Hyperlipidemia and Cardiovascular Disease. Kathmandu November 2010 Harold E. Lebovitz, MD, FACE

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1 Hyperlipidemia and Cardiovascular Disease Kathmandu November 21 Harold E. Lebovitz, MD, FACE

2 Diabetes and Lifetime Risk for CHD Adjusted cummula ative incidence Men 67% 3% Women Diabetes No Diabetes 57% Diabetes confers the highest lifetime risk for CHD of.4.4 any single risk factor Attained Age 16% Lloyd Jones et al Circ 26;113:791.

3 Type 2 diabetics are at a higher risk of CV mortality Incidence of morta ality 7 year follow-u up death from cardiovascu ular causes Without prior MI Diabetics without prior MI are at same level of CV death risk as non-diabetics with prior MI Non-diabetic subjects With prior MI Subjects with Type 2 diabetes Haffner et al. N Eng J Med 1998;339:

4 Rate of CVD Death, by Total Cholesterol, in Men With and Without Diabetes 14 CHD Mortalit ty*/1, p-y Diabetes (n=5136) No Diabetes (n=342,815) < >28 Serum Cholesterol (mg/dl) N Engl J Med 1999;31: : , 1993

5 Dyslipidemias in Adults with Diabetes Framingham Heart Study MEN WOMEN Norml DM Norml DM Increased chol Increased LDL Decreased HDL Inc TG Garg A et al. DiabetesCare 199;13:

6 Mechanisms of Dyslipidemia in the Metabolic Syndrome FACTORS: Environmental Biological Inherited Abdominal fat Hypertrophic adipocytes Insulin resistance Defect in the incorporation of FFAs into TG FFA trapping and retention by adipose tissue FFA: free fatty acids TG: triglycerides LPL: lipoprotein lipase HDL: high density lipoprotein CETP: cholesterol ester transfer protein CE: cholesterol ester VLDL: very low density lipoprotein FFA in plasma Clearance LPL, APO CIII Proteolysis of Apo B-1 TG TG in HDL Catabolism HDL-C TG CETP CE VLDL apo B TG CETP CE TG in LDL-C Hepatic Lipase HDL-C levels Small dense LDL-C Kolovo GD. Postgrad Med J. 25;81;

7 Effects of Statin Therapy on CVD Events

8 Effects of More Intensive Lipid Lowering in CHD Patients Patients with CH HD events (%) S = statin treated P = placebo treated CARE-S LIPID-S 4S-S TNT-S 8 TNT-S 1 HPS-S HPS-P Secondary Prevention CARE-P LIPID-P 4S-P (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) LDL-C, mg/dl (mmol/l)

9 Effects of More Intensive Lipid Lowering in Patients with CH HD events (%) CHD Patients With Diabetes S = statin treated P = placebo treated HPS-S LIPID-S* CARE-S* TNT-S 8 TNT-S 1 4S-S HPS-P Secondary Prevention CARE-P* LIPID-P* 4S-P (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) LDL-C, mg/dl (mmol/l) *LDL-C values from overall population

10 Effects of More Intensive Lipid Lowering in Patients With Diabetes Patients with CH HD events (%) S = statin treated P = placebo treated CARDS-S HPS-S ASCOT-S LIPID-S* CARE-S* TNT-S 8 TNT-S 1 HPS-S 4S-S CARDS-P HPS-P HPS-P ASCOT-P LDL-C, mg/dl (mmol/l) *LDL-C values from overall population Secondary Prevention CARE-P* LIPID-P* 4S-P Primary Prevention (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)

11 Aggressive Statin Intervention in Patients with Diabetes CHD event rat te in diabetic patients (%) S 1 Previous Statin Trials in Diabetes CARE 2 LIPID 3 HPS 4 TNT 1 Haffner SM, et al. Arch Intern Med. 1999;159: ; 2 Goldberg RB, et al. Circulation. 1998;98: ; 3 Keech A, et al. Diabetes Care. 23;26: ; 4 HPS Collaborative Group. Lancet. 23;361:25 16

12 CARDS: Primary Prevention of CVD with Atorvastatin in Patients with Type 2 Diabetes 15 placebo (n=141) atorvastatin 1 mg (n=1428) Major co oronary events (%) % relative risk reduction (P=.1) placebo: ATV: Years Colhoun HM et al. Lancet 24; 364:

13 CARDS: Effect of Atorvastatin 1 mg on CV Event Rate in Type 2 diabetes *** Event 1 *** 9. rate 8 (% of 5.8 patients) Placebo ATV 1 mg Primary ACS Stroke Any acute end point CVD event Primary end point: MI, unstable angina, acute CHD death, resuscitated cardiac arrest, coronary revascularisation or stroke ***p=.1 vs placebo Colhoun H et al. Lancet 24;364:

14 Study Design: Post-hoc Analysis of Patients With Diabetes Screening and wash-out Open-label run-in Atorvastatin 1 mg Baseline n=753 Double-blind blind period n=151 Atorvastatin 1 mg LDL-C target: 1 mg/dl (2.6 mmol/l) n=748 Atorvastatin 8 mg LDL-C target: 75 mg/dl (1.9 mmol/l) 1-8 weeks 8 weeks Median follow-up = 4.9 years Diabetes criteria: Cohort includes patients with previous history of diabetes at screening

15 Time to First Major Cardiovascular Event in Patients With Diabetes (TNT study) Cumulative incid dence of major cardiovascu ular events* HR =.75 (95% CI.58,.97) P=.26 Atorvastatin 1 mg Atorvastatin 8 mg Relative risk reduction = 25% Time (years) *CHD death, nonfatal non procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

16 Primary Event Rates in TNT Overall and the Subgroup of Patients With Diabetes Event rate (diabetes) 1 mg 8 mg Event rate (overall) 1 mg 8 mg Major CV event* CHD death Nonfatal, non-pr MI Resuscitated cardiac arrest Fatal/nonfatal stroke 17.9% 13.8% 5.6% 4.1% 8.5% 6.8%.5%.5% 6.4% 4.3% 1.9% 8.7% 2.5% 2.% 6.2% 4.9%.5%.5% 3.1% 2.3% Atorvastatin 8 mg better Atorvastatin 1 mg better *P =.689 for interaction between patients with and without diabetes

17 JUPITER Effects of rosuvastatin 2 mg on LDL, HDL, TG, and hs CRP LDL (mg/dl) LDL decrease 5 percent at 12 months HDL (mg/dl) HDL increase 4 percent at 12 months 5 14 hscrp (mg/l) hscrp decrease 37 percent at 12 months Months TG (mg/dl) TG decrease 17 percent at 12 months Months

18 JUPITER NEJM 28;359: Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Incidence.6.8 HR.56, 95% CI P <.1 Number Needed to Treat (NNT 5 ) = 25 Placebo 251 / % Cumulative Rosuvastatin 142 / 891 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,91 8,631 8,412 6,54 3,893 1,958 1, ,91 8,621 8,353 6,58 3,872 1,963 1,

19 Relationship Between Mean Low-Density Lipoprotein Cholesterol Levels and Median Change in Percent Atheroma Volume for Several Intravascular Ultrasound Trials Nissen, S. E. et al. JAMA 26;295:

20 Residual CVD Risk in Patients With Diabetes Treated With Statins HPS: Patients With Diabetes N = 5963 CARDS N = Major Vascular Event Rate, % % Risk 2.2 Reduction 12 32% Risk Reduction Residual CVD Risk Acute CVD Event Ra ate, % Residual CVD Risk Placebo Simvastatin Collins R et al. Lancet. 23;361: Placebo Atorvastatin CARDS, Collaborative Atorvastatin Diabetes Study. Colhoun HM et al. Lancet. 24;364:

21 Effects of Statin Therapy on CVD Events : Summary Statin therapy reduces CVD events in both primary prevention and secondary intervention Any lowering of the LDL-cholesterol levels is associated with a reduction in CVD events The lower the plasma LDL-cholesterol level the greater is the reduction in CVD events The percent reduction in CVD events by statin therapy in diabetic patients equals that in non-diabetics Statin-treated diabetic patients, however, have the same event rate as control populations not treated with statins Statin-treated patients still have residual CVD risk Regession of atherosclerotic lesions as measured by IVUS begins at plasma LDL cholesterol levels between 6 and 7 mg/dl

22 Plasma HDL-Cholesterol Levels and CVD

23 Coronary heart disease and HDL-C Haza ard Ratio N = 32,43 Adjusted for age and gender Adjusted for multiple factors HDL-C (mmol/l) The Emerging Risk Factors Collaboration. JAMA 29;32:

24 MCVE Frequency by HDL level in group with LDL-C < 7 mg/dl (Adjusted for baseline LDL) 5 y risk of MCVEs (%) No of Events No of Patients HR (95% CI) vs Q1 Q2.85 ( ) Q3.57 ( ).88) Q4.55 ( ).86) Q5.61 ( ).97) (<37) (37-42) (42-47) 47) (47-52) (>52) Quintile of HDL-C (mg/dl) Barter et al, NEJM 27, 357; 13,

25 Fibrate Therapy

26 VA-HIT Results: Gemfibrozil in 2 o Prevention Change From Ba aseline (%) HDL-C LDL-C TG Relative risk reduction (%) Nonfatal MI or CHD death (P=.6) Stroke (NS) Total death (NS) CHD death (NS) VA-HIT = The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial; NS = nonsignificant. Rubins HB, et al. N Engl J Med. 1999;341:

27 VA-HIT: CVD Risk Reduction with or w/o Diabetes Cumulative Event Rate Ch hange (%) Combined End Point 32 P=.4 18 P=.26 P=.7 Nonfatal MI 21 P= P=.9 CHD Death 41 P=.2 3 P=.88 Stroke 4 P=.46 1 P=.67 DM No DM Rubins HB et al. Arch Intern Med. 22;162:

28 Event Ra ate (%) FIELD: Primary and Secondary % Reduction P=.16 24% Reduction 5.2 End Points Placebo Fenofibrate 4.2 P= % Increase P= % Reduction P= % Reduction P= CHD Events* (Primary EP) Nonfatal MI Keech A, et al. Lancet. 25;366: CHD Death Total CVD Events (Secondary EP) *Nonfatal MI and CHD death; CHD events, stroke, CVD death, revascularizations. Coronary Revascularization

29 FIELD: Fenofibrate Reduces the Risk for Vascular Complications of Diabetes Risk Reducti ion, % Nonfatal MI -24% Macrovascular CVD -11% Coro onary Revasc. -21% Angina -18% Effective Add-on to Statin for Patients With Diabetes? P=.1 P=.35 P=.3 P=.11 P=.3 P=.2 P=.4 Keech A, et al. Lancet. 25;366(95): Keech A. Atherosclerosis Supplements. 26;7:342. Abstract. Amputations Retinal Laser Therapy

30 N Engl J Med 362: , 21 ACCORD LIPID SUBSTUDY

31 N Engl J Med 362: , 21 ACCORD LIPID SUBSTUDY

32 N Engl J Med 362: , 21 ACCORD LIPID SUBSTUDY

33 Trial (Drug) HHS (Gemfibrozil) BIP (Bezafibrate) FIELD (Fenofibrate) ACCORD (Fenofibrate) Primary Endpoint: Entire Cohort (P-value) -34% (.2) -7.3% (.24) -11% (.16) -8% (.32) Lipid Subgroup Criterion TG > 2 mg/dl LDL-C/HDL- C > 5. Primary Endpoint: Subgroup -71% TG > 2 mg/dl -39.5% TG > 24 mg/dl HDL-C < 42 mg/dl TG > 24 mg/dl HDL-C < 34 mg/dl -27% -31%

34 ACCORD RETINOPATHY STUDY N Engl J Med 363: , 21

35 Risk Reducti ion, % -1 FIELD: Fenofibrate Reduces the Risk for Vascular Complications of Diabetes Macrovascular Microvascular Nonfatal MI -24% CVD -11% Coro onary Revasc. -21% Angina -18% Effective Add-on to Statin for Patients With Diabetes? Amputations -38% Retinal Laser Therapy -3% Albuminuria -15% P=.1 P=.35 P=.3 P=.11 P=.3 P=.2 P=.4 Keech A, et al. Lancet. 25;366(95): Keech A. Atherosclerosis Supplements. 26;7:342. Abstract.

36 FIELD: Effect of Fenofibrate on Diabetic Retinopathy Lancet 37: , 27

37 FIELD: Effect of Fenofibrate on Diabetic Retinopathy Lancet 37: , 27

38 PPAR alpha agonists and vascular biology Nat Rev Endocrinol 6: , 21

39 Effects Of Niacin on CVD events

40 Change From Baseline, % Linear Dose-Response of Lipid Effects of ER Niacin 3 HDL-C Lp(a) = lipoprotein (a) a Greater-than-recommended daily doses LDL-C Lp(a) TG a 3 a Dose of ER-Niacin, mg Goldberg AC. Am J Cardiol. 1998;82:35U-38U.

41 HDL Atherosclerosis Treatment Study (HATS) Patients with Diabetes Mellitus or IGT 25 Clinical Events 6 5 Coronary Angiography * 5 +DM/IGT -DM/IGT +DM/IGT -DM/IGT N=34 N=112 N=34 N=112 * p<.5 No Niacin/Simva Niacin/Simva 2 1 * *

42 Patients Ex xperiencing Major CHD Events, % Residual CVD Risk With Monotherapy Versus Combination Therapy Statins High-dose statin Fibrate Niacin Niacin + BAS Niacin + Statin 4S 1 LIPID 2 HPS 3 WOS 4 TNT 5 VA-HIT 6 CDP 7 FATS 8 HATS 9 N S Group. Lancet. 1994;344: LIPID Study Group. N Engl J Med. 1998;339: HPS Collaborative Group. Lancet. 22;36: Shepherd J, et al. N Engl J Med. 1995;333: LaRosa JC, et al. N Engl J Med. 25;352: Rubins HB, et al. N Engl J Med. 1999;341: CDP Research Group. JAMA. 1975;231: Brown BG, et al. N Engl J Med. 199;323: Brown BG, et al. N Engl J Med. 21;345:

43 Niacin vs Fibrates: for Diabetic Dyslipidemia Favoring Fibrates Better TG lowering Reasonable LDL-C and HDL-C Good Lp(a) (feno only) Ezetimibe combo data Some CHD events (mono) Microvasc. dis. (feno) Better overall tolerability No flushing No glucose levels No gout/uric acid No PUD Less Hcy Favoring Niacin Better HDL-C raising Reasonable LDL-C and TG Better Lp(a) (esp vs. gemfib) CHD events (mono & combo) Total mortality Statin combo compatibility (better than gemfib only) Statin combo tablet (ERNL) Some tolerability advantages Fewer GI Sx (N & V) No creatinine No gallstones

44 Outcome Trials Using Statin With/Without Niacin AIM HIGH Simva vs Simva + Niacin extended release n=33 Reporting in 21 HPS2- Thrive Simva vs Simva + Niacin + Laropiprant n=2, Reporting 212

45 Japan EPA Lipid Intervention Study (JELIS) Cumulative Incidence of Major Coronary Events (% %) ,645 patients T. chol > 25 mg/dl Prava only vs EPA 18 mg plus prava 5-year follow-up Primary endpoint: MACE Control Years EPA 19% Hazard ratio =.81 (.69.95) p =.11 Lancet 27; 369: 19 98

46 Dose Range of P-OM3 Required to Reduce TG Dose of P-OM3 Placebo 2 g/d 4 g/d 8 g/d Change TG (mg g/dl) (%) % -12.% -3.% -43.% -6 TG mg/dl at baseline (after 8-week run-in) 8-week treatment Source: Pronova, data on file Bottom line: use full-dose POm3 (4g/d)

47 ADA/ACC 28 Consensus Statement: Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities Goals LDL-C Non HDL-C Apo B Highest-Risk Patients Known CVD Diabetes plus 1 additional major CVD risk factor a <7 mg/dl <1 mg/dl <8 mg/dl High-Risk Patients No diabetes or known CVD but 2 major CVD risk factors a Diabetes but no other major CVD risk factors a <1 mg/dl <13 mg/dl <9 mg/dl In individuals on statin therapy who continue to have low HDL-C or elevated non HDL-C, especially if Apo B levels remain elevated, combination therapy is recommended. The preferred agent to use in combination with a statin is nicotinic acid a Major risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD Brunzell JD, et al. Diabetes Care. 28;31:

48 Goals of Lipid Management 1. Management of LDL Cholesterol or atherogenic lipid particles as measured by Non-HDL Cholesterol or Apo B is supported by numerous studies 2. Achieving an HDL Cholesterol of > 4 mg/dl in men and > 5 mg/dl in women is recommended but the evidence to support this recommendation is not very strong 3. Achieving a fasting triglyceride < 15 mg/dl is recommended but has little evidence to support it

49 Drug Treatment of Dyslipidemia LDL-Cholesterol Simvistatin Atorvastatin Rosuvastatin Colesevalam Etizembe HDL-Cholesterol Gemfibrozil Fenofibrate ER Niacin Triglycerides ER Niacin Fenofibrate Omega-3 Fatty acids 2 to 4 mg/day 1 to 8 mg/day 1-2 mg/day 3.75 g/day 1 mg/day 12 mg/day 16 to 2 mg/day 2 to 3 mg/day 2 to 3 mg/day 16 to 2 mg/day 1 to 3 g/day Blocks glucuronidation and changes metabolism of many drugs

50 Selection of Pharmacologic Agents for Dyslipidemia Lipid Profile Agents Hypercholesterolemia (LDL-C) Combined hyperlipidemia (LDL-C and TG) Statins* Bile acid resin (combination therapy) Nicotinic acid** Ezetimibe Fish Oil & Statins (+ fibrate) Fibric acid (+ resin) Nicotinic acid** Ezetimibe Hypertriglyceridemia Fibric Acid ( + low HDL) Nicotinic acid** Ezetimibe * Use first in diabetes ** Associated with modest increases in glucose levels (treatable with adjustment to glycemic medications) For patients with very high levels