foot care microvascular.pdf

9. Microvascular Complicationsand Foot CareDiabetes Care 2015;38(Suppl. 1):S58S66 | DOI: 10.2337/dc15-S012

NEPHROPATHY

Recommendations

c Optimize glucose control to reduce the risk or slow the progression of diabetickidney disease. A

c Optimize blood pressure control to reduce the risk or slow the progression ofdiabetic kidney disease. A

Screeningc At least once a year, quantitatively assess urinary albumin (e.g., urine albumin-

to-creatinine ratio [UACR]) and estimated glomerular ltration rate (eGFR) inpatients with type 1 diabetes duration of$5 years and in all patients with type2 diabetes. B

Treatmentc An ACE inhibitor or angiotensin receptor blocker (ARB) is not recommended

for the primary prevention of diabetic kidney disease in patients with diabeteswho have normal blood pressure and normal UACR (,30 mg/g). B

c Either an ACE inhibitor or ARB is suggested for the treatment of the non-pregnant patient with modestly elevated urinary albumin excretion (30299mg/day) C and is recommended for those with urinary albumin excretion.300 mg/day. A

c When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinineand potassium levels for the development of increased creatinine or changesin potassium. E

c Continued monitoring of UACR in patients with albuminuria is reasonable toassess progression of diabetic kidney disease. E

c When eGFR is ,60 mL/min/1.73 m2, evaluate and manage potential compli-cations of chronic kidney disease (CKD). E

c Consider referral to a physician experienced in the care of kidney diseasewhenthere is uncertainty about the etiology of kidney disease, difcult manage-ment issues, or advanced kidney disease. B

Nutritionc For people with diabetic kidney disease, reducing the amount of dietary pro-

tein below the recommended daily allowance of 0.8 g/kg/day (based on idealbody weight) is not recommended because it does not alter glycemic mea-sures, cardiovascular risk measures, or the course of GFR decline. A

The terms microalbuminuria (30299 mg/24 h) and macroalbuminuria(.300 mg/24 h) will no longer be used, since albuminuria occurs on a continuum.Albuminuria is dened as UACR $30 mg/g.

Diabetic kidney disease occurs in 2040% of patients with diabetes and is theleading cause of end-stage renal disease (ESRD). Persistent increased albumin-uria in the range of UACR 30299 mg/g is an early indicator of diabetic kidneydisease in type 1 diabetes and a marker for development of diabetic kidneydisease in type 2 diabetes. It is a well-established marker of increased cardiovas-cular disease (CVD) risk (13). However, there is increasing evidence of sponta-neous remission of UACR levels 30299 mg/g in up to 40% of patients with type 1diabetes. About 3040% remain with UACR levels of 30299 mg/g and do not

Suggested citation: American Diabetes Association.Microvascular complications and foot care. Sec. 9.In Standards ofMedical Care in Diabetesd2015.Diabetes Care 2015;38(Suppl. 1):S58S66

2015 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor prot, and the work is not altered.

American Diabetes Association

S58 Diabetes Care Volume 38, Supplement 1, January 2015

POSITION

STATE

MEN

T

progress to higher levels ($300 mg/g)over 510 years of follow-up (47). Pa-tients with persistent albuminuria arelikely to develop ESRD (8,9).

Interventions

Glycemia

A number of interventions have beendemonstrated to reduce the risk andslow the progression of diabetic kid-ney disease. Intensive diabetes man-agement with the goal of achievingnear-normoglycemia has been shownin large prospective randomized stud-ies to delay the onset and progressionof increased urinary albumin excre-tion and reduced eGFR in patientswith type 1 (9) and type 2 diabetes(1014).

Despite prior concerns and publishedcase reports, current data indicate thatthe overall risk of metformin-associatedlactic acidosis is low (14). GFR may be amore appropriate measure to assesscontinued metformin use than serumcreatinine considering that the serumcreatinine level can translate intowidely varying eGFR levels dependingon age, ethnicity, and muscle mass(15). A recent review (16) proposesthat metformin use should be reeval-uated at an eGFR ,45 mL/min/1.73 m2

with a reduction in maximum dose to1,000 mg/day and discontinued wheneGFR ,30 mL/min/1.73 m2 or in clini-cal situations in which there is an in-creased risk of lactic acidosis, such assepsis, hypotension, and hypoxia, or inwhich there is a high risk of acute kid-ney injury resulting in a worseningof GFR, such as administration ofradiocontrast dye in those with eGFR,60 mL/min/1.73 m2.

Blood Pressure

The UK Prospective Diabetes Study(UKPDS) provided strong evidence thatblood pressure control can reduce thedevelopment of diabetic kidney disease(17). In addition, large prospective ran-domized studies in patients with type 1diabetes have shown that ACE inhibitorshave achieved lower systolic blood pres-sure levels (,140 mmHg) and haveprovided a selective benet over otherantihypertensive drug classes in delay-ing the progression of increased urinaryalbumin excretion and can slow the de-cline in GFR in patients with higher lev-els of albuminuria (18,19). In patientswith type 2 diabetes, hypertension,

and normoalbuminuria, renin-angiotensinsystem inhibition has been demon-strated to delay onset of elevated al-buminuria (20,21). Of note, in thelatter study, there was an unexpectedhigher rate of fatal cardiovascularevents with olmesartan comparedwith placebo among patients with pre-existing CVD.

ACE inhibitors have been shown toreduce major CVD outcomes (i.e.,myocardial infarction, stroke, death)in patients with diabetes (22), thusfurther supporting the use of theseagents in patients with elevatedalbuminuria, a CVD risk factor. ARBsdo not have the same benecial effecton cardiovascular outcomes or pre-vent the onset of elevated albuminuriain normotensive patients with type 1or type 2 diabetes (23). However, ARBshave been shown to reduce the pro-gression of albuminuria, as well asESRD, in patients with type 2 diabetes(2426). In those with diabetic kidneydisease, some evidence suggests thatARBs are associated with a smaller in-crease in serum potassium levels com-pared with ACE inhibitors (27).

Combination Therapy

Drug combinations that block the renin-angiotensin system (e.g., an ACE inhibi-tor plus an ARB, a mineralocorticoidantagonist, or a direct renin inhibitor)provide additional lowering of albumin-uria (28). However, compared withsingle-agent use, such combinationshave been found to provide no addi-tional benet on CVD or diabetic kid-ney disease and have higher adverseevent rates (hyperkalemia or acute kid-ney injury) (29). Therefore, the com-bined use of different inhibitors of therenin-angiotensin system should beavoided.

Diuretics, calcium channel blockers,andb-blockers can be used as additionaltherapy to further lower blood pressurein patients already treated with maxi-mum doses of ACE inhibitors or ARBs(30) or as alternate therapy in the rareindividual unable to tolerate ACE inhib-itors and ARBs.

Studies in patients with varyingstages of diabetic kidney diseasehave shown that the limitation of di-etary protein to avoid excess intakeslows the progression of albuminuria,GFR decline, and occurrence of ESRD

(3134), although more recent studieshave provided conicting results (35).Dietary protein limitation, if proteinintake is high, is a consideration par-ticularly in patients whose diabetickidney disease is progressing despiteoptimal glucose and blood pressurecontrol and use of an ACE inhibitor orARB (34).

Assessment of Albuminuria Status andRenal FunctionScreening for increased urinary albu-min excretion can be performed byUACR in a random spot urine collec-tion; 24-h or timed collections aremore burdensome and add little toprediction or accuracy (36,37). Mea-surement of a spot urine sample foralbumin alone (whether by immunoas-say or by using a sensitive dipstick testspecic for albuminuria) without si-multaneously measuring urine creati-nine is less expensive but susceptible tofalse-negative and false-positive deter-minations as a result of variation inurine concentration due to hydrationand other factors.

Abnormalities of albumin excretionand the linkage between UACR and24-h albumin excretion are dened inTable 9.1. Because of variability in urinaryalbumin excretion, two of three speci-mens collected within a 3- to 6-monthperiod should be abnormal beforeconsidering a patient to have developedalbuminuria. Exercise within 24 h, infec-tion, fever, congestive heart failure,marked hyperglycemia, and marked hy-pertension may elevate urinary albuminexcretion over baseline values.

Abnormal urine albumin excretionand GFR level may be used to stageCKD. The National Kidney Foundationclassication (Table 9.2) is primarilybased on GFR levels and may be super-seded by other systems in which staging

Table 9.1Denitions of abnormalitiesin albumin excretion

CategorySpot collection

(mg/g creatinine)

Normal ,30

Increased urinaryalbumin excretion* $30

*Historically, ratios between 30 and 299mg/g have been called microalbuminuriaand those .300 mg/g have been calledmacroalbuminuria (or clinicalalbuminuria).

care.diabetesjournals.org Position Statement S59

includes other variables such as urinaryalbumin excretion (38). Studies havefound decreased GFR without increasedurine albumin excretion in a substantialpercentage of adults with type 2 diabe-tes (39). Substantial evidence showsthat in patients with type 1 diabetesand persistent UACR 30299 mg/g,screening with albumin excretion ratealone would miss .20% of progressivedisease (7). Serum creatinine with eGFRshould therefore be assessed at leastannually in all adults with diabetes, re-gardless of the degree of urine albuminexcretion.

Serum creatinine should be used toestimate GFR and to stage the levelof CKD, if present. eGFR is commonlycoreported by laboratories or can beestimated using formulae such as theModication of Diet in Renal Disease(MDRD) study equation (40) or theChronic Kidney Disease EpidemiologyCollaboration (CKD-EPI) equation. Thelatter is the current preferred GFR es-timating equation. GFR calculators areavailable at http://www.nkdep.nih.gov.

The need for annual quantitative as-sessment of albumin excretion afterdiagnosis of albuminuria and institu-tion of ACE inhibitor or ARB therapyand blood pressure control is a subjectof debate. Continued surveillance canassess both response to therapy anddisease progression and may aid in as-sessing adherence to ACE inhibitor orARB therapy. Some suggest that reduc-ing UACR to normal (,30 mg/g) ornear normal may improve CKD andCVD prognosis, but this approach hasnot been formally evaluated in pro-spective trials, and evidence demon-strates spontaneous remission ofalbuminuria in up to 40% of type 1 di-abetic patients.

Conversely, patients with increasingalbumin levels, declining GFR, increas-ing blood pressure, retinopathy, macro-vascular disease, elevated lipids and/oruric acid concentrations, or a family his-tory of CKD are more likely to ex-perience a progression of diabetickidney disease (7).

Complications of kidney disease cor-relate with level of kidney function.When the eGFR is ,60 mL/min/1.73 m2,screening for complications of CKDis indicated (Table 9.3). Early vacci-nation against hepatitis B virus is

indicated in patients likely to progressto ESRD.

Referral to NephrologistConsider referral to a physician experi-enced in the care of kidney diseasewhen there is uncertainty about theetiology of kidney disease (heavy pro-teinuria, active urine sediment, absenceof retinopathy, rapid decline in GFR).Other triggers for referral may includedifcult management issues (anemia,secondary hyperparathyroidism, meta-bolic bone disease, resistant hyperten-sion, or electrolyte disturbance) oradvanced kidney disease. The thresholdfor referral may vary depending onthe frequency with which a providerencounters diabetic patients with sig-nicant kidney disease. Consultationwith a nephrologist when stage 4 CKDdevelops has been found to reduce cost,improve quality of care, and delay dial-ysis (41). However, other specialists andproviders should not delay educatingtheir patients about the progressive na-ture of diabetic kidney disease, the kid-ney preservation benets of proactive

treatment of blood pressure and bloodglucose, and the potential need for renaltransplant.

RETINOPATHY

Recommendations

c Optimize glycemic control to re-duce the risk or slow the progres-sion of retinopathy. A

c Optimize blood pressure controlto reduce the risk or slow the pro-gression of retinopathy. A

Screeningc Adults with type 1 diabetes

should have an initial dilated andcomprehensive eye examinationby an ophthalmologist or optom-etrist within 5 years after the on-set of diabetes. B

c Patients with type 2 diabetesshould have an initial dilated andcomprehensive eye examinationby an ophthalmologist or optom-etrist shortly after the diagnosis ofdiabetes. B

Table 9.2Stages of CKD

Stage Description GFR (mL/min/1.73 m2)

1 Kidney damage* with normal or increased GFR $90

2 Kidney damage* with mildly decreased GFR 6089

3 Moderately decreased GFR 3059

4 Severely decreased GFR 1529

5 Kidney failure ,15 or dialysis

*Kidney damage is dened as abnormalities on pathological, urine, blood, or imaging tests.Adapted from Levey et al. (37).

Table 9.3Management of CKD in diabetes (7)

GFR (mL/min/1.73 m2) Recommended management

All patients Yearlymeasurement of creatinine, urinary albumin excretion, potassium

4560 Referral to a nephrologist if possibility for nondiabetic kidneydisease exists (duration of type 1 diabetes,10 years, persistentalbuminuria, abnormal ndings on renal ultrasound, resistanthypertension, rapid fall in GFR, or active urinary sediment onultrasound)

Consider the need for dose adjustment of medicationsMonitor eGFR every 6 monthsMonitor electrolytes, bicarbonate, hemoglobin, calcium,

phosphorus, parathyroid hormone at least yearlyAssure vitamin D sufciencyConsider bone density testingReferral for dietary counseling

3044 Monitor eGFR every 3 monthsMonitor electrolytes, bicarbonate, calcium, phosphorus, parathyroid

hormone, hemoglobin, albumin, weight every 36 monthsConsider the need for dose adjustment of medications

,30 Referral to a nephrologist

S60 Position Statement Diabetes Care Volume 38, Supplement 1, January 2015

c If there is no evidence of retinopathyfor one or more eye exams, then ex-ams every 2 years may be consid-ered. If diabetic retinopathy ispresent, subsequent examinationsfor patients with type 1 and type 2diabetes shouldbe repeatedannuallyby an ophthalmologist or optome-trist. If retinopathy is progressing orsight-threatening, then examinationswill be required more frequently. B

c High-quality fundus photographscan detect most clinically signi-cant diabetic retinopathy. Inter-pretation of the images shouldbe performed by a trained eyecare provider. While retinal pho-tography may serve as a screeningtool for retinopathy, it is not a sub-stitute for a comprehensive eyeexam, which should be performedat least initially and at intervalsthereafter as recommended byan eye care professional. E

c Women with preexisting diabeteswho are planning pregnancy orwho have become pregnantshould have a comprehensive eyeexamination and be counseled onthe risk of development and/orprogression of diabetic retinopa-thy. Eye examination should occurin the rst trimester with closefollow-up throughout pregnancyand for 1 year postpartum. B

Treatmentc Promptly refer patients with any

level of macular edema, severenonproliferative diabetic retinop-athy (NPDR), or any proliferativediabetic retinopathy (PDR) to anophthalmologist who is knowl-edgeable and experienced in themanagement and treatment of di-abetic retinopathy. A

c Laser photocoagulation therapy isindicated to reduce the risk of visionloss in patients with high-risk PDR,clinically signicantmacular edema,and, in some cases, severe NPDR. A

c Antivascular endothelial growthfactor (VEGF) therapy is indicatedfor diabetic macular edema. A

c The presence of retinopathy isnot a contraindication to aspirintherapy for cardioprotection, asaspirin does not increase the riskof retinal hemorrhage. A

Diabetic retinopathy is a highly specicvascular complication of both type 1and type 2 diabetes, with prevalencestrongly related to the duration of dia-betes. Diabetic retinopathy is the mostfrequent cause of new cases of blind-ness among adults aged 2074 years.Glaucoma, cataracts, and other disor-ders of the eye occur earlier and morefrequently in people with diabetes.

In addition to diabetes duration, fac-tors that increase the risk of, or are as-sociated with, retinopathy includechronic hyperglycemia (42), nephropa-thy (43), and hypertension (44). Inten-sive diabetes management with thegoal of achieving near-normoglycemiahas been shown in large prospectiverandomized studies to prevent and/ordelay the onset and progression of di-abetic retinopathy (11,45). Loweringblood pressure has been shown to de-crease retinopathy progression, al-though tight targets (systolic ,120mmHg) do not impart additional benet(45). Several case series and a con-trolled prospective study suggest thatpregnancy in type 1 diabetic patientsmay aggravate retinopathy (46,47). La-ser photocoagulation surgery can mini-mize this risk (47).

ScreeningThe preventive effects of therapy andthe fact that patients with PDR or mac-ular edema may be asymptomatic pro-vide strong support for a screeningprogram to detect diabetic retinopathy.Because retinopathy is estimated totake at least 5 years to develop afterthe onset of hyperglycemia, patientswith type 1 diabetes should have an ini-tial dilated and comprehensive eye ex-amination within 5 years after thediabetes diagnosis (48). Patients withtype 2 diabetes whomay have had yearsof undiagnosed diabetes and have a sig-nicant risk of prevalent diabetic ret-inopathy at the time of diagnosisshould have an initial dilated and com-prehensive eye examination shortly af-ter diagnosis. Examinations should beperformed by an ophthalmologist or op-tometrist who is knowledgeable andexperienced in diagnosing diabetic reti-nopathy. Subsequent examinations fortype 1 and type 2 diabetic patients aregenerally repeated annually. Exams ev-ery 2 years may be cost-effective afterone or more normal eye exams, and

in a population with well-controlledtype 2 diabetes, there was essentiallyno risk of development of signicant ret-inopathy with a 3-year interval after anormal examination (49). Examinationswill be required more frequently if reti-nopathy is progressing.

Retinal photography, with remotereading by experts, has great potentialin areas where qualied eye care profes-sionals are not readily available (50). Italso may enhance efciency and reducecosts when the expertise of ophthalmol-ogists can be used for more complexexaminations and for therapy (51). In-person exams are still necessary whenthe photos are unacceptable and forfollow-up if abnormalities are detected.Photos are not a substitute for a com-prehensive eye exam, which should beperformed at least initially and at inter-vals thereafter as recommended by aneye care professional. Results of eye ex-aminations should be documented andtransmitted to the referring health careprofessional.

TreatmentOne of themainmotivations for screeningfor diabetic retinopathy is the long-established efcacy of laser photocoag-ulation surgery in preventing visual loss.Two large trials, the Diabetic Retinopa-thy Study (DRS) in patients with PDR andthe Early Treatment Diabetic RetinopathyStudy (ETDRS) in patients with macularedema, provide the strongest supportfor the therapeutic benets of photoco-agulation surgery. The DRS (52) showedthat panretinal photocoagulation surgeryreduced the risk of severe vision loss fromPDR from 15.9% in untreated eyes to6.4% in treated eyes, with the greatestrisk-benet ratio in those with baselinedisease (disc neovascularization or vitre-ous hemorrhage).

The ETDRS (53) established the ben-et of focal laser photocoagulation sur-gery in eyes with macular edema,particularly those with clinically signif-icant macular edema, with reduction ofdoubling of the visual angle (e.g., 20/50to 20/100) from 20% in untreated eyesto 8% in treated eyes. The ETDRS alsoveried the benets of panretinal pho-tocoagulation for high-risk PDR and inolder-onset patients with severe NPDRor less-than-high-risk PDR.

Laser photocoagulation surgery inboth trials was benecial in reducing


the risk of further visual loss, but gener-ally not benecial in reversing alreadydiminished acuity. Recombinant mono-clonal neutralizing antibody to VEGF im-proves vision and reduces the need forlaser photocoagulation in patients withmacular edema (54). Other emergingtherapies for retinopathy include sus-tained intravitreal delivery of uocin-olone (55) and the possibility ofprevention with fenobrate (56,57).

NEUROPATHY

Recommendations

c All patients should be screened fordiabetic peripheral neuropathy(DPN) starting at diagnosis oftype 2 diabetes and 5 years afterthe diagnosis of type 1 diabetesand at least annually thereafter,using simple clinical tests, suchas a 10-g monolament. B

c Screening for signs and symptoms(e.g., orthostasis, resting tachycar-dia) of cardiovascular autonomicneuropathy (CAN) shouldbe consid-eredwithmore advanced disease. E

c Tight glycemic control is the onlystrategy convincingly shown toprevent or delay the developmentof DPN and CAN in patients withtype 1 diabetes A and to slow theprogression of neuropathy in somepatients with type 2 diabetes. B

c Assess and treat patients to re-duce pain related to DPN B andsymptoms of autonomic neuropa-thy and to improve quality of life. E

The diabetic neuropathies are heteroge-neous with diverse clinical manifestations.They may be focal or diffuse. The mostprevalent neuropathies are DPN and auto-nomic neuropathy. Although DPN is a diag-nosis of exclusion, complex investigationsor referral for neurology consultation to ex-clude other conditions is rarely needed.

The early recognition and appropriatemanagement of neuropathy in the pa-tient with diabetes is important for anumber of reasons:

1. Nondiabetic neuropathies may bepresent in patients with diabetesand may be treatable.

2. A number of treatment options existfor symptomatic diabetic neuropathy.

3. Up to 50% of DPNmay be asymptom-atic, and patients are at risk for in-sensate injury to their feet.

4. Autonomic neuropathy, particularlyCAN, is an independent risk factorfor cardiovascular mortality (58,59).

Specic treatment for the underlyingnerve damage, other than improved gly-cemic control, is currently not available.Glycemic control was shown to effec-tively prevent DPN and CAN in type 1diabetes (60,61) and may modestlyslow progression in type 2 diabetes(13) but does not reverse neuronalloss. Therapeutic strategies (pharmaco-logical and nonpharmacological) for therelief of specic symptoms related topainful DPN or autonomic neuropathyare recommended because they can po-tentially reduce pain (62) and improvequality of life.

Diagnosis

Diabetic Peripheral Neuropathy

Patients with diabetes should bescreened annually for DPN symptomsusing simple clinical tests. Symptomsvary according to the class of sensorybers involved. The most commonsymptoms are induced by the involve-ment of small bers and include pain,dysesthesias (unpleasant abnormal sen-sations of burning and tingling), andnumbness. Clinical tests include assess-ment of pinprick sensation, vibrationthreshold using a 128-Hz tuning fork,light touch perception using a 10-gmonolament, and ankle reexes. As-sessment should follow the typicalDPN pattern, starting distally (the dorsalaspect of the hallux) on both sides andmove proximally until threshold is de-tected. Several clinical instrumentsthat combine more than one test have.87% sensitivity in detecting DPN(6365). Electrophysiological testing orreferral to a neurologist is rarely needed,except in situations where the clinicalfeatures are atypical or the diagnosis isunclear.

In patients with severe or atypical neu-ropathy, causes other than diabetesshould always be considered, such as neu-rotoxic medications, heavy metal poison-ing, alcohol abuse, vitamin B12 deciency(66), renal disease, chronic inammatorydemyelinatingneuropathy, inheritedneu-ropathies, and vasculitis (67).

Diabetic Autonomic Neuropathy

The symptoms and signs of autonomicdysfunction should be elicited care-fully during the history and physical

examination. Major clinical manifesta-tions of diabetic autonomic neuropathyinclude resting tachycardia, exerciseintolerance, orthostatic hypotension,gastroparesis, constipation, erectile dys-function, sudomotor dysfunction, im-paired neurovascular function, and,potentially, autonomic failure in responseto hypoglycemia.

Cardiovascular Autonomic Neuropathy

CAN is the most studied and clinicallyimportant form of diabetic autonomicneuropathy because of its associationwith mortality independent of othercardiovascular risk factors (58,68). Inearly stages, CAN may be completelyasymptomatic and detected by changesin heart rate variability with deepbreathing and abnormal cardiovascularreex tests (R-R interval response todeep breathing, standing, and Valsalvamaneuver tests). Advanced disease maybe indicated by resting tachycardia(.100 bpm) and orthostasis (a fall insystolic blood pressure .20 mmHg ordiastolic blood pressure of at least 10mmHg upon standing without an appro-priate heart rate response). The stan-dard cardiovascular reex tests (deepbreathing, standing, and Valsalvamaneuver) are noninvasive, easy toperform, reliable, and reproducible, es-pecially the deep breathing test, andhave prognostic value (69). Althoughsome societies have developed guide-lines for screening for CAN, the benetsof sophisticated testing beyond riskstratication are not clear (69).

Gastrointestinal Neuropathies

Gastrointestinal neuropathies (e.g.,esophageal enteropathy, gastroparesis,constipation, diarrhea, fecal inconti-nence) may involve any section of thegastrointestinal tract. Gastroparesisshould be suspected in individuals witherratic glucose control or with upper gas-trointestinal symptoms without anotheridentied cause. Evaluation of solid-phase gastric emptying using double-isotope scintigraphy may be done ifsymptoms are suggestive, but test re-sults often correlate poorly with symp-toms. Constipation is the most commonlower-gastrointestinal symptom but canalternate with episodes of diarrhea.

Genitourinary Tract Disturbances

Diabetic autonomic neuropathy is alsoassociated with genitourinary tract dis-turbances. In men, diabetic autonomic


neuropathy may cause erectile dysfunc-tion and/or retrograde ejaculation. Eval-uation of bladder dysfunction should beperformed for individuals with diabeteswho have recurrent urinary tract infec-tions, pyelonephritis, incontinence, or apalpable bladder.

Treatment

Glycemic Control

Tight glycemic control, implementedearly in the course of diabetes, hasbeen shown to effectively prevent or de-lay the development of DPN and CAN inpatients with type 1 diabetes (7073).While the evidence is not as strong fortype 2 diabetes, some studies havedemonstrated a modest slowing of pro-gression (74,75) without reversal ofneuronal loss. Several observationalstudies further suggest that neuropathicsymptoms improve not only with opti-mization of glycemic control but alsowith the avoidance of extreme bloodglucose uctuations.

Diabetic Peripheral Neuropathy

DPN symptoms, and especially neuro-pathic pain, can be severe, have suddenonset, and are associated with lowerquality of life, limited mobility, depres-sion, and social dysfunction (76). Thereis limited clinical evidence regarding themost effective treatments for individualpatients given the wide range of avail-able medications (77,78). Several drugshave been approved specically for re-lief of DPN pain in the U.S. (pregabalin,duloxetine, and tapentadol), but noneaffords complete relief, even whenused in combination. Venlafaxine, ami-triptyline, gabapentin, valproate, andother opioids (morphine sulfate, trama-dol, oxycodone controlled release) maybe effective and may be considered fortreatment of painful DPN. Head-to-head treatment comparisons and stud-ies that include quality-of-life outcomesare rare, so treatment decisions mustconsider each patients presentationand comorbidities and often follow atrial-and-error approach. Given therange of partially effective treatmentoptions, a tailored and stepwise phar-macological strategy with careful atten-tion to relative symptom improvement,medication adherence, and medicationside effects is recommended to achievepain reduction and improve quality oflife (62).

Autonomic Neuropathy

An intensive multifactorial cardiovascu-lar risk intervention targeting glucose,blood pressure, lipids, smoking, andother lifestyle factors has been shownto reduce the progression and develop-ment of CAN among patients with type 2diabetes (79). For those with signicantCAN, referral to a cardiologist may beindicated.

Orthostatic Hypotension

Treatment of orthostatic hypotension ischallenging. The therapeutic goal is tominimize postural symptoms ratherthan to restore normotension. Most pa-tients require the use of both pharma-cological and nonpharmacologicalmeasures (e.g., avoiding medicationsthat aggravate hypotension, using com-pressive garments over the legs and ab-domen). Midodrine is the only drugapproved by the U.S. Food and DrugAdministration for the treatment oforthostatic hypotension.

Gastroparesis Symptoms

Gastroparesis symptoms may improvewith dietary changes andprokinetic agentssuch as erythromycin. Recently, the Euro-pean Medicines Agency (www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146614.pdf)decided that risks of extrapyramidal symp-tomswithmetoclopramide outweigh ben-ets. In Europe, metoclopramide use isnow restricted to a maximum of 5 daysand is no longer indicated for the long-term treatment of gastroparesis. Althoughthe U.S. Food and Drug Administrationsdecision is pending, it is suggested thatmetoclopramide be reserved for only themost severe cases that are unresponsiveto other therapies. Side effects should beclosely monitored.

Erectile Dysfunction

Treatments for erectile dysfunction mayinclude phosphodiesterase type 5 inhibi-tors, intracorporeal or intraurethral prosta-glandins, vacuum devices, or penileprostheses. Interventions for other mani-festations of autonomic neuropathy aredescribed in the American Diabetes Asso-ciation (ADA) statement on neuropathy(78). As with DPN treatments, these inter-ventions do not change the underlyingpathology and natural history of the dis-ease process but may have a positive im-pact on the quality of life of the patient.

FOOT CARE

Recommendations

c For all patients with diabetes, per-form an annual comprehensivefoot examination to identify riskfactors predictive of ulcers andamputations. The foot examina-tion should include inspectionand assessment of foot pulses. B

c Patients with insensate feet, footdeformities, and ulcers shouldhave their feet examined at everyvisit. E

c Provide general foot self-careeducation to all patients with di-abetes. B

c A multidisciplinary approach isrecommended for individualswith foot ulcers and high-risk feet(e.g., dialysis patients and thosewith Charcot foot, prior ulcers, oramputation). B

c Refer patients who smoke or whohave a loss of protective sensation(LOPS), structural abnormalities,or a history of prior lower-extremity complications to footcare specialists for ongoing pre-ventive care and lifelong surveil-lance. C

c Initial screening for peripheralarterial disease (PAD) shouldinclude a history for claudicationand an assessment of the pedalpulses. C

c Refer patients with signicantclaudication or a positive ankle-brachial index (ABI) for furthervascular assessment and considerexercise, medications, and surgicaloptions. C

Amputation and foot ulceration, whichare consequences of diabetic neuropa-thy and/or PAD, are common and repre-sent major causes of morbidity anddisability in people with diabetes. Lossof 10-g monolament perception andreduced vibration perception predictfoot ulcers (78). Early recognition andmanagement of risk factors can preventor delay adverse outcomes.

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

Previous amputation Past foot ulcer history Peripheral neuropathy Foot deformities


Peripheral vascular disease Visual impairment Diabetic nephropathy (especially pa-

tients on dialysis) Poor glycemic control Cigarette smoking

Clinicians are encouraged to reviewADA screening recommendations forfurther details and practical descriptionsof how to perform components of thecomprehensive foot examination (80).

ExaminationAll adults with diabetes shouldundergo a comprehensive foot exami-nation at least annually to identifyhigh-risk conditions. Clinicians shouldask about history of previous foot ulcer-ation or amputation, neuropathic or pe-ripheral vascular symptoms, impairedvision, tobacco use, and foot care prac-tices. A general inspection of skin integ-rity and musculoskeletal deformitiesshould be done in a well-lit room. Vas-cular assessment would include inspec-tion and assessment of pedal pulses.

The neurological exam recommendedis designed to identify LOPS rather thanearly neuropathy. The clinical examinationto identify LOPS is simple and requires noexpensive equipment. Five simple clinicaltests (use of a 10-g monolament, vibra-tion testing using a 128-Hz tuning fork,tests of pinprick sensation, ankle reex as-sessment, and testing vibration percep-tion threshold with a biothesiometer),each with evidence from well-conductedprospective clinical cohort studies, areconsidered useful in the diagnosis ofLOPS in the diabetic foot. Any of the vetests listed above could be used by clini-cians to identify LOPS, although ideallytwo of these should be regularly per-formed during the screening examdnormally the 10-g monolament and oneother test. One or more abnormal testswould suggest LOPS, while at least twonormal tests (andnoabnormal test)wouldrule out LOPS. The last test listed, vibrationassessment using a biothesiometer or sim-ilar instrument, is widely used in the U.S.;however, identication of the patientwithLOPS can easily be carried out without thisor other expensive equipment.

ScreeningInitial screening for PAD shouldinclude a history for claudication andan assessment of the pedal pulses.

A diagnostic ABI should be consideredin patients with PAD. Due to the highestimated prevalence of PAD in patientswith diabetes and the fact that manypatients with PAD are asymptomatic,an ADA consensus report on PAD (81)suggested that a screening ABI be per-formed in patients over 50 years of ageand be considered in patients under 50years of age who have other PAD riskfactors (e.g., smoking, hypertension, hy-perlipidemia, or duration of diabetes.10 years). Refer patients with signi-cant symptoms or a positive ABI for fur-ther vascular assessment and considerexercise, medications, and surgicaloptions (81).

Patient EducationPatients with diabetes and high-risk footconditions should be educated abouttheir risk factors and appropriate man-agement. Patients at risk should under-stand the implications of LOPS; theimportance of footmonitoring on a dailybasis; the proper care of the foot, includ-ing nail and skin care; and the selectionof appropriate footwear. Patients withLOPS should be educated on ways tosubstitute other sensory modalities(hand palpation, visual inspection) forsurveillance of early foot problems. Pa-tients understanding of these issuesand their physical ability to conductproper foot surveillance and care shouldbe assessed. Patients with visual difcul-ties, physical constraints preventingmovement, or cognitive problems thatimpair their ability to assess the condi-tion of the foot and to institute appro-priate responses will need other people,such as family members, to assist intheir care.

TreatmentPeople with neuropathy or evidence ofincreased plantar pressure (e.g., ery-thema, warmth, callus, or measuredpressure) may be adequately managedwithwell-ttedwalking shoes or athleticshoes that cushion the feet and redis-tribute pressure. Calluses can be de-brided with a scalpel by a foot carespecialist or other health professionalwith experience and training in footcare. People with bony deformities (e.g.,hammertoes, prominent metatarsalheads, bunions) may need extra wideor deep shoes. People with extremebony deformities (e.g., Charcot foot)who cannot be accommodated with

commercial therapeutic footwear mayneed custom-molded shoes.

Most diabetic foot infections are poly-microbial, with aerobic gram-positivecocci (GPC). Staphylococci are the mostcommon causative organisms. Woundswithout evidence of soft-tissue or boneinfection do not require antibiotic ther-apy. Empiric antibiotic therapy can benarrowly targeted at GPC in manyacutely infected patients, but those atrisk for infection with antibiotic-resistantorganisms or with chronic, previouslytreated, or severe infections requirebroader-spectrum regimens and shouldbe referred to specialized care centers(82). Foot ulcers and wound care mayrequire care by a podiatrist, orthopedicor vascular surgeon, or rehabilitationspecialist experienced in the manage-ment of individuals with diabetes.Guidelines for treatment of diabeticfoot ulcers have recently been updated(82).

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