MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in patients with diabetes

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MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial
Authors	Collins R, Armitage J, Parish S, Sleigh P, Peto R
Journal	Lancet
Year/Volume(Issue)/Pages	2003;361(9374):2005-2016
Original Article Abstract
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Contents 1 Quick Summary 2 Hypothesis/Objectives 3 Methods/Design 3.1 Inclusion criteria 3.2 Exclusion criteria 3.3 Design 4 Results 4.1 Baseline characteristics 4.2 Primary endpoint results 4.3 Other 5 Limitations

Quick Summary

• At this point most diabetic patients do not receive cholesterol-lowering therapy, even though they are known to be at an increased risk of cardiovascular morbidity and mortality.
• This study included both diabetic and non-diabetics (the non-diabetics had occlusive arterial disease), and analyzed the effects of simvastatin on cardiovascular outcomes.
• After a mean 4.8 year follow up, the authors found about a 25% decreased risk for the first occurrence of major coronary events, strokes, and revascularizations in both diabetic and non-diabetics patients taking simvastatin compared to placebo.

Hypothesis/Objectives

At this point, the increased risk of macrovascular complications in diabetics is known, but few studies have evaluated the outcomes of these patients when on statin therapy. The objective of this study was to evaluate the effects of a significant reduction in LDL cholesterol, which was sustained over several years, in diabetic patients on vascular morbidity and mortality.

Methods/Design

		Y	Randomized?
		Y	Controlled?
		Y	Placebo-controlled?
		Y	Prospective?
		Y	Double-blind?
		*U = not reported

Inclusion criteria

• Men and women aged 40-80 years
• Non-fasting blood total cholesterol concentrations of at least 135mg/dL (3.5mmol/L)
• History of at least one of the following:
  • diabetes mellitus (type 1 or type 2)
  • coronary disease
  • occlusive disease of non-coronary arteries
  • treated hypertension (males >65 years)

Exclusion criteria

• If the primary physician determined statin therapy to be clearly indicated or contraindicated
• Myocardial infarction (MI) in the previous 6 months
• Stroke in the previous 6 months
• Hospital admission for angina in the previous 6 months
• Chronic liver disease or evidence of abnormal liver function
• Severe renal disease or evidence of substantially impaired renal function
• Inflammatory muscle disease or evidence of muscle problems
• Concurrent treatment with:
  • cyclosporine
  • fibrates
  • high-dose niacin
• Child-bearing potential
• Severe heart failure
• A life-threatening condition other than vascular disease or diabetes
• Condition which might limit long-term compliance

Design

The 5963 included patients with diabetes and 14,573 high-risk patients without diabetes were randomly assigned to receive simvastatin 40mg daily (n=10,269) or placebo (n=10,267), after completing a 4 week run-in period with placebo and 4-6 weeks of simvastatin. Participants were seen at 4, 8, and 12 months, and then every 6 months for follow-up visits, for a mean follow up time of 4.8 years. At each visit, monitoring of alanine aminotransferase was performed to monitor liver function, and non-fasting lipid profiles were perfomed yearly.

Results

Baseline characteristics

Among the patients with diabetes, 19% had a history of MI, 14% had a history of coronary disease, 18% had a history of occlusive arterial disease alone, and 49% had no history of any arterial disease. 10% had type 1 diabetes and 90% had type 2. Compared to the patients without diabetes, the patients with diabetes were more likely to be younger, less likely to be male or have occlusive artery disease, and had higher blood pressure and BMI. Regarding cholesterol levels, the diabetic patients had significantly lower total and LDL cholesterol and higher triglycerides than those without diabetes.

Primary endpoint results

The primary endpoint was defined as time to first coronary event (non-fatal MI or coronary death) and first major vascular event (major coronary event, stroke, or revascularization). In the simvastatin group there was a 27% reduction in the relative risk of first non-fatal MI or coronary death (relative risk (RR) 0.73 [95% CI 0.67-0.79], p<0.0001) when compared to placebo. Both the diabetic and non-diabetic patients in the simvastatin group had a 27% reduction in the relative risk of either of these events: diabetics: (95% CI 15-38, p<0.0001), non-diabetics: (95% CI 19-34, p<0.0001). Simvastatin treatment was also associated with a 24% reduction in the relative risk of first major vascular event (RR 0.76 [95% CI 0.72-0.81], p<0.0001), revascularization (RR 0.76 [95% CI 0.70-0.83], p<0.0001), and a 25% reduction in the relative risk of fatal or non-fatal stroke (RR 0.75 [95% 0.67-0.79], p<0.0001) when compared to placebo. The diabetic patients taking simvastatin had a 24% reduction in the relative risk of a stroke (95% CI 6-39, p=0.01), a 22% reduction in any major vascular event (95% CI 13-30, p<0.0001), and a 17% reduction in revascularizations (95% CI 3-30, p=0.02) compared to placebo. The non-diabetic patients had a 26% reduction in risk for both stroke and revascularization (stroke: 95% CI 14-36, p=0.0002) (revascularization: 95% CI 18-33, p<0.0001), and a 25% reduction for any vascular event (95% CI 19-30, p<0.0001).

Other

When adjusted for the baseline differences between the diabetics and the non-diabetics, the results were consistent with those stated above. In a subgroup of diabetic patients (n=2912) who did not have diagnosed coronary or other occlusive arterial disease at the start of the study there was a 33% reduction in the relative risk of first major vascular events (95% CI 17-46, p=0.0003). Use of simvastatin was associated with a 39 mg/dL (1.0 mmol/L) decrease in LDL cholesterol compared to placebo treatment, and there was no difference between the simvastatin and placebo groups for increase in A1C (difference: 0.03%, p=0.8). The simvastatin group did show a smaller increase in serum creatinine concentrations (difference: -0.02mg/dL (1.81micromol/L), p<0.0001) compared to the placebo group, however this change may not be clinically significant.

Limitations

• This study was partially funded by Merck, the manufacturers of simvastatin (Zocor).
• An average of 17% of placebo treated patients were taking a non-study statin during the study.
• The authors conclude that statin therapy is beneficial for all patients with diabetes, regardless of their cholesterol levels or pregression of coronary disease. There may be financial consequences for putting patients on a statin when they have normal cholesterol levels.