Niacin plus simvastatin reduces coronary stenosis progression among patients with metabolic syndrome despite a modest increase in insulin resistance: A subgroup analysis of the HDL-Atherosclerosis treatment study

BACKGROUND: Metabolic syndrome, insulin resistance, and diabetes are associated with an increased risk of cardiovascular disease. Niacin is known to increase insulin resistance and have adverse effects on blood glucose levels, but to have beneficial effects on plasma lipids and lipoproteins. We, therefore, aimed to determine whether intensive lipid therapy with a niacin-containing regimen would have a beneficial effect on cardiovascular disease, despite an expected increase in plasma glucose and insulin resistance in subjects with the metabolic syndrome, insulin resistance, or abnormal fasting plasma glucose levels. METHODS: The effect of 3 years' treatment with niacin plus simvastatin (N+S) on both angiographic and clinical outcomes was analyzed in the 160 subjects with coronary artery disease and low levels of high-density lipoproteins (HDL) from the HDL-Atherosclerosis Treatment Study. A subgroup analysis was performed on the basis of: (1) the presence or absence of the metabolic syndrome, (2) higher or lower insulin resistance, and (3) the presence or absence of impaired fasting glucose or diabetes (dysglycemia). Individuals classified as having the metabolic syndrome, increased insulin resistance or dysglycemia would be expected to have increased cardiovascular risk. RESULTS: N+S reduced the change in mean proximal percent stenosis (Delta%S) compared to placebo (PL) in subjects with the metabolic syndrome (Delta%Sprox 0.3 vs 3.0, P = 0.003) and in the more insulin-resistant group of subjects (Delta%Sprox 0.5 vs 2.7, P = 0.001), while subjects with dysglycemia (impaired fasting glucose or diabetes) showed a lesser benefit (Delta%Sprox 1 vs 3.2, P = 0.13). These changes occurred despite increased in-treatment fasting glucose levels (3%), fasting insulin (19%) and decreased insulin sensitivity (-10%). Overall primary clinical events were reduced by 60% with N+S compared to PL (P = 0.02). A similar reduction of the rate of primary events was seen in patients with metabolic syndrome, insulin resistance, and, to a lesser extent, in patients with dysglycemia in the N+S group compared to PL. CONCLUSIONS: These data indicate that, in coronary artery disease patients with low HDL, treating the atherogenic dyslipidemia with a combination of N+S leads to substantial benefits in terms of stenosis progression and clinical events, independently of whether the patient has the metabolic syndrome or is insulin-resistant. During a 3-year period, the beneficial effect of niacin in combination with siravastatin appears to offset the modest adverse effect of niacin on glucose metabolism and insulin resistance in at higher-risk patients, as long as careful attention is paid to glycemic control. (c) 2007 National Lipid Association. All rights reserved.