Presentation on theme: "Atherogenic Diabetic Dyslipidemia (ADD)"— Presentation transcript:
1Atherogenic Diabetic Dyslipidemia (ADD) - Time to Relook & Evaluate Treatment Options
23_8514339_8907/09/13Key questionsHow 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 LipaglynTM is different?Trial & evidence of LipaglynTM efficacy & safety?What is the proposed place for Lipaglyn in treatment of DD?Disease burden treatment options and emerging therapies…
307/09/13Research in 2004 forecast Indian diabetic population to reach ~80 Mn by 2030…2004 Diabetes Care publication predicted Indian diabetic population will reach 80 million by 2030, but…..*Number in the adult population (20 years of age).Wild S et al. Diabetes Care. 2004;27:
4…however, it has breached 60 Mn in 2011 itself 07/09/13…however, it has breached 60 Mn in 2011 itselfDiabetic population in India: ICMR INDIAB study 201162.4 million people with diabetes77.2 million people with pre-diabetesRM Anjana et. al in Diabetologia in 2011 report that it had already reached to 62.4 million in 2011 only, as per ICMR INDIAB data. Moreover, Diabetics are spread out across the country irrespective of Urban or Rural population.RM Anjana et. al. Diabetologia (2011) 54:3022–3027DOI /s
5Globally, dyslipidemia is a widespread condition in diabetics 07/09/13Globally, dyslipidemia is a widespread condition in diabeticsSelby et al report in Am J Manag Care 2004 that 3 out of 4 diabetics are also dyslipidemicConclusion : Every 3 out of 4 diabetic suffers from dyslipidemiaSelby JV et al. Am J Manag Care. 2004;10(part 2):
6Only 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 USAfrom 2008 to 2009, only 17.3%could achieve all the 3 ABC targetsAHbA1c < 7.0%BBP < 130/80 mm HgCLDL-C < 100 mg/dLSo novel therapeutic options arerequired for optimal managementSo current management options inadequate & So novel therapeutic options are required for optimal management of T2DMVouri Sm etal. Manag Care Pharm. 2011;17(4):304-12
7But in India, almost 9 out of 10 diabetics have dyslipidemia 07/09/13But in India, almost 9 out of 10 diabetics have dyslipidemiaThis suggests that there are >55 millions patients of diabeticdyslipidemia in IndiaPrevalence of Dyslipidemia (%) in Male T2 DMPrevalence of Dyslipidemia (%) in Female T2DM85.5%85.5 %97.8 %RM Parikh in Diabetes and Metabolic Syndrome: Clinical Research and Reviews report that in India, Prevalence of dyslipidemia in diabetic population is very high(9 out of 10), almost all diabetics (specially females) have dyslipidemia. 90% of 62 Mn T2DM patients is >55 Mn.Pre-diabetics also have insulin-resistance leading to dyslipidemia – that means another 70 million dyslipidemics.DyslipidemiaDyslipidemiaRM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12
820483_8507/09/13Lifestyle and genetic factors also contribute to higher incidence of dyslipidemia in IndiansDietDyslipidemic profile - seen in vegetarians*Indian diets rich in carbohydrate and low in Omega-3 PUFA- exacerbates hyper-triglyceridemia.*Physical ActivityAsian Indians-more physically inactive: May be due to fast economic development in recent years**Genetic FactorsAbnormal variants of ApoC 3 and ApoE 3 genes common in India^Indians have more abdominal adiposity*Thrifty gene to blame tooDiet:Dyslipidemic profile is commonly seen in the vegetarians*Indian diets rich in carbohydrate and low in Omega-3 poly-unsaturated fatty acids which exacerbates hyper-triglyceridemia.*Physical Activity:Asian Indians are more physically inactive as compared to many other ethnic groups**Genetic Factors:Abnormal variants of Apo C3(cause Lipoprotein lipase inhibition) and ApoE3 (formation of VLDL) genes are common in India which can lead to more dyslipidemia^Indians have excessive body fat and more abdominal adiposity which is harmful even if BMI is under control*Indians more prone to Syndrome X - The "Starvation Gene Theory" India suffered droughts for hundreds of years. Fats and carbohydrates provide energy to the body. So our genes adapted to survive long periods of drought by consuming fats and carbohydrates slowly to make them last longerNow our bodies get adequate supplies of food, but these genes are still in action as they take a long time to adapt, so our food continues to be metabolised slowly resulting in the dysfunctional biochemical profile that constitutes Syndrome X..*Misra & Vikram ,Nutrition May;20(5):482-91** Talwar & Misra,J Assoc Physicians India 2002;50:1521^Misra et al, J Assoc Physicians India 2004;52:137-42
9Besides, body composition of Asian Indians makes them more vulnerable 07/09/13Besides, body composition of Asian Indians makes them more vulnerableShorter height*Lower body mass index*Excess body fat in relation to body mass index †Abdominal adiposityHigh waist-to-hip ratio ‡Normal waist circumference*§High intra-abdominal fat*Truncal adiposityThick subscapular skinfold thickness*More abdominal subcutaneous fat*IILess lean body mass*¶Misra in Nutrition 2004 points out that Asian Indians have a high prevalence of insulin resistance syndrome that may underlie their greater than normal tendency to develop diabetes mellitus and early atherosclerosis. Important reasons could be their excess body fat and adverse body fat patterning including abdominal adiposity even when the body mass index is within the currently defined normal limits. Some of these features have been reported at birth and childhood. Whether Asian Indians also have tendency to develop insulin resistance de novo, independent of total or regional adiposity, needs further investigation. Underlying genetic tendency or early-life adverse events may contribute to such a phenotype, but lifestyle factors alone or modulated by inherited factors appear to play an important role because obesity and dyslipidemia become worse with urbanization and migration. Systemic stress may contribute to insulin resistance syndrome in the intra-country and inter-country migrant Asian Indians.High prevalence of excess body fat, adverse body fat patterning, hypertriglyceridemia, and insulin resistance beginning at a young age have been consistently recorded in Asian Indians irrespective of their geographic locations. These data suggest that primary prevention strategies should be initiated early in this ethnic group.* As compared with whites or blacks.† High body fat per unit of body mass index.II As estimated by skinfold thicknessmeasurements or imaging techniques.¶ Particularly in the lower extremities.‡ This may be due to less lean mass atthe hips resulting in a smaller hip circumference.§ Average value of waist circumference usuallydoes not exceed the currently accepted cutoffvalues for abdominal obesity.*Misra, Nutrition May;20(5):482-91
10Relative Serum Concentrations 07/09/13Indian dyslipidemia is different from its Western counterpart in terms of lipid parametersComparison of Indian vs. Western DyslipidemiaLipidRelative Serum ConcentrationsTCSimilarLDL-CSimilar (129 Vs 124 mg/dL)sd-LDL-CTGHigher (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)AtherogenicDyslipidemiaA study of Asian Indians living in the United States found that 54% of men had an HDL level below 40 mg/dL, and 68% of women had levels below 50 mg/dL. In the United States, 43% of Asian Indian males and 24% of Asian Indian females have levels that exceed 150 mg/dL. Lipoprotein(a) is still considered an emerging risk factor in the US population at large, but appears to be a major risk factor in Asian Indians.5,26-29A high level of Lp(a) is the most prevalent dislipidemia in patients with premature CHD. Lp(a) levels are governed almost exclusively by race, ethnicity, and genetics, unlike other lipids, where the levels are influenced by age, gender, diet, and other environmental factors.30-33Although Lp(a) levels >30 mg/dL are generally considered the threshold at which high risk of premature CHD increases rapidly, levels below 20 mg/dL are considered optimum, particularly in Asian Indians.14,28 Studies of Asian Indians in North America found that 25% to 50% of sampled populations have levels >30 mg/dL.Lp(a) – binds to plasminogen receptors and prevents activation of Plasminogen (which is fibrinolytic on activation to plasmin)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/dL20th Annual Convention of the American Association of Physicians of Indian OriginClinical Implications: Dyslipidemia in the Asian Indian Population June 29, 2002
11ADD affects TG, LDL-C and HDL-C 07/09/13ADD affects TG, LDL-C and HDL-C↔ LDL-C (>100) & ↑sd-LDL-C↑TG>150The Triad ofADDThis is the triad of diabetic dyslipidemia in Indians, mainly contributes to high TG & low HDL and high small dense LDL.↓HDL-C <40 for Males <50 for FemalesSarma ,IHJ, 2000, 52: Sarma, Am J Med, 1998, vol 105(1A), 48S-56S
123_8510_8907/09/13AgendaHow 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 Lipaglynin treatment of DD?
13Why diabetics are more prone to ADD? 07/09/13Why diabetics are more prone to ADD?↑HSLInsulin resistance in Type 2 diabetes mellitus leads to increased lipolysis in the fat cells in adipose tissue, because the inhibitory effect of insulin on hormone-sensitive lipase is removed, which leads to increased delivery of free fatty acids (FFAs) to the liver.Type II Diabetes is characterized by insulin resistanceIR: 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.
14Why diabetics are more prone to ADD? 07/09/13Why diabetics are more prone to ADD?↑HSLIncreased Delivery of FFA to liver increases VLDL formation (insulin resistance also increase Apo B formation in the Liver). So plasma VLDL (hence TG level) is increased.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.
15Why diabetics are more prone to ADD? 07/09/13Why diabetics are more prone to ADD?↑HSLVLDL exchanges its TGs with HDL via Cholesterol ester transfer protein (VLDL gives away TG and accepts cholesterol ester from HDL)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.
16Why diabetics are more prone to ADD? 07/09/13Why diabetics are more prone to ADD?↑HSLPathophysiology of Diabetic Dyslipidemia - HN Ginsberg in J Clin Invest 2000, explains the mechanism of dyslipidemia in Diabetics - Insulin resistance in Type 2 diabetes mellitus leads to increased lipolysis in the fat cells in adipose tissue, because the inhibitory effect of insulin on hormone-sensitive lipase is removed, which leads to increased delivery of free fatty acids (FFAs) to the liver. Increased Delivery of FFA to liver increases VLDL formation (insulin resistance also increase Apo B formation in the Liver). So plasma VLDL (hence TG level) is increased. VLDL exchanges its TGs with HDL via Cholesterol ester transfer protein (VLDL gives away TG and accepts cholesterol ester from HDL)By the same mechanism it exchanges its TG for CE from LDL as well. The TGs now acquired by HDL and LDL are digested by lipoprotein lipase and/or hepatic lipase. LDL thus gets converted to the more atherogenic small-dense LDL and HDL loses its Apo A – 1 which gets excreted through kidneys – lowering HDL levels.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.
173_858_8907/09/13AgendaHow 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 LipaglynTM is different?Trial & evidence of Lipaglyn efficacy & safety?What is the proposed place for Lipaglyn in treatment of DD?
18Mortality rate is doubled in individuals with diabetes* 07/09/13Mortality rate is doubled in individuals with diabetes*35Ratio 2.5Ratio 2.2Ratio 2.13025Mortality rate (deaths per 1,000 patient-years)2015105N= 6908N= 657Various studies have shown that mortality is double in diabetics than non-diabetics. NCEP guidelines suggest that diabetes alone is a “CHD equivalent” risk factorWhitehallStudyHelsinkiPolicemen StudyParis Prospective StudyN = 10087N= 6908N= 657Diabetes is CHD equivalent: NCEP ATP III guidelines^Control (non-diabetes)*Balkau B, et al. Lancet 1997; 350: ^SM Grundy et al,Circulation. 2004;110:Diabetes18
19Dyslipidemia is the single most important CV risk factor for MI 12_8407/09/13Dyslipidemia is the single most important CV risk factor for MIINTERHEART 9 Modifiable factors account for 90% of first-MI risk worldwideDyslipidemia alone accounts for CV risk in 50% of the populationYusuf S et al, Lancet; 364:937-52
2007/09/13In dyslipidemia patients with diabetes, CV risk is heightened by 3-4 times as compared to dyslipidemia without diabetesJ Stamler et al point out that the data of MRFIT (Multiple Risk Factor Intervention Trial) shows, CV risk is increased by 3-4 times in patients with DM + Dyslipidemia Compared to dyslipidemia alone.J Stamler et al, Diabetes Care February 1993:16:
21Hypertriglyceridemia has a direct relation with insulin resistance 07/09/13Hypertriglyceridemia has a direct relation with insulin resistanceTG levelsInsulin levels150 mg/dl150 pmol/L300 mg/dl325 pmol/LIncreased secretion of insulin after a fixed amount of glucose given orally is suggestive of insulin resistance. Such insulin secretion is increased in high TG patients, so high TG has direct relation with the insulin resistance.Insulin pmol/L*Total area under 3 hours response curve (mean of 2 tests)Olefsky JM et al. Am J Med. 1974;57:
22Hypertriglyceridemia is an independent CV risk factor 27650_85Hypertriglyceridemia is an independent CV risk factorFor every increase in TG level of 89 mg/dL, CVD risk increases by 32% in men and 76% in womenMeta-analysis of 17 studies (> 55,000 patients)A meta-analysis of 17 studies (> 55,000 patients) has shown that for every increase in TG level of 89 mg/dL, CVD risk increases by 32% in men and 76% in women. And concludes that Hypertriglyceridemia is an independent CV risk factorHokanson JE et al. J Cardiovasc Risk. 1996; 3:
23Hypertriglyceridemia in diabetes is an independent CV risk factor 27650_85Hypertriglyceridemia in diabetes is an independent CV risk factorAsian study of diabetic patients (followed up for 4.6 years)Hypertriglyceridemia in T2DM patients increase CV risk by 3 times compared to T2DM patients without high TG.Even an Asian study has pointed out that high TG in T2DM increases CV risk by 3 timesDiabetes Metab Res Rev Mar-Apr;21(2):183-8.
24Overall CHD Risk Ratio* 6_8507/09/13Patients in highest tertile of serum TG had 72% higher risk of CVD than those in lowest tertileMeta-Analysis of 29 StudiesGroupsCHD CasesCHD Risk Ratio* (95% CI)Duration of follow-up≥10 years5,902<10 years4,256SexMale7,728Female1,984Fasting statusFasting7,484Non-fasting2,674Adjusted for HDLYes4,469No5,689Overall CHD Risk Ratio*N = 2,62,525Triglyceride Level Is Significant CVD Risk Factor: Recent Meta-Analysis of 29 Studies:A recent meta-analysis by Sarwar et al1 included 29 prospective studies and was the largest and most comprehensive epidemiological assessment of the association between triglyceride values and CHD risk in Western populations ( participants; 10,158 CHD cases). A combined analysis of the 29 studies yielded an adjusted odds ratio of 1.72 (95% CI, ) in a comparison of extreme thirds of usual triglyceride values (ie, individuals with usual log-triglyceride values in the top third of the population compared with those in the bottom third). This odds ratio was adjusted in all but one study for at least age, sex, smoking status, lipid concentrations, and most studies also adjusted for blood pressure. The above figure shows the CHD risk ratio adjusted for several established risk factors and grouped according to several study characteristics (ie, duration of follow-up, sex, fasting status, and adjusted for HDL-cholesterol). The data indicate that the impact of triglycerides on CHD risk is similar in women and men and also regardless of duration of follow up. The data suggest no important differences in the strength of associations between triglycerides and CHD in studies of fasting participants compared with studies of nonfasting participants. Finally, adjustment for HDL-cholesterol attenuated the magnitude of the association between triglyceride level and CHD risk. The conclusion of the study is that there is a strong and highly significant association between triglyceride value and CHD risk.Reference1. Sarwar N, et al. Circulation. 2007;115:1.72 ( )123Increased RiskSarwar N, et al. Circulation. 2007;115:*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)24
25Hazard Ratio for CHD is directly related to TG concentration CHD risk is directly proportional to serum triglycerides in a large study of > 3,00,000 patients. The odds ratio for coronary heart disease was 1.18 (95% CI ; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI ) per 16% higher triglyceride concentration recorded in prospective studies T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI ]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [ ]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride. These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart diseaseThe Emerging Risk Factors CollaborationJAMA November 11; 302(18): 1993–2000
2660418_8507/09/13Increased CV risk can be due to other serious consequences of hypertriglyceridemiaLow levels of HDL-CThe presence of sd-LDL-C particlesThe presence of atherogenic triglyceride-rich lipoprotein remnants Insulin resistanceIncreases in coagulability and viscosityPro-inflammatory statusThe Above consequences may be related to high CV risk of high TGMiller M. Eur Heart J Jul;19 (Suppl H): H18-22
273_858_8907/09/13AgendaHow 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?
28Relevance of TG<100 mg/dL - lower the TG lower the sd-LDL-C 07/09/13Relevance of TG<100 mg/dL - lower the TG lower the sd-LDL-CAt 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 mg/dL may not be optimal to reduce atherosclerosisPattern B: a predominance of small, dense LDL particlesPattern A: large, more buoyant LDL particles predominateMost doctors believe that TG lowering drugs (PPAR Alpha agonists) are not required except when TG > 250 mg/dl. A following reference suggests that 85 % of total LDL will be Small Dense LDL(sdLDL). when TG is 250. so to reduce the sdLDL, TG should be reduced to 100 mg/dl (when sdLDL is just 15%). As sdLDL is known to be more atherogenic, keeping TG at may not reduce atherosclerosis completely. and target of TG < 100 mg/dl may be considered.ALP – Atherogenic Lipoprotein Phenotype"A threshold appears to exist for a fasting TG concentration above which there will be a predominance of small, dense LDL particles(pattern B) and below which large, more buoyant particles will predominate (pattern A). The TG concentration that produces a shift from one subclass pattern to another varies with each patient. At a fasting TG concentration ,100 mg/dL, 85% of the population has pattern A, whereas at a fasting TG concentration .250 mg/dL, 85% will have pattern B 17. Thus, lowering the TG concentration from 600 mg/dL to 260 mg/dL is unlikely to change a patient’s LDL particle size because most patients have a threshold for shifting LDL subclass pattern within the range of 100 to 250 mg/dL"Austin et al, Circulation. 1990; 82:
29Global Guidelines (Goal for TG) 07/09/13With the realization of importance of TG, the suggested target for TG has kept coming downTG Designate1984 NIHConsensus Panel1993 NCEP Guidelines2001 NCEP Guidelines2011 AHAStatement<100(optimal)Desirable<250<200<150Global Guidelines (Goal for TG)ESC< 150 mg/dlAHAACCADALink:As the importance of TGs in health is realized gradually, their normal value has gone lower and lower:ESC : European Society of CardiologyAHA: American Heart AssociationACC: American College of CardiologyADA: American Diabetes AssociationCirculation. published online April 18, 2011
30Lets look how TG reduction benefits in outcome… 07/09/13Lets look how TG reduction benefits in outcome…
3107/09/13Myth:There is a widespread myth that PPARalpha agonists do not reduce CV events in diabetics (e.g. primary analysis if FIELD and ACCORD)FACT : Sub-analysis of the above two trials show benefit in high TG and low HDL
32CV benefits of PPAR alpha agonists 07/09/13CV benefits of PPAR alpha agonistsVA-HIT:Primary Endpoint (non-fatal MI and CHD death)BIP study3090 CAD patients were randomized to bezafibrate vs Placebo, primary end point was fatal, nonfatal MI/sudden death Follow up:6.2 yrs2500 CHD patients randomized to gemfibrozil or placebo follow up; 5 yrsCV benefits were seen in studies like VA-HIT (Gemfibrozil – in all patients) and BIP (Bezafibrate in patients with TG > 200 mg/dl) studiesRubins HB et al, N Eng J Med, August 5, 1999 Vol. 341; BIP Study Group Circulation. 2000;102:21-27
334_85 10_8507/09/13Let’s understand what the FIELD trials show about the benefits of PPAR- α therapy9795 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/dLBaseline Lipid levels:LDL-C mg/dL (mean)TC mg/dL (mean)HDL-C 43 mg/dL (mean)TG mg/dL (median)PlaceboN=4900Fenofibrate(200 mg)N=4895Keech A et al found that Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.Thru this study they were also trying to find out if fenofibrate had a pleiotropic benefit like statins.EndpointsPrimary - Composite of CHD death or non-fatal MI at 5 year follow-upSecondary - Composite of total CV events, CV mortality, total mortality, stroke, coronary revascularization and all revascularization at 5 year follow-upKeech A et al, Lancet 2005; 366: 1849–61
34PPAR-α agonist showed no clear benefit in primary endpoints 34 34PPAR-α agonist showed no clear benefit in primary endpointsComposite CHD death or nonfatal MI at 5 Years (% of treatment arm)p=0.16N= 9795In FIELD study, the difference in primary outcome was insignificant between the two groups, which is responsible for the “perception” that the study failed. Fenofibrate did not show pleiotropic benefits.Perception is that FIELD trial failed, but lets look critically at high TG Population or Atherogenic Dyslipidemics..Lancet 2005; 366: 1849–61
3507/09/13PPAR-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%% patients developing events% patients developing eventsIn the subgroups of > 2000 patients (High TG and High TG + Low HDL) , PPAR alpha agonist therapy significantly reduced CV events by 23% and 27% respectivelyP=0.01N=2517P=0.005N=2014R Scott et al, Diabetes Care 32:493–498, 2009
36Let’s also look at what ACCORD trials show about the benefits of PPAR-α therapy 5518 patients with type 2 diabetes (HbA1c > 7.5%) who were being treatedAll patients were on open-label simvastatin. Median Age: 62.3 years % patients had CVD.Baseline:TG: 162 mg/dlTC: mgLDL: mg/dlHDL: 38.6 mg/dlFenofibrate 160 mgPlaceboIn ACCORD, the DM patients were given PPAR alpha agonist or placebo. All patients were on simvastatin at baselineThe 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:
37% patients developing primary end Point 07/09/13However, ACCORD results did not show any significant CV benefits in overall populationThe 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% patients developing primary end PointDifference in the 2 groups was not significantACCORD Study Group. N Engl J Med. 2010;362:
38% patients developing events 07/09/13ACCORD: PPAR-α agonist significantly reduce CV events in T2DM patients with TG>204 and HDL<34 (ADD)↓31%P=0.03N=941% patients developing eventsAlexander Tenenbaum and Enrique Z Fisman found that in a subgroup of 941 patients (out of 5518) of ACCORD study with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol, PPAR alpha agonist reduced primary end point significantly by 31%941 T2DM patients (already on simvastatin) were randomized to fenofibrate or placebo Mean Follow up: 4.7 yrs*MI, stroke and deathTenenbaum and Fisman, Cardiovascular Diabetology 2012, 11:125
39Limitation & Learning from FIELD & ACCORD Trial 51203_8507/09/13Limitation & Learning from FIELD & ACCORD TrialFIELD StudyLimitationMore patients in the placebo group (17%) than in the PPAR-alpha agonist group(8%) received the non-study lipid-lowering agents (predominantly statins) .LearningIf 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-CPPAR-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 trialFIELD StudyIn FIELD, PPAR agonist therapy was successful to improve CV outcome in T2DM patients with high TG and low HDL if the difference in statin therapy was adjustedWhile in ACCORD such benefits were seen in similar patients even were patients were on statin from the baselineACCORD Study
40Change in relative Risk (%) 07/09/13By lowering TG, PPAR-α agonists can reduce the macro- & microvascular complications of T2DMMajor CV eventsCoronary eventsAlbuminuriaRevascularizationRetinopathyP=0.048P=0.02Change in relative Risk (%)P<0.0001P=0.025Jun M et al Identified 18 trials providing data for participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0-18) for major cardiovascular events (p=0.048) and a 13% RR reduction (7-19) for coronary events (p<0.0001), but had no benefit on stroke (-3%, -16 to 9; p=0.69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, -8 to 7; p=0.92), cardiovascular mortality (3%, -7 to 12; p=0.59), sudden death (11%, -6 to 26; p=0.19), or non-vascular mortality (-10%, -21 to 0.5; p=0.063). Fibrates reduced the risk of albuminuria progression by 14% (2-25; p=0.028). Serious drug-related adverse events were not significantly increased by fibrates ( participants, 225 events; RR 1.21, ; p=0.19), although increases in serum creatinine concentrations were common (1.99, ; p<0.0001). Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemiaP<0.000118 trials metaanalysis, > patientsJun M et al, Lancet 2010; 375: 1875–84
41TG > 204 mg/dl and HDL < 34 mg/dl 8_8407/09/13In 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)P<0.05TG > 204 mg/dl and HDL < 34 mg/dlTG < 204 mg/dl and HDL > 34 mg/dlN=4726In a meta analysis of 5 landmark studies, PPAR agonist therapy reduced CV events significantly by 31% in 4726 patients with TG > 204 mg/dl and HDL < 34 mg/dl. The benefits were not seen in other remaining patientsN Engl J Med. 2010:363(7):692-4Diabetes Care 32:493–498, 2009
4207/09/13In 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)In patients with high TG and Low HDL, PPAR alpha agonist therapy reduced CV events, with or without statin in different large studies done in last 30 yrs
43Let’s look how good Glycemic Control helps… 07/09/13Let’s look how good Glycemic Control helps…
44As per UKPDS follow-up for another 10 years, optimal glycemic control can reduce the risk of microvascular complications, even till a decade later.4444Optimal glycemic control leads to ~24% risk reduction for microvascular diseases(Microvascular diseases included are photocoagulation, vitreous hemorrhage, renal failure)UKPDS 80. NEJM 2008;359:
45Baseline Values: TG – 160 mg/dL 4545 Let’s understand what the PROactive trial about the benefits of glycemic control and CV outcomes through PPAR γ therapyProspective, randomised, double-blind, placebo-controlled, study5238 patients with type 2 diabetes (with macrovascular disease)Pioglitazone15-45 mg(n=2605)Placebo(n=2633)Baseline Values:TG – 160 mg/dLJA Dormandy et al have published in the Lancet showing that there is also data that optimal glycemic control with PPAR gamma agonists can provide CV (Macrovascular) benefits as shown by PROACTIVE STUDY.End Point: Time to death, MI (except silent MI) and strokeFollow up: 34.5 monthsPROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events)JA Dormandy et al,Lancet 2005; 366: 1279–89
46Need redesign4646PPAR-γ agonist reduced CV end points (Death, MI, stroke) significantly (by 16%) in DM patients with baseline TG 160 mg/dL16% risk reductionIn this study, PPAR gamma agonist reduced CV events significantly by 16% over placebo.JA Dormandy et al, Lancet 2005; 366: 1279–89
47Need redesign4747A 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 % CI P=0.0054.4%Patients %PPAR gamma agonist (TZD - Pioglitazone) is associated with a significantly lower risk of death, myocardial infarction, or stroke (by 18%) among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortalityPioglitazoneControlLincoff et al. JAMA 2007;298:
4807/09/13We understood the importance of TG reduction and good Glycemic Control- now what next?
49Non-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.ConclusionNon-HDL-C was a stronger indicator of CV risk than LDL-CSelf-explanatoryPaul Ridkar JAMA. 2005;294:
50Non-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 aloneIf 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 levelsAACE Dyslipidemia GuidelinesSelf-explanatoryJellinger PS, et al. ENDOCRINE PRACTICE Vol 18 (Suppl 1) March/April 2012:1-78)
51Non-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)ConclusionNon-HDL-C decrease outperforms ApoB decrease for prediction of CHD and CVD risk.Its decrease is a better predictor of CHD and CVDImportance of non-HDL:Non-high-density lipoprotein (non-HDL) cholesterol decrease outperformed apoB decrease for prediction of coronary heart disease and is a better predictor of CHDRobinson J,,Am J Cardiol 2012;110: 1468–1476
52Importance 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.ConclusionNon-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)Among statin-treated patients, on-treatment levels of LDL-C, non–HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non–HDL-C than for LDL-C and apoB8 studies: 4S, LIPID , AFCAPS, WOSCOPS, CARDS, IDEAL, TNT, SPARCL JUPITERBoekholdt S, JAMA. 2012;307(12):
539_8507/09/13To sum up - Non-HDL-C is a better indicator of residual risk than LDL-CNon–HDL-C is as good as or better than LDL-C in the prediction of future cardiovascular eventsJAMA. 2005;294:When triglycerides are between mg/dl a non–HDL-C calculation provides better risk assessment than LDL-C aloneAACE 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 therapyAm J Cardiol 2012;110: 1468–1476Among statin-treated patients, the strength of this association with CVD is greater for non–HDL-C than for LDL-C and ApoBJAMA. 2012;307(12):1. Self-explanatory2. Non-high-density lipoprotein (non-HDL) cholesterol decrease outperformed apoB decrease for prediction of coronary heart disease3. Among statin-treated patients, on-treatment levels of LDL-C, non–HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non–HDL-C than for LDL-C and apoB4. Self-explanatory
54Non-HDL-C target (mg/dL) 07/09/13Non-HDL-C targets are related to LDL-C targets but differ by patient categoriesPatient CategoryLDL-C target (mg/dL)Non-HDL-C target (mg/dL)CHD + DM<70<100CHD/CHD risk equivalent<130No CHD, 2+ RF<160No CHD, <2 RF<190Non HDL goal is 30 mg/dl more than LDL-C goal (NCEP-ATP III)Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:
553_858_8907/09/13AgendaHow 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?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?
56Current Management of ADD 3_8507/09/13Current Management of ADDLifestyle changes and Rx of secondary causesPharmacologic therapyAnti-diabetic therapyLipid managementStatinsFibrateNiacinOmega-3 fatty acidsCombination therapyVarious life style changes (like 150 minutes of moderate exercise in a week, reduced intake of refined sugars and saturated fats, increased intake of dietary fibers and omega 3 PUFA(poly unsaturated fatty acid)s)) as well as drugs are used for management of High TG. Various drugs and lifestyle changes in combination can be used to get optimal control on serum TG
57ADA/EASD guidelines for management of diabetes Algorithm/treatment protocolADA-EASD has made a Joint statement in 2012 to guide management of diabetes based on the review of efficacy, major adverse events and cost of therapy and long term benefits of different drug groups used for diabetes management.Diabetes Care 2012:35:
58128002_8907/09/13Limitations of current treatment of uncontrolled hyperglycemia after metformin therapy in T2DMSulfonylurea/Meglitinides: they are known to lead to early Beta cell fatigue by excessive stimulation* + significant risk of hypoglycemia and weight gainPioglitazone: Significant weight gain, osteoporosis **Insulin: Parenteral administration, significant risk of hypoglycemiaGLP-1 analogues: Parenteral administration, severe GI disturbance in initial periodDPP-IV inhibitors: Possible risk of pancreatic metaplasia and pancreatitis^, URTICurrently used drugs for diabetes have multiple limitations, so newer drugs are required to achieve optimal glycemic control.* J Clin Endocrinol Metab. 2005;90:501–506, **Diabetes Care 2011; 34(4):^ JAMA Intern Med 2013 Feb 25:1-6
59Current Management of ADD 3_8507/09/13Current Management of ADDLifestyle changes and Rx of secondary causesPharmacologic therapyAnti diabetic therapyLipid managementStatinsFibrateNiacinOmega-3 fatty acidsCombination therapyVarious life style changes (like 150 minutes of moderate exercise in a week, reduced intake of refined sugars and saturated fats, increased intake of dietary fibers and omega 3 PUFA(poly unsaturated fatty acid)s)) as well as drugs are used for management of High TG. Various drugs and lifestyle changes in combination can be used to get optimal control on serum TG
6007/09/13Managing Dyslipidemia in T2DM reduces CV events CARDS: Atorvastatin Significantly Reduces Major CV Events in DM patients*In CARDS (Collaborative Atorvastatin Diabetes Study), atorvastatin 10 mg/day reduced CV events by 37% in diabetic patients without CVD.BaselineEnd of StudyTG173 mg/dl143 mg/dlLDL118.5 mg/dl82 mg/dlHDL54 mg/dl49 mg/dl*Acute CHD event, coronary revascularization, stroke.Colhoun HM et al. Lancet. 2004;364:
6107/09/13Managing Dyslipidemia in T2DM reduces CV events ASCOT-LLA: Total CV Events reduced by 23% with Atorvastatin in Patients With HT+DMIn ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial - lipid-lowering arm-LLA), Atorvastatin 10 mg/day reduced CV events by 23% in diabetic patientsBaselineEnd of StudyTG169 mg/dl128 mg/dlLDL129 mg/dl83 mg/dlHDL48 mg/dlServer PS et al. Diabetes Care, 2005; 28:
62Residual CHD risk in major statin trials Almost all major statin trials have shown that residual risk remains in many patients treated with statins62
63Statins alone are not sufficient in Diabetic Dyslipidemia 07/09/13Residual CVD risk remains in patients with diabetes treated with statinsHPS1: n = 5963*CARDS2: N = 283822% RiskReduction32% RiskReductionAcute CVD Event Rate (%)Major Vascular Event Rate (%)78% Residual CVD Risk68% Residual CVD RiskIn T2DM patients statins reduce CV risk by upto 20-30%. But still 70-80% events occur as statin cannot optimally control other lipids (e.g. high TG)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:
643_8507/09/13Fibrates do not seem to be the optimal solution for managing residual risk eitherPROS:Reduction in TG, LDL-C & raises HDL-C, used alone or in conjunction with statinsCONS:Increased risk of gall stonesAbnormal Liver Function Tests (increased AST and ALT levels) in 7.5% patientsIncreased serum creatinine levels.Fibrates are effective to control High TG, but they have many disadvantages like hepatotoxicity, gall stones, reduced serum creatinine, etcRef - TRICOR Prescribing Information
6507/09/13Fibrates have adverse effect on renal function in CKD patients A meta analysis of 10 studies, 16,800 patients with CKD (eGFR < 60 ml/min)In a meta-analysis, Fibrates significantly reduced eGFR in CKD patientsFibrate therapy significantly reduces eGFR by 2.67 ml/min(p=0.01) in CKD patientsJun M et al, (J Am Coll Cardlol 2012;60: )
66In mixed dyslipidemia, Statin + Fibrate combination is not always safe 07/09/13In mixed dyslipidemia, Statin + Fibrate combination is not always safeStatins combined with fibrate increases the incidence of statininduced myopathies, by 5.5-fold compared with statin use aloneMH Davidson et al, Am J Cardiol 2007;99[suppl]:3C–18CConcomitant therapy with statin and fibrate increases risk of muscle related Adverse events specially Rhabdomyolysis which is significantly increased by 5.5 times.So, newer drugs which can be well tolerated specially when administered with statins are neededJAMA 2004;292:2585–2590
67HPS 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)20Risk ratio 0.96 (95% CI 0.90 – 1.03)Log rank P=0.291515.0%14.5%Patients suffering events (%)10PlaceboERN/LRPT5Conclusion: The risk of myopathy was increased by adding ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ∼1 month, three-quarters continued to take it for ∼4 years.1234Years of follow-upERN/LRPT: Extended release niacin + Laropiprant25673 CVD patients were randomized to ERN/LRPT or placebo (all on simvastatin)European Heart Journal (2013) 34, 1279–129167
68Omega 3 Fatty AcidsEicosapentaenoic 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 ADRsTheir effects on CV events are disputed, some studies suggest that they reduce CV events, other studies report the opposite.High doses required, taste and smell may lead to non-compliance and at best they have shown inconsistent results
69Omega 3 Fatty acids have shown inconsistent effects on CV outcomes in different studies J Am Coll Cardiol 2011;58:2047–67
703_858_8907/09/13AgendaHow 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 ADD?How Lipaglyn is different?Trial & evidence of Lipaglyn efficacy & safety?What is the proposed place for Lipaglyn in treatment of DD?
71The importance of controlling both glucose and lipid levels in Diabetic dyslipidemia gave rise dual agonistsPPARα is found in the liver, kidney, heart, skeletal muscle and vasculature, is implicated in the uptake and oxidation of fatty acids and lipoprotein metabolism. PPARgamma is mainly expressed in adipose tissue with lower expression detected in a wide range of differing tissues like spleen, intestine, pancreas, colon, kidney, skeletal muscle and macrophages. PPARγ agonists have beneficial effects on glucose homeostasis by increasing insulin sensitivity and glucose disposal and prevent the loss of beta cell mass in the pancreas. Fibrates are PPARα agonist used for triglyceride lowering in clinics and PPAR gamma agonists, Rosiglitazone and Pioglitazone are proven to be efficacious as insulin sensitizing agents for the treatment of type 2 diabetes.Diabetes Aug;54(8):
72RGZ/FEB was more effective and safe than RGZ alone Combination therapy of PPARα & PPARγ agonists, results in reduction of TG & A1c levels without increasing body weight in T2DM patientsIn 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 aloneRGZ/FEB lowered fasting plasma FFA more effectively than RGZ alone (22 vs. 5%, P < 0.05), andMore 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)ConclusionThe combination of Rosi + Feno decreased FFA, TG, HbA1c more than Rosi alone. The combination also prevented the fluid retention associated with Rosi aloneBoden G, et al. Diabetes 56:248–255,2007
73Change in body water with Rosiglitazone Vs Rosiglitazone + Fenofibrate Water was retained in the Rosi alone groupR/F: Rosiglitazone/FenofibrateR: Rosiglitazone Boden G, et al. Diabetes 56:248–255,2007
74To sum up…. ADD is highly prevalent in the Indian diabetic population 07/09/13To sum up….ADD is highly prevalent in the Indian diabetic populationControl of hypertriglyceridemia is equally vital in reducing the CV events as is optimal glycemic controlNon-HDL-C is a better indicator of CV risk than ApoB and LDL –CMany unmet needs exist in the current management of ADD and a significant residual CV risk prevails despite the current optimal therapyCombined action of PPARα & PPARγ agonists results in reduction of TG & A1c levels without increasing body weight in T2DM patientsA 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 ADDADD is highly prevalent in the Indian diabetic populationControl of hypertriglyceridemia is equally vital in reducing the CV events as is optimal glycemic controlNon-HDL-C is a better indicator of CV risk than ApoB and LDL –CMany unmet needs exist in the current management of ADD and a significant residual CV risk prevails despite the current optimal therapyCombined action of PPARα & PPARγ agonists results in reduction of TG & A1c levels without increasing body weight in T2DM patientsA 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