1. Lipoprotein Metabolism Introduction to Diabetic dyslipidemia Extent of Diabetic dyslipidemia in India Lipid metabolism in Diabetes Mellitus Guidelines Treatment Recent advances in the management 2

2. Lipoproteins macromolecules that transport hydrophobic lipids (triglycerides, cholesterol & fat-soluble vitamins) through body fluids (plasma, interstitial fluid, and lymph) to and from tissues. Lipoproteins contain a core of hydrophobic lipids (triglycerides and cholesteryl esters) surrounded by hydrophilic lipids (phospholipids, unesterified cholesterol) and proteins that interact with body fluids. 3 3. Lipoprotein Metabolism 4 5 classes of lipoproteins classified based on the density Most plasma triglyceride is transported in chylomicrons or VLDLs Most plasma cholesterol is carried as cholesteryl esters in LDLs and HDLs. 4. Proteins associated with lipoproteins apolipoproteins Assembly, structure, and function of lipoproteins Activate enzymes of lipoprotein metabolism & are ligands for cell- surface receptors ApoA-I - found on virtually all HDL particles ApoA-II - second most abundant HDL apolipoprotein found on about 2/3rd of all HDL particles ApoB - major structural protein of chylomicrons, VLDLs, IDLs, and LDLs (apoB48 and apoB100) ApoE is present on chylomicrons, VLDLs, and IDLs & Three apolipoproteins of the C series - metabolism and clearance of triglyceride-rich particles Lipoprotein Metabolism 5 5. Lipoprotein Metabolism 6 6. Lipoprotein Metabolism 7 7. Cardiovascular disease - more common in diabetic patients than in the general population Dyslipidemia common in patients with both types of diabetes. Hyperglycemia microvascular complications Dyslipidemia macrovascular complications Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for CVD Aggressive lipid treatment goals have been recommended for patients with type 2 diabetes 8 8. Introduction 9 LDL-C sd-LDL-C HDL-C TG The Triad of Diabetic Dyslipidemia 9. Insulin resistance contributes to this characteristic dyslipidemia Propensity to develop atherosclerotic disease - much higher in these patients also called Atherosclerotic Diabetic Dyslipidemia (ADD) Disturbance of lipid metabolism early event, potentially preceding the disease by several years. Monitoring of the conventional (LDL-C) may be misleading in diabetic patients requires specific monitoring Introduction 10 10. Introduction 11 9 Modifiable factors account for 90% of first-MI risk worldwide 11. India has a large pool of diabetic patients ICMR-INDIAB study extrapolated estimations suggest 62.4 million people with diabetes and 77.2 million are prediabetic Estimates show ~ 85.5% men and 97.8% women who are diabetic in India have concomitant dyslipidemia Extent of DD in India 12 12. 13 Research in 2004 forecast that the Indian diabetic population would reach ~80 million by 2030 Extent of DD in India 13. Extent of DD in India 14 Worldwide 14. Extent of DD in India 15 85.5% 97.8 %85.5 % Prevalence of Dyslipidemia (%) in Male T2 DM Prevalence of Dyslipidemia (%) in Female T2DM In India Nearly 90% Indian diabetics compared to 72% worldwide >55 millions patients of diabetic dyslipidemia in India 15. Factors affecting higher prevalence in indians 1. Diet Dyslipidemic profile - seen in vegetarians Indian diets rich in carbohydrate and low in Omega-3 PUFA- exacerbates hypertriglyceridemia 2. Physical Activity Asian Indians-more physically inactive 3. Genetic Factors Abnormal variants of ApoC 3 and ApoE 3 genes common in India The "Starvation Gene Theory" 4. Body composition Excess body fat in relation to body mass index High waist-to-hip ratio High intra-abdominal fat Extent of DD in India 16 16. Extent of DD in India 17 Lipid Relative Serum Concentrations TC Similar LDL-C Similar (129 Vs 124 mg/dL) sd-LDL-C Similar TG Higher (174.5 Vs 146 mg/dL) HDL-C Lower (40.5 Vs 46.4 mg/dL) Comparison of Indian vs. Western Dyslipidemia 17. Lipid metabolism in Diabetes 18 18. Lipid metabolism in Diabetes 19 19. Lipid metabolism in Diabetes 20 20. Lipid metabolism in Diabetes 21 21. Triglycerides and VLDL Hypertriglyceridemia secondary to increase in VLDL Triglycerides increase by 50 100% above baseline only If TG >400 mg/dl likely genetic defect in lipoprotein metabolism High VLDL and TG - due to increased substrate* flow into liver VLDL does not get cleared easily VLDL apoB is over produced, but triglycerides increase more than apoB Thus VLDL is richer in TG (increased ratio of triglyceride to apoB ) Lipid metabolism in Diabetes 22 22. Triglycerides and VLDL Increased VLDL Insulin resisitance a) Glucose and Fatty acid levels - Increased substrate into the liver for VLDL synthesis b) Triglycerides in the liver inhibit apoB degradation Increased secretion of VLDL c) Lipoprotein lipase levels reduced in insulin resistance reduced VLDL clearance Altered VLDL composition - contributes to the atherosclerotic propensity Lipid metabolism in Diabetes 23 23. Lipid metabolism in Diabetes 24 Lipoprotein Alterations VLDL Increased production of triglyceride and apoB Decreased clearance of triglyceride and apoB Abnormal composition LDL Increased production of LDL apoB Triglyceride enrichment Decreased receptor mediated clearance Smaller (more dense) particle distribution Glycation Oxidation HDL Increased clearance of apoA Decreased proportion of large HDL Triglyceride enrichment Glycation Diminished reverse cholesterol transport 24. LIPOPROTEINS IN TYPE 1 DIABETES Triglyceride-rich lipoproteins - increased hypertriglyceridemia Severe insulin deficiency in DKA Poor lipoprotein lipase activity poor clearance of TG rich cholesterol molecules As TG rich molecules are not catabolized, LDL particles remain same or low HDL decreases in a mechanism similar to Type 2 Diabetes (High VLDL High rate of TG transfer to HDL faster clearance) Lipid metabolism in Diabetes 25 25. Widespread agreement that LDL cholesterol should be less than 130 mg/dL in almost all persons with diabetes American Diabetes Association recommends an LDL-cholesterol goal of less than 100 mg/dL in diabetic persons. Most persons with diabetes will require an LDL-lowering drug to reach the LDL goal of 200 mg/dl Non-HDL-C (Total cholesterol HDL) ApoB containing cholesterol Need not be a fasting sample LDL-C unreliable as a predictor of CV events when on lipid lowering agents, while Non-HDL-C continue to be a good predictor even on therapy* Non-HDL-C recommended normal levels are 30 mg/dl higher than LDL-C thresholds Very simple to calculate (unlike apoB) Guidelines 27 27. NonHDL-C is as good as or better than LDL-C in the prediction of future cardiovascular events JAMA. 2005;294:326-333 When triglycerides are between 200- 500 mg/dl a nonHDL-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: 14681476 Among statin-treated patients, the strength of this association with CVD is greater for nonHDL-C than for LDL-C and ApoB JAMA. 2012;307(12):1302-1309 Non-HDL-C is a better indicator of residual risk than LDL-C Guidelines 28 28. Global Guidelines (Goal for TG) ESC < 150 mg/dl AHA ACC ADA Guidelines 29 TG Designate 1984 NIH Consensus Panel 1993 NCEP Guidelines 2001 NCEP Guidelines 2011 AHA Statement