Improving Patient Outcomes: Insights From Recent Clinical Trials in Diabetes

Diabetes and CVD: Time To Act!

“With the rising tide of diabetes around the globe, the double jeopardy of diabetes and cardiovascular disease is set to result in an explosion of these and other complications — unless preventive action is taken.” Prof Sir George Alberti, IDF President International Diabetes Federation 2001

http://www.idf.org/webdata/docs/CVD_ExecSum.pdf

. Accessed May 25, 2004.

Impact of Type 2 Diabetes on Macrovascular Disease

• • • • •

Largest cause of morbidity and mortality Risk of CVD increased 2- to 4-fold Higher case fatality vs. non diabetic individuals Reduced survival post –MI, post–CABG, and particularly post –PTCA Risk of stroke and peripheral vascular disease substantially increased

Betteridge DJ.

Acta Diabetol.

1999;36:S25-S29. Nesto R.

Acta Diabetol

. 2001;38:S3-S8.

Atherosclerosis in Type 2 Diabetes

The Black Box

• • • • • •

Diabetic dyslipidemia Procoagulant state Insulin resistance/ hyperinsulinemia Glycation and advanced glycation of proteins “Glycoxidation” and oxidation Hormone-, growth factor-, and cytokine-enhanced SMC proliferation and foam cell formation

Bierman E.

Arterioscler Thromb.

1992;12:647-656.

Type 2 Diabetes Is a Vascular Disease

•

Hyperglycemia is just 1 risk factor among many for CVD

•

Intensive blood glucose control can reduce microvascular, but not macrovascular, complications of diabetes

•

CVD risk reduction should involve appropriate management of all major modifiable risk factors

De Backer G, et al.

Eur Heart J

. 2003;24:1601-1610. Holman R.

Acta Diabetol.

2001;38:S9-S14 .

UKPDS: Benefits of Tight BP Control in Type 2 Diabetes

Population:

1148 patients, mean age 56 y; mean BP at entry, 160/94 mm Hg

Treatment:

Tight control (aim < 150/85) vs less tight (aim < 180/105); captopril vs atenolol regimen; mean BP during follow-up 144/82 vs 154/87 mm Hg (

P

< 0.0001)

RRR:

24% diabetes-related end points 32% diabetes-related deaths 37% microvascular end points Adapted from UKPDS Group.

BMJ.

1998;317:703-713.

20 10

Stroke

RRR = 44% (95% CI,11-65%) Less tight control Tight control

P

= 0.013

0 0 1 2 3 4 5 6 7 8

Years from randomization

9

UKPDS: Strong Association Between SBP and Microvascular End Points and MI

Incidence of microvascular end points and MI by updated mean SBP

50 40 MI Microvascular end points

Adjusted for age, sex, and ethnic group

30

Expressed for white men, 50-54 y at baseline and with mean diabetes duration of 10 y

20 10 0 110 120 130 140 150 160

Updated mean SBP (mm Hg)

170 Adapted from Adler AI, et al.

BMJ.

2000;321:412-419.

Diabetic Dyslipidemia

Compared with nondiabetic individuals, patients with

• • • •

diabetic dyslipidemia may have: Elevated plasma triglyceride levels Decreased plasma HDL-C levels Relatively normal plasma LDL-C levels Relatively high proportion of small, dense LDL-C

American Diabetes Association.

Diabetes Care.

2004;27:S68-S71.

UKPDS: Risk Factors for CAD in Type 2 Diabetes

• 

LDL-C

• 

HDL-C

• 

TGs

• 

HbA 1c

• 

SBP

• 

Fasting plasma glucose

•

Smoking status

Turner RC, et al.

BMJ.

1998;316:823-828.

CHD Prevention Trials With Statins in Patients With Diabetes: Subgroup Analyses Drug CHD risk reduction CHD risk reduction Nondiabetics Diabetics Study

Primary Prevention

HPS 1†

Secondary Prevention

CARE 2†† 4S 3‡ 4S reanalysis 4‡‡ HPS 1† Simvastatin Pravastatin Simvastatin Simvastatin Simvastatin 25%* 23% 32% 32% 24%* 26% 25% 55% 42% 12% NS CHD end points: Cohorts: Footnote: † HPS = first major vascular event; †† CARE = absolute risk of coronary events; ‡ 4S = major CHD events; ‡‡ 4S reanalysis = major coronary events.

*HPS = risk reduction for the entire cohort (nondiabetics and patients with diabetes). NS = results not statistically significant.

1. HPS Collaborative Group.

Lancet.

2002;360:7-22.

2. Goldberg RB, Mellies MJ, Sacks FM, et al.

Circulation.

1998;98:2513-2519.

3. Py örälä K, Pedersen TR, Kjekshus J, et al.

Diabetes Care.

1997;20:614-620.

4. Haffner SM, Alexander CM, Cook TJ, et al.

Arch Intern Med.

1999;159:2661-2667.

Greek Atorvastatin and CHD Evaluation (GREACE) Study Population: 1600 CHD patients (344 women) Design: Randomized, open, 3-year study, atorvastatin (10-80 mg) vs usual care Atorvastatin titrated to achieve NCEP goal of LDL <2.6 mmol/L (< 100 mg/dL); mean dose, 24 mg/d Usual care group 14% lipid-lowering drugs Lipid changes: LDL-C



46%; non –HDL-C



44%; TGs



31% HDL-C



7% (absolute LDL-C



2.1 mmol/L [81 mg/dL]) Primary end points: Death, nonfatal MI, unstable angina, CHF, stroke, and revascularization

Athyros VG, et al.

Curr Med Res Opin.

2002;18:220-228.

GREACE: Risk Reduction With Atorvastatin in Diabetic Cohort

Risk reduction in composite primary end point: Diabetes 0.42

n = 313 (20%) P < 0.0001

All patients 0.49

n = 1297 Atorvastatin

Athyros VG, et al.

Curr Med Res Opin.

2002;18:220-228.

0

Usual care P < 0.0001

CARDS: Collaborative AtoRvastatin Diabetes Study

Patient Population      Type 2 diabetics (40-75 y) No prior MI or CVD Other risk factors + Lipid profile:  LDL-C  4.14 mmol/L  (160 mg/dL) TGs  6.78 mmol/L (600 mg/dL) Collaboration in the UK with Diabetes UK, NHS R&D, and Pfizer Colhoun HM, et al.

Diabet Med.

2002;19:201-211.

2838 Patients d/b PBO Atorvastatin 10 mg Min 4 y

Primary End Point  Time to major CV event (CHD death, nonfatal MI, revascularization, CABG, stroke)

CARDS Inclusion Criteria

• • • • • •

Type 2 DM (WHO criteria) for at least 6 months prior to screening Age 40-75 y No history of CVD LDL-C



4.14 mmol/L (160 mg/dL) TGs



6.78 mmol/L (600 mg/dL) At least 1 other risk factor :

– Hypertension (history of BP, or SBP  140 or DBP  90 mm Hg – Retinopathy – Micro-(albumin/creatinine ratio  2.5 mg/mmol/L) or macroalbuminuria (  25 mg/mmol/L) – Current smoker (all patients were counselled to quit) Colhoun HM, et al.

Diabet Med.

2002;19:201-211.

CARDS Patient Baseline Characteristics

Mean age (years) < 60 60-70 > 70 Women White ethnicity BMI kg/m 2 (SD) Obese (BMI > 30 kg/m 2 ) Placebo n (%) 61.8

529 (37.5%) 708 (50.2%) 173 (12.3%) 453 (32.1%) 1326 (94.0%) 28.8 (3.5) 537 (38.1%) Atorvastatin n (%) 61.5

558 (39.1%) 703 (49.2%) 167 (11.7%) 456 (31.9%) 1350 (94.5%) 28.7 (3.6) 515 (36.1%)

http://www.cardstrial.org/healthcare/slideresources.asp

. Accessed June 8, 2004.

CARDS Patient Baseline Characteristics

Placebo Mean (SD) or n (%) Atorvastatin Mean (SD) or n (%) BP SBP (mm Hg) DBP (mm Hg) On BP drug 144 (16.1) 83 (8.4) 940 (67) 144 (15.9) 83 (8.5) 956 (67) Smoking Current Ex-smoker Never 323 (22.9%) 601 (42.7%) 485 (34.4%) 308 (21.6%) 622 (43.6%) 498 (34.9%)

http://www.cardstrial.org/healthcare/slideresources.asp

. Accessed June 8, 2004.

CARDS Patient Baseline Lipids*

Placebo Median (IQR) Total cholesterol (mmol/L) (mg/dL) 5.4 (4.8-5.9) 207 (185-229) LDL-C (mmol/L) (mg/dL) 3.1 (2.6-3.6) 118 (100-137) HDL-C (mmol/L) (mg/dL) 1.4 (1.2-1.6) 53 (46-61) Atorvastatin Median (IQR) 5.4 (4.8-5.9) 207 (186-228) 3.1 (2.6-3.6) 119 (100-138) 1.3 (1.2-1.6) 52 (45-60)

*Subject to final verification.

http://www.cardstrial.org/healthcare/slideresources.asp

. Accessed June 8, 2004.

CARDS: Stopped Early Due to Significant Benefit of Atorvastatin Treatment

• • •

In June 2003, the independent Steering Committee stopped the trial after only 2 years because the magnitude of benefit for the primary end point exceeded the prespecified stopping rule Preliminary results of the CARDS trial showed a significant reduction in MI, stroke, and other coronary events in patients treated with atorvastatin CARDS became the second atorvastatin trial to end early because of observed treatment benefit (ASCOT LLA was the first)

AHA Prevention Conference VI Diabetes and Vascular Disease Goals of Therapy Glycemia BP HbA 1c < 7% (ADA) < 130/85 (JNC VI) < 130/80 (ADA) < 2.6 mmol/L (100 mg/dL) (NCEP) LDL-C HDL-C < 1 mmol/L (< 40 mg/dL) Raise HDL (no goal) TGs 2.2-5.6 mmol/L (200-499 mg/dL) Non –HDL-C < 3.4 mmol/L (130 mg/dL) BMI > 25 kg/m 2 Lose 10% body wt (OEI) Physical activity Cigarettes Prothrombotic state Exercise (ADA) Stop Low-dose aspirin (ADA)

Grundy SM, et al.

Circulation

. 2002;105:2231-2239.

Trends in Risk Factor Control

NHANES (1988-1994) NHANES (1999-2000)

HbA 1c < 7% BP < 130/80 mm Hg TC < 2.3 mmol/L (200 mg/dL) 44% 29% 33.9% 37% 35.8% 48.2% HbA 1c < 7% and BP < 130/80 mm Hg and TC < 2.3 mmol/L (200 mg/dL) 5.2% 7.3% Saydah SH, et al.

JAMA.

2004;291:335-342.

• • • •

LIPITOR (atorvastatin calcium) is indicated as an adjunct to diet to reduce elevated total cholesterol, LDL-cholesterol, apo B, and TG levels and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial) or combined hyperlipidemia. In clinical trials, the most common adverse events were constipation, flatulence, dyspepsia and abdominal pain, headache, nausea, myalgia, asthenia, diarrhea, insomnia. LIPITOR is contraindicated in patients with hypersensitivity to any component of this medication; in patients with active liver disease or unexplained persistent elevation of serum transaminases; myopathy; in women during pregnancy, in nursing mothers, and in women of child-bearing potential not using appropriate contraceptive measures.

Liver function tests should be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or elevation in dose, and periodically thereafter. LIPITOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

LIPITOR is available in 10-mg, 20-mg, 40-mg, and 80-mg film coated tablets, administered once daily.

For further information please see prescribing information.

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