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DIABETIC DYSLIPIDEMIA or Diabetes Lipidus

DIABETIC DYSLIPIDEMIA or Diabetes Lipidus. H. Delshad M.D Endocrinologist Research Institute for Endocrine Scienc es. Outlines :. Diabetes as a CHD risk equivalent How is dyslipidemia different in diabetes ? Diagnosis of dyslipidemia in diabetes

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DIABETIC DYSLIPIDEMIA or Diabetes Lipidus

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  1. DIABETIC DYSLIPIDEMIAorDiabetes Lipidus H. Delshad M.D Endocrinologist Research Institute for Endocrine Sciences

  2. Outlines : • Diabetes as a CHD risk equivalent • How is dyslipidemia different in diabetes ? • Diagnosis of dyslipidemia in diabetes • Evidence for drug therapy to improve outcomes • Which lipoprotein to target first and what should be the initial drug for your patient? • Should all patients with diabetes take statins? • How low should LDL-C go to minimize risk ? • What risk remains after LDL-C management ?

  3. Epidemiologic aspects of diabetic dyslipidemia • Atherosclerosis accounts for 80% of mortality in diabetics : 60% CAD 20% PVD • Risk for CAD : 2 Χ Men , 4 Χ Women • 77% of all hospitalizations of diabetics due to CAD

  4. Dyslipidemia Hypertension Cigarette smoking Obesity Sedentary lifestyle Poorly controlled diabetes Proteinuria Autonomic Neuropathy Emerging risk factors : (e.g., hs-CRP, Homocysteine, LP (a), Fibrinogen, PAI-1, postprandial hyperglycemia) Cardiovascular Risk Factors in Diabetes Modified from Diabetes Care, Vol 20, Suppl 1; Jan, 1997: p.S12

  5. Mortality in Diabetes 50 40 30 % of Deaths 20 10 0 Other Diabetes related causes Other Cancer Infection Other Ischemic Stroke heart heart disease disease Geiss LS et al. In: Diabetes in America 2nd ed. 1995; chap 11

  6. Elevated risk of CVD prior to diagnosis of type 2 DM The increased risk for CHD may precede the clinical diagnosis of diabetes by many years. 117,000 women in the NHS , of whom 6000 developed DM during 20 years of follow-up Hu FB et al. Diabetes Care. 2002;25:1129-1134

  7. Epidemiological studies, such as the Multiple Risk Factor Intervention Trial (MRFIT), have shown that type 2 diabetes is a strong, independent risk factor for CVD mortality. >280 200–220 <180 240–260 Plasma cholesterol, mg/dL MRFIT, an observational study of 348,000 men, of whom 5163 had DM , The presence of DM was associated with threefold to fourfold increased risk for age-adjusted CV mortality at comparable levels of cholesterol, BP, and cigarette smoking. MRFIT study. Stamler J, et al. Diabetes Care. 1993;16:434-444.

  8. Diabetes Increases Cardiovascular Mortality Two-fold in Men Four-fold in Women 60 60 Diabetes No Diabetes 50 50 2x 40 40 4-5x Mortality Rate Per 1000 Mortality Rate Per 1000 30 30 20 20 10 10 0 0 0-3 4-7 8-11 12-15 16-19 20-23 0-3 4-7 8-11 12-15 16-19 20-23 Duration of Follow-up (Years) Duration of Follow-up (Years) Krolewski AS et al. Evolving natural history of coronary disease in diabetes mellitus.Am J Med 1991;90(Supp 2A):56S-61S

  9. Incidence of MI in Finland The 10-year risk of major CHD events in diabetics exceeds 20% , Which is comparable to that observed in non-diabetic with CHD. 45 No Diabetes Diabetes (n=1373) (n=1059) P<0.001 P<0.001 40 35 30 25 7-year incidence of MI (%) 20 15 10 5 0 No MI MI No MI MI Haffner et al. N Engl J Med. 1998;339:229.

  10. The ATP III panel recommendations ,JAMA, 2001 Diabetes is regarded as a CHD risk equivalent. • 10-year risk for CHD  20% • High mortality with established CHD • High mortality with acute MI • High mortality post acute MI

  11. Outlines : • Diabetes as a CHD risk equivalent • How is dyslipidemia different in diabetes ? • Diagnosis of dyslipidemia in diabetes • Evidence for drug therapy to improve outcomes • Which lipoprotein to target first and what should be the initial drug for your patient? • Should all patients with diabetes take statins? • How low should LDL-C go to minimize risk ? • What risk remains after LDL-C management ?

  12. Characteristics and mechanism of Lipoprotein abnormalities in T2DM • The hallmarks of T2DM are : • Hyperglycemia • Insulin resistance • Insulin deficiency Insulin Resistance is central to the pathogenesis of T2DM and contributes to characteristics dyslipidemia  Enzymatic activity ( LPL,  HL , CETP)

  13. T2DM: Development of atherogenicdyslipidemia Insulin resistance NEFAs Large VLDL High TG Catabolism LPL LPL/HL Small LDL Remnants Catabolism Small dense LDL Chol TG HL CETP HDL Smaller HDL

  14. The atherogenic triad of the diabetes mellitus Low HDL-cholesterol The atherogenic triad Elevated TG rich particles Small, dense LDL particles

  15. Atherogenicity of small dense LDL

  16. Outlines : • Diabetes as a CHD risk equivalent • How is dyslipidemia different in diabetes ? • Diagnosis of dyslipidemia in diabetes • Evidence for drug therapy to improve outcomes • Which lipoprotein to target first and what should be the initial drug for your patient? • Should all patients with diabetes take statins? • How low should LDL-C go to minimize risk ? • What risk remains after LDL-C management ?

  17. Screening ● In most adult patients, measure fasting lipid profile at least annually. ● In adults with low-risk lipid values LDL = 100 mg/dl HDL = 50 mg/dl TG = 150 mg/dl lipid assessments may be repeated every 2 years.

  18. NCEP (Adult Treatment Panel III ) : Target Lipid Levels for T2DM , JAMA 2001

  19. Which one does provide more-useful information on CVD risk? • Traditional lipid profiles • Apolipoproteins

  20. Keaney JF Jr et al. N Engl J Med 2014;370:275-278. 2013 American College of Cardiology–American Heart Association Guidelines for Use of Statin Therapy in Patients at Increased Cardiovascular Risk.

  21. Guideline Recommended High, Moderate, and Low Intensity Statin Treatment

  22. Other Lipid Targets

  23. Managing Elevated Non-HDL-C

  24. Traditional lipid profiles •Most risk-score algorithms use total cholesterol or LDL and HDL •Calculating CV risk solely on this basis is a oversimplicaton •VLDL , IDL and Remnants that transport cholesteryl esters ( non-HDL) are also proatherogenic •non-HDL –C ( Total Chol. – HDL ) is more strongly associated with CVD risk than LDL alon. RR of future CHD in individuals with LDL< 100 and non-HDL >130 mg/dl was 1.84 ( 95% CI 1.12 – 3.04) Arsenaul B.J. Et al. J. Am. Coll. Cardiol. 2009 Non-HDL Cholesterol is a better predictor of the number of circulating atherogenic LDL particles than are levels of LDL

  25. Apolipoproteins •Apo A-I : principal apoprotein on HDL (antiatherogenic) •Apo B : principal apoprotein on LDL (proatherogenic) •Apo B molecules are also carried by VLDL & IDL •Apo B : Is a more accurate measure of the total atherogenic particles. Quebec Cardiovascular Study AMORIS INTERHEART Apo B / Apo A-I ratio was strongly associated with IHD

  26. Outlines : • Diabetes as a CHD risk equivalent • How is dyslipidemia different in diabetes ? • Diagnosis of dyslipidemia in diabetes • Evidence for drug therapy to improve outcomes • Which lipoprotein to target first and what should be the initial drug for your patient? • Should all patients with diabetes take statins? • How low should LDL-C go to minimize risk ? • What risk remains after LDL-C management ?

  27. Dose drug therapy improve outcomes? YES • Recent RCTs and a major meta-analysis ( CTT) , have emphasized the importance of LDL-C lowering for CVD risk reduction in DM • Lipid lowering therapy has proven to reduce CV morbidity and mortality in diabetes

  28. What Is The Evidence ? • Primary Prevention CARDS: Collaborative AtorvastatinDiabetes Study • Mixed HPS :HeartProtectionStudy FIELD : FenofibrateIntervention and Event Lowering in Diabetes ASPEN : AtorvastatinStudy for Prevention of Coronary Heart Endpoint in NIDDM ALLHAT: Antihypertensive and Lipid-Lowering Treatment of Prevent Heart Attack Trial ASCOT- LLA : Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm • Secondary Prevention 4S : Scandinavian SimvastatinSurvival Study TNT: Treating to New Target CARE: Cholesterol And Recurrent Events PROVE-IT: Pravastatinor AtorvastatinEvaluation and Infection Therapy-Thrombolysis in Myocardial Infarction

  29. Major Outcome Trials Summary Event rates - Treatment vs. Control Drug 34% Control SIMVA Absolute Risk 22% SIMVA 27.9 30 24% GEMFIB 25.4 21.7 23% 24% 17.3 19.4 19.9 20 PRAVA RR Reduction Event rate (%) PRAVA 15.7 31% 13.2 37% 12.3 10.2 PRAVA LOVA 10 7.5 5.3 5.5 3.5 0 HIT WOSCOPS 4S CARE LIPID AFCAPS HPS Primary Intervention Secondary Intervention

  30. Outlines : • Diabetes as a CHD risk equivalent • How is dyslipidemia different in diabetes ? • Diagnosis of dyslipidemia in diabetes • Evidence for drug therapy to improve outcomes • Which lipoprotein to target first and what should be the initial drug for your patient? • Should all patients with diabetes take statins? • How low should LDL-C go to minimize risk ? • What risk remains after LDL-C management ?

  31. Which lipoprotein to target first? LDL-cis the most atherogenic lipoprotein and is considered the primary target of therapy ● In individuals without overt CVD LDL cholesterol < 100 mg/dl ● In individuals with overt CVD LDL cholesterol < 70 mg/dl If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of 30–40% from baseline is an alternative therapeutic goal

  32. Which lipoprotein to target first? If more than one lipoprotein is not at goal: • TG > 500 mg/dl : focus should shift to TG • TG = 200-499 mg/dl : * Primary target is LDL * Secondary target is Non-HDL ( Non-HDL = Total Cho. – HDL ) • TG = 150-199 mg/dl : * Primary target is LDL * Secondary target is TG&HDL

  33. Initial drug for dyslipidemia in T2DM • Statins are indicated for the majority of patients with diabetes. • Statins discovered in the 1970 , and introduced into clinical practice in the 1980s • Statins are competitive inhibitors of the HMG-CoA reductase.

  34. Equivalent doses of statins and approximate effect on LDL-C

  35. Anti-dyslipidimic drugs

  36. Ezetimibe: Efficacy "Add On" Study After 8 weeks the addition of ezetimibe to ongoing statin therapy significantly reduced LDL-C , increased HDL-C, and decreased triglyceride levels compared with placebo plus statin. HDL LDL TG 1.0 2.7 (P<0.05) % Reduction from Baseline at Week 8 –2.9 –3.7 –14.0 (P< 0.01) –25.1 (P<0.001) Statin + placebo (n=390) Statin + ezetimibe 10 mg (n=379) Gagné C et al. Am J Cardiol 2002;90:1084-1091.

  37. Ezetimibe + Simvastatin: Efficacy Results on LDL-C EZE 10 mg + Simva.10 mg Simvastatin 10 mg 20 mg 40 mg 80 mg Mean % Change Davidson M et al. ACC 2002: Abstract.

  38. Outlines : • Diabetes as a CHD risk equivalent • How is dyslipidemia different in diabetes ? • Diagnosis of dyslipidemia in diabetes • Evidence for drug therapy to improve outcomes • Which lipoprotein to target first and what should be the initial drug for your patient? • Should all patients with diabetes take statins? • How low should LDL-C go to minimize risk ? • What risk remains after LDL-C management ?

  39. Should all patients with diabetes take statins? Primary and Secondary CVD prevention trials have shown that LDL reduction leads to highly significant reductions in the incidence of major CVD events

  40. Efficacy of cholestrol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a met-analysis. Cholestrol Treatment Trial ( CTT ) Collaborators . Lancet 2008 ;371: 117-125 Cholestrol Treatment Trial (CTT) A meta-analysis of 14 RCTs Mean follow-up 4.3 years

  41. NCEP-ATP III & ADA recommendation Statin therapy should be considered for all diabetic individuals who are at high risk of vascular events • Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients: ●with overt CVD. ● without CVD who are over age 40 years and have one or more other CVD risk factors. ● For patients at lower risk than above(-CVD,<40 y) statin therapy should be considered if : ○LDL cholesterol remains above 100 mg/dl or ○ Presence of multiple CVD risk factors.

  42. Outlines : • Diabetes as a CHD risk equivalent • How is dyslipidemia different in diabetes ? • Diagnosis of dyslipidemia in diabetes • Evidence for drug therapy to improve outcomes • Which lipoprotein to target first and what should be the initial drug for your patient? • Should all patients with diabetes take statins? • How low should LDL-C go to minimize risk ? • What risk remains after LDL-C management ?

  43. Rationale for Lower LDL-C Targets Log linear relation of LDL & CHD 3.7 RR CHD (log scale) 1-Epidemiological & Clinical Trials Data 2- ThePost-2001 Trials: HPS TNT ASCOT A to Z PROVE IT IDEAL 2.9 2.2 1.7 1.3 1.0 40 70 100 130 160 190 LDL (mg/dL) For every 30-mg/dL change in LDL-C, relative risk for CHD is changed in proportion by about 30% Grundy et al. Circulation. 2004;110:227-239.

  44. Meta –analysis of Cardiovascular Outcomes of Intensive vs Moderate Statin Therapy (n=27,548) Intensive therapy produced a further 16 % reduction in the incidence of coronary events and an 18 % further reduction in the incidence of stroke

  45. Efficacy and safety of more intensive lowering of LDL-C : a mete-analysis of data from 170,000 participants in 26 randomised trials Choleserol Treatment Trials ( CTT ) Collaborators Lancet. 2010 November 13; 376(9753): 1670-1681 Cholestrol Treatment Trial (CTT) A meta-analysis of 26 RCTs 5 RCTs More vs less intensive 21 RCTs Statinvs Control Further reduction in LDL safely produce definite further reductions ( 15 % ) in the incidence of heart attack, revascularisation and ischemic stroke

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