Diabetic Neuropathy: A PositionStatement by the AmericanDiabetes AssociationDiabetes Care 2017;40:136–154 | DOI: 10.2337/dc16-2042

Diabetic neuropathies are the most prevalent chronic complications of diabetes. Thisheterogeneous group of conditions affects different parts of the nervous system andpresents with diverse clinical manifestations. The early recognition and appropriateman-agement of neuropathy in thepatientwith diabetes is important for a number of reasons:

1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies maybe present in patients with diabetes and may be treatable by specific measures.

2. A number of treatment options exist for symptomatic diabetic neuropathy.3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not

recognized and if preventive foot care is not implemented, patients are at riskfor injuries to their insensate feet.

4. Recognition and treatment of autonomic neuropathy may improve symptoms,reduce sequelae, and improve quality of life.

Among the various forms of diabetic neuropathy, distal symmetric polyneurop-athy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular au-tonomic neuropathy (CAN), are by far the most studied (1–4). There are severalatypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes mayalso develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1provides a comprehensive classification scheme for the diabetic neuropathies.Due to a lack of treatments that target the underlying nerve damage, prevention

is the key component of diabetes care. Screening for symptoms and signs of diabeticneuropathy is also critical in clinical practice, as it may detect the earliest stages ofneuropathy, enabling early intervention. Although screening for rarer atypical formsof diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are themost common forms encountered in practice. The strongest available evidenceregarding treatment pertains to these forms.This Position Statement is based on several recent technical reviews, towhich the reader

is referred for detailed discussion and relevant references to the literature (3,4,11–16).

PREVENTION

Prevention of diabetic neuropathies focuses on glucose control and lifestyle modifica-tions. Available evidence pertains only to DSPN and CAN, and most of the large trialsthat have evaluated the effect of glucose control on the risk of complications haveincluded DSPN and CAN as secondary outcomes or as post hoc analyses rather than asprimary outcomes. In addition, in some of these trials, the outcome measures used toevaluate neuropathy may have limited ability to detect a benefit, if present.

Recommendations

c Optimize glucose control as early as possible to prevent or delay the devel-opment of distal symmetric polyneuropathy and cardiovascular autonomicneuropathy in people with type 1 diabetes. A

c Optimize glucose control to prevent or slow the progression of distal symmet-ric polyneuropathy in people with type 2 diabetes. B

c Consider amultifactorial approach targeting glycemia among other risk factors toprevent cardiovascular autonomic neuropathy in people with type 2 diabetes. C

1Division ofMetabolism, Endocrinology & Diabe-tes, Department of Internal Medicine, Universityof Michigan, Ann Arbor, MI2University of Manchester and the Royal Infirmary,Manchester, U.K.3Department of Neurology, University of Michigan,Ann Arbor, MI4Department of Neurology, University of Toronto,Toronto, Ontario, Canada5Department of Neurology, Harvard MedicalSchool, Boston, MA6Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar and New York, NY7Division of Endocrinology, University of MiamiMiller School of Medicine, Miami, FL8German Diabetes Center Dusseldorf, LeibnizCenter for Diabetes Research at Heinrich HeineUniversity, and Department of Endocrinologyand Diabetology, Medical Faculty, HeinrichHeine University, Dusseldorf, Germany

Corresponding author: Rodica Pop-Busui, rpbusui@umich.edu.

This position statement was reviewed and ap-proved by the American Diabetes AssociationProfessional Practice Committee in September2016 and ratified by the American Diabetes As-sociation Board of Directors in October 2016.

R.P.-B. and A.J.M.B. served as co-chairs of thewriting committee.

© 2017 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.

Rodica Pop-Busui,1 Andrew J.M. Boulton,2

Eva L. Feldman,3 Vera Bril,4 Roy Freeman,5

Rayaz A. Malik,6 Jay M. Sosenko,7 and

Dan Ziegler8

136 Diabetes Care Volume 40, January 2017

POSITION

STATEMEN

T

Glucose ControlEnhanced glucose control in people withtype 1 diabetes dramatically reduces theincidence of DSPN (78% relative risk re-duction) (17–19). In contrast, enhancedglucose control in people with type 2 di-abetes reduces the risk of developingDSPN modestly (5%–9% relative risk re-duction) (20,21). In a small trial of Japa-nese patients with early type 2 diabetes,intensive insulin treatment was associ-ated with improvement in selectedDSPN measures (22), and the Action toControl Cardiovascular Risk in Diabetes(ACCORD) trial reported a modest butsignificant DSPN risk reduction withthe glycemia intervention in individualswith type 2 diabetes after 5 years offollow-up (21). Yet, no effects are ob-served in other large trials (20,23–25).This discrepancy highlights the differ-ences between type 1 and type 2 diabe-tes and emphasizes the point that many

people with type 2 diabetes developDSPN despite adequate glucose control(20,25). The presence of multiple comor-bidities, polypharmacy, hypoglycemia,and weight gain might have attenuatedthe effects of glucose control in thesetrials and contributed to inconsistentfindings (25). Specific glucose-loweringstrategies may also contribute to the dis-crepancy. For example, participants, par-ticularly men, in the Bypass AngioplastyRevascularization Investigation in Type 2Diabetes (BARI 2D) study treated with in-sulin sensitizers had a lower incidence ofDSPN over 4 years than those treatedwith insulin/sulfonylurea (26). This out-come may be a result of less weight gainand less hypoglycemia (26). Last, the factthat many patients have had asymptom-atic hyperglycemia for many years priorto the diagnosis of type 2 diabetes mayalso explain the limited benefit in thesepatients.

Similar to the findings in DSPN, themost robust evidence for CAN preven-tion was reported in type 1 diabetes.Intensive glucose control designed toachieve near-normal glycemia reducedthe risk of incident CAN during the Di-abetes Control and Complications Trial(DCCT) by 45% andby 31% in its follow-upstudy, the Epidemiology of Diabetes In-terventions and Complications (EDIC)study (27). The highly reproducible andsensitive testing protocol, the robustdefinitions used for CAN, and the largesample size in DCCT/EDIC enhance thevalidity of the results and support therationale for implementing and main-taining tight glucose control as early aspossible in the course of type 1 diabetes.In contrast, glycemic control in type 2diabetes has not consistently loweredthe risk of CAN (25). However, a multi-factorial intervention, including a life-style component, targeting glucose andcardiovascular disease risk factors re-duced the risk of CAN by 60% in peoplewith type 2 diabetes (28).

Lifestyle ModificationsThe best models to date regarding pa-rameters for an evidence-based, inten-sive lifestyle intervention come from theDiabetes Prevention Program (DPP)(29), the Steno-2 Study (28), the Italiansupervised treadmill study (30), and theUniversity of Utah type 2 diabetes study(31). The latter study recently reportednerve fiber regeneration in patients withtype 2 diabetes engaged in an exerciseprogram compared with loss of nerve fi-bers in those who only followed standardof care. Overall, such an approach focuseson either exercise alone (supervised aer-obic and/or resistance training) (30,31) orcombined dietary modification and exer-cise. There is no consensus regarding di-etary regimens, and although the DPPused a low-calorie, low-fat diet, othershave championed a Mediterranean dietthat is moderately lower in carbohydrate(45%) and higher in fat (35%–40%), withless than 10% of saturated fat.

Although theDPP (32) and the ImpairedGlucose Tolerance Neuropathy (IGTN)study (33) reported benefits of lifestyleinterventions on measures of CAN andDSPN, respectively, these trials did not in-clude subjects with established diabetes.In addition, in the DPP, indices of CANimproved with the lifestyle interventionand did not change in the other arms (32).

Table 1—Classification for diabetic neuropathies

Diabetic neuropathiesA. Diffuse neuropathyDSPN

c Primarily small-fiber neuropathyc Primarily large-fiber neuropathyc Mixed small- and large-fiber neuropathy (most common)

AutonomicCardiovascular

c Reduced HRVc Resting tachycardiac Orthostatic hypotensionc Sudden death (malignant arrhythmia)

Gastrointestinalc Diabetic gastroparesis (gastropathy)c Diabetic enteropathy (diarrhea)c Colonic hypomotility (constipation)

Urogenitalc Diabetic cystopathy (neurogenic bladder)c Erectile dysfunctionc Female sexual dysfunction

Sudomotor dysfunctionc Distal hypohydrosis/anhidrosis,c Gustatory sweating

Hypoglycemia unawarenessAbnormal pupillary function

B. Mononeuropathy (mononeuritis multiplex) (atypical forms)Isolated cranial or peripheral nerve (e.g., CN III, ulnar, median, femoral, peroneal)Mononeuritis multiplex (if confluent may resemble polyneuropathy)

C. Radiculopathy or polyradiculopathy (atypical forms)Radiculoplexus neuropathy (a.k.a. lumbosacral polyradiculopathy, proximal motor

amyotrophy)Thoracic radiculopathy

Nondiabetic neuropathies common in diabetesPressure palsiesChronic inflammatory demyelinating polyneuropathyRadiculoplexus neuropathyAcute painful small-fiber neuropathies (treatment-induced)

care.diabetesjournals.org Pop-Busui and Associates 137

DSPN

Most common among diabetic neurop-athies is chronic DSPN, accounting forabout 75% of the diabetic neuropathies(1,3). A simple definition of DSPN forclinical practice is the presence of symp-toms and/or signs of peripheral nervedysfunction in people with diabetes af-ter the exclusion of other causes.Experimental studies suggest a mul-

tifactorial pathogenesis of DSPN (Fig. 1),but the causes remain unknown(34–37). A prevailing view of the patho-genesis is that oxidative and inflamma-tory stress may, in the context ofmetabolic dysfunction, damage nervecells (34–37).Estimates of the incidence and prev-

alence of DSPN vary greatly (25,38–40),but evidence from several large obser-vational cohorts (41,42) and the DCCT/EDIC (27,43) suggests that DSPN occursin at least 20% of people with type 1 di-abetes after 20 years of disease dura-tion. DSPN may be present in at least10%–15% of newly diagnosed patientswith type 2 diabetes (44,45), with ratesincreasing to 50% after 10 years of diseaseduration (25,26). Rates in youth withtype 1 and type 2 diabetes approach those

observed in adult populations (46).DSPN has been associated with glyce-mia (14,33–35), height (47) (perhapsas a proxy for nerve length), smoking(48), blood pressure, weight, and lipidmeasures (49,50).

There is emerging evidence thatDSPN, especially the painful small-fiberneuropathy subtype, may be present in10%–30% of subjects with impaired glu-cose tolerance, also known as prediabe-tes (5–10) or metabolic syndrome (51).

DSPN is the most important cause offoot ulceration, and it is also a prereq-uisite in the development of Charcotneuroarthropathy (CN) (52). The readeris referred to several other reviews thatcover this topic (52,53). Foot ulcerationand CN are both recognized as late com-plications of DSPN (52,54). These latecomplications drive amputation riskand economic costs of diabetic neurop-athy and are also predictors of mortality.

DSPN is also a major contributor tofalls and fractures (55–57), throughmore advanced small- and large-fiberdysfunction, with loss of sensory, pro-prioception, temperature discrimina-tion, and pain, all ultimately leading tounsteadiness, recurrent minor injuries,

and an increased risk of falls. These re-current minor injuries may further con-tribute to the pathogenesis of CN (58).

Screening and Diagnosis

Recommendations

c All patients should be assessed fordistal symmetric polyneuropathystarting at diagnosis of type 2 di-abetes and 5 years after the diag-nosis of type 1 diabetes and atleast annually thereafter. B

c Consider screening patients withprediabetes who have symptomsof peripheral neuropathy. B

c Assessment should include a care-ful history and either temperatureor pinprick sensation (small-fiberfunction) and vibration sensationusinga128-Hz tuning fork (large-fiberfunction). All patients should have anannual 10-g monofilament testing toassess for feet at risk for ulcerationand amputation. B

c Electrophysiological testing or re-ferral to a neurologist is rarelyneeded for screening, except insituations where the clinical fea-tures are atypical, the diagnosis isunclear, or a different etiology issuspected. Atypical features in-clude motor greater than sensoryneuropathy, rapid onset, or asym-metrical presentation. B

Patients with type 1 diabetes for 5 ormore years and all patients with type 2diabetes should be assessed annuallyfor DSPN using medical history andsimple clinical tests. Up to 50% of pa-tients may experience symptoms ofDSPN (Table 2), whereas the rest areasymptomatic. Patients may not volun-teer symptoms but on inquiry may revealthat they are experiencing numbness orother positive symptoms of DSPN.

Symptoms vary according to the classof sensory fibers involved. The mostcommon early symptoms are inducedby the involvement of small fibers andinclude pain and dysesthesias (unpleas-ant sensations of burning) (1,4,59,60).Neuropathic pain may be the first symp-tom that prompts patients to seek med-ical care and is present in up to 25% ofindividuals with DSPN (61–63). Charac-teristically, the pain is burning, lancinating,tingling, or shooting (electric shock–like);occurs with paresthesias; presents in

Figure 1—Mechanisms of diabetic neuropathy. Factors linked to type 1 diabetes (yellow), type 2diabetes (blue), and both (green) cause DNA damage, endoplasmic reticulum stress, mitochon-drial dysfunction, cellular injury, and irreversible damage. The relative importance of the path-ways in this network will vary with cell type, disease profile, and time. ER, endoplasmicreticulum; FFA, free fatty acids; PI3-K, phosphatidylinositol-3 kinase; RNS, reactive nitrogenspecies; ROS, reactive oxygen species. Adapted and reprinted from Callaghan et al. (20), withpermission from Elsevier.

138 Position Statement Diabetes Care Volume 40, January 2017

varying combinations; and is typicallyworse at night. Neuropathic pain may beaccompanied by an exaggerated responseto painful stimuli (hyperalgesia) and painevoked by contact, e.g., with socks, shoes,and bedclothes (allodynia). Neuropathicpain can lead to interference with dailyactivities, disability, psychosocial impair-ment, and reduced health-related qualityof life (64–66). The direct and indirect eco-nomic burden associated with neuro-pathic pain is substantial (67–69).The involvement of large fibers may

cause numbness, tingling without pain,and loss of protective sensation. Loss ofprotective sensation indicates the pres-ence of DSPN and is a risk factor for di-abetic foot ulceration. Patients can alsoinitially present with an insensate, numbfoot due to the loss of largefibers. Patientsfrequently state that their feet feel likethey arewrapped inwool or they arewalk-ing on thick socks. It is the loss of the “giftof pain” that permits patients with plantarneuropathic ulcers to walk on the lesions,inducing chronicity, frequently complicatedby infection (70).The following clinical tests may be

used to assess small- and large-fiberfunction distal to proximal (Table 2):

1. Small-fiber function: pinprick andtemperature sensation

2. Large-fiber function: vibration per-ception, proprioception, 10-g mono-filament, and ankle reflexes

A 128-Hz tuning fork can be used forthe assessment of vibration perception.Assessment of light-touch perceptionusing a 10-g monofilament should includeevaluation on the dorsal aspect of thegreat toe bilaterally as previously validatedby Perkins et al. (71). The 10-g monofila-ment is a useful clinical tool mainly fordetecting more advanced neuropathyand identifying patients at increased riskof ulceration and amputation (72).

Assessments should follow the typicalDSPN pattern, starting distally (the dor-sal aspect of the hallux) on both sidesand move proximally until a sensorythreshold is identified (72). Combiningat least two examinations will increasethe sensitivity and specificity of detect-ing DSPN, as demonstrated in severalcohorts of patients with type 1 andtype 2 diabetes including children andadolescents (26,46,73–79).

The diagnosis of DSPN is principally aclinical one (Table 2). A combination of

typical symptomatology and symmetrical

distal sensory loss or typical signs in the

absence of symptoms in a patient with

diabetes is highly suggestive of DSPNandmay not require additional evaluationor referral. As up to half of the patientsmay be asymptomatic, a diagnosis mayonly be made on examination or, insome cases, when the patient presentswith a painless foot ulcer.

Clinicians should note that the 10-gmonofilament test included for theannual DSPN screening and diagnosisis different than the diagnosis of the“high-risk foot” for ulceration, a lateDSPN complication that requires thatfour sites (first, third, and fifth metatarsalheads and plantar surface of distal hallux)be tested on each foot (80).

Consider excluding neuropathy withcauses other than diabetes (Table 3) byundertaking a family andmedication historyand performing relevant investigations (e.g.,serum B12, folic acid, thyroid function, com-plete blood count, metabolic panel, and aserumprotein immunoelectrophoresis) (81).

Electrophysiological testing or referralto a neurologist is rarely needed for di-agnosis, except in situations where theclinical features are atypical, the diagnosisis unclear, or a different etiology is sus-pected (2,38,40,80). Atypical features thatwarrant referral includemotor greater thansensory neuropathy, asymmetry of symp-toms and signs, and rapid progression.

Foot ComplicationsThe simple yet comprehensive clinicalexam is principally designed to identifythose at risk for the late complicationswho need education on preventativefoot self-care and regular podiatricfoot care. Recently an even simpler

Table 2—Symptoms and signs of DSPN

Large myelinated nerve fibers Small myelinated nerve fibers

Function Pressure, balance Nociception, protective sensation

Symptoms§ Numbness, tingling, poor balance Pain: burning, electric shocks, stabbing

Examination(clinically diagnostic)**

Ankle reflexes: reduced/absentVibration perception: reduced/absent10-g monofilament: reduced/absentProprioception: reduced/absent

Thermal (cold/hot) discrimination: reduced/absent**Pinprick sensation: reduced/absent**

§To document the presence of symptoms for diagnosis; **Documented in symmetrical, distal to proximal pattern.

Table 3—Differential diagnosis ofdiabetic neuropathiesMetabolic diseaseThyroid disease (common)Renal disease

Systemic diseaseSystemic vasculitisNonsystemic vasculitisParaproteinemia (common)Amyloidosis

InfectiousHIVHepatitis BLyme

InflammatoryChronic inflammatory demyelinating

polyradiculoneuropathy

NutritionalB12*PostgastroplastyPyridoxineThiamineTocopherol

Industrial agents, drugs, and metalsIndustrial agents

AcrylamideOrganophosphorous agents

DrugsAlcoholAmiodaroneColchicineDapsoneVinka alkaloidsPlatinumTaxol

MetalsArsenicMercury

HereditaryHereditary motor, sensory, and

autonomic neuropathies

*B12 deficiency is more commonlyassociated with malabsorption rather thannutritional deficiency.

care.diabetesjournals.org Pop-Busui and Associates 139

foot exam, the “3-minute diabetic footexam,” has been proposed (82). This isintended not only for physicians but alsofor other health care professionals whomay only have 15 min for the entire dia-betes annual review; it requires no equip-ment and provides simple advice oneducation on preventative foot self-care.

Management

Recommendations

c Tight glucose control targetingnear-normal glycemia in patientswith type 1 diabetes dramaticallyreduces the incidence of distalsymmetric polyneuropathy and isrecommended for distal symmet-ric polyneuropathy prevention intype 1 diabetes. A

c In patients with type 2 diabeteswith more advanced disease andmultiple risk factors and comorbid-ities, intensive glucose controlalone is modestly effective in pre-venting distal symmetric polyneur-opathy and patient-centered goalsshould be targeted. B

c Lifestyle interventions are recom-mended for distal symmetric poly-neuropathy prevention in patientswith prediabetes/metabolic syn-drome and type 2 diabetes. B

Prevention

Please refer to PREVENTION on page 136.

Pathogenetic TherapiesDespite the recent major advances inelucidating the pathogenesis of diabeticneuropathy, there remains a lack oftreatment options that effectively tar-get the natural history of DSPN (83) orreverse DSPN once established. Severalpathogenetic pharmacotherapies havebeen investigated (36), but evidencefrom randomized clinical trials is verylimited (81,83,84). Advances in DSPNdisease modification need to be con-firmed with further robust evidencefrom clinical trials, together with a bet-ter understanding of the mechanisms ofaction of promising treatments (83).

Pain Management

Recommendations

c Consider either pregabalin orduloxetine as the initial approachin the symptomatic treatment forneuropathic pain in diabetes. A

c Gabapentin may also be used asan effective initial approach, takinginto account patients’ socioeco-nomic status, comorbidities, andpotential drug interactions. B

c Although not approved by the U.S.Food and Drug Administration, tri-cyclic antidepressants are also ef-fective for neuropathic pain indiabetes but should be used withcaution given the higher risk of se-rious side effects. B

c Given the high risks of addictionand other complications, the useof opioids, including tapentadolor tramadol, is not recommendedas first- or second-line agents fortreating the pain associated withDSPN. E

No compelling evidence exists in supportof glycemic control or lifestyle manage-ment as therapies for neuropathic pain indiabetes or prediabetes (33,85), whichleaves only pharmaceutical interventions.

At present, pregabalin and duloxetinehave received regulatory approval for thetreatment of neuropathic pain in diabetesby the U.S. Food and Drug Administration(FDA), Health Canada, and the EuropeanMedicines Agency. The opioid, tapentadol,has regulatory approval in the U.S. andCanada, but the evidence of its use isweaker (15).

A large evidence base supports phar-macological treatment of neuropathicpain in diabetic neuropathy using otheragents of different classes, as docu-mented by several recent guidelinesand systematic reviews (15,16,20,86,87).It is important to mention that only afew trials that targeted pain in peripheralneuropathic painwere carried out in DSPNalone. However, the results of studies per-formed on peripheral nondiabetic neuro-pathic pain ormixed neuropathic painmaybe applicable to patients with neuropathicpain due to DSPN.

Although there are broad generalagreements among the recommenda-tions, there are some inconsistencies thatare, in part, a consequence of whether theguidelines are specific for painful DSPN orwhether they address neuropathic paindue to all causes (15,16,20,86,87).

Below we summarize the available ev-idence on the most effective agents forDSPN pain starting with the currently ap-proved drugs and continuing with the

other agents based on mechanism of ac-tion and strength of evidence. Evidencelevels are assigned based on the strengthof the published clinical evidence for theefficacy and safety of the agents for thetreatment of DSPN pain, which should beconsidered in clinical decision making.However, a certain degree of publicationbias should be considered, given thatmany negative trials may not have beenpublished (15).

Additional information on dose titra-tion, adverse effects, number needed totreat, and safety is presented in Table 4.

Approved Medications

Pregabalin and duloxetine have re-ceived regulatory approval for the treat-ment of neuropathic pain in diabetes inthe U.S., Europe, and Canada.

Pregabalin, a calcium channel a2-dsubunit ligand, is an effective treatmentfor neuropathic pain associated withDSPN. It is the most extensively studieddrug by far in DSPN, with the majorityof studies being positive regardingthe proportion of responders with atleast 30%–50% improvement in pain(15,86,88–94). There is also some evi-dence suggesting a dose response, with aweaker effect with 300 vs. 600 mg/day(88). However, not all trials with pregaba-lin have been positive (15,86,95,96), espe-cially when treating advanced refractorypatients (93). Pregabalin, in contrast togabapentin (see below), has a linear,dose-proportional absorption in the thera-peutic dose range (150–600 mg/day)(88). In addition, pregabalin has a morerapid onset of action and more limiteddosage range that requiresminimal titra-tion. Adverse effects may be more se-vere in older patients (97) and may beattenuated by lower starting doses andmore gradual titration.

Duloxetine is a selective norepineph-rine and serotonin reuptake inhibitor.Doses of 60 and 120 mg/day showed ef-ficacy in the treatment of pain associatedwith DSPN in multicenter randomized tri-als, although some of these had a ratherhigh drop-out rate (15,86,94,96,98–101).Duloxetine was also suggested to in-duce improvement in neuropathy-relatedquality of life (100). In longer-term stud-ies, a small increase in A1C was reportedin people with diabetes treated with du-loxetine compared with placebo (102).Adverse eventsmay again bemore severein older people but may be attenuated

140 Position Statement Diabetes Care Volume 40, January 2017

Table

4—Treatm

entforpain

associatedwithDSP

N(15,16,20,86,87)

Drugclass

Agent

Dose

NNTrange

30–50

%im

provemen

t**

Commonadverse

even

tsMajoradverse

even

tsInitial

Effective

Anticonvulsan

ts

Pregabalin*(15,86

,88–

94)

25–75

mg,1–

33/day

300–60

0mg/day

3.3–

8.3

cSomnolence

cAngioed

ema

cDizziness

cHep

atotoxicity

cPeripheraled

ema

cRhab

domyolysis

cHeadache

cSuicidalthoughtsandbeh

avior

cAtaxia

cSeizuresafterrapid

discontinuation

cFatigue

cThrombocytopen

ia

cXerostomia

cWeigh

tgain

Gabap

entin(15,86

,96,10

5–11

1)100–300mg,1–33

/day

900–3,60

0mg/day

3.3–

7.2

cSomnolence

cSteven

s-Johnsonsyndrome

cDizziness

cSuicidalthoughtsandbeh

avior

cAtaxia

cSeizuresafterrapid

discontinuation

cFatigue

Antidep

ressants

Serotonin-norepinephrine

reuptake

inhibitors

Duloxetine*

(15,86

,94,96

,98–10

1)20

–30

mg/day

60–12

0mg/day

3.8–

11cNausea

cSteven

s-Johnsonsyndrome

cSomnolence

cHep

atotoxicity

cDizziness

cHypertensive

crisis

cConstipation

cGastrointestinalhem

orrhage

cDyspep

sia

cDelirium

cDiarrhea

cMyocardialinfarction

cXerostomia

cCardiacarrhythmias

cAnorexia

cGlaucoma

cHeadache

cSuicidalthoughtsandbeh

avior

cDiaphoresis

cShiftto

maniain

patients

with

bipolardisorder

cInsomnia

cSeizures

cFatigue

cSevere

hyponatremia

cDecreased

libido

cFragility

bonefractures

cSerotonin

syndrome

cNeurolepticmalignant

syndrome

Ven

lafaxine(15,16

,20,86

,87,126

,127

)37

.5mg/day

75–22

5mg/day

5.2–

8.4

cNausea

cSameas

duloxetine

cSomnolence

cDizziness

cConstipation

cDyspep

sia

cDiarrhea

cXerostomia

cAnorexia

Con

tinuedon

p.14

2

care.diabetesjournals.org Pop-Busui and Associates 141

Table

4—Continued

Drugclass

Agent

Dose

NNTrange

30–50

%im

provemen

t**

Commonadverse

even

tsMajoradverse

even

tsInitial

Effective

cHeadache

cDiaphoresis

cInsomnia

cFatigue

cDecreased

libido

Tricyclic

antidep

ressants

Amitriptyline(16,11

0,11

2–11

6)10

–25

mg/day

25–10

0mg/day

2.1–

4.2

cXerostomia

cDelirium

cSomnolence

cCardiacarrhythmias

cFatigue

cConductionabnorm

alities

cHeadache

cMyocardialinfarction

cDizziness

cHeartfailure

exacerbation

cInsomnia

cStroke

cOrthostatichypotension

cSeizures

cAnorexia

cHep

atotoxicity

cNausea

cBonemarrowsuppression

cUrinaryretention

cSuicidalthoughtsandbeh

avior

cConstipation

cShiftto

maniain

bipolardisorder

cBlurred

vision

cNeu

rolepticmalignan

tsyndrome

cAccommodation

cSerotonin

syndrome

cDisturbance

cSevere

hyponatremia

cMydriasis

cFragility

bonefractures

cWeigh

tgain

Desipramine(113

,118

–12

1,12

2)cSameas

above

cSameas

above

Nortriptyline

(15,16

,86,87

,113

,114

,120

,121

,123

)cSameas

above

cSameas

above

Opioids

Tram

adol(15

,16,86

,87,10

9,13

0)50

mg,1–

23/day

210mg/day

3.1–

6.4

cSomnolence

cConfusion

cNausea

cSeizures

cVomiting

cCardiacarrhythmias

cConstipation

cHypertension

cLigh

t-headed

ness

cHypersensitivity

reactions

cDizziness

cSteven

s-Johnsonsyndrome

cHeadache

Tapen

tadol*(103

,104

,135

)Im

med

iate

release:

50–10

0mg,

4–63

/day

Immediate-release:d

ay1:

700mg;afterday1,

60mg/day

N/A

cSomnolence

cRespiratory

dep

ression

cNausea

cSerotonin

syndrome

Extended

release:

50mg,23

/day

Extended

release:

50mg,23

/day

cVomiting

cSeizures

cConstipation

cHypertension

cDizziness

cNeo

natalopioid

withdrawal

syndrome

NNT,number

needed

totreat.*FDAapproved.**FD

Aconsiders30

–50

%im

provemen

tto

besign

ificant.

142 Position Statement Diabetes Care Volume 40, January 2017

with lower doses and progressive titra-tions of duloxetine.Tapentadol extended release is a

novel centrally acting opioid analgesicthat exerts its analgesic effects throughboth m-opioid receptor agonism andnoradrenaline reuptake inhibition.Extended-release tapentadol was ap-proved by the FDA for the treatmentof neuropathic pain associated withdiabetes based on data from two multi-center randomized withdrawal, placebo-controlledphase3 trials (103,104).However,both used an enriched design and there-fore are not generalizable, and a recentsystematic review and meta-analysis bythe International Association for theStudy of Pain Special Interest Group onNeuropathic Pain (NeuPSIG) found theevidence of the effectiveness of tapenta-dol in reducing neuropathic pain incon-clusive (15). Therefore, given the highrisk for addiction and safety concernscompared with the relatively modestpain reduction, the use of tapentadolextended release is not recommendedas first- or second-line treatment.

Anticonvulsants

Gabapentin, like pregabalin, also bindsthe calcium channel a2-d subunit andhas shown efficacy in a number of clin-ical trials for treating the pain associatedwith DSPN (15,86,96,105–111). How-ever, not all painful DSPN studies,some of which are unpublished, havebeen positive (15,107).Given its pharmacokinetic profile,

gabapentin requires gradual titrationand doses up to 1,800–3,600 mg are gen-erally needed to be clinically effective(96,105–107). Adverse effects may bemore severe in older patients (97).

Monoamine Reuptake Inhibitors

The monoamine reuptake inhibitorsdtricyclic antidepressants, selectiveserotoninreuptake inhibitors, and norepinephrineand serotonin reuptake inhibitorsdincrease synaptic monoamine levels anddirectly influence the activity of the de-scending neurons.Amitriptyline, although not FDA ap-

proved, is the most used of the tricyclicagents. Many previous guidelines rec-ommend the medication as a first-linetreatment based on few randomized,blinded, placebo-controlled clinical tri-als that reported significant improvementin neuropathic pain (110,112–116). Theeffectiveness appeared unrelated to the

antidepressant effect (112). A recent Co-chrane Review questioned the quality ofevidence on amitriptyline by raising con-cerns for bias given the small sample sizein most and concluded that in fact thereis no clear evidence for a beneficial effectfor amitriptyline on DSPN pain, especiallywhen balanced against spectrum of sideeffects (117). However, there was nogood evidence of a lack of effect either(117).

The secondary amines, nortriptylineand desipramine, have a less trouble-some side effect profile than the tertiaryamines, amitriptyline and imipramine,although fewer randomized controlledtrials were performed with these agents,and the potential for bias was high giventhe small size (113,118–123). The use ofthese agents is preferable, particularly inolder and side effect–prone patients(113,118–121).

Several studies have suggested thatthere is an increased risk of myocardialischemia and arrhythmogenesis associ-atedwith tricyclic agents (124,125).Becauseof concerns of possible cardiotoxicity, tricy-clic antidepressants should be used withcaution inpatientswithknownor suspectedcardiac disease.

Venlafaxine, a selective norepineph-rine and serotonin reuptake inhibitor,in doses between 150 and 225 mg/dayhas shown some effectiveness in thetreatment of painful DSPN (126,127).Both venlafaxine and duloxetine (seeabove) inhibit the reuptake of serotoninand norepinephrine without the musca-rinic, histaminic, and adrenergic side ef-fects that accompany the use of thetricyclic agents (98–100,102). However,the level of evidence for pain reductionassociated with DSPN is higher with du-loxetine (see above). Venlafaxine maylower the seizure threshold, and gradualtapering is recommended to avoid theemergence of adverse events upon dis-continuation (126,127).

Opioid and Atypical Opioid Analgesics

Tramadol is a centrally acting analgesicwith pain relief mediated by a weakm-opioid receptor agonist activity andinhibition of norepinephrine and seroto-nin reuptake (128,129). It is an effectiveagent in the treatment of painful dia-betic peripheral neuropathy comparedwith placebo as demonstrated by twolarge multicenter trials (129,130), andit appears to have long-term effects

(131). Although tramadol has a lowerpotential for abuse compared with otheropioids, given these safety concerns, itis not recommended for use as first- orsecond-line agent.

Controlled-release oxycodone im-proved pain scores in two single-centertrials in patients with painful diabeticneuropathy, one of which had a smallsample size (132,133). It may provideadditional analgesia for patients on a2-dligand treatment (134). As with all opioids,it is not recommended for use as first-,second-, or third-line agent.

Warnings on All Opioids

Despite the demonstrated effectivenessof opioids in the treatment of neuro-pathic pain (15,132,134,135), there is ahigh risk of addiction, abuse, sedation,and other complications and psychoso-cial issues even with short-term opioiduse. For these reasons, opioids are notrecommended in the treatment of pain-ful DSPN before failure of other agentsthat do not have these associated con-cerns (136–138).

Although add-on therapy with strongopioids may be required in some pa-tients who do not respond to all othercombinations, referral to specialized painclinics is recommended in these cases toavoid risks.

Additional Considerations for Pain

Management

Combination therapy, including combi-nations with opioids, may provide effec-tive treatment for diabetic neuropathicpain at lower doses (94,139). A detailedapproach for pain management is amplycovered in other literature (15,109),and a simple algorithm for clinical prac-tice use is shown in Fig. 2.

Treatment of Foot ComplicationsDetailed treatment of foot ulcerationand CN is beyond the scope of this state-ment, and the reader is referred to arelevant review (54). Effective off-loadingthat prevents patients with plantar neu-ropathic ulcers to walk on the lesions isthe key to successful management(52,54). Off-loading, usually with casting,and careful follow-up and repeated in-vestigations are also key componentsfor the management of CN (52,54). On-going education and regular podiatry fol-low-up can reduce the incidence of footcomplications in those found to be at“high risk.” Early intervention for foot

care.diabetesjournals.org Pop-Busui and Associates 143

lesions and CN or suspected CN can slowor reverse progression.

Fall Prevention

Recommendation

c Tests assessing gait and balancemay be considered in people withdistal symmetric polyneuropathyto evaluate the risk of falls. E

DSPN may also compromise balance indaily activities (58). For instance, pro-gressive loss of proprioception (dimin-ished sensation) and later weakness,superimposed on age-related functionalimpairments, lead to imbalance and un-steadiness in gait, with increased like-lihood of a fall (55,58). A decline incognitive function, polypharmacy, andneuropathic pain may further contribute.In addition, treatment of neuropathicpain often requires dosages and drugcombinations that may further increasethe fall risk due to cognitive impair-ment, drowsiness, dizziness, blurred vi-sion, and gait disturbances (97,109).Older patients are the most susceptible(97,109). Therefore, tests assessing gaitand balance may be considered in

clinical practice to evaluate risk of fallsin patients at risk (55,58).

Psychosocial Factors

Recommendations

c Consider treatment with duloxe-tine, pregabalin, and gabapentin toimprove quality of life in patientswith neuropathic pain. C

c Assess the effects of distal symmet-ric polyneuropathy on quality of lifeto improve adherence and responseto neuropathic pain treatment. E

Assessing the effects of DSPN on a pa-tient’s quality of life is emerging as acomponent of patient care and mayplay an important part in the adher-ence and the response to therapiesin patients with neuropathic pain(140). Some studies report an improve-ment in quality of life in people withpainful DSPN treated with duloxetine(100), pregabalin (141), and gabapentin(106,142). A longitudinal study hasshown that DSPN is a risk factor for de-pression and the strongest symptomassociated with depression was un-steadiness. Pain with DSPN may also

give rise to symptoms of anxiety(143). Two research tools that can beused to assess quality of life that areneuropathy specific are the Neuro-QoL (Quality of Life in Neurological Dis-orders) (144) and QOL-DN (NorfolkQuality of Life-Diabetic Neuropathy)instruments (145).

DIABETIC AUTONOMICNEUROPATHIES

Autonomic neuropathies affect the auto-nomic neurons (parasympathetic, sympa-thetic, or both) and are associated with avariety of site-specific symptoms. Thesymptoms and signs of autonomic dys-function should be elicited carefully dur-ing the medical history and physicalexamination. Major clinical manifesta-tions of diabetic autonomic neuropathyinclude hypoglycemia unawareness, rest-ing tachycardia, orthostatic hypotension,gastroparesis, constipation, diarrhea, fe-cal incontinence, erectile dysfunction,neurogenic bladder, and sudomotor dys-function with either increased or de-creased sweating.

Although CAN is themost studied andclinically relevant of the diabetic auto-nomic neuropathies, gastrointestinal,genitourinary, and sudomotor dysfunc-tion should be considered in the optimalcare of patients with diabetes.

CANAlthough CAN prevalence is very low innewly diagnosed patients with type 1diabetes (146), CAN prevalence in-creases substantially with diabetes du-ration (13,25), and prevalence rates ofat least 30% were observed in theDCCT/EDIC cohort after 20 years of di-abetes duration (27,147). In type 2 di-abetes, the prevalence of CAN alsoincreases with diabetes duration andmay be present in up to 60% of patientswith type 2 diabetes after 15 years(13,148,149). CAN may affect youth, es-pecially young women and those withelevated A1C levels, with prevalencerates of at least 20% reported in youthwith type 1 or type 2 diabetes (150). Inaddition, CAN is present in patients withimpaired glucose tolerance, insulinresistance, or metabolic syndrome(10,32,151).

A timely diagnosis of CAN may haveimportant clinical implications, as CAN isan independent risk factor for cardio-vascular mortality, arrhythmia, silent

Figure 2—Algorithm for management of the patient with pain because of DSPN. AE, adverseevents.*Pregabalin is FDA approved for painful DSPN, whereas gabapentin is not. Pharmaco-kinetic profile, spectrum of AEs, drug interactions, comorbidities, and costs to be consideredin selecting the agent of choice. **Duloxetine is FDA approved for painful DSPN, whereasvenlafaxine is not. Pharmacokinetic profile, spectrum of AEs, drug interactions, comorbidities,and costs to be considered in selecting the agent of choice. #None is FDA approved for painfulDSPN. Spectrum of AEs, drug interactions, and comorbidities need be considered if selectingthese agents.

144 Position Statement Diabetes Care Volume 40, January 2017

ischemia, any major cardiovascularevent, and myocardial dysfunction(152–157). Data from two large cardio-vascular outcomes trials that included31,531 patients with stable heart dis-ease and/or diabetes followed for a me-dian of 5 years reported that heart rate,an indirect measure of CAN, analyzed aseither categorical (baseline heart rate.70 vs. #70 bpm) or across heart ratequintile, was independently associatedwith significant increases in cardiovas-cular disease (CVD) events and all-causedeath (158). CANmay also be associatedwith hemodynamic instability or cardio-respiratory arrest (159). CAN was thestrongest risk factor for mortality in alarge cohort of patients with type 1 di-abetes participating in the EURODIABProspective Cohort Study (160), and ameta-analysis of several trials reportedhigher mortality risk with worse mea-sures of CAN (152).Conclusive evidence that supports

CAN as an independent predictor ofmortality was confirmed in more than8,000 participants with type 2 diabetesin the ACCORD trial (154). Hazard ratiosfor all-cause and CVD mortality in thosewith CAN were as high as 2.14 after ad-justing for all traditional CVD risk factors

and many other risk factors, includinguse of various classes of medicationuse (154).

It was also suggested that intensifi-cation of glucose and blood pressuremanagement may increase the risk ofa cardiovascular event in people withsigns of CAN (161–165). Similarly, emerg-ing evidence demonstrates an associa-tion between CAN and glucose variability,especially in the hypoglycemic range(150,164).

In addition, CAN independently predictsthe progression of diabetic nephropathyand chronic kidney disease in diabetes(13,166–168).

Screening and Diagnosis

Recommendations

c Symptoms and signs of autonomicneuropathy should be assessed inpatients with microvascular andneuropathic complications. E

c In the presence of symptoms orsigns of cardiovascular autonomicneuropathy, tests excluding othercomorbidities or drug effects/interactions that could mimic car-diovascular autonomic neuropa-thy should be performed. E

c Consider assessing symptoms andsigns of cardiovascular autonomicneuropathy in patients with hypo-glycemia unawareness. C

The most common symptoms of CANoccur upon standing and include light-headedness, weakness, palpitations, faint-ness, and syncope (13,169,170) (Table 5).The patient should be asked about thesesymptoms when a medical history is takenin the office, although the correlation ofsymptoms with overall autonomic deficitsis weak (149,171). However, these symp-toms may occur quite late in the diseasecourse (25,27,147,149). Itmaybe appropri-ate to screen patients with hypoglycemiaunawareness, as this may be associatedwith CAN (81).

In its early stages, CAN may be com-pletely asymptomatic and detected onlyby decreased heart rate variability (HRV)with deep breathing (13,169,170). Test-ing HRV may be done in the office byeither 1) taking an electrocardiogram re-cording as a patient begins to rise from aseated position or 2) taking an electro-cardiogram recording during 1–2 min ofdeep breathing with calculation of HRV(11,81,170).

Table 5—Symptoms and signs associated with diabetic autonomic neuropathy

CAN Gastrointestinal Urogenital Sudomotor

Resting tachycardia Gastroparesis (Gastropathy) Bladder dysfunction Dry skinAbnormal blood pressure regulation

c Nondippingc Reverse dipping

c Nauseac Bloatingc Loss of appetitec Early satietyc Postprandial vomitingc Brittle diabetes

c Frequencyc Urgencyc Nocturiac Hesitancyc Weak streamc Dribblingc Urinary incontinencec Urinary retention

c Anhidrosisc Gustatorysweating

Orthostatic hypotension (all with standing) Esophageal dysfunction Male sexual dysfunctionc Light-headednesscWeaknessc Faintnessc Visual impairmentc Syncope

c Heartburnc Dysphagia for solids

c Erectile dysfunctionc Decreased libidoc Abnormal ejaculation

Orthostatic tachycardia or bradycardiaand chronotropic incompetence(all with standing)

Diabetic diarrhea Female sexual dysfunction

c Light-headednesscWeaknessc Faintnessc Dizzinessc Visual impairmentc Syncope

c Profuse and watery diarrheac Fecal incontinencec May alternate with constipation

c Decreased sexual desirec Increased pain during intercoursec Decreased sexual arousalc Inadequate lubrication

Exercise intolerance Constipationc May alternate with explosive diarrhea

care.diabetesjournals.org Pop-Busui and Associates 145

In more advanced cases, patients maypresent with resting tachycardia (.100bpm) and exercise intolerance (13,170).Advanced disease may also be associatedwith orthostatic hypotension (a fall in sys-tolic or diastolic blood pressure by.20 mmHg or .10 mmHg, respectively,upon standing without an appropriate in-crease in heart rate) (172). Orthostatichypotension is usually easy to documentin the office. In most cases of CAN, thereis no compensatory increase in the heartrate, despite hypotension (173).The diagnosis includes documentation

of symptoms (Table 5) and signs of CAN,which include impaired HRV, higher rest-ing heart rate, and presence of ortho-static hypotension. In a symptomaticpatient presenting with resting tachycar-dia, with a history of poor glucose control,

or when the diagnosis of CAN is likely,clinicians may not need to perform addi-tional tests given costs and burden.

Exclusion of other comorbidities ordrug effects/interactions thatmaypresentwith the symptoms or signs of CAN andthat mimic CAN may be needed (81,174)(Table 6). In addition, polypharmacy mayalso directly or indirectly impact CAN.

Treatment

Prevention. Please refer to PREVENTION onpage 136.

Recommendations

c Optimize glucose control as earlyas possible to prevent or delay thedevelopment of cardiovascularautonomic neuropathy in peoplewith type 1 diabetes. A

c Consider a multifactorial approachtargeting glycemia among otherrisk factors to prevent cardiovas-cular autonomic neuropathy inpeople with type 2 diabetes. C

c Consider lifestyle modifications toimprove cardiovascular autonomicneuropathy in patients with predia-betes. C

Aswith DSPN,multiple other therapies tar-geting various pathogenetic mechanismshave failed to reverse established CAN.CAN treatment is generally focusedonalle-viating symptoms and should be targetedto the specific clinical manifestation.Symptomatic Treatment of Orthostatic

Hypotension. Treatment for orthostatichypotension is challenging and usually

Table 6—Diagnostic algorithm for CAN

Symptoms Signs/diagnostic tests Differential workup

Resting tachycardia Palpitations Clinical exam: resting heartrate .100 bpm

c AnemiaCould be asymptomatic c Hypothyroidism

c Fever

c CVD (atrial fibrillation, flutter, other)

c Dehydration

c Adrenal insufficiency

c Medications

c Sympathomimetic agents (asthma)

c Over-the-counter cold agents containingephedrine or pseudoephedrine

c Dietary supplements (e.g., ephedra alkaloids)

c Smoking, alcohol, caffeine

c Recreational drugs (cocaine, amphetamines,methamphetamine, mephedrone)

Orthostatic hypotension Light-headedness Clinical exam: a reduction of.20 mmHg inthe systolic blood pressure or.10mmHgin diastolic blood pressure

c Adrenal insufficiencyWeakness c Intravascular volume depletionFaintness c Blood loss/acute anemiaVisual impairment c DehydrationSyncope c Pregnancy/postpartum

c CVDc Arrhythmiasc Heart failurec Myocarditisc Pericarditisc Valvular heart disease

c Alcoholc Medicationc Antiadrenergicsc Antianginalsc Antiarrhythmicsc Anticholinergicsc Diureticsc ACE inhibitors/angiotensin receptor blockerc Narcoticsc Neurolepticsc Sedatives

146 Position Statement Diabetes Care Volume 40, January 2017

involves both pharmacological and non-pharmacological interventions. Physicalactivity and exercise should be encour-aged to avoid deconditioning, which isknown to exacerbate orthostatic into-lerance. Volume repletion with fluidsand salt is central to the management oforthostatic hypotension. Low-dose flu-drocortisone may be beneficial in sup-plementing volume repletion in somepatients, although there are growing con-cerns on risk of supine hypertension.As neurogenic orthostatic hypoten-

sion is in large part a consequence ofthe failure of norepinephrine releasefrom sympathetic neurons, the adminis-tration of sympathomimetic medicationsis central to the care of patients whosesymptoms are not controlled with othermeasures (173). Midodrine, a peripheral,selective, direct a1-adrenoreceptor ago-nist, is an FDA-approved drug for the treat-ment of orthostatic hypotension (175).Midodrine should be titrated gradually toefficacy. It should be used only when pa-tients intend to be upright or seated tominimize supine hypertension (173). Re-cently, droxidopa was approved by theFDA for the treatment of neurogenic or-thostatic hypotension but not specificallyfor patients with orthostatic hypotensiondue to diabetes (176).

Gastrointestinal NeuropathiesGastrointestinal neuropathies may involveany portion of the gastrointestinal tractwith manifestations including esophagealdysmotility, gastroparesis (delayed gastricemptying), constipation, diarrhea, and fe-cal incontinence. The prevalence data ongastroparesis are limited, as most reportswere from selected case series rather thanlarger populations, and therewas inconsis-tency in the outcome measures used(177). In the only community-based study,the cumulative incidence of gastroparesisover 10 yearswas higher in type 1 diabetes(5%) than in type 2 diabetes (1%) and incontrol subjects (1%) (178).Gastroparesis may directly affect gly-

cemic management (e.g., insulin dose orother antidiabetes agents) and may be acause of glucose variability and unex-plained hypoglycemia due to the disso-ciation between food absorption andthe pharmacokinetic profiles of insulinand other agents (12,179–182). Gastro-paresis is mainly found in patients withlong-standing diabetes (183).

Screening and Diagnosis

Recommendations

c Evaluate for gastroparesis in peo-ple with diabetic neuropathy, ret-inopathy, and/or nephropathy byassessing for symptoms of unex-pected glycemic variability, earlysatiety, bloating, nausea, andvomiting. C

c Exclusion of other causes docu-mented to alter gastric emptying,such as use of opioids or glucagon-like peptide 1 receptor agonistsandorganic gastric outlet obstruction,is needed before performing special-ized testing for gastroparesis. C

c To test for gastroparesis, eithermea-sure gastric emptying with scintigra-phy of digestible solids at 15-minintervals for 4 h after food intakeor use a 13C-octanoic acid breathtest. B

Gastroparesis may manifest with abroad spectrum of symptoms and signs(12,177,179,181). As part of a medicalhistory, providers are encouraged todocument symptoms of gastroparesis,such as early satiety, fullness, bloating,nausea, vomiting, dyspepsia, and ab-dominal pain. However, gastroparesismay be clinically silent in the majorityof cases, and symptoms do not neces-sarily correspond with severity of gas-troparesis and are poorly associatedwith abnormal gastric emptying (184,185).Symptoms such as anorexia, nausea,vomiting, and dyspepsia are nonspecificand resemble many other conditions(186) and may just be associated withthe presence of diabetes (181). Impor-tantly, hyperglycemia, hypoglycemia,and acute changes in blood glucose arewell documented to alter gastric emptying(182,187,188), as are some medications,especially opioids, other pain manage-ment agents, and glucagon-like pep-tide 1 receptor agonists (189,190).Therefore, all these factors known toaffect gastric emptying should alwaysbe considered before a firm diagnosis isestablished.

Exclusion of organic causes of gastricoutlet obstruction or peptic ulcer dis-ease (with esophagogastroduodenoscopyor a barium study of the stomach) isneeded before considering specializedtesting for gastroparesis. The diagnostic

gold standard is the measurement ofgastric emptying with scintigraphy of di-gestible solids at 15-min intervals for 4 hafter food intake; the use of 13C-octanoicacid breath test is emerging as a viablealternative (12,179). Optimization ofglucose levels prior to scanning isneeded (182,186–188) to avoid false-positive results.

Treatment

Recommendation

c Consider short-term metoclopra-mide in the treatment of diabeticgastroparesis. E

Treatment for diabetic gastroparesismay be very challenging. Dietary changesmay be useful, such as eating multiplesmall meals and decreasing dietary fatand fiber intake. Withdrawing drugs witheffects on gastrointestinal motility, suchas opioids, anticholinergics, tricyclicantidepressants, glucagon-like peptide1 receptor agonists, pramlintide, andpossibly dipeptidyl peptidase 4 inhibi-tors, may also improve intestinal motility(180,191). In cases of severe gastropare-sis, pharmacological 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 for themanagement of gastroparesis is weak,and given the risk for serious adverseeffects (extrapyramidal symptoms, suchas acute dystonic reactions; drug-induced parkinsonism; akathisia; andtardive dyskinesia), its use in the treat-ment of gastroparesis beyond 5 days isno longer recommended by the FDA andthe European Medicines Agency. Itshould be reserved for severe casesthat are unresponsive to other therapies(191).

Urogenital NeuropathiesDiabetic autonomic neuropathy mayalso cause genitourinary disturbances,including sexual dysfunction and blad-der dysfunction. In men, diabetic auto-nomic neuropathy may cause erectiledysfunction (ED) and/or retrogradeejaculation. ED is three timesmore com-mon in men with diabetes than thosewithout the disease (192–194). Sexualdysfunction is also more common inwomen with diabetes (195–199).

care.diabetesjournals.org Pop-Busui and Associates 147

Recommendations

c Consider screening men with otherforms of diabetic neuropathy annu-ally for erectile dysfunctionwith sim-ple questions about a patient’s libidoand ability to reach and maintain anerection. C

c Consider screening patients withother forms of diabetic neuropathyfor lower urinary tract symptomsand female sexual dysfunction inthe presence of recurrent urinarytract infections using targeted ques-tioning regarding symptoms, suchas nocturia, pain during intercourse,and others. E

ED

ED may be a consequence of autonomicneuropathy, as autonomic neurotrans-mission controls the cavernosal and de-trusor smooth muscle tone and function(200). The etiology, however, is multi-factorial, and clinicians should also eval-uate other vascular risk factors such ashypertension, hyperlipidemia, obesity,endothelial dysfunction, smoking, CVD,concomitant medication, and psycho-genic factors (12). There is evidence ofassociations between ED and other di-abetes complications, including CAN(201–203).A diagnosis should be made after es-

tablishing the signs and symptoms of EDand after excluding alternate causes. Cli-nicians should consider performing hor-monal evaluation (luteinizing hormone,testosterone, free testosterone, pro-lactin) to rule out hypogonadism. Inaddition, a variety of medications andorganic causes should be excluded (12).Glucose control was associated with a

lower incidence of erectile dysfunctionin men with type 1 diabetes (204,205).Evidence is less strong for type 2 diabe-tes. Control of other risk factors such ashypertension and hyperlipidemia mayalso improve the condition (12). Pharma-cological treatment includes phosphodi-esterase type 5 inhibitors as first-linetherapy and transurethral prostaglan-dins, intracavernosal injections, vacuumdevices, and penile prosthesis in moreadvanced cases.

Lower Urinary Tract Symptoms and Female

Sexual Dysfunction

Lower urinary tract symptoms manifestas urinary incontinence and bladder dys-function (nocturia, frequent urination,

urination urgency, weak urinary stream)and is linked to the presence of diabeticneuropathy in both men and women(12,206). Female sexual dysfunction oc-curs more frequently in women with di-abetes than in those without diabetes(196,207) and presents as decreasedsexual desire, increased pain during in-tercourse, decreased sexual arousal,and inadequate lubrication.

Evaluation of bladder function shouldbe performed for individuals with diabe-tes who have recurrent urinary tract in-fections, pyelonephritis, incontinence,or a palpable bladder. The medical his-tory should include simple questions tounveil symptoms of lower urinary tractsymptoms and female sexual dysfunc-tion (196,207,208).

Sudomotor DysfunctionSudomotor dysfunctionmaymanifest asdry skin, anhidrosis, or heat intolerance(209,210). A rare form of sudomotordysfunction is gustatory sweating thatcomprises excessive sweating limitedexclusively to the head and neck regiontriggered by food consumption or, insome cases, the smell of food. Originallydescribed as being solely due to auto-nomic neuropathy, gustatory sweatingis also described in patients with dia-betic nephropathy on dialysis (211).

On the basis of the available evi-dence, the routine screening for sudo-motor dysfunction in clinical practiceis not recommended at this time. Theefficacy of the topical antimuscarinicagent glycopyrrolate in the treatmentof gustatory sweating was confirmedin a randomized controlled trial, anddaily application attenuates this compli-cation in most patients for at least 24 h(212).

ATYPICAL NEUROPATHIES

MononeuropathiesMononeuropathies occur more com-monly in patients with diabetes thanin those without diabetes (1) and canoccur as a result of involvement of themedian, ulnar, radial, and common pe-roneal nerves (213). Cranial neuropa-thies present acutely and are rare;primarily involve cranial nerves III, IV,VI, and VII; and usually resolve sponta-neously over several months (213).Electrophysiological studies are mosthelpful in identifying nerve conductionslowing or conduction block at the site

of nerve entrapment. Nerve entrap-ments may require surgical decompres-sion. The improvement in symptomseverity and functional status score isno different between patients withand without diabetes (213).

Diabetic Radiculoplexus NeuropathyDiabetic radiculoplexus neuropathy,a.k.a. diabetic amyotrophy or diabeticpolyradiculoneuropathy, typically involvesthe lumbosacral plexus (214–216). Thecomplication occurs mostly in men withtype 2 diabetes. People with the condi-tion routinely present with extreme uni-lateral thigh pain and weight loss,followed by motor weakness. Electro-physiological assessment is required todocument the extent of disease andalternative etiologies, including degen-erative disc disease or neoplastic, infec-tious, and inflammatory spinal disease(215,216). The disorder is usually self-limiting, and patients improve overtime with medical management andphysical therapy (214,215). There ispresently no evidence from randomizedtrials to support any recommendationon the use of any immunotherapy treat-ment in this condition (217).

Treatment-Induced NeuropathyTreatment-induced neuropathy in diabe-tes (also referred to as insulin neuritis) isconsidered a rare iatrogenic small-fiberneuropathy caused by an abrupt im-provement in glycemic control in the set-ting of chronic hyperglycemia, especiallyin patientswith very poor glucose control(218). The prevalence and risk factors ofthis disorder are not known but are cur-rently under study.

NEUROPATHY END POINTS FORRESEARCH AND CLINICAL TRIALS

There are currently no approved disease-modifying therapies for DSPN, CAN, orother forms of diabetic neuropathy,and multiple clinical trials for theseconditions have failed. Important con-tributing factors include a lack of agree-ment and uniformity in the use of themost sensitive DSPN measures that cap-ture the natural history of the diseaseand detect repair in the specific nervefiber populations, as well as the inclusionof appropriate patient populations.Thus, a valid and careful diagnosis forDSPN in clinical research is critical forcorrectly identifying the appropriatepatient population targeted for either a

148 Position Statement Diabetes Care Volume 40, January 2017

specific intervention or for prognosticimplications.The use of validated clinical instru-

ments such as the Michigan NeuropathyScreening Instrument (MNSI) (mostwidely used in large cohorts of pa-tients with type 1 and type 2 diabetes)(21,26,27,46,74,75), the modified Tor-onto Clinical Neuropathy Scale (mTCNS)(73), the Utah Early Neuropathy Scale(UENS) (77), or the Neuropathy Disabil-ity Score (NDS) (44) are recommended.These may be combined with electro-physiology; measures of small-fiberdamage and repair, such as intraepider-mal nerve fiber density (219–221) orcorneal confocal microscopy (222); andobjective measures of patient functionin the design of DSPN trials.The recommended CAN measures for

clinical trials targeting either a specificintervention or for prognostic implica-tions include 1) standardized cardiovas-cular autonomic reflex tests that aresimple, sensitive, specific, reproducible,and assess the changes in the R-R inter-val on electrocardiogram recordings inresponse to simple clinical maneuvers(deep breathing, Valsalva, and standing)(13,81,191,223); 2) indices of HRV (seeabove) (11,151,169); and 3) restingheart rate and QTc (154,156,157). Othermethods such as baroreflex sensitivity,cardiac sympathetic imaging, and micro-neurography require sophisticated infra-structure and highly trained personnel andare quite expensive and time-consuming(11,13,224).

Duality of Interest. No potential conflicts ofinterest relevant to this article were reported.

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