Kim Chong Hwa MD,PhD Sejong general hospital, Division of endocrine & metabolism

Transcription

1 Kim Chong Hwa MD,PhD Sejong general hospital, Division of endocrine & metabolism

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3 Contetns Prevalence of DPN Clinical impacts of DPN Managements of DPN

4 Prevalence of Diabetic peripheral neuropathy in Korea DPN(+) DPN DPN(-) DPN(+) DPN DPN(-) 46% 54% 67% 33% N = 875, (%) N = 3999, (%) Diabetic DSPN patient survey,2005 Kim CH et al. 8 th IDF-WPR, 2010

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6 Painful Diabetic Neuropathy is More Than Pain Alone Do Patients With DPNP Have High Rates of Anxiety, Mood and Sleep Difficulties? and, does this overlap impact patient lives and clinical outcomes?

7 Clinical Consequences of Diabetic P eripheral Neuropathy (DPN) Symptomatic Neuropathy Pathogenic Pain Burning Paresthesia Hyperesthesia Allodynia Nocturnal exacerbation Autonomic Orthostatic hypotension Cardiac autonomic neuropathy Gastroparesis Diarrhea Constipation Incontinence Erectile dysfunction Quality of life Insensitivity Foot ulceration Infection Amputation Falls Charcot foot

8 DSPN: Impact on the quality of life Personal Relationship Leisure Occupational activity Daily activity Walking Sleep Mood 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Diabetic DSPN patient survey,2005 N = 472, (%)

9 Multidimensionality of DPNP Anxiety Depression Anger Fear Loss of conf idence Psychological CVA = Cerebrovascular accident; IHD = Ischaemic heart disease; PVD = Peripheral vascular disease.

10 Multidimensionality of DPNP Anxiety Depression Anger Fear Loss of conf idence Psychological Social Job loss Marital disha rmony Isolation Loss of socia l status CVA = Cerebrovascular accident; IHD = Ischaemic heart disease; PVD = Peripheral vascular disease.

11 Important consideration for NICE! Anxiety Depression Anger Fear Loss of conf idence Obesity Psychological Social Job loss Marital disha rmony Isolation Loss of socia l status Visual loss Nephropathy Ulcers Unsteadiness and Falls Autonomic n europathy Vasculopathy PVD/IHD/CVA CVA = Cerebrovascular accident; IHD = Ischaemic heart disease; PVD = Peripheral vascular disease.

12 Frequency of Comorbidities Record ed Within Selected Nations DPN Patients (%) France Italy Spain UK CHD=Coronary heart disease. Rubino A, et al. Prim Care Diabetes. 2007;1:129 34

13 Risk Factors for Incident Neuropathy: Model 1: Without cardiovascular disease and retinopathy Hypertension History of Smoking 1.38 Hb A1c 1.48 Change in Hb A1c 1.36 Diabetes duration BMI Triglycerides Total cholesterol The EURODIAB PCS Odds ratios (95% CI) N=1,101 with Type 1 DM; Follow-up: 7.3±0.6 years *p=0.03; **p=0.001; ***p< BMI = Body mass index; CI = Confidence interval; Hb A1c = Glycated hemoglobin; PCS = Prospective complications study. Tesfaye S, et al. N Engl J Med. 2005;352: * *** * *** ** *** * 3 4

14 Treatment based on four cornerstones Causal treatment aimed at (near) normoglycemia Treatment based on pathogenetic mechanisms Symptomatic treatment Avoidance of risk factors and complications

15 DCCT: Effect of intensive vs conventional glycemic control on neuropathy in type 1 diabetes

16 Effect of long-term intensive insulin vs conventional control on peripheral neuropathy in T2DM (cont)

17 The indirect evidence in treating TG for reducing DPNP Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study) - Lancet 2009

18 ACCORD Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Lancet Vol 376 August 7, 2010

19 DPN: Treatment N = 472, (%) Unkown, 1% No, 52% Yes, 47% Others Opiod analgesics γ-linoleic acid Anticonvulsant Antidepressant Alpha lipoic acid N = 222, (%) 0% 10% 20% 30% 40% 50% N = 1338, (%) Diabetic DSPN patient survey,2005 Kim CH et al. 8 th IDF-WPR, 2010

20 Treatment of DPNP up to 2003 Near normoglycemia (Hb A1c 6 7%) 1,2 Tricyclic compounds/ssris 1 Anticonvulsants 1,2 Carbamazepine Gabapentin Tramadol, oxycodone 1,3,4 Capsaicin 1 TENS, acupuncture, ESCS etc. 1,5 ESCS = Epidural spinal cord stimulation; TENS = Transcutaneous electrical nerve stimulation. 1. Tesfaye S, Kempler P. Diabetologia. 2005;48: ; 2. Backonja M, et al. JAMA. 1998;280: ; 3. Gimbel JS, et al. Neurology. 2003;60: ; 4. Watson CP, et al. Pain. 2003; 105:71 78; 5. Tesfaye S, et al. Lancet. 1996;348:

21 SNRIs New Medications for Painful DPN ( ) Duloxetine indicated for painful DPN Venlafaxine Anticonvulsants Pregabalin indicated for painful DPN Topiramate Oxcarbazepine Lamotrigine Sodium Valproate Lacosamide Botulinum Toxin VEGF gene transfer Actovegin Sativex (cannabis) α-lipoic acid SNRI = serotonin noradrenaline reuptake inhibitor

22 Improvement Duloxetine Improves 24-Hour Average Pain Severity in DPNP Mean baseline score 5.83 Mean Change in 24-hour Average Pain Severity Score * * 1.5 * 2.0 * * * * * * * 2.5 * * * * * * * * 3.0 * * * * * * Time (Weeks) MMRM = Mixed model repeated measures. 1. Goldstein D, et al. Pain. 2005;116: ; 2. Wernicke J, et al. J Pain. 2004;5:S48; 3. Raskin J, et al. Pain Medicine. 2005;6: Placebo (n=330) Duloxetine 20 mg QD (n=111) Duloxetine 60 mg QD (n=334) Duloxetine 60 mg BID (n=333) *p 0.05 vs placebo MMRM Pooled data from 3 studies

23 Most Common Adverse Events Associated with Duloxetine in DPNP Duloxetine Adverse Events that Occurred 5% and Twice Placebo Incidence of Adverse Events (%) Placebo (n=339) Duloxetine 20 mg/day (n=115) Duloxetine 60 mg/day (n=334) Duloxetine 120 mg/day (n=341) Pooled data from 3 studies Duration* 6 days 4 days Duration* * Median duration data: 14 days 23 days Duration* 5 days 5 days Duloxetine (60 mg and 120 mg) Placebo Nausea Somnolence Dizziness Constipation Sweating Dry Mouth Appetite Robinson M, et al. Presented at: 8th International Conference on the Mechanisms and Treatment of Neuropathic Pain; 5 Nov 2005; San Francisco, CA, USA.

24 Duloxetine Improves Response Rates in DPNP After 12 weeks 30% Reduction in 24-hour Average Pain 50% Reduction in 24-hour Average Pain Patients (%) ** ** ** *** *** ** Patients (%) * *** *** *** * ** 0 0 Study 1 1 Study 2 3 Study 3 1 Study 1 2 Study 2 3 Study 3 4 Placebo Duloxetine 20 mg QD Duloxetine 60 mg QD Duloxetine 60 mg BID * p<0.05 vs placebo ** p<0.01 vs placebo *** p<0.001 vs placebo 1. Presentation: Raskin J, et al. 41st European Association for the Study of Diabetes (EASD) Annual Meeting; Athens, Greece, September 12 15, 2005; 2. Goldstein DJ, et al. Pain. 2005;116: ; 3. Wernicke JF, et al. Neurology. 2006;67: ; 4. Raskin J, et al. Pain Med. 2005;6:

25 Duloxetine Decreased the Impact of Pain on Daily Activity, Function and Enjoyment of Life (BPI-I) Decreased Impact/Improvement Pooled data from 3 studies LS Mean Change from Baseline BPI-I Score BPI Avg Score General Activity *** *** *** *** Mood *** *** BPI = Brief pain inventory; LS = Least squares. Armstrong DG, et al. Pain Med. 2007;8: Walking Ability *** *** Normal Work ** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID Relationship With Others * *** Sleep Enjoyment of Life ** *** *** * p<0.05 vs placebo ** p<0.01 vs placebo *** p<0.001 vs placebo ***

26 Pregabalin for Painful DPN Pregabalin 300 mg/day and 600 mg/day improved SF-MPQ and sleep interference, and improved some domains of the SF-36 Least-squares Mean Pain Score * Placebo (n=115) Pregabalin 75 mg (n=77) Pregabalin 300 mg (n=81) Pregabalin 600 mg (n=81) * * Time (Weeks) * * *** ** *p= vs placebo **p< vs placebo ***p<0.001 vs placebo 5 SF-MPQ = Short-form McGill Pain Questionnaire; SF-36 = Short-Form 36 Quality-of-Life Questionnaire. Lesser H, et al. Neurology. 2004;63:

27 Pregabalin: Adverse Events Adverse Placebo Pregabalin Pregabalin event (%) (n=97) 300 mg/day (n=81) 600 mg/day (n=82) Dizziness Somnolence Edema Amblyopia Ataxia Confusion Constipation Lesser H, et al. Neurology. 2004;63:

28 Pregabalin: Proportion of Patients Meeting 50% and 30% Improvement in Mean Pain Score Responders (%) % Improvement from Baseline 30% Improvement from Baseline Placebo (n=550) Pregabalin 150 mg (n=175) Pregabalin 300 mg (n=265) Pregabalin 600 mg (n=507) NNT 300 mg= mg=4.0 NNT = Number needed to treat. Freeman R, et al. Diabetes Care. 2008;31:

29 Number Needed to Treat (NNTs) for >50% Pain Reduction Tricyclic Antidepressants 397 Valproate 83 Carbamazepine/Lamotrigine/Phenytoin 109 Opioids 149 Tramadol Gabapentin/Pregabalin Antidepressants, SNRI Mexiletine* NMDA Antagonists* Capsaicin Antidepressants, SSRI Topiramate* Topical Lidocaine N/A Approximately 1/3 Pain Relief >50% *At least half of the conducted trials showed no significant effect NMDA = N-methyl-D-aspartic acid. Jensen TS, et al. Diab Vasc Dis Res. 2006;3: NNT

30 Treatment Algorithm for PDN Painful diabetic neuropathy Consideration of contraindications and comorbidities α 2 -δ agonist (pregabalin or gabapentin) TCA SNRI (duloxetine) If pain control is inadequate and considering contraindications TCA or SNRI SNRI or α 2 -δ agonist (pregabalin or gabapentin) TCA or α 2 -δ agonist (pregabalin or gabapentin) If pain control is still inadequate Add opioid agonist as combination therapy PDN = Peripheral diabetic neuropathy; SNRI = Serotonin-norepinephrine reuptake inhibitor; TCA = Tricyclic antidepressants. Tesfaye et al. Diabetes Care 2010; 33:

31 Pathogenesis of DPN Dyslipidemia Diabetes EFA dysmetabolism Polyol pathway flux ARIs Antioxidants α -Lipoic acid NEUROPATHY A-V shunting Hyperglycemia PKCß Free transition metal ions Inhibitor Autoxidation AGE formation Endogenous scavengers Reactive Oxygen Species Ischemia/ reperfusion AGE Inhibitors Nerve and ganglion blood flow ONOO - Endoneurial hypoxia DAG PKC ß AII ACE-I., ARB ET C-Peptide NO PGI 2 EDHF Vascular dysfunction Linoleic acid GLA DGLA AA GLA Modified from Cameron et al., Diabetologia, 2001

32 Treatment of diabetic neuropathy based on the putative pathogenetic mechanisms Ziegler D. Diabetes Care 31 (Suppl.2): S255-S261, 2008

33 Conclusions Patients With DPNP Have High Rates of Anxiety, Mood and Sleep Difficulties Symptomatic treatments only relieve pain without targeting the underlying neuropathy, which is associated with a poor prognosis (ulcers, amputations). Pathogenic treatments may be added, given its safety and potential for improving neuropathic symptoms Therefore, treatment based on the combination of symptomatic and pathogenetic mechanisms of DPN, which would be effective despite persisting hyperglycemia, is preferred.