Clinical Trials and Guidelines for Lipid Management in the Diabetic Patient Steven Haffner, MD

Slide Source: Lipids Online www.lipidsonline.org

UKPDS Design
Aim
To determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetes

Patients
3867 newly diagnosed type 2 diabetic patients who were asymptomatic after 3 months of diet; fasting glucose 6.1-15 mmol/L (110-270 mg/dl); treat for 10 years
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Slide Source: Turner R et al. Ann Intern Med 1996;124:136-145. Lipids Online

www.lipidsonline.org

UKPDS 10-Year Follow-up Results:

11 Median (mmol/L) 10 9 8 7 6 0 7.5 5 2.5 0 -2.5

Glycemic Control, Weight, and Plasma Insulin

Fasting plasma glucose
Median (%) Conventional Intensive 9 8 7 6 0 40 30 20 10 0 -10 -20 Baseline = 89 pmol/L 0 1 2 3 4 5 6 7 Conventional 8 9 10 11 12

Hemoglobin A1c
Conventional Intensive

Mean Change (kg)

Weight
Intensive

Median Change (pmol/L)

Plasma insulin
Intensive

Conventional Baseline = 75 kg 0 1 2 3 4 5 6 7 8 9 10 11 12

Years from Randomization

Years from Randomization

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UKPDS Group. Lancet 1998;352:837-853.

UKPDS: Proportion of Patients Taking Different Therapies in the Conventional-Therapy Group

100 80 60 40 20 1
Courtesy of Dr. Amanda Adler

% of patients

Additional pharmacologic therapy

Diet alone

3 5 7 9 11 Years from randomization

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UKPDS: Causes of Death by Glucose Treatment Group

Cause MI Stroke Sudden death PVD All macrovascular Renal disease Cancer Other specified Unknown Total Intensive Rate/1000 patient-years % 7.6 1.6 0.9 0.1 10.2 0.3 4.4 2.4 0.5 17.8 43 9 5 1 58 2 25 13 3 100 Conventional Rate/1000 patient-years % 8.0 1.3 1.6 0.3 11.2 0.2 4.4 2.7 0.2 18.7 43 7 8 2 60 1 24 14 1 100

UKPDS Group. Lancet 1998;352:837-853.

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UKPDS: Endpoints by Glucose Treatment Group

Intensive Conventional

Cause
Any diabetes-related* MI Stroke PVD** Microvascular

Rate/1000 Rate/1000 Patient-Years Patient-Years 40.9 14.7 5.6 1.1 8.6 46.0 17.4 5.0 1.6 11.4

P 0.029 0.052 0.52 0.15 0.0099

% Risk Reduction 12 16 25

*Combined microvascular and macrovascular events **Amputation or death from PVD UKPDS Group. Lancet 1998;352:837-853.

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UKPDS: Impact of Glucose-Lowering Agents on MI and Stroke

Sulphonylurea or exogenous insulin (n=2729) MI 16% reduction (P = 0.052)

Stroke 11% increase (P = 0.52) Metformin in overweight subjects (n = 342) MI 39% reduction (P = 0.01)

Stroke 41% reduction (P = 0.13)

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865. Slide Source: Lipids Online
www.lipidsonline.org

UKPDS Results: Intensive Blood Pressure Control

Intensive Blood Pressure Control Any diabetes-related endpoint Deaths related to diabetes Myocardial infarction Stroke Microvascular disease Reduction (%) 24 32 21 44 37 P Value 0.0046 0.019 NS 0.013 0.092
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Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.

Comparison of Captopril vs. Atenolol in UKPDS

Clinical Endpoint
Primary Any diabetes-related endpoint Death related to diabetes All-cause mortality Secondary Myocardial infarction Stroke Peripheral vascular disease Microvascular disease 1.20 (0.821.76) 1.12 (0.592.12) 1.48 (0.356.19) 1.29 (0.802.10) 0.35 0.74 0.59 0.30
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RR for Captopril

P Value
0.43 0.28 0.44

1.10 (0.861.41) 1.27 (0.821.97) 1.14 (0.811.61)

Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:713-720.

Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDS

Intensive Blood Intensive Blood Glucose Control (n=2729) Pressure Control (n=758)

Reduction % Any diabetes-related endpoint Myocardial infarction Stroke Microvascular disease

= Increase in risk

P Value 0.029 0.052 NS 0.0099

Reduction % 24 21 44 37

P Value 0.0046 NS 0.013 0.092

12 16 11 25

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. Slide Source:

Lipids Online www.lipidsonline.org

Treatment Strategies for Diabetic Dyslipidemia

Primary Strategy - Lower LDL cholesterol Secondary Strategy - Raise HDL cholesterol - Lower triglycerides Other Approaches - Non-HDL cholesterol - ApoB - Remnants
Adapted from American Diabetes Association. Diabetes Care. 2000;23(suppl 1):S57-S60; Chait A, Brunzell JD. Diabetes Mellitus. A Fundamental and Clinical Text. Philadelphia: Lippincott Raven, 1996;772-779; Slide Source: European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730. Lipids Online
www.lipidsonline.org

CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses

Baseline LDL-C, mg/dl (mmol/L) 150 (3.9) 136 (3.6) 186 (4.8) 150* (3.9) LDL-C Lowering 25% 28% 36% 25%*

Study Primary Prevention AFCAPS/TexCAPS Secondary Prevention CARE 4S LIPID

*Values for overall group

Drug Lovastatin Pravastatin Simvastatin Pravastatin

No. 239 586 202 782

Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyrl K et al. Diabetes Care 1997;20:614-620; Haffner SM et al. Arch Intern Med 1999;159:2661-2667; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357. Slide Source:
Lipids Online www.lipidsonline.org

CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses (contd)
Study Primary Prevention AFCAPS/TexCAPS Secondary Prevention CARE 4S LIPID 4S-Extended Pravastatin Pravastatin 586 782 23% 32% 25% 32% 25% (p=0.05) 55% (p=0.002) 19% 42% (p=0.001) Simvastatin 202 Simvastatin 483 Lovastatin 239 37% 43% Drug CHD Risk Reduction No. (overall) CHD Risk Reduction (diabetes)

Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyrl K et al. Diabetes Care 1997;20:614-620; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357; Haffner SM et al. Arch Intern Med 1999;159:2661-2667.
Slide Source: Lipids Online www.lipidsonline.org

Diabetic vs. Nondiabetic Patients in 4S

Simvastatin Better Placebo Better

Total mortality CHD mortality Major CHD event Cerebrovascular event Any atherosclerotic event 0
No diabetes Diabetes

P=0.001 P=0.087 P<0.0001 P=0.242 P<0.0001 P=0.002 P=0.097 P=0.071 P<0.0001 P=0.018

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Relative Risk with 95% Confidence Intervals Reduced Increased

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Adapted from Pyrl et al. Diabetes Care 1997;20:614-620.

Major Coronary Events in 4S Patients with or without Diabetes by History (n=202)

1.0 Proportion without Major CHD Event 0.9 0.8 0.7 0.6 0.5 0 0
Diabetes by Hx, simvastatin Diabetes by Hx, placebo P=0.002 P=0.0001

No diabetes by Hx, simvastatin No diabetes by Hx, placebo

2 3 4 5 Years Since Randomization

6
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Adapted from Pyrl et al. Diabetes Care 1997;20:614-620.

4S: Extended Diabetic Subgroup Analysis:

Diabetes (n=483; 251 on Simvastatin) Fasting Glucose >7 mmol/L (126 mg/dl)
CHD mortality (P=0.26) Total mortality (P=0.34) Revascularizations (P=0.005) Major coronary events (P=0.001) 0.0 0.2 0.4
0.52 0.58 0.72 0.79

0.6 0.8 1.0 Relative Risk

1.2

1.4

Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667

Slide Source: Lipids Online www.lipidsonline.org

4S: Extended Diabetic Subgroup Analysis:

Impaired Fasting Glucose (n=678; 343 on Simvastatin) Fasting Glucose 6.0-6.9 mmol/L (110-125 mg/dl)
CHD mortality (P=0.007) Total mortality (P=0.02) Revascularizations (P=0.01) Major coronary events (P=0.003) 0.0 0.2 0.4
0.45 0.57

0.57 0.62

0.6 0.8 1.0 Relative Risk

1.2

1.4

Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667

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4S: Effect of Statin Therapy on Hospital Stay

1200
Bed Days (per 100 Pts)

1000 800 600 400 200 0

Simvastatin Placebo Simvastatin Placebo

(p<0.001) (p<0.001)

55%

28%

(p=0.005)

38%

Simvastatin

Placebo

Normal fasting glucose

Impaired fasting glucose

Diabetes mellitus
Slide Source: Lipids Online www.lipidsonline.org

Adapted from Herman WH et al. Diabetes Care 1999;22:1771-1778.

CARE: Major Coronary Events in Diabetic Subgroups

45 Percent with Event 35 30 25 20 15 10 5 0 0 1 2 3 4 5 6 Follow-up Time (years) Pravastatin Placebo

No Diabetes by History
Percent with Event
Relative risk = 0.77 P<0.001

45 35 30 25 20 15 10 5 0 0

Diabetes by History
Relative risk = 0.75 P=0.05

Placebo Pravastatin

1 2 3 4 5 6 Follow-up Time (years)

Slide Source: Lipids Online www.lipidsonline.org

Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519.

AFCAPS/TexCAPS: Subgroup Analysis

0 -10
% Risk Reduction Men Women Older Smokers HTN Diabetes

-20 -30 -40 -50 -60 -70

-37 -46 -58 Lovastatin Reduced the Risk of Acute MCE
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-31 -38 -42

Downs JR et al. JAMA 1998;279:1615-1622.

CARE: Major Coronary Events in Diabetic Subgroups

45 40 35 30 25 20 15 10 5 0

No Diabetes by History
Percent with Event
Relative risk = 0.77 P<0.001

Placebo

Pravastatin 0 1 2 3 4 5 6 Follow-up Time (years)

45 40 35 30 25 20 15 10 5 0

Diabetes by History
Relative risk = 0.75 P=0.05

Percent with Event

Placebo Pravastatin

1 2 3 4 5 6 Follow-up Time (years)

Slide Source: Lipids Online www.lipidsonline.org

Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519.

POST-CABG: Effect of Aggressive Lipid Lowering on Progression in a Diabetic Subgroup

Per-Patient % of Grafts

50 40 30 20 10 0

Diabetes (n=116)

No Diabetes (n=1235)

51%

40%

99% CI (0.20-1.19)
Aggressive Moderate Rx Rx

99% CI (0.46-0.79)
Aggressive Moderate Rx Rx
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Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294.

CHD Prevention Trials with Fibrates in Diabetic Subjects: Subgroup Analyses

Drug Dose Baseline LDL-C, mg/dl No. (mmol/L) LDL-C Lowering CHD Reduction

Study Primary Prevention Helsinki Heart Study

Gemfibrozil 135 (1200 mg/d)

203 (5.2)

6%

68% NS

Secondary Prevention VA-HIT Gemfibrozil 627 (1200 mg/d) 112 (2.9) 24% p=0.05
Slide Source: Lipids Online www.lipidsonline.org

Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825; Rubins HB et al. N Engl J Med 1999;341:410-418.

Primary CHD* Prevention in Type 2 Diabetic Patients: The Helsinki Heart Study
5-Year Incidence of CHD (%)

15
P<0.02 7.4 10.5

P=0.19

10

3.3

3.4

Type 2 (n=135)

Others (n=3946)

*Myocardial infarction or cardiac death Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825.

Type 2 on Placebo (n=76)

Type 2 on Gemfibrozil (n=59)

Slide Source: Lipids Online www.lipidsonline.org

VA-HIT: Incidence of Death from CHD and Nonfatal MI

Cumulative Incidence (%)

25 20 15 10 5 0 1 2 3
Year

Placebo Gemfibrozil

5
Slide Source: Lipids Online www.lipidsonline.org

Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418.

VA-HIT: Death Due to CHD, Nonfatal MI, and Confirmed Stroke in Diabetic Patients
Placebo* Diabetes 116/318 (36) No diabetes 214/949 (23) Gemfibrozil* 88/309 (28) 170/955 (18) 24% 0.009 Risk Reduction 24% P Value 0.05

*Values are numbers with events/total numbers (%) Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418.
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Future Directions
Ongoing Trials with Lipid-Lowering Focus HPS ASPEN CARDS LDS DAIS FIELD Drug Simvastatin Atorvastatin Atorvastatin Cerivastatin + fenofibrate micronized Fenofibrate micronized Fenofibrate micronized

HPS = Heart Protection Study; ASPEN = Atorvastatin Study in Preventing Endpoints in NIDDM; CARDS = Collaborative Atorvastatin Diabetes Study; LDS = Lipids in Diabetes Study; DAIS = Diabetes Atherosclerosis Intervention Study; FIELD = Fenofibrate Intervention Slide Source: and Event Lowering in Diabetes

Lipids Online www.lipidsonline.org

Heart Protection Study

Primary prevention with risk factors (hypertension, diabetes, and CVA) 2x2 factorial design simvastatin 40 mg/day, antioxidant cocktail (600 mg vitamin E, 250 mg vitamin C, 20 mg beta carotene) N = 20,000; subgroups include: Women (n ~ 5,000) Elderly (>65, n ~ 10,000) Diabetics (n ~ 6,000) Stroke (n ~ 3,000) Hypertension (n ~ 8,000) Noncoronary vascular disease (n ~ 7,000) Low to average blood cholesterol (n ~ 8,000) FPI 1996, fully enrolled, results 2001
Medical Research Council. August 1994
Slide Source: Lipids Online www.lipidsonline.org

Endpoint Studies: Treating to New Targets (TNT): Study Design

Atorvastatin 80 mg LDL 75 mg/dL

10,000 CAD Patients

5 Years
Atorvastatin LDL 10 mg 100 mg/dL

Site Selection November 1997

Investigator Meeting March 1998

Recruitment Complete June 1999

Study End Dec 2004

Slide Source: Lipids Online www.lipidsonline.org

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin B12 (SEARCH): Study Design
Primary objective: To determine whether the greater cholesterol reductions achieved with simvastatin 80 mg produce greater CHD reductions in post-MI patients than achieved with simvastatin 20 mg Secondary prevention 2x2 factorial design: simvastatin 20 or 80 mg; 2 mg folic acid/1 mg Vitamin B12 N = 12,000 FPI 12/97, results 2003
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Lipids in Diabetes Study (LDS): Two-by-Two Factorial Randomization

Cerivastatin Arm Fenofibrate Arm
2,500 active fenofibrate

Cerivastatin Fenofibrate (n=1,250) Cerivastatin Placebo (n=1,250)

n=2,500 active cerivastatin

Placebo Fenofibrate (n=1,250) Placebo Placebo (n=1,250)

n=2,500 placebo cerivastatin

2,500 placebo fenofibrate

5,000 pts in total

Slide Source: Lipids Online www.lipidsonline.org

Conclusions
CHD risk is extremely high in diabetic subjects Benefits of risk-factor modification in intervention trials also apply to subgroups with diabetes Results of strict glycemic control on macrovascular disease are inconclusive

Slide Source: Lipids Online www.lipidsonline.org

Slide Source: Lipids Online www.lipidsonline.org