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Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients

      Abstract

      Background

      Lipophilic and hydrophilic statins have different effects on adiponectin and insulin resistance in experimental studies and different effects on the rate of onset of new diabetes in large scale clinical studies. Therefore, we hypothesized that simvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients.

      Methods

      This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Forty-three patients were given placebo, simvastatin 20 mg, or pravastatin 40 mg, respectively once daily for 2 months.

      Results

      Simvastatin and pravastatin therapy significantly changed lipoprotein levels and improved flow-mediated dilation after 2 months when compared with baseline (P < 0.001) or placebo treatment (P < 0.001 by ANOVA). Simvastatin therapy significantly increased insulin levels (mean % changes; 127%, P = 0.014) and decreased plasma adiponectin levels (10%, P = 0.012) and insulin sensitivity as assessed by QUICKI (6%, P = 0.007) when compared with baseline. By contrast, pravastatin therapy did not significantly change insulin levels (−3%, P = 0.437) but significantly increased plasma adiponectin levels (9%, P = 0.011) and insulin sensitivity (6%, P = 0.008) when compared with baseline. In addition, these effects of simvastatin were significant when compared with pravastatin (P< 0.001 for insulin levels by ANOVA on Ranks, P< 0.001 for adiponectin and P = 0.001 for QUICKI by ANOVA). When compared with baseline, simvastatin significantly increased plasma leptin levels (35%, P = 0.028), but pravastatin did not (1%, P = 0.822).

      Conclusions

      Despite causing comparable changes in lipoprotein and endothelium-dependent dilation, simvastatin and pravastatin therapy had differential metabolic effects in hypercholesterolemic patients that may be clinically relevant.

      Keywords

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      References

        • Sacks F.M.
        • Tonkin A.M.
        • Shepherd J.
        • et al.
        Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project.
        Circulation. 2000; 102: 1893-1900
        • Kim J.
        • Montagnani M.
        • Koh K.K.
        • Quon M.J.
        Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms.
        Circulation. 2006; 113: 1888-1904
        • Han S.H.
        • Quon M.J.
        • Koh K.K.
        Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction.
        Curr Opin Lipidol. 2007; 18: 58-65
        • Muniyappa R.
        • Montagnani M.
        • Koh K.K.
        • Quon M.J.
        Cardiovascular actions of insulin.
        Endocr Rev. 2007; 28: 463-491
        • Paolisso G.
        • Barbagallo M.
        • Petrella G.
        • et al.
        Effects of simvastatin and atorvastatin administration on insulin resistance and respiratory quotient in aged dyslipidemic non-insulin dependent diabetic patients.
        Atherosclerosis. 2000; 150: 121-127
        • Farrer M.
        • Winocour P.H.
        • Evans K.
        • et al.
        Simvastatin in non-insulin-dependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures.
        Diabetes Res Clin Pract. 1994; 23: 111-119
        • Ohrvall M.
        • Lithell H.
        • Johansson J.
        • Vessby B.
        A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia.
        Metabolism. 1995; 44: 212-217
        • Yada T.
        • Nakata M.
        • Shiraishi T.
        • Kakei M.
        Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet beta-cells.
        Br J Pharmacol. 1999; 126: 1205-1213
        • Chamberlain L.H.
        Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes.
        FEBS Lett. 2001; 507: 357-361
        • Kanda M.
        • Satoh K.
        • Ichihara K.
        Effects of atorvastatin and pravastatin on glucose tolerance in diabetic rats mildly induced by streptozotocin.
        Biol Pharm Bull. 2003; 26: 1681-1684
        • Jick S.S.
        • Bradbury B.D.
        Statins and newly diagnosed diabetes.
        Br J Clin Pharmacol. 2004; 58: 303-309
        • Heart Protection Study Collaborative Group
        MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
        Lancet. 2002; 360: 7-22
        • Sever P.S.
        • et al.
        Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT–LLA): a multicentre randomised controlled trial.
        Lancet. 2003; 361: 1149-1158
        • Chan P.
        • Tomlinson B.
        • Lee C.B.
        • et al.
        Beneficial effects of pravastatin on fasting hyperinsulinemia in elderly hypertensive hypercholesterolemic subjects.
        Hypertension. 1996; 28: 647-651
        • Guclu F.
        • Ozmen B.
        • Hekimsoy Z.
        • Kirmaz C.
        Effects of a statin group drug, pravastatin, on the insulin resistance in patients with metabolic syndrome.
        Biomed Pharmacother. 2004; 58: 614-618
        • Sugiyama S.
        • Fukushima H.
        • Kugiyama K.
        • et al.
        Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease.
        Atherosclerosis. 2007; 194: e43-e51
        • Gannage-Yared M.H.
        • Azar R.R.
        • Amm-Azar M.
        • et al.
        Pravastatin does not affect insulin sensitivity and adipocytokines levels in healthy nondiabetic patients.
        Metabolism. 2005; 54: 947-951
        • Freeman D.J.
        • Norrie J.
        • Sattar N.
        • et al.
        Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.
        Circulation. 2001; 103: 357-362
        • Ford I.
        • et al.
        Long-term follow-up of the West of Scotland Coronary Prevention Study.
        N Engl J Med. 2007; 357: 1477-1486
        • Han S.H.
        • Quon M.J.
        • Kim J.A.
        • Koh K.K.
        Adiponectin and cardiovascular disease: response to therapeutic interventions.
        J Am Coll Cardiol. 2007; 49: 531-538
        • Yu J.G.
        • Javorschi S.
        • Hevener A.L.
        • et al.
        The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects.
        Diabetes. 2002; 51: 2968-2974
        • Koh K.K.
        • Han S.H.
        • Quon M.J.
        • et al.
        Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia.
        Diabetes Care. 2005; 28: 1419-1424
        • Koh K.K.
        • Quon M.J.
        • Han S.H.
        • et al.
        Anti-inflammatory and metabolic effects of candesartan in hypertensive patients.
        Int J Cardiol. 2006; 108: 96-100
        • Koh K.K.
        • Quon M.J.
        • Lee S.J.
        • et al.
        Efonidipine simultaneously improves blood pressure, endothelial function, and metabolic parameters in non-diabetic patients with hypertension.
        Diabetes Care. 2007; 30: 1605-1607
        • Koh K.K.
        • Quon M.J.
        • Han S.H.
        • et al.
        Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients.
        Circulation. 2004; 110: 3687-3692
        • Correia M.L.
        • Haynes W.G.
        Leptin, obesity and cardiovascular disease.
        Curr Opin Nephrol Hypertens. 2004; 13: 215-223
        • Koh K.K.
        • Park S.M.
        • Quon M.J.
        Leptin and cardiovascular disease: response to therapeutic interventions.
        Circulation. 2008; 117: 3238-3249
        • Skurk T.
        • van Harmelen V.
        • Blum W.F.
        • Hauner H.
        Angiotensin II promotes leptin production in cultured human fat cells by an ERK1/2-dependent pathway.
        Obes Res. 2005; 13: 969-973
        • Koh K.K.
        • Quon M.J.
        • Han S.H.
        • et al.
        Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes.
        Hypertension. 2005; 45: 1088-1093
        • Koh K.K.
        • Ahn J.Y.
        • Han S.H.
        • et al.
        Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients.
        J Am Coll Cardiol. 2003; 42: 905-910
        • Katz A.
        • Nambi S.S.
        • Mather K.
        • et al.
        Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.
        J Clin Endocrinol Metab. 2000; 85: 2402-2410
        • Muniyappa R.
        • Lee S.
        • Chen H.
        • Quon M.J.
        Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage.
        Am J Physiol Endocrinol Metab. 2008; 294: e15-e26
        • Ouchi N.
        • Kihara S.
        • Funahashi T.
        • et al.
        Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue.
        Circulation. 2003; 107: 671-674
        • de Courten M.
        • Zimmet P.
        • Hodge A.
        • et al.
        Hyperleptinaemia: the missing link in the metabolic syndrome?.
        Diabet Med. 1997; 14: 200-208
        • Takagi T.
        • Matsuda M.
        • Abe M.
        • et al.
        Effect of pravastatin on the development of diabetes and adiponectin production.
        Atherosclerosis. 2007; 196: 114-121
        • Koh K.K.
        • Han S.H.
        • Quon M.J.
        Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions.
        J Am Coll Cardiol. 2005; 46: 1978-1985
        • Mita T.
        • Watada H.
        • Kawamori R.
        Recently revealed pleiotropic effects of statins.
        Endocrinol Diabetol. 2004; 18: 527-533
        • ter Avest E.
        • Abbink E.J.
        • de Graaf J.
        • et al.
        Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia.
        Eur J Clin Invest. 2005; 35: 558-564
        • Koh K.K.
        • Quon M.J.
        • Han S.H.
        • et al.
        Simvastatin improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients.
        Diabetes Care. 2008; 31: 776-782
        • Jula A.
        • Marniemi J.
        • Huupponen R.
        • et al.
        Effects of diet and simvastatin on serum lipids, insulin, and antioxidants in hypercholesterolemic men: a randomized controlled trial.
        JAMA. 2002; 287: 598-605
        • Cohen B.
        • Novick D.
        • Rubinstein M.
        Modulation of insulin activities by leptin.
        Science. 1996; 274: 1185-1188
        • Hennige A.M.
        • Stefan N.
        • Kapp K.
        • et al.
        Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1.
        FASEB J. 2006; 20: 1206-1208
        • Kleemann R.
        • Verschuren L.
        • de Rooij B.J.
        • et al.
        Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro.
        Blood. 2004; 103: 4188-4194
        • Arnaud C.
        • Burger F.
        • Steffens S.
        • et al.
        Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1231-1236
        • Koh K.K.
        • Son J.W.
        • Ahn J.Y.
        • et al.
        Comparative effects of diet and statin on NO bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease.
        Arterioscler Thromb Vasc Biol. 2002; 22: e19-e23