Body weight, plasma insulin, and coronary events with gemfibrozil in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT)



      The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that gemfibrozil significantly reduced major coronary events in men with known coronary heart disease (CHD). To better understand why therapy was especially effective with obesity, diabetes, and hyperinsulinemia, changes in body weight and plasma insulin were determined after 1 year of gemfibrozil or placebo therapy and related to changes in lipids and CHD events.


      With gemfibrozil significantly more subjects lost weight (51.7% versus 38.6%, P < 0.0001) and significantly fewer subjects gained weight (42.5% versus 54.0%, P < 0.0001) than with placebo. Both a greater loss and smaller gain in weight with gemfibrozil were age-related and significant in subjects ≥66 years (median age), but not in younger subjects. Weight change was paralleled by changes in insulin. With gemfibrozil, CHD events were significantly reduced with weight loss (hazard ratio [HR], 0.61; 95% CI, 0.44–0.84; P = 0.002) and, particularly, with diabetes or hyperinsulinemia (HR, 0.53; 95% CI, 0.34–0.83; P = 0.006). In contrast, CHD events were not significantly reduced without weight loss (HR, 0.83; 95% CI, 0.62–1.12; P = 0.22).


      In VA-HIT, gemfibrozil resulted in weight loss associated with reductions in insulin. With weight loss gemfibrozil produced a significant reduction in CHD events that did not occur in the absence of weight loss.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rubins H.B.
        • Robins S.J.
        • Collins D.
        • et al.
        Gemfibrozil for the secondary prevention of coronary heart disease in men with low HDL-cholesterol.
        N Engl J Med. 1999; 341: 410-418
        • Rubins H.B.
        • Robins S.J.
        • Collins D.
        The Veterans Affairs High-Density Lipoprotein Intervention Trial: baseline characteristics of normocholesterolemic men with coronary artery disease and low levels of high-density lipoprotein cholesterol.
        Am J Cardiol. 1996; 78: 572-575
        • Rubins H.B.
        • Robins S.J.
        • Collins D.
        • et al.
        Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT).
        Arch Intern Med. 2002; 162: 2597-2604
        • Robins S.J.
        • Rubins H.B.
        • Faas F.H.
        • et al.
        Insulin resistance and cardiovascular events with low high-density lipoprotein cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT).
        Diabetes Care. 2003; 26: 1513-1517
        • Li P.
        • Zhengxian Z.
        • Lu Y.
        • Granneman J.G.
        Metabolic and cellular plasticity in white adipose tissue: II. Role of peroxisome proliferators activated receptor-α.
        Am J Physiol Endocrinol Metab. 2005; 289: E617-E626
        • Tsuchida A.
        • Yamauchi T.
        • Takekawa S.
        • et al.
        Peroxisome proliferator-activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue.
        Diabetes. 2005; 54: 3358-3370
        • Guerre-Millo M.
        • Gervois P.
        • Raspe E.
        • et al.
        Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity.
        J Biol Chem. 2002; 275: 16638-16642
        • Ferreira A.V.M.
        • Parreira G.G.
        • Green A.
        • Botion L.M.
        Effects of fenofibrate on lipid metabolism in adipose tissue of rats.
        Metab Clin Exp. 2006; 55: 731-735
        • Chaput E.
        • Saladin R.
        • Silvestre M.
        • Edgar A.D.
        Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight.
        Biochem Biophys Res Commun. 2000; 271: 445-450
        • Jeong S.
        • Kim M.
        • Han M.
        • Lee H.
        • et al.
        Fenofibrate prevents obesity and hypertriglyceridemia in low-density lipoprotein receptor-null mice.
        Metabolism. 2004; 53: 607-613
        • Muls E.
        • Van Gaal L.
        • Autier P.
        • Vansant G.
        Effects of initial BMI and on-treatment weight change on the lipid-lowering efficacy of fibrates.
        Int J Obes. 1997; 21: 155-158
        • Robins S.J.
        Lipid therapy for cardiovascular disease with insulin resistance, diabetes, or the metabolic syndrome.
        Curr Cardiol Rep. 2005; 7: 457-464
        • Retzlaff B.M.
        • Dowdy A.A.
        • Walden C.E.
        • Bovbjerg V.E.
        • Knopp R.H.
        The Northwest Lipid Research Clinic Fat Intake Scale: validation and utility.
        Am J Public Health. 1997; 87: 181-185
        • Tenkanen L.
        • Manttari M.
        • Manninen V.
        Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study.
        Circulation. 1995; 92: 1779-1785
        • Tenenbaum A.
        • Motro M.
        • Fisman E.Z.
        • et al.
        Bezafibrate for the secondary prevention of myocardial infarction in patients with the metabolic syndrome.
        Arch Intern Med. 2005; 165: 1154-1160
      1. Higgins M, Kannel W, Garrisan R, Pinsky J, Stokes J 3rd. Hazards of obesity—the Framingham experience. Acta Med Scand Suppl 1988; 723: 23–36.

        • Balagopal P.
        • George D.
        • Yarandi H.
        • Funanage V.
        • Bayne E.
        Reversal of obesity-related hypoadiponectinemia by lifestyle intervention: a controlled randomized study in obese adolescents.
        J Clin Endocrinol Metab. 2005; 90: 6192-6197
        • Frick M.H.
        • Elo O.
        • Haapa K.
        • et al.
        Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia.
        N Engl J Med. 1987; 317: 1237-1245
        • Tenenbaum A.
        • Fisman E.Z.
        • Boyko V.
        • et al.
        Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate.
        Arch Intern Med. 2006; 166: 737-741
        • Willson T.M.
        • Brown P.J.
        • Sternbach D.D.
        • Henke B.R.
        The PPARs: from orphan receptors to drug discovery.
        J Med Chem. 2000; 43: 527-550
        • Leiss O.
        • Von Bergmann K.
        • Gnasso A.
        • Augustin J.
        Effect of gemfibrozil on biliary lipid metabolism in normolipemic subjects.
        Metabolism. 1985; 34: 74-82
        • Bertolotti M.
        • Concari M.
        • Loria P.
        • et al.
        Effects of different phenotypes of hyperlipoproteinemia and of treatment with fibric derivatives on the rates of cholesterol 7α-hydroxylation in humans.
        Arterioscler Thromb Vasc Biol. 1995; 15: 1064-1069
        • Post S.M.
        • Duez H.
        • Gervois P.P.
        • et al.
        Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-α-hydroxylase and sterol 27-hydroxylase expression.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1840-1845
        • Grundy S.M.
        • Ahrens Jr., E.H.
        • Salen G.
        • Schreibman P.H.
        • Nestel P.J.
        Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia.
        J Lipid Res. 1972; 13: 531-551
        • Umeda Y.
        • Kako Y.
        • Mizutani K.
        • et al.
        Inhibitory action of gemfibrozil on cholesterol absorption in rat intestine.
        J Lipid Res. 2001; 42: 1214-1219
        • Vanhanen H.T.
        • Miettinen T.A.
        Cholesterol absorption and synthesis during pravastatin, gemfibrozil and their combination.
        Arteriosclerosis. 1995; 115: 135-146
        • Einarsson K.
        • Nilsell K.
        • Leijd B.
        • Angelin B.
        Influence of age on secretion of cholesterol and synthesis of bile acids by the liver.
        N Engl J Med. 1985; 313: 277-282
        • Staels B.
        • Dallongeville J.
        • Auwerx J.
        • et al.
        Mechanism of action of fibrates on lipid and lipoprotein metabolism.
        Circulation. 1998; 98: 2088-2093
        • Chinetti G.
        • Fruchart J.-C.
        • Staels B.
        Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation.
        Inflamm Res. 2000; 49: 497-505