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 (HATS).

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 three years' treatment with niacin plus simvastatin (N+S) on both angiographic and clinical outcomes were analyzed in the 160 subjects with coronary artery disease (CAD) and low levels of high density lipoproteins (HDL) from the HDL-Atherosclerosis Treatment Study (HATS). 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 MS, increased insulin resistance or dysglycemia would be expected to have increased cardiovascular risk. RESULTS: N+S reduced the change in mean proximal percent stenosis (Δ%S) compared to placebo (PL) in subjects with the metabolic syndrome (Δ%Sprox 0.3 vs 3.0, p=0.003) and in the more insulin resistant group of subjects (Δ%Sprox 0.5 vs 2.7, p=0.001), while subjects with dysglycemia (impaired fasting glucose or diabetes) showed a lesser benefit (Δ%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 CAD 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. Over a 3 year period, the beneficial effect of niacin in combination with simvastatin 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.

Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study).

The high-density lipoprotein (HDL)-Atherosclerosis Treatment Study showed that simvastatin plus niacin (mean daily dose 13 mg and 2.4 g, respectively) halt angiographic atherosclerosis progression and reduce major clinical events by 60% in patients with coronary artery disease (CAD) who have low HDL, in comparison with placebos, over 3 years. How safe and well-tolerated is this combination? One hundred sixty patients with CAD, including 25 with diabetes mellitus, with mean low-density lipoprotein cholesterol of 128 mg/dl, HDL cholesterol of < or =35 mg/dl (mean 31), and mean triglycerides of 217 mg/dl were randomized to 4 factorial combinations of antioxidant vitamins or their placebos and simvastatin plus niacin or their placebos. Patients were examined monthly or bimonthly for 38 months; side effects (gastrointestinal upset, nausea, anorexia, vision, skin, and energy problems, or muscle aches) were directly queried and recorded. Aspartate aminotransferase, creatine phosphokinase (CPK), uric acid, homocysteine, and fasting glucose levels were regularly monitored. A safety monitor reviewed all side effects and adjusted drug dosages accordingly. Patients who received simvastatin plus niacin and those on placebo had similar frequencies of clinical or laboratory side effects: any degree of flushing (30% vs 23%, p = NS), symptoms of fatigue, nausea, and/or muscle aches (9% vs 5%, p = NS), aspartate aminotransferase (SGOT) > or =3 times upper limit of normal (3% vs 1%, p = NS), CPK > or =2 times upper limit of normal (3% vs 4%, p = NS), CPK > or =5 times upper limit of normal, new onset of uric acid > or =7.5 mg/dl (18% vs 15%, p = NS), and homocysteine > or =15 micromol/L (9% vs 4%, p = NS). Glycemic control among diabetics declined mildly in the simvastatin-niacin group but returned to pretreatment levels at 8 months and remained stable for rest of the study. This combination regimen was repeatedly described by 91% of treated patients and 86% of placebo subjects as "very easy" or "fairly easy" to take. Thus, the simvastatin plus niacin regimen is effective, safe, and well tolerated in patients with or without diabetes mellitus.

Change in alpha1 HDL concentration predicts progression in coronary artery stenosis.

OBJECTIVE: We examined the effects of simvastatin-niacin and antioxidant vitamins on changes in high-density lipoprotein (HDL) subpopulations and alterations in coronary artery stenosis, as assessed by angiography. METHODS AND RESULTS: Lipids, lipoproteins, and HDL particles were measured on and off treatment in 123 subjects of the HDL-Atherosclerosis Treatment Study. Patients were assigned to 4 treatment groups, simvastatin-niacin, simvastatin-niacin-antioxidant vitamins, antioxidant vitamins, and placebo. Subjects were followed for 3 years on treatment and then for 2 months off treatment. Simvastatin-niacin significantly increased the 2 large apoA-I-containing HDL subpopulations, alpha1 and prealpha1, and significantly decreased the 2 smallest particles, prebeta1 and alpha3, compared with values obtained from the same patients off treatment. Adding antioxidant vitamins to the lipid-modifying agents blunted these effects (not significant). A significant negative correlation (r=-0.235; P<0.01) between the changes in alpha1 HDL particle concentration and coronary artery stenosis was noted. Subjects in the third tertile (157% increase in alpha1) had no progression of stenosis in the 3-year follow-up period, whereas subjects in the first tertile (15% decrease in alpha1) had an average of 2.1% increase in stenosis. CONCLUSIONS: Simvastatin-niacin therapy significantly increased the large apoA-I-containing alpha1 HDL particles. This increase was significantly associated with less progression of coronary stenosis even after adjusting for traditional risk factors.