Diabetes (type 2, 26%; type 1, 3%) History of stroke or other cerebrovascular disease (16 those with diabetes. LDL cholesterol is a strong predictor …

Aggressive Lipid Management Aggressive Lipid Management to Prevent CHD in Diabetes to Prevent CHD in Diabetes

Wm James Howard, MD Washington Hospital Center Washington, DC May 17 2005

Prevalence of Obesity in the United States

Prevalence of Diabetes in the United States

Atherosclerosis in Diabetes
About 80 of all diabetic mortality 75 from coronary atherosclerosis; 25 from cerebral or peripheral vascular disease 75 of all hospitalizations for diabetic complications 50 of patients with newly diagnosed NIDDM have CHD

Evolution of the Treatment Approach
1970s NCEP ATP I Guidelines 1988 NCEP ATP II Guidelines 1993 NCEP ATP III Guidelines 2001

Framingham MRFIT LFC-CPPT Coronary Drug Project Helsinki Heart CLAS anglo

Angiographic Trials FATS, POSCH, SCOR, STARS, Omish, MARS Meta-Analyses Holme, Rossouw

4S, WOSCOPS CARE, LIPID, AFCAPS/TexCAPS, VAHIT, Others

ATP III Lipid and Lipoprotein Classification
LDL Cholesterol mg/dL 100 100129 optimal 130159 160189 190 Optimal Near optimal/above Borderline high High Very high

New Features of ATP III
CHD Risk Equivalents:

1 Type 2 Diabetes Mellitus
2 Non-Cardiac Forms of Athero 3 Framingham Projection of 10 yr Risk 20 identifies
individuals with multiple risk factors in need of more aggressive lipid lowering The Metabolic Syndrome

The Metabolic Syndrome as a Secondary Target of Therapy
General Features of the Metabolic Syndrome Abdominal obesity Atherogenic dyslipidemia Elevated triglycerides Small LDL particles Low HDL cholesterol Raised blood pressure Insulin resistance glucose intolerance Proatherosclerotic state Prothrombotic state Proinflammatory state

Prevalence of MS among non-diabetic American Indians, by age and gender, the Strong Heart Study, N2,407
Men
Women

60 50 Prevalence 40 30 20 10 0 45-54 n1277 55-64 n731 280 376 265 394 260

532

65-74 n399

Prevalence of Diabetes
Strong Heart Study, by Gender and Center
100 80

Women

Men

60
40 20 0 AZ OK ND/SD AZ OK ND/SD

Diabetes

IGT

Non-HDL Cholesterol Non-HDL Chol TC - HDL
Known predictor of CHD in epidemiology Represents the sum of LDL, Lpa, IDL, and VLDL: All atherogenic apo B containing lipoproteins Lipid Equivalent of HbA1C

Comparison of LDL-C and Non-HDL-C Goals

Risk Category
CHD and CHD Risk Equivalent 10-year risk for CHD 20 Multiple 2 Risk Factors and 10-year risk 20

LDL-C Goal mg/dL
100

Non-HDL-C Goal
mg/dL
130

130

160

The Pyramid of Recent Trials
Relative Size of the Various Segments of the Population

Relation Between CHD Events and LDL-C in Recent Statin Trials
30 25 20 4S-Rx 4S-PI 2 Prevention

with LIPID-Rx 15 CHD event LIPID-PI 1 Prevention CARE-Rx CARE-PI 10 WOSCOPS-PI AFCAPS/TexCAPS-PI 5 WOSCOPS-Rx AFCAPS/TexCAPS-Rx 0 90 110 130 150 170 190 210 Mean LDL-C level at follow-up mg/dL
PIplacebo; Rxtreatment Shepherd J et al N Engl J Med 1995;333:1301-1307 4S Study Group Lancet 1995;345:1274-1275 Sacks FM et al N Engl J Med 1996;335:1001-1009 Downs JR et al JAMA 1998;279:1615-1622 Tonkin A Presented at AHA Scientific Sessions, 1997

GREek Atorvastatin and Coronary Heart Disease Evaluation Study GREACE TRIAL

Current Medical Research and Opinions, 2002; 18: 220-227

GREACE TRIAL
RESULTS:
Total Mortality
CHD Mortality non fatal MI Revascularization CHF Stroke Women Diabetics 60-75 yoa

-43 -47 -59 -51 -50 -47 -54 -58 -49

Heart Protection Study HPS Design
Large, multicenter, placebo-controlled, double-blind study Mean duration: 5 years Patients N20,536, 97 Caucasian allocated to
Simvastatin 40mg/day n10,269 Placebo n10,267

Mean age 64 years range 40 to 80 years
Patients were at high risk of a major coronary event because of

Existing coronary heart disease CHD 65 Diabetes type 2, 26; type 1, 3 History of stroke or other cerebrovascular disease 16 Peripheral vessel disease 33 Hypertension in males aged 65 years and older 6

Patients were allocated to treatment using a covariate adaptive method, which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups

HPS: MCE by Metabolic History
Incidence n 5,963 3,982 1,981 14,573 Simvastatin 94 55 174 85 Placebo 126 84 210 115 MCE Risk Ratio 95 CI

Baseline Characteristics Diabetes mellitus Without CHD With CHD Without diabetes mellitus

04 06 08 10 12
Favors simvastatin Favors placebo

SIMVASTATIN: VASCULAR EVENT by LDL
Baseline feature LDL mg/dl 100 26 mmol/l 100 130 130 34 mmol/l ALL PATIENTS 285 670 1087 2042 199 360 881 1365 2606 254 04 06 08 10 12 14 24SE 26 reduction 2P000001 Het 2 08
2

STATIN 10269

PLACEBO 10267

Risk ratio and 95 CI STATIN better STATIN worse

Implications of Recent Clinical Trials for ATP III Goals
Recent trials provide greater
rationale for lower target LDL-C levels and more intensive LDL-lowering therapy Key modifications to ATP III treatment algorithm for LDL-C: LDL-C goal 70 mg/dL is therapeutic option for patients at very high risk Addition of fibrate or nicotinic acid should be considered for high-risk patients with high TG or low HDL-C LDL-C goal 100 mg/dL is therapeutic option for moderately high-risk patients At least 30 to 40 reduction in LDL-C recommended for high-risk and moderately high-risk patients

Grundy et al Circulation 2004;110:227-239

HMG CoA Reductase Inhibitors Statins
Statin Lova statin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosavustatin Cerivastatin Dose Range 2080 mg 2040 mg 2080 mg 2080 mg 1080 mg 5–40mg 0408 mg

Percentage Change in LDL-C: Pairwise Comparisons
The STELLAR Trial
0 -5 -10 -15 -20 -25 -30 -35 -40 -45 -50 -55 -60 10 mg 10 mg 20 mg 40 mg 20 mg 80 mg 40 mg

10 mg

20 mg

40 mg

80 mg

Rosuvastatin Atorvastatin Simvastatin Pravastatin

10 mg

20 mg

40 mg

STELLAR Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin

P002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg P002 vs atorvastatin
20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg P002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg Adapted from Jones et al Am J Cardiol 2003;92:152160

Non-Statin Lipid Lowering Drugs
Niacin–extended release, OTC immediate Bile Acid Sequestrants–colesevelam Fibric Acids–gemfibrozil, fenofibrate Intestinal acting–ezetimibe Omega 3 fatty acids–fish oil EPA, DHA Dietary adjuncts–plant sterol/stanol ester margerines, viscous fiber supplements

Mechanism of Intestinal-Acting Agents

REMAINING QUESTION: What Should be the Goal for LDL-C and non-HDL-C for Primary CHD Prevention in Type 2 Diabetes Mellitus???

Clinical Trials of Lipid Lowering to Prevent CHD in Diabetes
Trial HPS ALL HAT ASCOT CARDS Results Prevention No Prevention No Prevention Prevention

SANDS
Stop Atherosclerosis in Native Diabetics Study

What We Learned from SHS
Most CVD in SHS communities occurs in those with diabetes LDL cholesterol is a strong predictor even though levels are generally low in Indians Blood pressure is a strong predictor, and it leads to nephropathy which also causes CVD

Four Clinical Centers
Phoenix Charlton Wilson, MD; Marie Russell, MD Oklahoma Brice
Poolaw, MD South Dakota Jeffrey Henderson, MD Chinle James Galloway, MD 496 Men and Women 124/center

HYPOTHESIS and DESIGN
Lowering LDL cholesterol and Blood Pressure to lower targets than are currently recommended will retard CVD Duration–3 years Control Interv LDL chol mg/dl 100 70 SBP mm/Hg 130/80 115/75 Primary End Points: Carotid IMT and Echo Cardiography Secondary: Clinical Outcomes

Inclusion Criteria
Diabetic Men and Women 40 yrs without CHD LDL100 mg/dl SBP130 mm Able to measure carotid IMT

SUMMARY
There is a rising tide of CVD in diabetes LDL and blood pressure are strong risk factors We believe SANDS will validate a strategy to prevent/retard CVD in diabetes STRONG HEART will continue to work to identify future strategies for therapy or prevention of CVD in diabetes

Anti-atherothrombotic Actions of HDL

Anti-oxidant

Anti-inflammatory

HDL
Anti-thrombotic
- antiplatelet - protein C activation

Pro-fibrinolytic

Enhanced Reverse Cholesterol Transport

Anti-atherothrombotic effect

Diabetes and an Excess of Fat
With an excess of fat diabetes begins and from an excess of fat diabetics die
- EP Joselin, 1927

PROVE IT
4162 CHD Patients Randomized to Pravastatin 40 vs
Atorvastatin 80 Followed for 2 1/2 Years Pravastatin—LDL decreased from 106 to 95 mg/dl Atorvastatin–LDL decreased from 106 to 62 mg/dl Atorvastatin showed added benefit vs Pravastatin: 16 decrease in Angina, Revasc, MI 30 decrease in CHD Death 28 decrease in Total Mortality

Benefit seen within 30 Days

TNT: Design
Patient population
250 centers in 14 countries N 10,001 LDL 130250 mg/dL TG 600 mg/dL
Atorvastatin 10 mg Atorvastatin 80 mg

Atorvastatin 10 mg

8 weeks

49 years

Waters DD et al Am J Cardiol 2004;93:154-8

TNT: Treatment effects on primary outcome
015 Atorvastatin 10 mg 010 Major CV events 005 Atorvastatin 80 mg 22 risk reduction

000 0 1 2 3 Years
HR 078 069089 P 0001

LaRosa JC et al N Engl J Med 2005;352

CARDS
Primary Prevention Study: 2838 T2DM randomized atorva 10 mg or placebo Additional risk factor Terminated at 39 years–2 years early End of study LDL: atorva 78 mg/dl and placebo 120 mg/dl End of Study non-HDL: atorva 100 mg/dl and placebo 155 mg/dl No excess of adverse events in atorvastatin group

CARDS RESULTS
All Cause Mortality: CHD Events: Revascularizations: Stroke:
Lancet 2004: 364; 685-696

- 27 - 36 - 31 - 48

Comprehensive
Medical Therapy For Patients with CHD or Other Vascular Disease
Risk Reduction

ASA Beta Blockers ACE inhibitors Statins

20-30 20-35 22-25 25-50

The four medications every atherosclerosis patient should be treated with, unless contraindications exist and are documented
Adapted from the UCLA CHAMP Guidelines 1994

CHAMP Impact on Clinical Outcomes in the First Year Post Hospital Discharge
Death or Recurrent MI 18 16 14 12 10 8 6 4 2 0
148
RR 043 p001

Pre-CHAMP

Post-CHAMP

256 AMI pts discharged in 92/93 pre-CHAMP compared to 302 pts in 94/95 post-CHAMP ASA 78 vs 92; Beta Blocker 12 vs 61; ACEI 4 vs 56; Statin 6 vs 86 Fonarow Am J Cardiol 2001;87;819-822

LDL target

Algorithm for LDL Therapy
Dose per LDL level

Statin

LDL target Non HDL target Monitor

LDL target Non HDL target Fish Oil Follow Protocol B

LDL target Increase Statin

LDL target Non HDL target

Monitor

Follow Protocol B LDL target

LDL target Non HDL target

LDL target Non HDL target Add Fenofibrate or Niacin

LDL target Non HDL target Monitor