Lipid Disorders and Management in Diabetes Om P. Ganda MD Joslin Diabetes Center Harvard Medical school Boston, MA Web-conference, April 8, 2010

MRFIT: Cholesterol and CVD Mortality in Men With Type 2 Diabetes Age-Adjusted CVD deaths per 10,000 person-years Age adjusted CVD mortality in > 350, 000 subjects participating in the MRFIT study. More than 5000 had diabetes. 280 Plasma cholesterol (mg/dL) Stamler et al. Diabetes Care. 1993;16:434-444.

Pathophysiology of Dyslipidemia in Type 2 Diabetes TG pool High Low Smaller VLDL IDL Larger VLDL Large LDL Small LDL HDL Smaller HDL Remnants Smaller LDL LPL LPL/HL CETP TG HL LDLR Krauss RM. Diabetes Care. 2004;27:1496-1504.

HPS: Major Vascular Events by LDL-C and Prior Diabetes Rate ratio & 95% CI STATIN better PLACEBO better 0.4 0.6 0.8 1.0 1.2 1.4 HPS: Major Vascular Events by LDL-C and Prior Diabetes LDL-C & DIABETES SIMVASTATIN (10,269) PLACEBO (10,267) < 116 mg/dL Diabetes 191 (15.7%) 252 (20.9%) No diabetes 407 (18.8%) 504 (22.9%) 116 mg/dL 410 (23.3%) 496 (27.9%) 1,025 (20.0%) 1,333 (26.2%) ALL PATIENTS 2,033 (19.8%) 2,585 (25.2%) 24% SE 3 reduction (2P<.00001) There were similar proportional reductions in risk of major vascular events irrespective of various lipid values at baseline, both in those with and those without diabetes. The Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016.

Hazard Ratio Risk Reduction (CI) CARDS: Treatment Effect on the Primary End Points by Subgroup Subgroup* Placebo** Atorva** Hazard Ratio Risk Reduction (CI) LDL-C ≥3.06 (120) 66 (9.5) 44 (6.1) 38% (9-58) LDL-C <3.06 (120) 61 (8.5) 39 (5.6) 37% (6-58) p=0.96 HDL-C ≥1.35 (54) 62 (8.4) 36 (5.2) 41% (11-61) HDL-C <1.35 (54) 65 (9.6) 47 (6.4) 35% (5-55) P=.71 Trig. ≥1.7 (150) 67 (9.6) 40 (5.5) 44% (18-62) Trig. <1.7 (150) 60 (8.4) 43 (6.1) 29% (-5-52) P=.40 * units in mmol/L (mg/dL) ** N (% of randomised) .2 .4 .6 .8 1 1.2 Favors Atorvastatin Favors Placebo Colhoun HM, et al. Lancet 2004;364:685-696

Major Vascular Events with or without Diabetes: Effect per 1mM/L reduction in LDL-cholesterol 14 RCTs 18686 with DM 71370 without DM No differences by Presence or absence of vascular disease, Other risk-factors, or baseline lipid levels Meta –analysis of 95000 participants in 14 megatrials of statin therapy. CTT Collaborators Lancet 2008, 371: 117-125 Total mortality RR 0-88 (0.84-0.91) 6

Meta-analysis of Intensive Statin Trials: Coronary Death or Myocardial Infarction DM : Similar outcome Cannon,CP et al JACC 2006; 48: 438-445

ARR : 0.77 vs 1.36 %/yr

Statins and Primary End Points Risk of Primary Event (%) In all of these major statin trials, significant residual cardiovascular risk remains even after reducing LDL-C Kastelein et al. Eur Heart J. 2005;7(suppl F):F27-F33. 10

TG <150 mg/dL Associated With Lower Risk of CHD Events Independent of LDL-C Level PROVE IT-TIMI 22 Trial N = 4162 Referent HR: 0.85 P=.180 CHD Eventa Rate After 30 Daysc, % HR: 0.84 P=.192 A subgroup analyses of the PROVE- IT trial based on baseline triglyceride concentrations and achieved LDL. HR: 0.72 P=.017 LDL-C ≥70 LDL-C <70 TG <150 TG ≥150 Death, MI, and recurrent ACS ACS patients on atorvastatin 80 mg or pravastatin 40 mg Adjusted for age, gender, low HDL-C, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment Miller M, et al. J ACC. 2008;51:724-730. 11

TNT: major CVD Events in Patients with LDL < 70 mg/dl A re- analysis of TNT trial according to HDL quintiles in those achieving intensive LDL – C reduction. Barter,P et al NEJM 2007; 357: 1301-1310 12 12 12

Management of Dyslipidemia beyond LDL Lifestyle changes and secondary causes Pharmacologic therapy Fibrate Niacin Omega-3 Fatty acids Combination therapy 13 13 13

ACCORD- Lipid Results Shown are mean plasma levels of total cholesterol (Panel A), low-density lipoprotein (LDL) cholesterol (Panel B), and high-density lipoprotein (HDL) cholesterol (Panel C) and median levels of triglycerides (Panel D) at baseline, 4 months, 8 months, 1 year, and annually thereafter. Nominal P values for differences between the study groups at 4 months and at the end of the study were, respectively: total cholesterol, P<0.001 and P=0.02; LDL cholesterol, P=0.11 and P=0.16; HDL cholesterol, P<0.001 and P=0.01; and triglycerides, P<0.001 for both comparisons with the use of nonparametric tests. End-of-study visits were those that occurred in early 2009 and included follow-up at years 4, 5, 6, and 7. The I bars represent 95% confidence intervals. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282 14

ACCORD Lipid: Primary Outcome in Prespecified Subgroups Hazard Ratios for the Primary Outcome in Prespecified Subgroups. The horizontal bars represent 95% confidence intervals, and the vertical dashed line indicates the overall hazard ratio. The size of each square is proportional to the number of patients. P values are for tests for interaction. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282 15

ADA Lipid Goals and Recommendations 2009 Lifestyle modifications Primary LDL –C goal < 100 mg/dl ; If CVD:LDL-C < 70 mg/dl is an option Statin therapy added to lifestyle changes, regardless of baseline LDL , if Overt CVD; Without CVD but age > 40 yr + one or more other CVD risk factors Without overt CVD and age < 40 yr -Consider statin if LDL-C > 100 mg/dl or multiple risk factors , despite lifestyle therapy. In drug treated patients, a reduction in LDL-C of ~30-40% from baseline , if LDL targets not achieved with maximum tolerated statin therapy. Triglycerides < 150 mg/dl; HDL-C > 40 mg/dl (men),> 50 mg/dl (women): Desirable Combination therapy to achieve lipid goals may be needed but outcome studies pending. Diabetes Care 2009; 32(suppl1): S13-S61 16 16

ADA and ACC Consensus Statement on Lipoprotein Management TREATMENT GOALS LDL-C (mg/dL) Non–HDL-C (mg/dL) ApoB (mg/dL) Highest-risk patients Including those with 1) Known CVD or 2) Diabetes plus one or more additional CVD risk factor* < 70 < 100 < 80 High-risk patients Including those with 1) No diabetes or known clinical CVD but 2 or more additional major CVD risk factors or 2) Diabetes but no other CVD risk factors < 130 < 90 *Smoking, HBP, f/h premature CHD Brunzell JD et al. Diabetes Care. 2008;31:811-822.

Algorithm for Apo-B Testing in Patients with Dyslipidemia Order Lipid profile LDL-C > 100mg/dl TG >500 mg/dl Lifestyle + Statin Rx Goal: LDL-C < 100 mg/dl Treat TG to < 500 mg/dl Fibrates and/or Fish oil if > 1000 mg/dl CVD-No CVD-yes Statin Rx if LDL > 100 Intensify Statin Rx LDL< 100, TG > 200* LDL< 70, TG > 200* Measure Apo-B Apo-B >80mg/dl ApoB< 90mg/dl Intensify LDL Rx or add Fibrate/Niacin Continue current Rx; may need Fibrate/ Niacin * 150 if fasting Ganda, OP Endocrine Practice 2009; 15: 370-376 18 18 18