Medical Management of Diabetic Peripheral Neuropathy Jeffrey J. Tramonte, M.D. Baylor Scott & White Healthcare Round Rock Director of Neurology December 5, 2013

Goals Show familiarity with the following: • Diagnosis of diabetic polyneuropathy • The clinical importance of recognizing diabetic polyneuropathy • The treatment of diabetic polyneuropathy

Epidemiology of Diabetes • 2011 CDC Diabetes Fact Sheet – 25.8 million Americans (8.3% population) w/ DM • 18.8 million were diagnosed • 7 million were undiagnosed

– 1.9 million new Dx / year

Prevalence of DM by age in 2008

2011 CDC Diabetes Fact Sheet

Epidemiology of Diabetes Complications FOOT PROBLEMS: Amputation Ulcer Neuropathy

Deshpande. Phys Therapy 88: 1254-1264, 2008

Epidemiology of Prediabetes • 2011 CDC Diabetes Fact Sheet – 79 million Americans ≥ 20 yrs of age (35% population) with prediabetes • 50% of population ≥ 65 yrs of age

– Diabetes + prediabetes = #1 cause of PN • 2/3 pts with “idiopathic PN” are either DM or prediabetic

– Diabetes Prevention Program – lifestyle change with weight loss + exercise decreased development of DM by 58% over 3 years • Metformin reduced risk by 31% 2011 CDC Diabetes Factsheet Hoffman-Snyder. Arch Neurol 2006

DPN is an independent risk factor for mortality 134 Type 2 DM patients followed 9 years •38 patients died (29%) •26 (68%)from cardiovascular Dz (MI/CHF/CVA)

Forsblom. Diabetologia 41: 1253-1262, 1998

DPN is an independent risk factor for mortality Multivariate analysis of independent risk factors for mortality •Neuropathy is an independent risk factor for death in all models

Forsblom. Diabetologia 41: 1253-1262, 1998

Diabetic autonomic neuropathy is a risk factor for mortality •3.65 ↑ risk of death with cardiovascular autonomic neuorpathy (CAN) •1.96 ↑ risk of silent MI with cardiovascular autonomic neuropathy (CAN)

Vinik. Circulation 115: 387-397, 2007

Diabetic autonomic neuropathy is a risk factor for mortality Kaplan-Meier Survival Curves for death and CAN

146 diabetic patients followed for avg 5 years (17 deaths) • CAN associated with mortality • CAN + abnormal thallium-201 SPECT = ↑ mortality risk

Lee. Am J Card 92: 1458-1461, 2003

Epidemiology of Diabetic Neuropathies •

Type 1 DM – 66% patients have a form of neuropathy • • • • •

•

54% polyneuropathy (symptomatic in only 15% of all patients) 22% asymptomatic carpal tunnel syndrome 11% symptomatic carpal tunnel syndrome 7% autonomic neuropathy 3% other neuropathies

Type 2 DM – 59% have a form of neuropathy • • • • •

•

45% polyneuropathy (symptomatic in only 13% of all patients) 29% asymptomatic carpal tunnel syndrome 6% symptomatic carpal tunnel syndrome 5% autonomic neuropathy 3% other neuropathies

10% of patients have a neuropathic condition not related to DM – Other neuropathy (alcohol, inherited, paraproteinemic, amyloid) – Lumbar radiculopathy or spinal stenosis

Dyck. Neurology 43: 817-824, 1993

Epidemiology of Diabetic Neuropathies • Presence & severity of DPN correlates with: – Duration of diabetes – Comorbid diabetic retinopathy and/or nephropathy N0 = no PN N1 = subclinical N2a = mild PN N2b = mod PN

Dyck. Neurology 43: 817-824, 1993

Effect of strict glycemic control on DPN – DCCT 1995 Primary Prevention of Retinopathy after 5 years (no retinopathy at baseline) Intensive Control (HgbA1c=7.2%)

Poor Control (HgbA1c=9.1%)

5 year Risk Reduction

Clinical Neuropathy Baseline 4.9% 5 years 2.8%

2.1% 9.6%

71%

NCS Neuropathy Baseline 5 years

21.8% 40.2%

59%

19.7% 16.5%

Diabetes Control & Complications Trial. Ann Int Med 122: 561-568, 1995

Effect of strict glycemic control on DPN – DCCT 1995 Secondary Prevention of Retinopathy after 5 years (retinopathy at baseline) Intensive Control (HgbA1c=7.2%)

Poor Control (HgbA1c=9.1%)

5 year Risk Reduction

Clinical Neuropathy Baseline 5 years

9.4% 6.7%

9.4% 16.9%

61%

NCS Neuropathy Baseline 5 years

42.7% 32.7%

47.7% 52.4%

38%

Diabetes Control & Complications Trial. Ann Int Med 122: 561-568, 1995

Effect of strict glycemic control on DPN – DCCT 1995 • Strict glycemic control not only delays or prevents development of neuropathy, but may reverse it (clinically and by NCS data)

Diabetes Control & Complications Trial. Ann Int Med 122: 561-568, 1995 Diabetes Control & Complications Trial. Ann Neurol 38: 869-880, 1995

Risk Factors for DPN – EURODIAB Study 2005 1172 DM1 patients prospectively followed for 7.3 years (mean)

EURODIAB Prospective Complications Study Group. NEJM 352:341-350, 2005

Risk Factors, DM, and Development of Complications Early intervention to prevent or delay complications is needed

Complications begin prior to Dx of DM • 50% have macrovascular complications at Dx of DM • 20% retinopathy, 9% neuropathy, 10% nephropathy at Dx of DM Steinmetz. Diab Met Res Rev 24: 286-293, 2008

Risk Factors for DPN – EURODIAB Study 2005 1172 DM1 patients prospectively followed for 7.3 years (mean)

Independent of HgBA1C & duration of diabetes, cardiovascular risk factors are all associated with the risk of developing neuropathy: total cholesterol, LDL, TG, BMI, HTN, & Smoking EURODIAB Prospective Complications Study Group. NEJM 352:341-350, 2005

Pathogenesis of Diabetic Microvascular Complications Rx of dyslipidemia may prevent microvascular complications

Treatment with Fenofibrate in early stage Type 2 DM • 31% decreased need for retinal laser therapy • 38% reduction in leg amputations • decreased albuminuria

Steinmetz. Diab Met Res Rev 24: 286-293, 2008 FIELD Study. Lancet 370: 1687-1697, 2007

Elevated Triglycerides Correlate with Progression of DPN Progressive neuropathy over 1 year related to elevated TGs

2 groups of DM patients followed for 1 year • The group that developed progressive neuropathy (↓ fibers on nerve Bx) were equal on all variables (age, duration of Dz, HgBA1c, BMI) except triglycerides (significantly higher in the group with progressive neuropathy) Wiggin TD. Diabetes: published online 5/1/09

Exercise to Treat DPN • Exercise – well known to improve neuropathic pain – Small trial of 17 diabetics in 10 week aerobic exercise program in U.S. • Improved neuropathic pain • Increased intraepidermal nerve fiber branching

Kluding Patricia M, et al. J Diabetes Complications 26; 2012

Exercise to Treat DPN • 10 Week Exercise – improved neuropathic pain scores

Kluding Patricia M, et al. J Diabetes Complications 26; 2012

Exercise to Treat DPN • 10 Week Exercise – increased cutaneous nerve fibers (B) compared to (A)

Kluding Patricia M, et al. J Diabetes Complications 26; 2012

Risk Factors for DPN • Risk Factors for Diabetic Polyneuropathy – Hyperglycemia • 1% drop in HgBA1c = 40% ↓ risk of microvascular complications

– – – –

Age Duration of DM Cigarette smoking HTN • 10 mm Hg ↓ in BP = 12% ↓ risk of any DM complication

– Elevated triglycerides • Tight control = 20%-50% ↓ risk of CV complications

– Higher BMI – Alcohol consumption – Taller height

Deshpande. Phys Therapy 88: 1254-1264, 2008

Complications of DPN • Foot ulceration and amputation • Pain • Increase health care consumption – Time off from work

• Autonomic neuropathy and death • Sensory loss, imbalance, falls

Deshpande. Phys Therapy 88: 1254-1264, 2008

Treatment of DPN • Begins with early recognition & Dx of DPN • Aggressive Rx of DM to prevent, slow, or reverse DPN – Lifestyle changes – Modifiable risk factors – Meds

• Foot care – Proper-fitting footwear – Daily foot care • Clean/inspect feet twice daily • Annual foot exam

• Pain control

Argoff. Mayo Clin Proc 81: S3-S11, 2006

Pain Control in Diabetic Neuropathy

Pain Control in DPN • Set realistic expectations – 100% pain relief is ideal, should be sought, but is usually unrealistic • Most patients achieve 30-50% pain reduction, but have improved quality of life and can then return to work or social activities • Currently 25% patients with painful DPN are NOT treated

Argoff. Mayo Clin Proc 81: S12-S25, 2006

Pain Control in DPN Approaches to pain management vary “Reflecting old school habits, I prefer starting with TCAs (amitriptyline and nortriptyline); in an otherwise healthy adult, I start with 25mg QHS; if a patient is small, frail, or sensitive to medications, however, I begin with 10mg QHS and increase the dose every week by 10-25mg. Most patients seem to improve at a dose of 25mg to 75mg QHS. Most of my colleagues begin with gabapentin (300mg QHS) and increase weekly (to 300mg TID). Should that fail, the next agents generally used in my universe are pregabalin and duloxetine” . . . page 328)

Pascuzzi. Med Clin N Am 93: 317-342, 2009

Pain Control in DPN Approaches to pain management vary • •

Odds ratio for 50% pain relief with Capsaicin = 2.37 Odds ratio for discontinuation of Capsaicin due to adverse event = 4.26

Wong. BMJ 335: 87 published online, 2007

Pain Control in DPN Approaches to pain management vary

Argoff. Mayo Clin Proc 81: S12-S25, 2006

Spollett. Nurs Clin N Am 41: 697-717, 2006

Evidence based rating scale Class 0: Things I believe Class 0a: Things I believe despite the available data Class 1: Randomized controlled clinical trials that agree with what I believe Class 2: Other prospectively collected data Class 3: Expert opinion Class 4: Randomized controlled clinical trials that don’t agree with what I believe Class 5: What you believe that I don’t

Bleck TP. BMJ 321: 239, 2000

Tramonte’s Treatment Guidelines for Diabetic Neuropathic Pain

Top Five Take-Home Points 1. 2. 3. 4. 5.

Diabetic polyneuropathy is a risk factor for mortality Diabetic autonomic neuropathy is a risk factor for mortality Strict glycemic control can slow, halt, and potentially reverse DPN Numerous microvascular risk factors for DPN besides hyperglycemia (TG, smoking, HTN, BMI) Be realistic in treating diabetic neuropathic pain 30-50% reduction is reasonable