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A therogenic D iabetic D yslipidemia ( ADD ) - Time to Relook & Evaluate Treatment Options

A therogenic D iabetic D yslipidemia ( ADD ) - Time to Relook & Evaluate Treatment Options. 14339_89. 3_85. K ey questions. How big is the challenge of Atherogenic Diabetic dyslipidemia (ADD ) in INDIA? Why diabetics are more prone to dyslipidemia?

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A therogenic D iabetic D yslipidemia ( ADD ) - Time to Relook & Evaluate Treatment Options

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  1. Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options

  2. 14339_89 3_85 Key questions • How big is the challenge of Atherogenic Diabetic dyslipidemia (ADD) in INDIA? • Why diabetics are more prone to dyslipidemia? • Why management of Diabetes & Dyslipidemia becomes important? • What is the evidence to support benefits from TG reduction? • What is the current management approach in ADD? • What are the current limitations of treating dyslipidemia in diabetics? • What’s new in ADD? • How LipaglynTMis different? • Trial & evidence of LipaglynTMefficacy & safety? • What is the proposed place for Lipaglyn in treatment of DD?

  3. Research in 2004 forecast Indian diabetic population to reach ~80 Mn by 2030… *Number in the adult population (20 years of age). Wild S et al. Diabetes Care. 2004;27:1047-1053.

  4. …however, it has breached 60 Mn in 2011 itself Diabetic population in India: ICMR INDIAB study 2011 62.4 million people with diabetes 77.2 million people with pre-diabetes RM Anjana et. al. Diabetologia (2011) 54:3022–3027 DOI 10.1007/s00125-011-2291-5

  5. Globally, dyslipidemia is a widespread condition in diabetics Conclusion : Every 3 out of 4 diabetic suffers from dyslipidemia Selby JV et al. Am J Manag Care. 2004;10(part 2):163-70.

  6. Only a minority (<18%) of patients with T2DM achieve ABC goals • The “ABCs” of optimal CV health in diabetes are: • Most T2DM patients fail to achieve these targets: • In a study of 5426 diabetic patients • (who were on treatment) in USA • from 2008 to 2009, only 17.3% • could achieve all the 3 ABC targets A HbA1c < 7.0% BP < 130/80 mm Hg B LDL-C < 100 mg/dL C So novel therapeutic options are required for optimal management VouriSmetal. ManagCare Pharm. 2011;17(4):304-12

  7. But in India, almost 9 out of 10 diabetics have dyslipidemia This suggests that there are >55 millions patients of diabetic dyslipidemia in India Prevalence of Dyslipidemia (%) in Male T2 DM Prevalence of Dyslipidemia (%) in Female T2DM 85.5% 85.5 % 97.8 % Dyslipidemia Dyslipidemia RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12

  8. 20483_85 Lifestyle and genetic factors also contribute to higher incidence of dyslipidemia in Indians • Diet • Dyslipidemic profile - seen in vegetarians* • Indian diets rich in carbohydrate and low in Omega-3 PUFA- exacerbates hyper-triglyceridemia.* • Physical Activity • Asian Indians-more physically inactive: May be due to fast economic development in recent years** • Genetic Factors • Abnormal variants of ApoC 3 and ApoE 3 genes common in India^ • Indians have more abdominal adiposity* • Thrifty gene to blame too *Misra & Vikram ,Nutrition. 2004 May;20(5):482-91 ** Talwar & Misra,JAssoc Physicians India 2002;50:1521 ^Misra et al, J Assoc Physicians India 2004;52:137-42

  9. Besides, body composition of Asian Indians makes them more vulnerable • Shorter height* • Lower body mass index* • Excess body fat in relation to body mass index † • Abdominal adiposity • High waist-to-hip ratio ‡ • Normal waist circumference*§ • High intra-abdominal fat* • Truncal adiposity • Thick subscapular skinfold thickness* • More abdominal subcutaneous fat*II • Less lean body mass*¶ * As compared with whites or blacks. † High body fat per unit of body mass index. II As estimated by skinfold thickness measurements or imaging techniques. ¶ Particularly in the lower extremities. ‡ This may be due to less lean mass at the hips resulting in a smaller hip circumference. § Average value of waist circumference usually does not exceed the currently accepted cutoff values for abdominal obesity. *Misra, Nutrition. 2004 May;20(5):482-91

  10. Indian dyslipidemia is different from its Western counterpart in terms of lipid parameters Comparison of Indian vs. Western Dyslipidemia Atherogenic Dyslipidemia Indians living in the US - 54% of men and 68% of women had low HDL levels. Similarly, 43% of Indian males and 24% Indian females have high TG levels that exceed 150 mg/dL 20th Annual Convention of the American Association of Physicians of Indian OriginClinical Implications: Dyslipidemia in the Asian Indian Population June 29, 2002

  11. ADD affects TG, LDL-C and HDL-C ↔ LDL-C (>100)&↑sd-LDL-C ↑TG>150 The Triad of ADD ↓HDL-C<40 for Males <50 for Females Sarma ,IHJ, 2000, 52: 173-177Sarma, Am J Med, 1998, vol 105(1A), 48S-56S

  12. 10_89 3_85 Agenda • How big is the challenge of Diabetic dyslipidemia (DD) in INDIA? • Why diabetics are more prone to dyslipidemia? • Why management of Dyslipidemia and Diabetes becomes important? • What is the evidence to support benefits from TG reduction? • What is the current management approach in DD? • What are the current limitations of treating dyslipidemia in diabetics? • What’s new in DD? • How Lipaglyn is different? • Trial & evidence of Lipaglyn efficacy & safety? • What is the proposed place for Lipaglynintreatment of DD?

  13. Why diabetics are more prone to ADD? ↑HSL Type II Diabetes is characterized by insulin resistance IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,JClin Invest. 2000;106:453–458.

  14. Why diabetics are more prone to ADD? ↑HSL IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,JClin Invest. 2000;106:453–458.

  15. Why diabetics are more prone to ADD? ↑HSL IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,JClin Invest. 2000;106:453–458.

  16. Why diabetics are more prone to ADD? ↑HSL IR: Insulin Resistance CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. CETP: Cholesterol Ester Transport Protein HN Ginsberg,JClin Invest. 2000;106:453–458.

  17. 8_89 3_85 Agenda • How big is the challenge of Atherogenic Diabetic dyslipidemia (ADD) in INDIA? • Why diabetics are more prone to dyslipidemia? • Why management of Diabetes and Dyslipidemia becomes important? • What is the evidence to support benefits from TG reduction? • What is the current management approach in ADD? • What are the current limitations of treating dyslipidemia in diabetics? • What’s new in ADD? • How LipaglynTMis different? • Trial & evidence of Lipaglyn efficacy & safety? • What is the proposed place for Lipaglyn in treatment of DD?

  18. Mortality rate is doubled in individualswith diabetes* 35 Ratio 2.5 Ratio 2.2 Ratio 2.1 30 25 Mortality rate(deaths per 1,000 patient-years) 20 15 10 N= 657 N= 6908 5 0 Helsinki Policemen Study Whitehall Study Paris ProspectiveStudy N = 10087 N= 657 N= 6908 Diabetes is CHD equivalent: NCEP ATP III guidelines^ Control (non-diabetes) *Balkau B, et al. Lancet 1997; 350:1680. ^SM Grundy et al,Circulation. 2004;110:227-239 Diabetes

  19. 12_84 Dyslipidemia is the single most important CV risk factor for MI INTERHEART9 Modifiable factors account for 90% of first-MI risk worldwide Yusuf S et al, Lancet; 364:937-52

  20. In dyslipidemia patients with diabetes, CV risk is heightened by 3-4 times as compared to dyslipidemia without diabetes J Stamler et al, DiabetesCare February 1993:16:434-444

  21. Hypertriglyceridemia has a direct relation with insulin resistance *Total area under 3 hoursresponsecurve (mean of 2 tests) OlefskyJM et al. Am J Med. 1974;57:5551-560

  22. 27650_85 Hypertriglyceridemia is an independent CV risk factor • For every increase in TGlevel of 89 mg/dL, CVD risk increases by 32% in men and 76% in women Meta-analysis of 17 studies (> 55,000 patients) HokansonJE et al. J Cardiovasc Risk. 1996; 3: 213-219

  23. Hypertriglyceridemia in T2DM patients increase CV risk by 3 timescompared to T2DM patients without high TG. 27650_85 Hypertriglyceridemia in diabetes is an independent CV risk factor Asian study of diabetic patients (followed up for 4.6 years) Diabetes Metab Res Rev. 2005 Mar-Apr;21(2):183-8.

  24. 6_85 Patients in highest tertile of serum TG had 72% higher risk of CVD than those in lowest tertile Meta-Analysis of 29 Studies Groups CHD Cases CHD Risk Ratio* (95% CI) N = 2,62,525 1.72 (1.56-1.90) 1 2 3 Increased Risk Sarwar N, et al. Circulation. 2007;115:450-458. *Individuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most)

  25. Hazard Ratio for CHD is directly related to TG concentration N=302,430 The Emerging Risk Factors Collaboration JAMA. 2009 November 11; 302(18): 1993–2000

  26. 60418_85 Increased CV risk can be due to other serious consequences of hypertriglyceridemia • Low levels of HDL-C • The presence of sd-LDL-C particles • The presence of atherogenic triglyceride-rich lipoprotein remnants   • Insulin resistance • Increases in coagulability and viscosity • Pro-inflammatory status Miller M. Eur Heart J. 1998 Jul;19 (Suppl H): H18-22

  27. 8_89 3_85 Agenda • How big is the challenge of Diabetic dyslipidemia (DD) in INDIA? • Why diabetics are more prone to dyslipidemia? • Why management of Dyslipidemia and Diabetes becomes important? • What is the evidence to support benefits from TG reduction? • What is the current management approach in DD? • What are the current limitations of treating dyslipidemia in diabetics? • What’s new in DD? • How Lipaglyn is different? • Trial & evidence of Lipaglyn efficacy & safety? • What is the proposed place for Lipaglyn in treatment of DD?

  28. Relevance of TG<100 mg/dL - lower the TG lower the sd-LDL-C • At fasting TG<100 mg/dL, 85% population has predominant large buoyant LDL particles while if fasting TG>250 mg/dL 85% of population has predominant sd-LDL-C particles. • sd-LDL is known to be more atherogenic, keeping TG at 200-250 mg/dL may not be optimal to reduce atherosclerosis Pattern B: a predominance of small, dense LDL particles Pattern A: large, more buoyant LDL particles predominate Austin et al, Circulation. 1990; 82:495-506

  29. With the realization of importance of TG, the suggested target for TG has kept coming down Circulation. published online April 18, 2011

  30. Lets look how TG reduction benefits in outcome…

  31. CV benefits of PPAR alpha agonists VA-HIT: Primary Endpoint (non-fatal MI and CHD death) BIP study 3090 CAD patients were randomized to bezafibratevs Placebo, primary end point was fatal, nonfatal MI/sudden death Follow up:6.2 yrs 2500 CHD patients randomized to gemfibrozil or placebo follow up; 5 yrs • Rubins HB et al, N Eng J Med, August 5, 1999 Vol. 341;410-418 BIP Study Group Circulation. 2000;102:21-27

  32. 4_85 10_85 Let’s understand what the FIELD trials show about the benefits of PPAR- α therapy 9795 patients, Age 50-75 years, type 2 diabetes diagnosed after age 35 years, no clear indication for cholesterol-lowering therapy at baseline (total cholesterol 116-251 mg/dL, plus either total cholesterol to HDL ratio ≥4.0 or triglyceride >88.6 mg/dL • Baseline Lipid levels: • LDL-C 120 mg/dL (mean) • TC 195 mg/dL (mean) • HDL-C 43 mg/dL (mean) • TG 155 mg/dL (median) Placebo N=4900 Fenofibrate (200 mg) N=4895 • Endpoints • Primary - Composite of CHD death or non-fatal MI at 5 year follow-up • Secondary - Composite of total CV events, CV mortality, total mortality, stroke, coronary revascularization and all revascularization at 5 year follow-up Keech A et al, Lancet 2005; 366: 1849–61

  33. PPAR-α agonistshowed no clear benefit in primary endpoints Composite CHD death or nonfatal MI at 5 Years (% of treatment arm) p=0.16 N= 9795 Perception is that FIELD trial failed, but lets look critically at high TG Population or AtherogenicDyslipidemics.. Lancet 2005; 366: 1849–61

  34. PPAR-α agonists reduce CV events in T2DM patients with high TG and low HDL (ADD) FIELD: Sub-analysis :Total CV events in patients with Metabolic Syndrome ↓23% ↓27% % patientsdeveloping events % patientsdeveloping events P=0.01 N=2517 P=0.005 N=2014 R Scott et al, Diabetes Care 32:493–498, 2009

  35. Let’s also look at what ACCORD trials show about the benefits of PPAR-αtherapy • 5518 patients with type 2 diabetes (HbA1c > 7.5%) who were being treated • All patients were on open-label simvastatin. Median Age: 62.3 years. 36.5% patients had CVD. • Baseline: • TG: 162 mg/dl • TC: 175.2 mg • LDL: 100.6 mg/dl • HDL: 38.6 mg/dl Placebo Fenofibrate 160 mg The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

  36. However, ACCORD results did not show any significant CV benefits in overall population The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32) P=0.32 % patientsdeveloping primary end Point ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

  37. ACCORD: PPAR-α agonist significantly reduce CV events in T2DM patients with TG>204 and HDL<34 (ADD) ↓31% P=0.03 N=941 % patientsdeveloping events 941 T2DM patients (already on simvastatin) were randomized to fenofibrate or placebo Mean Follow up: 4.7 yrs *MI, stroke and death Tenenbaum and Fisman, Cardiovascular Diabetology 2012, 11:125

  38. 51203_85 Limitation & Learning from FIELD & ACCORD Trial FIELD Study FIELD Study Limitation More patients in the placebo group (17%) than in the PPAR-alpha agonist group(8%) received the non-study lipid-lowering agents (predominantly statins) . Learning If adjustment is done for statin therapy then PPAR-alpha agonist reduces CHD risk by 19% (p = 0.01) PPAR-α agonist significantly reduces CV events by 27% in patients with TG>204 & low HDL-C PPAR-α agonist therapy reduced CV events significantly by 31% in patients with high TG and Low HDL who were already on statin at the time of randomization and continued throughout the trial ACCORD Study

  39. By lowering TG, PPAR-α agonists can reduce the macro- & microvascular complications of T2DM Major CV events Coronary events Albuminuria Revascularization Retinopathy P=0.048 P=0.02 Change in relative Risk (%) P<0.0001 P=0.025 P<0.0001 18 trials metaanalysis, > 45000 patients Jun M et al, Lancet 2010; 375: 1875–84

  40. 8_84 In a meta analysis of 5 landmark studies (n = 4726), PPAR-α agonists reduced CV events significantly by 35% in patients with high TG≥ 204 mg/dLand low HDL ≤ 34 mg/dL(Atherogenic Dyslipidemia) TG > 204 mg/dl and HDL < 34 mg/dl TG < 204 mg/dl and HDL > 34 mg/dl P<0.05 N=4726 N Engl J Med. 2010:363(7):692-4 Diabetes Care 32:493–498, 2009

  41. In different studies in last 30 years, TG reduction, with or without statin, has been proven to cause significant risk reduction in patients with high TG and low HDL-C (Atherogenic Dyslipidemia)

  42. Let’s look how good Glycemic Control helps…

  43. Optimal glycemic control leads to ~24% risk reduction for microvasculardiseases (Microvascular diseases included are photocoagulation, vitreous hemorrhage, renal failure) UKPDS 80. NEJM 2008;359:1577-89

  44. Let’s understand what the PROactive trial about the benefits of glycemic control and CV outcomes through PPAR γ therapy Prospective, randomised, double-blind, placebo-controlled, study 5238 patients with type 2 diabetes (with macrovascular disease) Pioglitazone 15-45 mg (n=2605) Placebo (n=2633) Baseline Values: TG – 160 mg/dL End Point: Time to death, MI (except silent MI) and stroke Follow up: 34.5 months PROactive Study (PROspectivepioglitAzone Clinical Trial In macroVascular Events) JA Dormandy et al,Lancet 2005; 366: 1279–89

  45. Need redesign PPAR-γ agonist reduced CV end points (Death, MI, stroke) significantly (by 16%) in DM patients with baseline TG 160 mg/dL 16% risk reduction JA Dormandy et al, Lancet 2005; 366: 1279–89

  46. Need redesign A meta analysis of 19 trials, 16,390 patients with T2DM suggested that PPAR-γ agonist agent reduces CV events by 18% Composite Events (Death, Nonfatal MI, Stroke) 5.7% HR 0.8295% CI 0.72-0.94P=0.005 4.4% Patients % Control Pioglitazone Lincoff et al. JAMA 2007;298:1180-1188

  47. We understood the importance of TG reduction and good Glycemic Control- now what next?

  48. Non-HDL-C VsLDL-C for CV risk in healthy women • In a prospective study of healthy 15,632 women who were followed up for 10 years, strength of association between different lipid parameters (HDL-C, LDL-C, non-HDL-C) and CV risk were measured. Conclusion Non-HDL-C was a stronger indicator of CV risk than LDL-C Paul Ridkar JAMA. 2005;294:326-333

  49. Non-HDL-C is a better indicator of residual risk than LDL-C • When triglycerides are > 200 mg/dL but < 500 mg/dL, a non–HDL-C calculation will provide better risk assessment than LDL-C alone • If insulin resistance is suspected, evaluate non–HDL-C to gain useful information regarding the patient’s total atherogenic lipoprotein burden. • Non–HDL-C targets are 30 mg/dL higher than estab­lished LDL-C risk levels AACE 2012 - Dyslipidemia Guidelines • Jellinger PS, et al. ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78)

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