The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)☆

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Abstract

The metabolic syndrome, which is a set of lipid and nonlipid risk factors of metabolic origin linked with insulin resistance, is believed to be associated with an elevated risk for cardiovascular disease, but few have studied this association in prospective long-term cardiovascular outcomes trials. Placebo data from the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) were used post hoc to estimate the long-term relative risk of major coronary events (MCEs) associated with the metabolic syndrome, after excluding diabetes mellitus. In 4S and AFCAPS/TexCAPS, respectively, placebo-treated patients with the metabolic syndrome were 1.5 (95% confidence interval 1.2 to 1.8) and 1.4 (95% confidence interval 1.04 to 1.9) times more likely to have MCEs than those without it. Of the components of the metabolic syndrome, low high-density lipoprotein levels were associated with elevated risk of MCEs in both studies, whereas high triglycerides in 4S and elevated blood pressure and obesity in AFCAPS/TexCAPS were associated with significantly increased relative risk. Patients with the metabolic syndrome showed increased risk of MCEs irrespective of their Framingham-calculated 10-year risk score category (>20% vs ≤20%). These data demonstrate that the metabolic syndrome is associated with increased risk of MCEs in both hypercholesterolemic patients with coronary heart disease in 4S and in those with low high-density lipoprotein cholesterol but without coronary heart disease in AFCAPS/TexCAPS. It appears that the metabolic syndrome is associated with risk that is not entirely accounted for by traditional risk scoring paradigms.

Section snippets

Study design

These post hoc analyses included only those patients who received placebo from the 4S and AFCAPS/TexCAPS trials. Methods for 4S and AFCAPS/TexCAPS have been previously described.2, 3, 4, 5, 6 Briefly, the 4S study was a double-blind randomized, placebo-controlled clinical trial assessing the effects of simvastatin (Zocor, Merck & Co., Inc., Rahway, New Jersey) 20 mg (titrated to 40 mg as needed) versus placebo on mortality and morbidity; 4,444 men and women with a history of angina pectoris or

Baseline characteristics

Mean ± SD age of the patients who received placebo in both studies was approximately 58 ± 7 years, and most patients were men (79% to 85%) (Table 1). Average baseline body mass index was approximately 26 to 27 kg/m2 and mean systolic blood pressure was 138 to 139 mm Hg. As expected by study design, mean low-density lipoprotein (LDL) levels were higher in 4S than in AFCAPS/TexCAPS, whereas average HDL was lower and triglycerides higher in AFCAPS/TexCAPS than in 4S.

Prevalence of the metabolic syndrome and components:

At baseline in 4S, 411 of

Discussion

Results of post hoc analyses of 4S and AFCAPS/TexCAPS trials demonstrate a clear, statistically significant increase in risk of MCEs for placebo-treated patients meeting criteria for the metabolic syndrome. The risk of MCEs for placebo-treated patients with clinically established CHD and high LDL cholesterol levels (4S) or no CHD but low HDL (AFCAPS/TexCAPS) was increased 1.4 to 1.5-fold after excluding patients with diabetes mellitus. One might have expected a somewhat weaker association in

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The 4S and AFCAPS/TexCAPS clinical trials were supported by Merck & Co., Inc., Rahway, New Jersey.

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