Other Long-termOutcomes With Semaglutide in SubjectsWith Type 2 Diabetes) (42,44,47,51).

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Specifically, compared with placebo, em-pagliflozin reduced the risk of incidentor worsening nephropathy (a compositeof progression to UACR .300 mg/g Cr,doubling of serum Cr, ESRD, or deathfrom ESRD) by 39% and the risk ofdoubling of serum Cr accompanied byeGFR #45 mL/min/1.73 m2 by 44%;canagliflozin reduced the risk of pro-gression of albuminuria by 27% and therisk of reduction in eGFR, ESRD, or deathfrom ESRD by 40%; liraglutide reducedthe risk of new or worsening nephrop-athy (a composite of persistent macro-albuminuria, doubling of serumCr, ESRD,or death from ESRD) by 22%; and sem-aglutide reduced the risk of new orworsening nephropathy (a compositeof persistent UACR .300 mg/g Cr, dou-bling of serum Cr, or ESRD) by 36% (eachP , 0.01).These analyses were limited by eval-

uation of study populations not selectedprimarily for CKD and examination ofrenal effects as secondary outcomes.However, all of these trials included largenumbers of people with kidney disease(for example, the baseline prevalenceof albuminuria in EMPA-REG OUTCOMEwas 53%), and some of the cardiovascularoutcomes trials (CANVAS and LEADER)were enriched with patients with kidneydisease through eligibility criteria basedon albuminuria or reduced eGFR. Inaddition, subgroup analyses of CANVASand LEADER suggested that the renalbenefits of canagliflozin and liraglutidewere as great or greater for participantswith CKD at baseline (19,46) and inCANVAS were similar for participantswith or without atherosclerotic cardio-vascular disease (ASCVD) at baseline (52).Smaller, shorter-term trials also demon-strate favorable renal effects of medica-tions in these classes (53, 53a). Together,these consistent results suggest likelyrenal benefits of both drug classes.Several large clinical trials of SGLT2

inhibitors focused on patients with CKD,and assessment of primary renal out-comes are completed or ongoing. Can-agliflozin and Renal Endpoints inDiabetes with Established Nephropa-thy Clinical Evaluation (CREDENCE), aplacebo-controlled trial of canagliflozinamong 4,401 adults with type 2 diabetes,UACR $300 mg/g, and eGFR 30–90mL/min/1.73 m2, has a primary compositeend point of ESRD, doubling of serum Cr,or renal or cardiovascular death (54). It

was stopped early due to positive efficacy,with detailed results expected in 2019.

Inaddition to renal effects, someSGLT2inhibitors and GLP-1 RA have demon-strated cardiovascular benefits. Namely,in EMPA-REG OUTCOME, CANVAS, andLEADER, empagliflozin, canagliflozin, andliraglutide, respectively, each reducedcardiovascular events, evaluated as pri-mary outcomes, compared with placebo(see Section 10 “Cardiovascular Diseaseand Risk Management” for further dis-cussion). The glucose-lowering effects ofSGLT2 inhibitors are blunted with eGFR(18,51). However, the cardiovascular ben-efits of empagliflozin, canagliflozin, andliraglutide were similar among partici-pants with and without kidney disease atbaseline (42,44,51,55). Most participantswith CKD in these trials also had diagnosedASCVD at baseline, though approximately28% of CANVAS participants with CKDdid not have diagnosed ASCVD (19).

Important caveats limit the strength ofevidence supporting the recommenda-tion of SGLT2 inhibitors and GLP-1 RA inpatients with type 2 diabetes and CKD.As noted above, published data addressa limited group of CKD patients, mostlywith coexisting ASCVD. Renal eventshave been examined primarily as sec-ondary outcomes in published largetrials. Also, adverse event profiles ofthese agents must be considered. Pleaserefer to Table 9.1 for drug-specific fac-tors, including adverse event infor-mation, for these agents. Therefore,additional clinical trials are needed tomore rigorously assess the benefits andrisks of these classes of drugs amongpeople with CKD.

For patients with type 2 diabetes andCKD, the selection of specific agents maydepend on comorbidity and CKD stage.SGLT2 inhibitors may be more usefulfor patients at high risk of CKD progres-sion (i.e., with albuminuria or a historyof documented eGFR loss) (Fig. 9.1)because they appear to have large ben-eficial effects on CKD incidence. Empagli-flozin and canagliflozin are only approvedby the FDA for use with eGFR $45 mL/min/1.73 m2 (though pivotal trials foreach included participants with eGFR$30mL/min/1.73m2 and demonstratedbenefit in subgroups with low eGFR)(18,19), and dapagliflozin is only ap-proved for eGFR $60 mL/min/1.73 m2.Some GLP-1 RA may be used with lowereGFR and may have greater benefits for

reduction of ASCVD than for CKD pro-gression or heart failure.

Cardiovascular Disease and Blood Pressure

Hypertension is a strong risk factor forthe development and progression of CKD(56). Antihypertensive therapy reducesthe risk of albuminuria (57–60), andamong patients with type 1 or 2 diabeteswith established CKD (eGFR ,60 mL/min/1.73 m2 and UACR $300 mg/g Cr),ACE inhibitor or ARB therapy reducesthe risk of progression to ESRD (61–63).Moreover, antihypertensive therapy re-duces risks of cardiovascular events(57).

Blood pressure levels,140/90mmHgare generally recommended to reduceCVD mortality and slow CKD progressionamong people with diabetes (60). Lowerblood pressure targets (e.g., ,130/80 mmHg) may be considered for pa-tients based on individual anticipatedbenefits and risks. Patients with CKDare at increased risk of CKD progression(particularly those with albuminuria) andCVD and thereforemay be suitable in somecases for lower blood pressure targets.

ACE inhibitors or ARBs are the pre-ferred first-line agent for blood pressuretreatment amongpatientswith diabetes,hypertension, eGFR ,60 mL/min/1.73m2, and UACR$300 mg/g Cr because oftheir proven benefits for prevention ofCKD progression (61–64). In general, ACEinhibitors and ARBs are considered tohave similar benefits (65,66) and risks. Inthe setting of lower levels of albumin-uria (30–299 mg/g Cr), ACE inhibitor orARB therapy has been demonstrated toreduce progression to more advancedalbuminuria ($300 mg/g Cr) and car-diovascular events but not progressionto ESRD (64,67). While ACE inhibitors orARBs are often prescribed for albumin-uria without hypertension, clinical trialshave not been performed in this settingto determine whether this improvesrenal outcomes.

Absent kidney disease, ACE inhibitorsor ARBs are useful to control bloodpressure but may not be superior toalternative proven classes of antihyper-tensive therapy, including thiazide-likediuretics and dihydropyridine calciumchannel blockers (68). In a trial of peoplewith type 2 diabetes and normal urinealbumin excretion, an ARB reduced orsuppressed the development of albu-minuria but increased the rate of

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cardiovascular events (69). In a trial ofpeople with type 1 diabetes exhibitingneither albuminuria nor hypertension,ACE inhibitors or ARBs did not preventthe development of diabetic glomerulop-athy assessed by kidney biopsy (70).Therefore, ACE inhibitors or ARBs arenot recommended for patients withouthypertension to prevent the developmentof CKD.Two clinical trials studied the combi-

nations of ACE inhibitors and ARBs andfound no benefits on CVD or CKD, andthe drug combination had higher ad-verse event rates (hyperkalemia and/orAKI) (71,72). Therefore, the combined useof ACE inhibitors and ARBs should beavoided.Mineralocorticoid receptor antago-

nists (spironolactone, eplerenone, andfinerenone) in combination with ACEinhibitors or ARBs remain an area ofgreat interest. Mineralocorticoid recep-tor antagonists are effective for manage-ment of resistant hypertension, havebeen shown to reduce albuminuriain short-term studies of CKD, and mayhave additional cardiovascular benefits(73–75). There has been, however, anincrease in hyperkalemic episodes inthose on dual therapy, and larger,longer trials with clinical outcomesare needed before recommendingsuch therapy.

Referral to a Nephrologist

Consider referral to a physician experi-enced in the care of kidney disease whenthere is uncertainty about the etiology ofkidney disease, difficult managementissues (anemia, secondary hyperparathy-roidism,metabolic bonedisease, resistanthypertension, or electrolyte disturban-ces), or advanced kidney disease (eGFR,30 mL/min/1.73 m2) requiring discus-sion of renal replacement therapy forESRD. The threshold for referral mayvary depending on the frequency withwhich a provider encounters patientswith diabetes and kidney disease. Con-sultation with a nephrologist when stage4 CKD develops (eGFR ,30 mL/min/1.73 m2) has been found to reducecost, improve quality of care, and delaydialysis (76). However, other specialistsand providers should also educate theirpatients about the progressive natureof CKD, the kidney preservation bene-fits of proactive treatment of bloodpressure and blood glucose, and the

potential need for renal replacementtherapy.

DIABETIC RETINOPATHY

Recommendations

11.13 Optimize glycemic control toreduce the risk or slow theprogression of diabetic reti-nopathy. A

11.14 Optimize blood pressure andserum lipid control to reducethe risk or slow theprogressionof diabetic retinopathy. A

Screening11.15 Adults with type 1 diabetes

should have an initial dilatedand comprehensive eye exam-ination by an ophthalmologistor optometrist within 5 yearsafter the onset of diabetes. B

11.16 Patients with type 2 diabetesshouldhavean initial dilatedandcomprehensive eye examina-tion by an ophthalmologist oroptometrist at the time ofthe diabetes diagnosis. B

11.17 If there is no evidence of ret-inopathy for one or more an-nual eye exam and glycemia iswell controlled, then examsevery 1–2 years may be con-sidered. If any level of diabeticretinopathy is present, subse-quent dilated retinal examina-tions should be repeated atleast annually by an ophthal-mologist or optometrist. Ifretinopathy is progressing orsight-threatening, then exami-nations will be required morefrequently. B

11.18 Telemedicine programs thatuse validated retinal photog-raphy with remote reading byan ophthalmologist or optome-trist and timely referral for acomprehensive eye examina-tion when indicated can be anappropriate screening strategyfor diabetic retinopathy. B

11.19 Women with preexisting type1 or type 2 diabetes who areplanning pregnancy or whoare pregnant should be coun-seled on the risk of develop-ment and/or progression ofdiabetic retinopathy. B

11.20 Eye examinations should occurbefore pregnancy or in the first

trimester in patients with pre-existing type1or type2diabetes,and then patients should bemon-itored every trimester and for 1-year postpartum as indicated bythe degree of retinopathy. B

Treatment11.21 Promptly refer patients with

any level of macular edema,severe nonproliferative dia-betic retinopathy (a precursorof proliferative diabetic reti-nopathy), or any proliferativediabetic retinopathy to anophthalmologist who is knowl-edgeable and experienced inthe management of diabeticretinopathy. A

11.22 The traditional standard treat-ment, panretinal laser photo-coagulation therapy, is indicatedto reduce the risk of vision loss inpatients with high-risk prolifera-tive diabetic retinopathy and, insome cases, severe nonprolifer-ative diabetic retinopathy. A

11.23 Intravitreous injections of anti–vascular endothelial growth fac-tor ranibizumab are not inferiorto traditional panretinal laserphotocoagulation and are alsoindicated to reduce the risk ofvision loss in patients with pro-liferative diabetic retinopathy. A

11.24 Intravitreous injections of anti–vascular endothelial growthfactor are indicated for central-involved diabetic macular edema,which occurs beneath the fovealcenter and may threaten readingvision. A

11.25 The presence of retinopathy isnot a contraindication to aspi-rin therapy for cardioprotection,as aspirin does not increase therisk of retinal hemorrhage. A

Diabetic retinopathy is a highly specificvascular complication of both type 1and type 2 diabetes, with prevalencestrongly related to both the durationof diabetes and the level of glycemiccontrol (77). Diabetic retinopathy isthe most frequent cause of new casesof blindness among adults aged 20–74years in developed countries. Glaucoma,cataracts, and other disorders of theeye occur earlier and more frequentlyin people with diabetes.

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In addition to diabetes duration, fac-tors that increase the risk of, or are asso-ciated with, retinopathy include chronichyperglycemia (78), nephropathy (79), hy-pertension (80), and dyslipidemia (81).Intensive diabetes management with thegoal of achieving near-normoglycemiahas been shown in large prospective ran-domized studies to prevent and/or delaythe onset and progression of diabetic ret-inopathy and potentially improve patient-reported visual function (30,82–84).Several case series and a controlled

prospective study suggest that preg-nancy in patients with type 1 diabetesmay aggravate retinopathy and threatenvision, especially when glycemic controlis poor at the time of conception (85,86).Laser photocoagulation surgery can mini-mize the risk of vision loss (86).

ScreeningThe preventive effects of therapy andthe fact that patients with proliferativediabetic retinopathy (PDR) or macularedema may be asymptomatic providestrong support for screening to detectdiabetic retinopathy.An ophthalmologist or optometrist

who is knowledgeable and experiencedin diagnosing diabetic retinopathy shouldperform the examinations. Youth withtype 1 or type 2 diabetes are also atrisk for complications and need to bescreened for diabetic retinopathy (87). Ifdiabetic retinopathy is present, promptreferral to an ophthalmologist is recom-mended. Subsequent examinations forpatients with type 1 or type 2 diabetesare generally repeated annually for pa-tients with minimal to no retinopathy.Exams every 1–2 years may be cost-effective after one or more normal eyeexams, and in a population with well-controlled type 2 diabetes, there wasessentially no risk of development ofsignificant retinopathy with a 3-year in-terval after a normal examination (88).Less frequent intervals have been foundin simulated modeling to be potentiallyeffective in screening for diabetic reti-nopathy in patients without diabeticretinopathy (89). More frequent exami-nations by the ophthalmologist will berequired if retinopathy is progressing.Retinal photography with remote

reading by experts has great potentialto provide screening services in areaswhere qualified eye care professionals

are not readily available (82,83). High-quality fundus photographs can detectmost clinically significant diabetic reti-nopathy. Interpretation of the imagesshould be performed by a trained eyecare provider. Retinal photography mayalso enhance efficiency and reduce costswhen the expertise of ophthalmologistscan be used for more complex examina-tions and for therapy (90,91). In-personexams are still necessary when theretinal photos are of unacceptablequality and for follow-up if abnormal-ities are detected. Retinal photos arenot a substitute for comprehensiveeye exams, which should be performedat least initially and at intervals there-after as recommended by an eye careprofessional. Results of eye examina-tions should be documented and trans-mitted to the referring health careprofessional.

Type 1 Diabetes

Because retinopathy is estimated to takeat least 5 years to develop after the onsetof hyperglycemia, patients with type 1diabetes should have an initial dilated andcomprehensive eye examination within5 years after the diagnosis of diabetes (92).

Type 2 Diabetes

Patients with type 2 diabetes who mayhave had years of undiagnosed diabetesand have a significant risk of prevalentdiabetic retinopathy at the time of di-agnosis should have an initial dilated andcomprehensive eye examination at thetime of diagnosis.

Pregnancy

Pregnancy is associated with a rapidprogression of diabetic retinopathy(93,94). Women with preexisting type 1or type 2 diabetes who are planningpregnancy orwho have become pregnantshould be counseled on the risk of de-velopment and/or progression of diabeticretinopathy. In addition, rapid implemen-tation of intensive glycemic managementin the setting of retinopathy is associatedwith early worsening of retinopathy (86).Womenwhodevelopgestationaldiabetesmellitus do not require eye examinationsduring pregnancy anddonot appear to beat increased risk of developing diabeticretinopathy during pregnancy (95).

TreatmentTwo of the main motivations for screen-ing for diabetic retinopathy are to

prevent loss of vision and to intervenewith treatment when vision loss can beprevented or reversed.

Photocoagulation Surgery

Two large trials, the Diabetic RetinopathyStudy (DRS) in patients with PDR and theEarly Treatment Diabetic RetinopathyStudy (ETDRS) in patients with macularedema, provide the strongest support forthe therapeutic benefits of photocoag-ulation surgery. The DRS (96) showed in1978 that panretinal photocoagulationsurgery reduced the risk of severe visionloss from PDR from 15.9% in untreatedeyes to 6.4% in treated eyes with thegreatest benefit ratio in those with moreadvanced baseline disease (disc neovas-cularization or vitreous hemorrhage). In1985, the ETDRS also verified the benefitsof panretinal photocoagulation for high-risk PDR and in older-onset patients withsevere nonproliferative diabetic retinop-athyor less-than-high-risk PDR. Panretinallaser photocoagulation is still commonlyused to manage complications of diabe-tic retinopathy that involve retinal neo-vascularization and its complications.

Anti–Vascular Endothelial Growth Factor

Treatment

Recent data from the Diabetic Retinop-athy Clinical Research Network andothers demonstrate that intravitreal in-jections of anti–vascular endothelialgrowth factor (anti-VEGF) agent, specif-ically ranibizumab, resulted in visualacuity outcomes that were not inferiorto those observed in patients treatedwith panretinal laser at 2 years of follow-up (97). In addition, it was observedthat patients treated with ranibizumabtended tohave less peripheral visualfieldloss, fewer vitrectomy surgeries for sec-ondary complications from their prolif-erative disease, and a lower risk ofdeveloping diabetic macular edema.However, a potential drawback in usinganti-VEGF therapy to manage prolifera-tive disease is that patients were re-quired to have a greater number ofvisits and received a greater numberof treatments than is typically requiredfor management with panretinal laser,which may not be optimal for somepatients. Other emerging therapies forretinopathy that may use sustained intra-vitreal delivery of pharmacologic agentsare currently under investigation. The FDAapproved ranibizumab for the treatmentof diabetic retinopathy in 2017.

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While the ETDRS (98) established thebenefit of focal laser photocoagulationsurgery in eyes with clinically significantmacular edema (defined as retinaledema located at or within 500 mmof the center of themacula), current datafrom well-designed clinical trials demon-strate that intravitreal anti-VEGF agentsprovide a more effective treatment reg-imen for central-involved diabetic mac-ular edema than monotherapy or evencombination therapy with laser (99–101).There are currently three anti-VEGFagents commonly used to treat eyeswith central-involved diabetic macularedemadbevacizumab, ranibizumab, andaflibercept (77).In both the DRS and the ETDRS, laser

photocoagulation surgery was benefi-cial in reducing the risk of further visualloss in affected patients but generallynot beneficial in reversing already di-minished acuity. Anti-VEGF therapyimproves vision and has replaced theneed for laser photocoagulation in thevast majority of patients with diabeticmacular edema (102). Most patients re-quire near-monthly administration ofintravitreal therapywith anti-VEGF agentsduring the first 12 months of treatment,with fewer injections needed in subse-quent years to maintain remission fromcentral-involved diabetic macular edema.

Adjunctive Therapy

Loweringbloodpressurehasbeen shownto decrease retinopathy progression, al-though tight targets (systolic bloodpressure ,120 mmHg) do not impartadditional benefit (83). ACE inhibitorsand ARBs are both effective treatmentsin diabetic retinopathy (103). In patientswith dyslipidemia, retinopathy progres-sion may be slowed by the addition offenofibrate, particularly with very mildnonproliferative diabetic retinopathy atbaseline (81,104).

NEUROPATHY

Recommendations

Screening11.26 All patients should be assessed

for diabetic peripheral neurop-athy starting at diagnosis oftype 2 diabetes and 5 yearsafter the diagnosis of type 1diabetes and at least annuallythereafter. B

11.27 Assessment for distal symmet-ric polyneuropathy should in-clude a careful history andassessment of either tempera-ture or pinprick sensation (small-fiber function) and vibrationsensation using a 128-Hz tuningfork (for large-fiber function).All patients should have annual10-g monofilament testing toidentify feet at risk for ulcera-tion and amputation. B

11.28 Symptoms and signs of auto-nomic neuropathy should beassessed in patients with mi-crovascular complications. E

Treatment11.29 Optimize glucose control to

prevent or delay the develop-ment of neuropathy in patientswith type 1 diabetes A and toslow the progression of neu-ropathy in patients with type 2diabetes. B

11.30 Assess and treat patients toreduce pain related to diabeticperipheral neuropathy B andsymptoms of autonomic neu-ropathy and to improve qualityof life. E

11.31 Pregabalin, duloxetine, orgabapentin are recommendedas initial pharmacologic treat-ments for neuropathic pain indiabetes. A

The diabetic neuropathies are a hetero-geneous group of disorders with diverseclinical manifestations. The early recog-nition and appropriate management ofneuropathy in the patient with diabetesis important.

1. Diabetic neuropathy is a diagnosis ofexclusion. Nondiabetic neuropathiesmay be present in patients with di-abetes and may be treatable.

2. Numerous treatmentoptions exist forsymptomatic diabetic neuropathy.

3. Up to 50% of diabetic peripheralneuropathy (DPN)maybe asymptom-atic. If not recognized and if preven-tive foot care is not implemented,patients are at risk for injuries to theirinsensate feet.

4. Recognition and treatment of auto-nomic neuropathy may improvesymptoms, reduce sequelae, and im-prove quality of life.

Specific treatment for the underlyingnerve damage, other than improvedglycemic control, is currently not avail-able. Glycemic control can effectivelyprevent DPN and cardiac autonomicneuropathy (CAN) in type 1 diabetes(105,106) and may modestly slow theirprogression in type 2 diabetes (32), butdoes not reverse neuronal loss. Thera-peutic strategies (pharmacologic andnonpharmacologic) for the relief of pain-ful DPN and symptoms of autonomicneuropathy can potentially reduce pain(107) and improve quality of life.

Diagnosis

Diabetic Peripheral Neuropathy

Patients with type 1 diabetes for 5 ormore years and all patients with type 2diabetes should be assessed annually forDPNusing themedical history and simpleclinical tests. Symptoms vary accordingto the class of sensory fibers involved.The most common early symptoms areinduced by the involvement of smallfibers and include pain and dysesthesia(unpleasant sensations of burning andtingling). The involvement of large fibersmay cause numbness and loss of pro-tective sensation (LOPS). LOPS indicatesthe presence of distal sensorimotor poly-neuropathy and is a risk factor for diabeticfootulceration. The following clinical testsmay be used to assess small- and large-fiber function and protective sensation:

1. Small-fiber function: pinprick and tem-perature sensation

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

3. Protective sensation: 10-g monofila-ment

These tests not only screen for thepresence of dysfunction but also predictfuture risk of complications. Electrophys-iological testingor referral toaneurologistis rarely needed, except in situationswhere the clinical features are atypicalor the diagnosis is unclear.

In all patients with diabetes and DPN,causes of neuropathy other than diabe-tes should be considered, includingtoxins (e.g., alcohol), neurotoxic med-ications (e.g., chemotherapy), vitaminB12 deficiency, hypothyroidism, renaldisease, malignancies (e.g., multiplemyeloma, bronchogenic carcinoma), in-fections (e.g., HIV), chronic inflamma-tory demyelinating neuropathy, inherited

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neuropathies, and vasculitis (108). SeetheAmericanDiabetesAssociation (ADA)position statement “Diabetic Neuropa-thy” for more details (107).

Diabetic Autonomic Neuropathy

The symptoms and signs of autonomicneuropathy should be elicited carefullyduring the history and physical exami-nation. Major clinical manifestations ofdiabetic autonomic neuropathy includehypoglycemiaunawareness, resting tachy-cardia, orthostatic hypotension, gastro-paresis, constipation, diarrhea, fecalincontinence, erectile dysfunction, neu-rogenicbladder, andsudomotordysfunc-tion with either increased or decreasedsweating.

Cardiac Autonomic Neuropathy. CAN isassociated with mortality independentlyof other cardiovascular risk factors(109,110). In its early stages, CAN maybe completely asymptomatic and de-tected only by decreased heart ratevariability with deep breathing. Ad-vanced disease may be associatedwith resting tachycardia (.100 bpm)and orthostatic hypotension (a fall insystolic or diastolic blood pressureby .20 mmHg or .10 mmHg, respec-tively, upon standing without an appro-priate increase in heart rate). CANtreatment is generally focused on alle-viating symptoms.

Gastrointestinal Neuropathies. Gastroin-testinal neuropathies may involve anyportion of the gastrointestinal tract withmanifestations including esophagealdysmotility, gastroparesis, constipation,diarrhea, and fecal incontinence. Gastro-paresis should be suspected in individ-uals with erratic glycemic control or withupper gastrointestinal symptoms with-out another identified cause. Exclusionof organic causes of gastric outletobstruction or peptic ulcer disease(with esophagogastroduodenoscopyor a barium study of the stomach) isneeded before considering a diagnosis ofor specialized testing for gastroparesis.The diagnostic gold standard for gastro-paresis is the measurement of gastricemptying with scintigraphy of digestiblesolids at 15-min intervals for 4 h afterfood intake. The use of 13C octanoicacid breath test is emerging as a viablealternative.

Genitourinary Disturbances. Diabetic au-tonomic neuropathy may also cause

genitourinary disturbances, includingsexual dysfunction and bladder dysfunc-tion. In men, diabetic autonomic neu-ropathy may cause erectile dysfunctionand/or retrograde ejaculation (107). Fe-male sexual dysfunction occurs morefrequently in those with diabetes andpresents as decreased sexual desire, in-creased pain during intercourse, de-creased sexual arousal, and inadequatelubrication (111). Lower urinary tractsymptoms manifest as urinary inconti-nence and bladder dysfunction (nocturia,frequent urination, urination urgency,and weak urinary stream). Evaluationof bladder function should be performedfor individuals with diabetes who haverecurrent urinary tract infections, pyelo-nephritis, incontinence, or a palpablebladder.

Treatment

Glycemic Control

Near-normal glycemic control, imple-mented early in the course of diabetes,has been shown to effectively delay orprevent the development of DPN andCAN in patients with type 1 diabetes(112–115). Although the evidence forthe benefit of near-normal glycemic con-trol is not as strong for type 2 diabetes,some studies have demonstrated amod-est slowing of progression without re-versal of neuronal loss (32,116). Specificglucose-lowering strategies may havedifferent effects. In a post hoc analysis,participants, particularly men, in theBypass Angioplasty Revascularization In-vestigation in Type 2 Diabetes (BARI 2D)trial treatedwith insulin sensitizers had alower incidence of distal symmetric poly-neuropathy over 4 years than thosetreated with insulin/sulfonylurea (117).

Neuropathic Pain

Neuropathic pain can be severe and canimpact quality of life, limit mobility, andcontribute to depression and social dys-function (118). No compelling evidenceexists in support of glycemic control orlifestyle management as therapies forneuropathic pain in diabetes or predia-betes, which leaves only pharmaceuticalinterventions (119).

Pregabalin and duloxetine have re-ceived regulatory approval by the FDA,Health Canada, and the European Med-icines Agency for the treatment of neu-ropathic pain in diabetes. The opioidtapentadol has regulatory approval in

the U.S. and Canada, but the evidenceof its use is weaker (120). Comparativeeffectiveness studies and trials that in-clude quality-of-life outcomes are rare,so treatment decisions must considereach patient’s presentation and comor-bidities and often follow a trial-and-errorapproach. Given the range of partiallyeffective treatment options, a tailoredand stepwise pharmacologic strategywith careful attention to relative symp-tom improvement, medication adher-ence, and medication side effects isrecommended to achieve pain reductionand improve quality of life (121–123).

Pregabalin, a calcium channel a2-dsubunit ligand, is the most extensivelystudied drug for DPN. The majority ofstudies testing pregabalin have reportedfavorable effects on the proportion ofparticipants with at least 30–50% im-provement in pain (120,122,124–127).However, not all trials with pregabalinhave been positive (120,122,128,129),especially when treating patients withadvanced refractory DPN (126). Adverseeffects may be more severe in olderpatients (130) and may be attenuatedby lower starting doses and more gradualtitration. The related drug, gabapentin,has also shownefficacy for pain control indiabetic neuropathy and may be lessexpensive, although it is not FDA ap-proved for this indication (131).

Duloxetine is a selective norepineph-rine and serotonin reuptake inhibitor.Doses of 60 and 120 mg/day showedefficacy in the treatment of pain associ-ated with DPN in multicenter random-ized trials, although some of these hadhigh drop-out rates (120,122,127,129).Duloxetine also appeared to improveneuropathy-related quality of life (132).In longer-term studies, a small increase inA1Cwas reported in people with diabetestreated with duloxetine compared withplacebo (133). Adverse events may bemore severe in older people but may beattenuated with lower doses and slowertitrations of duloxetine.

Tapentadol is a centrally acting opioidanalgesic that exerts its analgesic effectsthrough bothm-opioid receptor agonismand noradrenaline reuptake inhibition.Extended-release tapentadol was ap-proved by the FDA for the treatmentof neuropathic pain associated with di-abetes based on data from two multi-center clinical trials in which participantstitrated to an optimal dose of tapentadol

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were randomly assigned to continue thatdose or switch to placebo (134,135).However, both used a design enrichedfor patients who responded to tapentadoland therefore their results are not gen-eralizable. A recent systematic reviewandmeta-analysis by the Special InterestGroup on Neuropathic Pain of the In-ternational Association for the Studyof Pain found the evidence support-ing the effectiveness of tapentadol inreducing neuropathic pain to be incon-clusive (120). Therefore, given the highrisk for addiction and safety concernscompared with the relatively modestpain reduction, the use of extended-release tapentadol is not generally rec-ommended as a first- or second-linetherapy. The use of any opioids formanagement of chronic neuropathicpain carries the risk of addiction andshould be avoided.Tricyclic antidepressants, venlafaxine,

carbamazepine, and topical capsaicin, al-though not approved for the treatmentof painful DPN, may be effective andconsidered for the treatment of painfulDPN (107,120,122).

Orthostatic Hypotension

Treating orthostatic hypotension is chal-lenging. The therapeutic goal is to min-imize postural symptoms rather than torestore normotension. Most patients re-quire both nonpharmacologic measures(e.g., ensuringadequate salt intake,avoid-ing medications that aggravate hypoten-sion, or using compressive garments overthe legs and abdomen) and pharmaco-logic measures. Physical activity and ex-ercise should be encouraged to avoiddeconditioning, which is known to exac-erbate orthostatic intolerance, and vol-ume repletion with fluids and salt iscritical. Midodrine and droxidopa areapproved by the FDA for the treatmentof orthostatic hypotension.

Gastroparesis

Treatment for diabetic gastroparesis maybe very challenging. A low-fiber, low-fateating plan provided in small frequentmeals with a greater proportion of liquidcalories may be useful (136–138). Inaddition, foods with small particle sizemay improve key symptoms (139). With-drawing drugs with adverse effectson gastrointestinal motility includingopioids, anticholinergics, tricyclic anti-depressants, GLP-1 RA, pramlintide, andpossibly dipeptidyl peptidase 4 inhibitors

may also improve intestinal motility(136,140). In cases of severe gastropa-resis, pharmacologic interventions areneeded. Only metoclopramide, a proki-netic agent, is approved by the FDA forthe treatment of gastroparesis. How-ever, the level of evidence regardingthe benefits of metoclopramide forthe management of gastroparesis isweak, and given the risk for seriousadverse effects (extrapyramidal signssuch as acute dystonic reactions,drug-induced parkinsonism, akathisia,and tardive dyskinesia), its use in thetreatment of gastroparesis beyond12 weeks is no longer recommendedby the FDA or the European MedicinesAgency. It should be reserved for se-vere cases that are unresponsiveto other therapies (140). Other treat-ment options include domperidone(available outside of the U.S.) and eryth-romycin, which is only effective forshort-term use due to tachyphylaxis(141,142). Gastric electrical stimulationusing a surgically implantable devicehas received approval from the FDA,although its efficacy is variable anduse islimited to patients with severe symp-toms that are refractory to other treat-ments (143).

Erectile Dysfunction

In addition to treatment of hypogonad-ism if present, treatments for erectiledysfunction may include phosphodies-terase type5 inhibitors, intracorporeal orintraurethral prostaglandins, vacuumde-vices, or penile prostheses. As with DPNtreatments, these interventions do notchange the underlying pathology andnatural history of the disease processbut may improve the patient’s qualityof life.

FOOT CARE

Recommendations

11.32 Perform a comprehensive footevaluation at least annually toidentify risk factors for ulcersand amputations. B

11.33 Patients with evidence of sen-sory loss or prior ulceration oramputation should have theirfeet inspected at every visit. C

11.34 Obtain a prior history of ulcer-ation, amputation, Charcot foot,angioplasty or vascular surgery,cigarette smoking, retinopathy,

and renal disease and assesscurrent symptoms of neurop-athy (pain, burning,numbness)and vascular disease (leg fa-tigue, claudication). B

11.35 The examination should includeinspection of the skin, assessmentof foot deformities, neurologicalassessment (10-g monofilamenttesting with at least one otherassessment: pinprick, tempera-ture, vibration), and vascular as-sessment including pulses in thelegs and feet. B

11.36 Patients with symptoms ofclaudication or decreased orabsent pedal pulses should bereferred for ankle-brachial in-dex and for further vascularassessment as appropriate. C

11.37 A multidisciplinary approach isrecommended for individualswith foot ulcers and high-riskfeet (e.g., dialysis patients andthose with Charcot foot orprior ulcers or amputation). B

11.38 Refer patients who smoke orwho have histories of priorlower-extremity complications,loss of protective sensation,structural abnormalities, or pe-ripheral arterial disease to footcare specialists for ongoing pre-ventive care and lifelong sur-veillance. C

11.39 Provide general preventivefoot self-care education to allpatients with diabetes. B

11.40 The use of specialized thera-peutic footwear is recommen-ded for high-risk patients withdiabetes including those withsevere neuropathy, foot de-formities, or history of ampu-tation. B

Foot ulcers and amputation, whichare consequences of diabetic neuropa-thy and/or peripheral arterial disease(PAD), are commonand representmajorcauses of morbidity and mortality inpeople with diabetes. Early recognitionand treatment of patients with diabetesand feet at risk for ulcers and amputa-tions can delay or prevent adverseoutcomes.

The risk of ulcers or amputations isincreased in people who have the fol-lowing risk factors:

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○ 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)

Clinicians are encouraged to review ADAscreening recommendations for furtherdetails and practical descriptions of howto perform components of the compre-hensive foot examination (144).

Evaluation for Loss of ProtectiveSensationAll adults with diabetes should undergo acomprehensive foot evaluation at leastannually. Detailed foot assessments mayoccur more frequently in patients withhistories of ulcers or amputations, footdeformities, insensate feet, and PAD(145). To assess risk, clinicians shouldask about history of foot ulcers or am-putation, neuropathic and peripheralvascular symptoms, impaired vision, re-nal disease, tobacco use, and foot carepractices. A general inspection of skinintegrity and musculoskeletal deform-ities should be performed. Vascular as-sessment should include inspection andpalpation of pedal pulses.The neurological exam performed as

part of the foot examination is designedto identify LOPS rather than early neurop-athy. The 10-g monofilament is the mostuseful test to diagnose LOPS. Ideally, the10-g monofilament test should be per-formed with at least one other assessment(pinprick, temperature or vibration sensa-tion using a 128-Hz tuning fork, or anklereflexes). Absent monofilament sensationsuggests LOPS, while at least two normaltests (andnoabnormal test) rules out LOPS.

Evaluation for Peripheral ArterialDiseaseInitial screening for PAD should includea history of decreased walking speed, legfatigue, claudication, and an assessmentof the pedal pulses. Ankle-brachial indextesting should be performed in patientswith symptoms or signs of PAD.

Patient EducationAll patients with diabetes and particu-larly those with high-risk foot conditions

(history of ulcer or amputation, defor-mity, LOPS, or PAD) and their familiesshould be provided general educationabout risk factors and appropriate man-agement (146). Patients at risk shouldunderstand the implications of foot de-formities, LOPS, andPAD; theproper careof the foot, including nail and skin care;and the importance of foot monitoringon a daily basis. Patients with LOPSshouldbeeducatedonways to substituteother sensory modalities (palpation orvisual inspection using an unbreakablemirror) for surveillance of early footproblems.

The selection of appropriate footwearand footwear behaviors at home shouldalso be discussed. Patients’ understand-ing of these issues and their physicalability to conduct proper foot surveil-lance and care should be assessed. Pa-tients with visual difficulties, physicalconstraints preventing movement, orcognitive problems that impair their abil-ity to assess the condition of the foot andto institute appropriate responses willneed other people, such as family mem-bers, to assist with their care.

TreatmentPeople with neuropathy or evidenceof increased plantar pressures (e.g.,erythema, warmth, or calluses) maybe adequately managed with well-fittedwalking shoes or athletic shoes thatcushion the feet and redistribute pres-sure. People with bony deformities(e.g., hammertoes, prominent metatarsalheads, bunions) may need extra wide ordeep shoes. People with bony deform-ities, including Charcot foot, who cannotbe accommodated with commercialtherapeutic footwear, will requirecustom-molded shoes. Special consider-ation and a thorough workup should beperformed when patients with neurop-athy present with the acute onset ofa red, hot, swollen foot or ankle, andCharcot neuroarthropathy should be ex-cluded. Early diagnosis and treatment ofCharcot neuroarthropathy is the bestway to prevent deformities that increasethe risk of ulceration and amputation.The routine prescription of therapeuticfootwear is not generally recommended.However, patients should be providedadequate information to aid in selectionof appropriate footwear. General foot-wear recommendations include a broadand square toe box, laces with three or

four eyes per side, padded tongue, qual-ity lightweight materials, and sufficientsize to accommodate a cushioned insole.Use of custom therapeutic footwear canhelp reduce the risk of future foot ulcersin high-risk patients (145,147).

Most diabetic foot infections are poly-microbial, with aerobic gram-positivecocci. Staphylococci and streptococciare the most common causative organ-isms. Wounds without evidence of softtissue or bone infection do not requireantibiotic therapy. Empiric antibiotictherapy can be narrowly targeted atgram-positive cocci in many patientswith acute infections, but those at riskfor infection with antibiotic-resistantorganisms or with chronic, previouslytreated, or severe infections requirebroader-spectrum regimens and shouldbe referred to specialized care centers(148). Foot ulcers and wound care mayrequire care by a podiatrist, orthopedicor vascular surgeon, or rehabilitationspecialist experienced in the manage-ment of individuals with diabetes (148).

Hyperbaric oxygen therapy (HBOT) inpatients with diabetic foot ulcers hasmixed evidence supporting its use asan adjunctive treatment to enhancewound healing and prevent amputation(149–151). In a relatively high-qualitydouble-blind study of patients with chronicdiabetic foot ulcers, hyperbaric oxygenas an adjunctive therapy resulted insignificantly more complete healing ofthe index ulcer in patients treated withHBOT compared with placebo at 1 yearof follow-up (152). However, multiplesubsequently published studies haveeither failed to demonstrate a benefitof HBOT or have been relatively smallwith potential flaws in study design (150).A well-conducted randomized controlledstudy performed in 103 patients foundthat HBOT did not reduce the indicationfor amputation or facilitate wound healingcompared with comprehensive woundcare in patients with chronic diabeticfoot ulcers (153). A systematic reviewby the International Working Group onthe Diabetic Foot of interventions toimprove the healing of chronic diabeticfoot ulcers concluded that analysis ofthe evidence continues to present meth-odological challenges as randomizedcontrolled studies remain few, with amajority being of poor quality (150).HBOT also does not seem to have asignificant effect onhealth-related quality

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of life in patients with diabetic footulcers (154,155). A recent review con-cluded that the evidence to date remainsinconclusive regarding the clinical andcost-effectiveness of HBOT as an adjunc-tive treatment to standard wound carefor diabetic foot ulcers (156). Results fromthe recently published Dutch DAMOCLES(Does Applying More Oxygen Cure LowerExtremity Sores?) trial demonstrated thatHBOT in patients with diabetes and is-chemic wounds did not significantly im-prove complete wound healing and limbsalvage (157). The Centers forMedicare&Medicaid Services currently covers HBOTfor diabetic foot ulcers that have failed astandard course of wound therapy whenthere are no measurable signs of healingfor at least 30 consecutive days (158).HBOT should be a topic of shared decisionmaking before treatment is consideredfor selected patients with diabetic footulcers (158).

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