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

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Presentation on theme: "Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options."— Presentation transcript:

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

2 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? Whats new in ADD? How Lipaglyn TM is different? Trial & evidence of Lipaglyn TM efficacy & safety? What is the proposed place for Lipaglyn in treatment of DD? Key questions

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

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

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

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 So novel therapeutic options are required for optimal management Vouri Sm etal. Manag Care Pharm. 2011;17(4): A B C HbA1c < 7.0% BP < 130/80 mm Hg LDL-C < 100 mg/dL

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

8 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 May;20(5): ** Talwar & Misra,J Assoc Physicians India 2002;50:1521 ^Misra et al, J Assoc Physicians India 2004;52: Lifestyle and genetic factors also contribute to higher incidence of dyslipidemia in Indians

9 *Misra, Nutrition May;20(5): 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. Besides, body composition of Asian Indians makes them more vulnerable

10 LipidRelative Serum Concentrations TCSimilar LDL-CSimilar (129 Vs 124 mg/dL) sd-LDL-CSimilar TGHigher (174.5 Vs 146 mg/dL) HDL-CLower (40.5 Vs 46.4 mg/dL) Lp(a)Higher (29.3 Vs 25.9 mg/dL) Comparison of Indian vs. Western Dyslipidemia 20th Annual Convention of the American Association of Physicians of Indian OriginClinical Implications: Dyslipidemia in the Asian Indian Population June 29, 2002 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 Indian dyslipidemia is different from its Western counterpart in terms of lipid parameters

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

12 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? Whats new in DD? How Lipaglyn is different? Trial & evidence of Lipaglyn efficacy & safety? What is the proposed place for Lipaglyn i n treatment of DD? Agenda

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,J Clin Invest. 2000;106:453–458.

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

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,J Clin Invest. 2000;106:453–458.

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

17 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? Whats new in ADD? How Lipaglyn TM is different? Trial & evidence of Lipaglyn efficacy & safety? What is the proposed place for Lipaglyn in treatment of DD? Agenda

18 Diabetes is CHD equivalent: NCEP ATP III guidelines^ *Balkau B, et al. Lancet 1997; 350:1680. ^SM Grundy et al,Circulation. 2004;110: N= 6908 N= Control (non-diabetes) Diabetes Ratio 2.5 Ratio 2.2 Ratio 2.1 Whitehall Study Mortality rate (deaths per 1,000 patient-years) Paris Prospective Study Helsinki Policemen Study N = N= 6908 N= 657 Mortality rate is doubled in individuals with diabetes*

19 INTERHEART 9 Modifiable factors account for 90% of first-MI risk worldwide Yusuf S et al, Lancet; 364: Dyslipidemia is the single most important CV risk factor for MI

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

21 *Total area under 3 hours response curve (mean of 2 tests) Olefsky JM et al. Am J Med. 1974;57: TG levelsInsulin levels 150 mg/dl150 pmol/L 300 mg/dl325 pmol/L Hypertriglyceridemia has a direct relation with insulin resistance

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

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

24 *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) Meta-Analysis of 29 Studies Duration of follow-up 10 years 5,902 <10 years 4,256 Sex Male 7,728 Female 1,984 Fasting status Fasting 7,484 Non-fasting 2,674 Adjusted for HDL Yes 4,469 No 5,689 Overall CHD Risk Ratio* GROUPSCHD CASES 1.72 ( ) 2 N = 2,62,525 3 CHD Risk Ratio* (95% CI) Sarwar N, et al. Circulation. 2007;115: Patients in highest tertile of serum TG had 72% higher risk of CVD than those in lowest tertile 1 Increased Risk

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

26 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 Jul;19 (Suppl H): H18-22

27 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? Whats new in DD? How Lipaglyn is different? Trial & evidence of Lipaglyn efficacy & safety? What is the proposed place for Lipaglyn in treatment of DD? Agenda

28 At 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 mg/dL may not be optimal to reduce atherosclerosis Austin et al, Circulation. 1990; 82: Pattern B: a predominance of small, dense LDL particles Pattern A: large, more buoyant LDL particles predominate Relevance of TG<100 mg/dL - lower the TG lower the sd-LDL-C

29 TG Designate 1984 NIH Consensus Panel 1993 NCEP Guidelines 2001 NCEP Guidelines 2011 AHA Statement <100 (optimal) Desirable<250<200<150 Global Guidelines (Goal for TG) ESC < 150 mg/dl AHA ACC ADA Circulation. published online April 18, 2011 With the realization of importance of TG, the suggested target for TG has kept coming down

30 Lets look how TG reduction benefits in outcome…

31

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

33 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 Placebo N= patients, Age years, type 2 diabetes diagnosed after age 35 years, no clear indication for cholesterol-lowering therapy at baseline (total cholesterol mg/dL, plus either total cholesterol to HDL ratio 4.0 or triglyceride >88.6 mg/dL Keech A et al, Lancet 2005; 366: 1849–61 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) Lets understand what the FIELD trials show about the benefits of PPAR- α therapy

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

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

36 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. ACCORD Study Group. N Engl J Med. 2010;362: Baseline: TG: 162 mg/dl TC: mg LDL: mg/dl HDL: 38.6 mg/dl 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. Fenofibrate 160 mg Placebo Lets also look at what ACCORD trials show about the benefits of PPAR-α therapy

37 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) ACCORD Study Group. N Engl J Med. 2010;362: P=0.32 % patients developing primary end Point However, ACCORD results did not show any significant CV benefits in overall population

38 P=0.03 N= 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 % patients developing events 31% ACCORD: PPAR-α agonist significantly reduce CV events in T2DM patients with TG>204 and HDL<34 (ADD)

39 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 Limitation & Learning from FIELD & ACCORD Trial FIELD Study ACCORD Study

40 18 trials metaanalysis, > patients Jun M et al, Lancet 2010; 375: 1875–84 P=0.048 P< P=0.025 P=0.02 P< Change in relative Risk (%) Major CV eventsCoronary eventsAlbuminuriaRevascularizationRetinopathy By lowering TG, PPAR-α agonists can reduce the macro- & microvascular complications of T2DM

41 N Engl J Med. 2010:363(7):692-4 Diabetes Care 32:493–498, 2009 P<0.05 TG > 204 mg/dl and HDL < 34 mg/dlTG 34 mg/dl N=4726 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/dL and low HDL 34 mg/dL (Atherogenic Dyslipidemia)

42 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)

43 Lets look how good Glycemic Control helps…

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

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

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

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

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

49 Non-HDL-C Vs LDL-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. Paul Ridkar JAMA. 2005;294: Non-HDL-C was a stronger indicator of CV risk than LDL-C Conclusion

50 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 patients total atherogenic lipoprotein burden. Non–HDL-C targets are 30 mg/dL higher than estab­lished LDL-C risk levels Jellinger PS, et al. ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78) AACE Dyslipidemia Guidelines

51 Non-HDL-C is better than ApoB for the CV risk prediction A meta analysis was carried out including 25 trials of different types of lipid lowering therapies (12 on statin, 4 on fibrate, 5 on niacin, 2 on simvastatin–ezetimibe, 1 on ileal bypass surgery, and 1 on aggressive versus standard low-density lipoprotein (LDL) cholesterol, n=131,134) Robinson J,,Am J Cardiol 2012;110: 1468–1476 Non-HDL-C decrease outperforms ApoB decrease for prediction of CHD and CVD risk. Its decrease is a better predictor of CHD and CVD Conclusion

52 Importance of Non-HDL-C vis-à-vis LDL-C and ApoB for CV events in statin treated patients A meta-analysis was carried out from 8 landmark statin trials (38,153 patients), to evaluate the relative strength of the associations of LDL-C, non–HDL-C, and ApoB with cardiovascular risk among patients treated with statin therapy. 8 studies: 4S, LIPID, AFCAPS, WOSCOPS, CARDS, IDEAL, TNT, SPARCL JUPITER Boekholdt S, JAMA. 2012;307(12): Non-HDL-C was a better indicator of CV risk than ApoB (p=0.02) and LDL –C (p=0.002) (1 SD increase in non-HDL-C, ApoB and LDL-C increase CV risk by 16, 14 and 13% respectively) Conclusion

53 Non–HDL-C is as good as or better than LDL-C in the prediction of future cardiovascular events JAMA. 2005;294: When triglycerides are between mg/dl a non–HDL-C calculation provides better risk assessment than LDL-C alone AACE 2012 dyslipidemia guidelines (ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78) Non-HDL outperforms Apo-B for prediction of CVD: A meta-analysis of 25 trials (n=131,134) on lipid lowering therapy Am J Cardiol 2012;110: 1468–1476 Among statin-treated patients, the strength of this association with CVD is greater for non–HDL-C than for LDL-C and ApoB JAMA. 2012;307(12): To sum up - Non-HDL-C is a better indicator of residual risk than LDL-C

54 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: Patient CategoryLDL-C target (mg/dL) Non-HDL-C target (mg/dL) CHD + DM<70<100 CHD/CHD risk equivalent<100<130 No CHD, 2+ RF<130<160 No CHD, <2 RF<160<190 Non-HDL-C targets are related to LDL-C targets but differ by patient categories

55 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 ADD? What are the current limitations of treating dyslipidemia in diabetics? Whats new in DD? How Lipaglyn is different? Trial & evidence of Lipaglyn efficacy & safety? What is the proposed place for Lipaglyn in treatment of DD? Agenda

56 Lifestyle changes and Rx of secondary causes Pharmacologic therapy Anti-diabetic therapy Lipid management - Statins - Fibrate - Niacin - Omega-3 fatty acids Combination therapy Current Management of ADD

57 Algorithm/treatment protocol Diabetes Care 2012:35: ADA/EASD guidelines for management of diabetes

58 Sulfonylurea/Meglitinides : they are known to lead to early Beta cell fatigue by excessive stimulation* + significant risk of hypoglycemia and weight gain Pioglitazone: Significant weight gain, osteoporosis ** Insulin: Parenteral administration, significant risk of hypoglycemia GLP-1 analogues: Parenteral administration, severe GI disturbance in initial period DPP-IV inhibitors: Possible risk of pancreatic metaplasia and pancreatitis^, URTI * J Clin Endocrinol Metab. 2005;90:501–506, **Diabetes Care 2011; 34(4): ^ JAMA Intern Med 2013 Feb 25:1-6 Limitations of current treatment of uncontrolled hyperglycemia after metformin therapy in T2DM

59 Lifestyle changes and Rx of secondary causes Pharmacologic therapy Anti diabetic therapy Lipid management - Statins - Fibrate - Niacin - Omega-3 fatty acids Combination therapy Current Management of ADD

60 *Acute CHD event, coronary revascularization, stroke. Colhoun HM et al. Lancet. 2004;364: BaselineEnd of Study TG173 mg/dl143 mg/dl LDL118.5 mg/dl82 mg/dl HDL54 mg/dl49 mg/dl Managing Dyslipidemia in T2DM reduces CV events CARDS: Atorvastatin Significantly Reduces Major CV Events in DM patients*

61 BaselineEnd of Study TG 169 mg/dl128 mg/dl LDL 129 mg/dl83 mg/dl HDL48 mg/dl Server PS et al. Diabetes Care, 2005; 28: Managing Dyslipidemia in T2DM reduces CV events ASCOT-LLA: Total CV Events reduced by 23% with Atorvastatin in Patients With HT+DM

62 Residual CHD risk in major statin trials

63 Statins alone are not sufficient in Diabetic Dyslipidemia *Patients with diabetes. (HPS also enrolled 14,573 high-risk patients without diagnosed diabetes.) 1.HPS Study Group, Lancet. 2003;361: ; 2. Colhoun HM, Lancet. 2004;364: CARDS 2 : N = 2838HPS 1 : n = 5963* 22% Risk Reduction 32% Risk Reduction Major Vascular Event Rate (%) 78% Residual CVD Risk 68% Residual CVD Risk Acute CVD Event Rate (%) Residual CVD risk remains in patients with diabetes treated with statins

64 PROS: Reduction in TG, LDL-C & raises HDL-C, used alone or in conjunction with statins CONS: Increased risk of gall stones Abnormal Liver Function Tests (increased AST and ALT levels) in 7.5% patients Increased serum creatinine levels. Ref - TRICOR Prescribing Information Fibrates do not seem to be the optimal solution for managing residual risk either

65 Jun M et al, (J Am Coll Cardlol 2012;60: ) Fibrate therapy significantly reduces eGFR by 2.67 ml/min (p=0.01) in CKD patients Fibrates have adverse effect on renal function in CKD patients A meta analysis of 10 studies, 16,800 patients with CKD (eGFR < 60 ml/min)

66 JAMA 2004;292:2585–2590 Statins combined with fibrate increases the incidence of statin induced myopathies, by 5.5-fold compared with statin use alone MH Davidson et al, Am J Cardiol 2007;99[suppl]:3C–18C In mixed dyslipidemia, Statin + Fibrate combination is not always safe

67 Years of follow-up Patients suffering events (%) 15.0% 14.5% Placebo ERN/LRPT Log rank P=0.29 Risk ratio 0.96 (95% CI 0.90 – 1.03) European Heart Journal (2013) 34, 1279–1291 ERN/LRPT: Extended release niacin + Laropiprant CVD patients were randomized to ERN/LRPT or placebo (all on simvastatin) HPS 2 THRIVE Study - No CV benefits with Niacin, ADRs like myopathy & skin reactions were increased ( ADRs were 10 times higher in Asians than European patients)

68 Omega 3 Fatty Acids Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) At therapeutic doses (4 gm/day), reduce TGs by 30-40% Eructation (belching), dyspepsia, fishy smell in mouth and taste perversion are most common ADRs Their effects on CV events are disputed, some studies suggest that they reduce CV events, other studies report the opposite.

69 Omega 3 Fatty acids have shown inconsistent effects on CV outcomes in different studies J Am Coll Cardiol 2011;58:2047–67

70 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? Whats new in ADD? How Lipaglyn is different? Trial & evidence of Lipaglyn efficacy & safety? What is the proposed place for Lipaglyn in treatment of DD? Agenda

71 Diabetes Aug;54(8): The importance of controlling both glucose and lipid levels in Diabetic dyslipidemia gave rise dual agonists

72 Combination therapy of PPARα & PPARγ agonists, results in reduction of TG & A1c levels without increasing body weight in T2DM patients In a study, obese, T2DM patients were treated with placebo for 2 months and then rosiglitazone (8 mg/day) + Fenofibrate (160 mg/day)(RGZ/FEB) or rosiglitazone (8 mg/day) (RGZ) alone for 2 months. RGZ/FEB was more effective and safe than RGZ alone RGZ/FEB lowered fasting plasma FFA more effectively than RGZ alone (22 vs. 5%, P < 0.05), and More effective than RGZ alone in lowering A1c (0.9 vs. 0.4%)and TGlevels (38 vs. 5%) RGZ/FFB prevented the fluid retention usually associated with RGZ (1.6 vs. 5.6%, P < 0.05) Boden G, et al. Diabetes 56:248–255,2007 Conclusion

73 Change in body water with Rosiglitazone Vs Rosiglitazone + Fenofibrate R/F: Rosiglitazone/Fenofibrate R: Rosiglitazone Boden G, et al. Diabetes 56:248–255,2007

74 To sum up…. ADD is highly prevalent in the Indian diabetic population Control of hypertriglyceridemia is equally vital in reducing the CV events as is optimal glycemic control Non-HDL-C is a better indicator of CV risk than ApoB and LDL –C Many unmet needs exist in the current management of ADD and a significant residual CV risk prevails despite the current optimal therapy Combined action of PPARα & PPARγ agonists results in reduction of TG & A1c levels without increasing body weight in T2DM patients A dual PPAR α/γ agonist is the need of the hour – to achieve optimal glycemic and lipid targets with better safety in the comprehensive management of ADD

75 Thank You


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