Lipid Disorders and Management in Diabetes- Part 1 Om P. Ganda MD Joslin Diabetes Center Harvard Medical school Boston, MA

Cardiovascular Mortality in Type 2 Diabetic Patients vs Nondiabetic Cohort Diabetes No diabetes Men Women 60 60 Mortality Rate per 1000 Mortality Rate per 1000 50 50 2x 40 40 4-5 x 30 30 20 20 10 10 0–3 4-7 8-11 12-15 16-19 20-23 0–3 4-7 8-11 12-15 16-19 20-23 Years of Follow-up Years of Follow-up Krolewski et al. Am J Med. 1991;90(suppl 2A):56S-61S.

MRFIT: Cholesterol and CVD Mortality in Men With Type 2 Diabetes Age-Adjusted CVD deaths per 10,000 person-years 280 Plasma cholesterol (mg/dL) Stamler et al. Diabetes Care. 1993;16:434-444.

The 10-Year Cumulative Incidence of CHD by Numbers of Baseline Risk Factors Strong Heart Study (n=4,465; age 45-74 yrs) Fatal Risk factor list Sex LDL-C>100 Albuminuria >300 Hypertension HDL-C<40 Trig >150 Current smoking Fibrinogen (4th qtle) Diabetes >20 yrs Non-fatal Percent No Prev CHD Prev CHD Howard, B. et al. Diabetes Care 2006;29: 391-397

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.

Atherogenic Dyslipidemia in Patients With Diabetes and the Metabolic Syndrome High Triglyceride levels TG-rich remnant lipoproteins (VLDL) Altered metabolism of LDL and HDL particles Although LDL-C may not be increased, LDL particle number may be significantly increased Predominantly small, dense LDL particles Low levels of HDL-C (may reduce RCT) Haffner SM. Diabetes Care. 2003;26(suppl 1):S83-S86.Garvey WT, et al. Diabetes. 2003;52:453-462.

UKPDS : Stepwise Selection of Risk Factors* in Type 2 Diabetes Coronary Artery Disease (n=280) Position in Model First Second Third Fourth Fifth Variable Low-Density Lipoprotein Cholesterol High-Density Lipoprotein Cholesterol Hemoglobin A1c Systolic Blood Pressure Smoking P Value <0.0001 0.0001 0.0022 0.0065 0.056 *Adjusted for age and sex. Turner RC et al. BMJ 1998;316:823-828.

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TLC Measures to Lower LDL-C Saturated fats (<7% total calories) and cholesterol (<200 mg/day) Limit Trans Fats Therapeutic options Plant stanols/sterols (2 g/d) Increased viscous fiber (10–25 g/d) Expert Panel. JAMA. 2001;285:2486-2497. 9 9

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) The Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016.

Occlusive arterial disease alone Both arterial disease and diabetes HPS: Effects of Simvastatin on 5-year rates of first major vascular event Risk reductions (SE): Proportional 32.9% (9.1) 24.5% (3.1) 18.4% (5.7) Absolute/1000 44 (12) 62 (8) 66 (21) P-value 0.0003 <0.0001 0.002 40 Diabetes alone Occlusive arterial disease alone Both arterial disease and diabetes 9% 13% 20% 25% 31% 36% S P 30 20 10 S=simvastatin-allocated P=placebo-allocated Proportion with first major vascular event (%)

Patient Population: Type 2 Diabetes 4-y double-blind treatment CARDS: Study Design Patient Population: Type 2 Diabetes Atorvastatin 10 mg/d Age 40-75 y No previous MI or CHD LDL-C <160 mg/dL TG <600 mg/dL At least 1 other CHD risk factor (BP, retinopathy, MAlb/Alb, smoking) Placebo 6-wk placebo baseline Patient Randomization n=2,838 4-y double-blind treatment or 304 primary end points The study comprises 3 periods: 1. A screening visit to determine patient eligibility to participate in the study 2. A 6-week placebo period to establish baseline values of various study entry parameters Placebo is prescribed once daily Randomization occurs following the placebo period 3. A minimum 4-year, double-blind treatment period Atorvastatin 10 mg or placebo are administered once daily Colhoun HM, Thomason MJ, Mackness MI, et al. Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with Type 2 diabetes. Diabet Med. 2002;19:201-211. Primary end point: Time to the occurrence of a major CV event Completion date: Study terminated early in 2003 due to significant benefit observed in atorvastatin arm Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.

Atorvastatin Mean (SD) CARDS: Patient Baseline Characteristics Placebo Mean (SD) Atorvastatin Mean (SD) Mean age (range 40-75 y) 61.8 61.5 Women 453 (32.1%) 456 (31.9%) BMI (kg/m2) (SD) 28.8 (3.5) 28.7 (3.6) Duration of DM (y) 7.8 (6.3) 7.9 (6.4) A1C % 7.8 (1.4) 7.9 (1.4) LDL-C (mg/dL) 118 (100-137) 119 (100-138) (25% <100, 25% >137) (25% <100, 25% >138) HDL-C (mg/dL) 53 (46-61) 52(45-60) Triglycerides (mg/dL) 150 (106-212) 150 (106-212) Colhoun HM, et al. Lancet 2004;364:685-696

Total cholesterol (mmol/L) CARDS: Median Lipid Levels by Treatment Total cholesterol (mmol/L) LDL-C (mmol/L) Average difference 26% 1.4 mmol/L (54mg/dL) P<.0001 Average difference 40% 1.2 mmol/L (46mg/dL) P <.0001 6 4 3 4 2 2 1 1 2 3 4 4.5 1 2 3 4 4.5 Study (y) Study (y) Placebo Atorvastatin Colhoun HM, et al. Lancet 2004;364:685-696

Relative Risk Reduction 37% (95% CI: 17-52) CARDS: Cumulative Hazard for Primary End Point* Relative Risk Reduction 37% (95% CI: 17-52) 5 10 15 1 2 3 4 4.75 Placebo 127 events P=.001 Cumulative hazard (%) Atorvastatin 83 events (y) Placebo 1,410 1,351 1,306 1,022 651 305 Atorva 1,428 1,392 1,361 1,074 694 328 * Primary endpoints: Acute CHD death, Non-fatal MI including silent MI, Hospitalized unstable angina, Resuscitated cardiac arrest, Coronary revascularization, Stroke Colhoun HM, et al. Lancet 2004;364:685-696

Hazard Ratio Risk Reduction (CI) CARDS: Treatment Effect on Primary End Points 21 (1.5%) 24 (1.7%) 51 (3.6%) 83 (5.8%) Atorva* 48% (11-69) 39 (2.8%) 31% (-16-59) 34 (2.4%) 36% (9-55) 77 (5.5%) 37% (17-52) P=.001 127 (9.0%) Primary end point Hazard Ratio Risk Reduction (CI) Placebo* Event Acute coronary events Coronary revascularization Stroke .2 .4 .6 .8 1 1.2 * N (% randomized) Favors Atorvastatin Favors Placebo Colhoun HM, et al. Lancet 2004;364:685-696

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

Relative Risk Reduction 27% (95% CI: -1-48) CARDS: Cumulative Hazard for All-Cause Mortality Relative Risk Reduction 27% (95% CI: -1-48) P=.059 1 2 3 4 4.75 6 8 10 Placebo 82 deaths Cumulative hazard (%) Atorvastatin 61 deaths (y) Placebo 1,410 1,395 1,370 1,094 709 332 Atorva 1,428 1,418 1,401 1,110 730 351 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 CTT Collaborators Lancet 2008, 371: 117-125 Total mortality RR 0.88 (0.84-0.91) 19

Meta-analysis of Intensive Statin Trials: LDL- Cholesterol Cannon,CP et al JACC 2006; 48: 438-445

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

Meta-analysis of Intensive Statin Trials: Stroke Cannon,CP et al JACC 2006; 48: 438-445

SPARCL Stroke Reduction after Stroke or TIA N=4,731 patients with stroke or TIA 1-6 months before study; no known CHD Rx Atorvastatin 80 mg or placebo DM : Similar outcome ALT or AST > 3x ULN x 2 : 2.2 vs 0.5% Hemorrhagic Stroke HR 1.66 (1.08-2.55) 55 vs 33 patients SPARCL Investigators NEJM 2006; 355: 549-559

Intensive Statin Trials: Severe Adverse Events Cannon,CP et al JACC 2006; 48: 438-445

Log-Linear Relationship Between LDL-C Levels and Relative Risk for CHD 3.7 2.9 2.2 1.7 1.3 1.0 Relative Risk for Coronary Heart Disease (Log Scale) 40 70 100 130 160 190 LDL-Cholesterol (mg/dL) Grundy, S. et al., Circulation 2004;110:227-39.

ATP III Update: Very High Risk Category LDL-C Goal < 70 mg/dl Established CVD plus one of the following: Patients with acute coronary syndromes Multiple major risk factors (especially diabetes) Severe and poorly controlled risk factors (especially continued cigarette smoking) Multiple risk factors of metabolic syndrome (especially high TG> 200mg/dl + non-HDL-C >130 mg/dl with HDL-C <40 mg/dl Grundy, SM et al Circulation 2004; 110:227-239

JUPITER – Study Design Rosuvastatin 20 mg (n = 8901) Placebo run-in No history of CAD or DM Men aged ≥50 years; women aged ≥60 years LDL-C  130 mg/dL (3.4 mmol/L) CRP levels ≥2.0 mg/L Placebo run-in Placebo (n = 8901) Visit: Week: 1 –6 2 –4 3 0 4 13 Final 3–4 y 6-monthly Lead-in/ eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Lipids CRP Tolerability HbA1C Median follow-up 1.9 years; Maximum follow-up 5 years Ridker PM. Circulation 2003; 108: 2292–2297 27 27

ARR : 0.77 vs 1.36 %/yr

Risk Reduction With Statins in Diabetic vs Non-Diabetic Patients 4S-P % Major Coronary Events 4S-Rx HPS-P Lipid-P 4S-P Care-P Lipid Rx Care Rx 4S-RX Lipid-P HPS Rx Lipid Rx HPS-P Care-P HPS Rx Care Rx LDL-C Diabetic Non-Diabetic

Gastrointestinally Acting Lipid Lowering Agents Bile Acid Sequestrants (BAS) Colesevelam, cholestyramine, colestipol Bind to bile acids > increase excretion of cholesterol Cholesterol Absorption Inhibitor Ezetimibe Reduces cholesterol absorption by binding to intestinal cholesterol transporter 32

LRC-CPPT: Bile Acid Sequestrant and CVD Events. LDL-C reduction of 12.6% with cholestyramine CHD death and/or Nonfatal MI Nonfatal MI CHD Death 19 %* 19 % * P <0.05 vs placebo 24 % LRC-CPPT. JAMA. 1984;251:351-364.

Mean % Change in LDL-C From Untreated Baseline Ezetimibe + Statin Lovastatin Mono. + EZE (n=220) (n=192) Pravastatin Mono. + EZE (n=205) (n=204) Simvastatin Mono. + EZE (n=263) (n=274) Atorvastatin Mono. + EZE (n=248) (n=255) Mean % Change in LDL-C From Untreated Baseline * All data are pooled across doses. *P<.01 for EZE (Ezetimibe) + statin, vs statin alone.

ENHANCE Trial N=720 patients with Familial Hypercholesterolemia (FH) Design: RCT, Simvastatin (S80) + E 10, vs S80 alone Primary endpoint: CIMT, at 2 years Mean LDL-C: 319; mean LDL reduction: 56% vs 39% (p<0.01) Result: mean change in CIMT: +0.011 vs +0.0058 mm (P=0.29) No significant difference in liver or muscle toxicity IMPROVE-IT: In progress CIMT = Carotid intimal medial thickness Kastelein, JJ et al 2008; 358: 1431-1443

Doses of Currently Available Statins Required to Attain an Approximate 30% to 40% Reduction of LDL-C Levels (Standard Doses) Drug Dose, mg/d LDL Reduction, % Atorvastatin 10 † 39 Lovastatin 40 † 31 Pravastatin 34 Simvastatin 20-40 † 35-41 Fluvastatin 40-80 25-35 Rosuvastatin 5-10 ‡ 39-45 † All of these are available at doses up to 80 mg. For every doubling of the dose above the standard dose, an approximate 6% decrease in LDL-C level can be obtained. ‡ For rosuvastatin, doses available up to 40 mg; the efficacy for 5 mg is estimated by subtracting 6% from the FDA reported efficacy at 10 mg Grundy, S. et al., Circulation 2004;110:227-39.

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 37 37