Hyperlipidemia and Cardiovascular Disease Kathmandu November 21 Harold E. Lebovitz, MD, FACE
Diabetes and Lifetime Risk for CHD Adjusted cummula ative incidence.7.6.5 Men 67% 3%.7.6.5 Women Diabetes No Diabetes 57% Diabetes confers the highest lifetime risk for CHD of.4.4 any single risk factor.3.2.1 5 6 7 8 9.3.2.1 Attained Age 16% 5 6 7 8 9 Lloyd Jones et al Circ 26;113:791.
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 45 4 35 3 25 2 15 1 5 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;339:229 234
Rate of CVD Death, by Total Cholesterol, in Men With and Without Diabetes 14 CHD Mortalit ty*/1, p-y 12 1 8 6 4 2 Diabetes (n=5136) No Diabetes (n=342,815) <18 18-199 2-219 22-239 24-259 26-279 >28 Serum Cholesterol (mg/dl) N Engl J Med 1999;31:65-8 16: 434-444, 1993
Dyslipidemias in Adults with Diabetes Framingham Heart Study MEN WOMEN Norml DM Norml DM Increased chol 14 13 21 24 Increased LDL 11 9 16 15 Decreased HDL 12 21 1 25 Inc TG 9 19 8 17 Garg A et al. DiabetesCare 199;13:153-169.
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;358-366.
Effects of Statin Therapy on CVD Events
Effects of More Intensive Lipid Lowering in CHD Patients Patients with CH HD events (%) 4 35 3 25 2 15 1 5 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 6 8 1 12 14 16 18 2 (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) LDL-C, mg/dl (mmol/l)
Effects of More Intensive Lipid Lowering in Patients with CH HD events (%) 4 35 3 25 2 15 1 5 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 6 8 1 12 14 16 18 2 (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
Effects of More Intensive Lipid Lowering in Patients With Diabetes Patients with CH HD events (%) 4 35 3 25 2 15 1 5 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 6 8 1 12 14 16 18 2 (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)
Aggressive Statin Intervention in Patients with Diabetes CHD event rat te in diabetic patients (%) 45 4 35 3 25 2 15 1 5 4S 1 Previous Statin Trials in Diabetes CARE 2 LIPID 3 HPS 4 TNT 1 Haffner SM, et al. Arch Intern Med. 1999;159:2661 67; 2 Goldberg RB, et al. Circulation. 1998;98:2513 19; 3 Keech A, et al. Diabetes Care. 23;26:2713 21; 4 HPS Collaborative Group. Lancet. 23;361:25 16
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 (%) 1 5 37% relative risk reduction (P=.1) placebo: ATV: 1 2 3 4 4.75 141 1351 136 122 651 35 1428 1392 1361 174 694 328 Years Colhoun HM et al. Lancet 24; 364: 685 696
CARDS: Effect of Atorvastatin 1 mg on CV Event Rate in Type 2 diabetes 16 14 *** 13.4 12 Event 1 *** 9. rate 8 (% of 5.8 patients) 6 5.5 9.4 Placebo ATV 1 mg 4 2 3.6 2.8 1.5 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;364:685 696
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
Time to First Major Cardiovascular Event in Patients With Diabetes (TNT study) Cumulative incid dence of major cardiovascu ular events*.2.15.1.5 HR =.75 (95% CI.58,.97) P=.26 Atorvastatin 1 mg Atorvastatin 8 mg Relative risk reduction = 25% 1 2 3 4 5 6 Time (years) *CHD death, nonfatal non procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke
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%.2.5 1 2 3 4 1 Atorvastatin 8 mg better Atorvastatin 1 mg better *P =.689 for interaction between patients with and without diabetes
JUPITER Effects of rosuvastatin 2 mg on LDL, HDL, TG, and hs CRP 14 6 12 5 LDL (mg/dl) 1 8 6 4 2 LDL decrease 5 percent at 12 months HDL (mg/dl) 4 3 2 1 HDL increase 4 percent at 12 months 5 14 hscrp (mg/l) 4 3 2 1 hscrp decrease 37 percent at 12 months 12 24 36 48 Months TG (mg/dl) 12 1 8 6 4 2 TG decrease 17 percent at 12 months 12 24 36 48 Months
JUPITER NEJM 28;359:2195-227 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Incidence.6.8 HR.56, 95% CI.46-.69.69 P <.1 Number Needed to Treat (NNT 5 ) = 25 Placebo 251 / 891-44 % Cumulative..2.4 1 2 3 4 Rosuvastatin 142 / 891 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,91 8,631 8,412 6,54 3,893 1,958 1,353 983 544 157 8,91 8,621 8,353 6,58 3,872 1,963 1,333 955 534 174
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;295:1556-1565.
Residual CVD Risk in Patients With Diabetes Treated With Statins HPS: Patients With Diabetes N = 5963 CARDS N = 2838 3 16 Major Vascular Event Rate, % 25 2 15 1 5 25.1 14 13.4 22% Risk 2.2 Reduction 12 32% Risk Reduction 1 9.4 Residual CVD Risk Acute CVD Event Ra ate, % 8 6 4 2 Residual CVD Risk Placebo Simvastatin Collins R et al. Lancet. 23;361:25-216. Placebo Atorvastatin CARDS, Collaborative Atorvastatin Diabetes Study. Colhoun HM et al. Lancet. 24;364:685-696.
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
Plasma HDL-Cholesterol Levels and CVD
Coronary heart disease and HDL-C Haza ard Ratio 3.5 3. 2.5 2. 1.5 N = 32,43 Adjusted for age and gender Adjusted for multiple factors 1..8.75 1. 1.25 1.5 1.75 2. HDL-C (mmol/l) The Emerging Risk Factors Collaboration. JAMA 29;32:1993-2. 2.
MCVE Frequency by HDL level in group with LDL-C < 7 mg/dl (Adjusted for baseline LDL) 5 y risk of MCVEs (%) 1 8 6 4 2 No of Events No of Patients HR (95% CI) vs Q1 Q2.85 (.57-1.25) Q3.57 (.36-.88).88) Q4.55 (.35-.86).86) Q5.61 (.38-.97).97) (<37) (37-42) (42-47) 47) (47-52) (>52) Quintile of HDL-C (mg/dl) 57 5 34 34 35 473 525 55 569 544 Barter et al, NEJM 27, 357; 13, 131-131131
Fibrate Therapy
VA-HIT Results: Gemfibrozil in 2 o Prevention Change From Ba aseline (%) 1 5-5 -1-15 -2-25 -3-35 HDL-C LDL-C TG Relative risk reduction (%) -5-1 -15-2 -25-3 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;341:41-418.
VA-HIT: CVD Risk Reduction with or w/o Diabetes Cumulative Event Rate Ch hange (%) 5 1 15 2 25 3 35 4 45 Combined End Point 32 P=.4 18 P=.26 P=.7 Nonfatal MI 21 P=.17 22 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;162:2597-264
Event Ra ate (%) 14 12 1 8 6 4 2 FIELD: Primary and Secondary 5.9 11% Reduction P=.16 24% Reduction 5.2 End Points Placebo Fenofibrate 4.2 P=.1 3.2 19% Increase P=.22 1.9 2.2 13.9 11% Reduction P=.35 12.5 21% Reduction P=.3 7.4 5.9 CHD Events* (Primary EP) Nonfatal MI Keech A, et al. Lancet. 25;366:1849-1861. CHD Death Total CVD Events (Secondary EP) *Nonfatal MI and CHD death; CHD events, stroke, CVD death, revascularizations. Coronary Revascularization
FIELD: Fenofibrate Reduces the Risk for Vascular Complications of Diabetes Risk Reducti ion, % -1-2 -3-4 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):1849-1861. Keech A. Atherosclerosis Supplements. 26;7:342. Abstract. Amputations Retinal Laser Therapy
N Engl J Med 362: 1563-1574, 21 ACCORD LIPID SUBSTUDY
N Engl J Med 362: 1563-1574, 21 ACCORD LIPID SUBSTUDY
N Engl J Med 362: 1563-1574, 21 ACCORD LIPID SUBSTUDY
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%
ACCORD RETINOPATHY STUDY N Engl J Med 363:233-244, 21
Risk Reducti ion, % -1 FIELD: Fenofibrate Reduces the Risk for Vascular Complications of Diabetes Macrovascular Microvascular -2-3 -4 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):1849-1861. Keech A. Atherosclerosis Supplements. 26;7:342. Abstract.
FIELD: Effect of Fenofibrate on Diabetic Retinopathy Lancet 37: 1687-1697, 27
FIELD: Effect of Fenofibrate on Diabetic Retinopathy Lancet 37: 1687-1697, 27
PPAR alpha agonists and vascular biology Nat Rev Endocrinol 6: 454-463, 21
Effects Of Niacin on CVD events
Change From Baseline, % Linear Dose-Response of Lipid Effects of ER Niacin 3 HDL-C 3 29 2 26 22 1-1 -2-3 -4-5 -5 1-3 Lp(a) = lipoprotein (a) a Greater-than-recommended daily doses 15-9 -11-12 -28-14 -2-17 -35-24 -22-21 LDL-C -39-3 -26 Lp(a) TG -44 5 1 15 2 25 a 3 a Dose of ER-Niacin, mg Goldberg AC. Am J Cardiol. 1998;82:35U-38U.
HDL Atherosclerosis Treatment Study (HATS) Patients with Diabetes Mellitus or IGT 25 Clinical Events 6 5 Coronary Angiography 2 4 15 3 1 * 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 * *
Patients Ex xperiencing Major CHD Events, % 4 3 2 1 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 4444 914 2 536 6595 1 1 665 2531 146 16 1 4S Group. Lancet. 1994;344:1383-1389. 2 LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 3 HPS Collaborative Group. Lancet. 22;36:7-22. 4 Shepherd J, et al. N Engl J Med. 1995;333:131-137. 5 LaRosa JC, et al. N Engl J Med. 25;352:1425-1435. 6 Rubins HB, et al. N Engl J Med. 1999;341:41-418. 7 CDP Research Group. JAMA. 1975;231:36-381. 8 Brown BG, et al. N Engl J Med. 199;323:1289-1298. 9 Brown BG, et al. N Engl J Med. 21;345:1583-1592.
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
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
Japan EPA Lipid Intervention Study (JELIS) Cumulative Incidence of Major Coronary Events (% %) 4 3 2 1 18,645 patients T. chol > 25 mg/dl Prava only vs EPA 18 mg plus prava 5-year follow-up Primary endpoint: MACE Control 1 2 3 4 5 Years EPA 19% Hazard ratio =.81 (.69.95) p =.11 Lancet 27; 369: 19 98
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) (%) -2-4 -8.2% -12.% -3.% -43.% -6 TG 177-442 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)
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;31:811-822.
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
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
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