diabetes and neuropathy

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Diabetes and Neuropathy Latest in Treatment Options

Andrew Day, MDAssistant Clinical ProfessorDavid Geffen School of Medicine at UCLADepartment of MedicineDivision of Endocrinology, Diabetes, and Metabolism

Disclosures

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• I have no actual or potential conflict of interest in relation to this presentation.

• I will be discussing off-label uses of medication.

Case

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J. S. is a 55-year-old male who presents to discuss foot discomfort. PMH is significant for type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity. He is a NICU nurse who used to smoke. Medications include metformin, empagliflozin, atorvastatin, and losartan. BP 140/90 mmHg. BMI 34.6 kg/m2. HbA1c 7.2%. He describes burning, tingling, and stabbing pain in both feet. Symptoms are worse at night. Symptoms interfere with sleep and with his ability to perform his job. He is concerned that he may not be able to continue his beloved profession.

Agenda

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• The Clinical Problem

• Diagnosis and Evaluation

• Clinical Management

• Pharmacotherapy and Beyond

Nat Rev Dis Primers. 2019 Jun 13;5(1):41

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Patterns of Nerve Injury in Patients with Diabetes

Definitions

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• 2009 Toronto Symposium• “a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvessel alterations as a result of chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates.”

• 2017 ADA• “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes”

Presentation

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• Distal Symmetric Sensorimotor Polyneuropathy• Motor symptoms less common

• Large and small fiber dysfunction

• Nerve-length-dependent symptoms• Positive Symptoms: tingling, burning, stabbing pain, other abnormal sensations

• Negative Symptoms: sensory loss, weakness, numbness

• Symptoms may be worse with rest and at night

Painful Diabetic Neuropathy

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Small-Fiber Dysfunction

Large-Fiber Dysfunction

• Superficial• Burning sensations• Allodynia• Hyperalgesia • Paresthesias• “bees stinging

through the socks”• “standing on hot

coals”

• Deep-seated• “dog knowing at the

bones”• “feet encased in

concrete”

Williams Textbook of Endocrinology, 13th Ed

Pathophysiology

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Pain Perception is Complex

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Current Diabetes Reports (2019) 19: 32

Epidemiology

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• 8% of population may have diabetes mellitus; global prevalence expected to rise

• Peripheral neuropathy may be the most common long-term complication of diabetes mellitus

• Global prevalence of clinically-diagnosed neuropathy in patients with diabetes mellitus is

estimated around 30%

• Lifetime incidence of neuropathy may be over 50%

• 11-13% of patients with prediabetes may have peripheral neuropathy

• Up to 50% of neuropathic patients may be asymptomatic

• Up to 20-30% of patients with diabetes mellitus develop painful neuropathy


Risk Factors

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• Duration of diabetes mellitus

• HbA1c / glycemic control

• Insulin resistance

• Hypertension

• Obesity / Adiposity

• Hypertriglyceridemia

• Low HDL levels

• Tobacco use

• Alcohol abuse

• Increased height

• Older age

• Genetic polymorphisms


Implications

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• Increased lifetime risk of foot ulceration, Charcot arthropathy, and amputation

• Imbalance, unsteadiness of gait, falls, and fractures

• Sleep disruption and decreased quality of life

• Less productivity at work; disability

• Mental health disorders

• Increased risk of hospitalizations

• Annual costs of diabetic neuropathy and its complications are thought to be more

than $10 billion in the United States.

Worse than Cancer?

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Int Wound J. 2007 Dec;4(4):286-7.

Screening and Diagnosis

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Approach

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

• Assess symptoms

• Conduct physical examination

• Consider differential diagnosis

• Conduct diagnostic tests as needed

Standards of Medical Care in Diabetes--2021

Comprehensive Diabetic Foot Examination

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• Dermatologic

• Vascular

• Neurologic

• Musculoskeletal

Diabetes Care. 2008 Aug; 31(8): 1679–1685.1

3 Minute Diabetic Foot Exam

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ASK• HISTORY: ulcers, peripheral vascular disease, smoking• SYMPTOMS: burning/tingling/pain, skin changes or lesions, numbness

LOOK

• SKIN: nails, hypertrophic lesions, calluses, corns, wounds, maceration• NEURO: Ipswich touch test• MSK: range of motion, deformities, midfoot hot/red/inflamed• VASCULAR: hair patterns, pedal pulses, temperature differences

TEACH

• FOOT CARE: look at feet daily, regularly changes socks and shoes• SHOES: no ill-fitting shoes, yearly shoe replacement, no walking barefoot• RISK FACTORS: smoking cessation, glycemic control

Adapted from J Fam Pract. 2014 Nov;63(11):646-56.

Differential Diagnosis of Diabetic Neuropathies

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• Metabolic: thyroid disease, renal disease• Systemic Disease: vasculitis, paraproteinemia, amyloidosis• Infectious: HIV, HBV, Lyme disease• Inflammatory: CIDP• Nutritional: vitamin B12, postgastroplasty, pyridoxine, thiamine, tocopherol• Industrial Agents: acrylamide, organophosphates• Drugs: alcohol, amiodarone, colchicine, dapsone, vinka alkaloids,

platinum, paclitaxel• Metals: arsenic, mercury• Hereditary

Additional Considerations

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• AAN recommends CMP, CBC, Vit B12, SPEP with immunofixation

• Consider referral to Neurology if presentation is atypical• NCS

• Small fiber testing

• Imaging of central nervous system rarely required

Point of Care Testing?

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• DPNCheck: sural nerve conduction velocity

• NeuroQuick: cold thermal perception

• NeuroPad, SUDOSCAN: sweat production

• Biothesiometer: assessment of vibration threshold

• Corneal confocal microscopy: structural parameters of small corneal nerve fibers

Lancet Diabetes Endocrinol. 2019 Dec;7(12):938-948.8.

Clinical Management

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Glucose Control and Risk Factor Modification

DCCT/EDIC

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Outcome Measure Group DCCT Baseline

DCCT Closeout

EDIC Year 13/14

Clinically Evident DPN

INTCON

57 (10%)48 (8%)

88 (15%) *128 (22%)

204 (34%)*240 (41%)

Abnormal Nerve Conduction Studies

INTCON

185 (31%)196 (34%)

164 (28%)*288 (50%)

326 (54%)*401 (69%)

Confirmed DPN INTCON

39 (7%)31 (5%)

52 (9%)*97 (17%)

152 (25%)*204 (35%)

Adapted from Diabetes Care 2014;37:31–38

ACCORD

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Outcome Measure Group Events Hazard Ratio p value NNTMNSI score > 2.0 Intensive

Standard55.6%58.6%

0.92 (0.86-0.99) 0.0268 33

Loss of vibratory sensation IntensiveStandard

23.2%24.9%

0.93 (0.85-1.01) 0.0808

Loss of ankle jerk IntensiveStandard

45.7%49.3%

0.90 (0.84-0.97) 0.0050 28

Loss of sensation to light touch

IntensiveStandard

12.1%14.1%

0.85 (0.76-0.95) 0.0043 49

Adapted from Lancet 2010; 376: 419–30

Glycemic Intervention: Differential Affects T1DM vs T2DM

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Trial Size Length of Study (years) Positive effects of enhanced glycemic control?

T1DM

Holman et al 1983 74 2 yes

Dahl-Jorgensen et al 1986 45 2 yes

DCCT 1993 1,441 5 yes

Reichard et al 1993 102 7.5 yes

Linn et al 1996 49 5 yes

T2DM

UKPDS 1998 3,867 10 mixed

VA CSDM 1999 153 2 no

Steno-2 Study 2003 160 8 no

VADT 2009 1,791 5.6 no

ACCORD 2010 10,251 3.7 Yes, though modest

Adapted from Neuron. 2017 Mar 22;93(6):1296-1313

Cochrane Review

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Cochrane Database Syst Rev. 2012 Jun 13;6(6):CD007543.

Other Considerations

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• Exercise training may modify natural history of diabetic neuropathy

• Look AHEAD suggests that lifestyle intervention may be beneficial

• Observational studies have shown statin use is associated with reduced incidence of diabetic neuropathy

• BARI 2D trial suggests that insulin-sensitizing medication may be more helpful than insulin-providing medications

Recommendations

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• Tight glucose control targeting near-normal glycemia in patients with type 1 diabetes

dramatically reduces the incidence of distal symmetric polyneuropathy and is

recommended for distal symmetric polyneuropathy prevention in type 1 diabetes. A

• In patients with type 2 diabetes with more advanced disease and multiple risk

factors and comorbidities, intensive glucose control alone is modestly effective in

preventing distal symmetric polyneuropathy and patient-centered goals should be

targeted. B

• Lifestyle interventions are recommended for distal symmetric polyneuropathy

prevention in patients with prediabetes/metabolic syndrome and type 2 diabetes. B

Diabetes Care 2017;40:136–1541

Disease-Modifying Therapies?

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α-Lipoic Acid

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• Antioxidant

• Not FDA approved

• Included in German and IDF guidelines

• RTC’s and meta-analyses have shown some improvements in symptom scores and deficits

• NATHAN 1 trail failed to show significant difference in composite primary end point

Diabetes Care. 2011 Sep;34(9):2054-60.

Benfotiamine

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• Synthetic derivative of thiamine (vitamin B1) with better bioavailability

• Inhibits advanced glycation end products (AGEs)

• Not FDA approved

• Not included in treatment guidelines

• Small, short-duration, RTC’s have shown some improvements in symptom scores though longer studies have shown no benefit

Exp Clin Endocrinol Diabetes. 2008 Nov;116(10):600-5.

Pain Management

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Pharmacologic Options

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Anticonvulsants SNRIs TCAs Opioid Agonists TopicalsPregabalinGabapentin

DuloxetineVenlafaxine

Amitriptyline Tapentadol*Tramadol*Oxycodone*

OxcarbazepineLamotrigineLacosamideCarbamazepine TopiramateSodium valproate

Desvenlafaxine NortriptylineDesipramineImipramine

CapsaicinLidocaineIsosorbide dinitrate

Adapted from Diabetes Res Clin Pract. 2021 Sep 18;109063.

Clinical Guidelines

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• 2011: AAN

• 2011: Toronto Consensus

• 2017: ADA

• 2017: IDF

• 2018: Diabetes Canada

• 2021: DDG

• 2021: International Consensus Conference

ADA 2017 Guidelines

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Diabetes Care 2017;40:136–1541

An Updated Algorithm

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Nat Rev Dis Primers. 2019 Jun 13;5(1):41.

Pregabalin

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• FDA approved for diabetic peripheral neuropathic pain

• Initial dose: 150 mg per day in divided doses

• Effective dose: 300-600 mg per day in divided doses

• NNT: 3.3-8.3

• Cost: $10.30 per name-brand tablet, less for generic

• Adverse Events: somnolence, dizziness, peripheral edema, headache, ataxia, fatigue, xerostomia, weight gain

Pregabalin

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Lancet Neurol 2015; 162–73

Gabapentin

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• Not FDA approved for diabetic peripheral neuropathic pain

• Initial dose: 100-300 mg per day

• Effective dose: 900-3600 mg per day in divided doses

• NNT: 3.3-7.2

• Cost: <$3 per generic capsule

• Adverse Events: somnolence, dizziness, ataxia, fatigue

Gabapentin

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Duloxetine

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• FDA approved for diabetic peripheral neuropathic pain


• Effective dose: 60 mg per day

• NNT: 3.8-11

• Cost: ~$10 per name-brand capsule, less for generic

• Adverse Events: nausea, somnolence, dizziness, constipation, dyspepsia, diarrhea, xerostomia, anorexia, headache, diaphoresis, insomnia, fatigue, decreased libido

Venlafaxine

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• Initial dose: 37.5 mg per day

• Effective dose: 75-225 mg per day

• NNT: 5.2-8.4

• Cost: ~$17-21 per name-brand capsule, less for generic

• Adverse Events: nausea, somnolence, dizziness, constipation, dyspepsia, diarrhea, xerostomia, anorexia

SNRI’s

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Tricyclic Antidepressants

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• Amitriptyline is best studied


• Effective dose: 25-100 mg per day

• NNT: 2.1-4.2

• Cost: <$3 per tablet

• Adverse Events: anticholinergic, potential long-term cardiovascular effects

Tricyclic Antidepressants

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Considerations

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SNRIs Gabapentinoids TCAs

Depression ↑↑ ↔ ↑↑Anxiety ↑↑ ↑↑ ↑↑Insomnia ↑↑ ↑↑ ↑↑Autonomic Neuropathy ↔ ↔ ↓Obesity ↔ ↓↓ ↓↓CAD ↔ ↔ ↓↓Hyperglycemia ↓ ↔ ↓Liver Failure ↓↓ ↔ Dose adjustmentSevere Renal Insufficiency ↓↓ Dose adjustment Dose adjustmentInteractions ↓↓ ↔ ↓↓

Adapted from Diabetes Res Clin Pract. 2021 Sep 18;109063.

Topical Therapies and Non-Pharmacologic Options

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• 0.075% capsaicin cream

• 5% lidocaine

• TENS

• Acupuncture

• Psychological coping strategies

Diabetes Res Clin Pract. 2021 Sep 18;109063.

Refractory Pain

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• Reassess diagnosis and consider evaluation for alternate etiologies

• Referral to Pain Management

• 8% Capsaicin patch

• Spinal Cord Stimulation

8% Capsaicin Patch

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J Pain. 2017;18(1):42-53.

Spinal Cord Stimulation

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JAMA Neurol. 2021;78(6):687-698.

Other Considerations

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• Appropriate foot care

• Psychological support

• Physical therapy

• Multidisciplinary Team

An Eye to the Future

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• Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM) trial

• Mirogabalin has completed phase II and III trials

• Trazodone/gabapentin Fixed-Dose Combination (Study NCT03749642)

• Precision Medicine: Phenotyping DN and treating based on phenotype

Back to our case…

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• History

• Comprehensive foot examination

• Counseling; appropriate foot care

• Labs

• Glycemic control, weight loss, optimize lipids and blood pressure

• Discuss risks and benefits of different treatment options

• Consider a first-line agent

• Appropriate follow-up and dose titration

Summary

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• Diabetic neuropathy is a common diabetic complication, and its prevalence is expected to increase world-wide.

• Diabetic neuropathy is and will continue to be an enormous clinical and economic burden.

• It is important to screen for this condition and detect cases early.

• For patients with T1DM, there is compelling evidence that targeting near-normal glycemic control provides clear and

persistent benefits in terms of preventing or delaying progression of diabetic neuropathy.

• For patients with T2DM, it is likely important to focus on managing insulin resistance, adiposity, and cardiovascular risk

factors in addition to glycemic control.

• There are multiple evidence-based, guideline-recommended medications available for the treatment of painful diabetic

neuropathy.

• Holistic care of the patient with diabetic neuropathy includes strategies to prevent disease progression, treatment of

associated symptoms, and providing appropriate foot care.

diabetes and neuropathy

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