Abstract
Introduction
Besides its critical role in metabolic homeostasis, peroxisome proliferator-activated receptor (PPAR)-γ modulates several cellular responses involved in atherothrombosis. This multicenter, double-blind, randomized study investigated the effects of two oral hypoglycemic agents on markers of inflammation, platelet activation, thrombogenesis, and oxidative stress in patients with type 2 diabetes.
Methods and Results
The primary objective of this study was to evaluate the effect on C-reactive protein (CRP) after a 16-week treatment period with either pioglitazone or metformin. Additionally, markers of vascular inflammatory response, platelet activation, thrombogenesis, oxidative stress, glucose, and lipid metabolism, as well as liver function, were measured. In total, 50 patients completed the study. Pioglitazone-treated patients were found to have statistically significantly larger decreases in mean CRP levels (−0.4 mg/dL) compared to those treated with metformin (−0.2 mg/dL) (P = 0.04), as well as greater reductions in levels of mean fasting plasma glucose (−27 vs. −9 mg/dL; P = 0.01), serum insulin (−2 vs. −1.9 mU/L; P = 0.014), homeostatic model assessment (HOMA) (−1.2 vs. −0.9; P = 0.015), and E-selectin (−12.4 vs. +3.4 μg/mL; P = 0.01). Mean glycated hemoglobin (HbA1c) levels decreased in both treatment groups from baseline to week 16 (−0.4% in the pioglitazone group, −0.2% in the metformin group; P = 0.36). Pioglitazone treatment was also found to be associated with a statistically significant increase in total cholesterol levels (+10 mg/dL in the pioglitazone arm, −3 mg/dL in the metformin arm; P = 0.05) and a decrease in liver enzyme levels.
Conclusions
The favorable changes in markers of systemic and vascular inflammatory response with pioglitazone suggest that it may positively influence the atherothrombotic process in type 2 diabetes.
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References
Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. 2004;24:816–823.
Jokl R, Laimins M, Klein RL, Lyons TJ, Lopes-Virella MF, Colwell JA. Platelet plasminogen activator inhibitor 1 in patients with type II diabetes. Diabetes Care. 1994;17:818–823.
Imperatore G, Riccardi G, Iovine C, Rivellese AA, Vaccaro O. Plasma fibrinogen: a new factor of the metabolic syndrome. A population-based study. Diabetes Care. 1998;21:649–654.
Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843.
Dandona P. Effects of antidiabetic and antihyperlipidemic agents on C-reactive protein. Mayo Clin Proc. 2008;83:333–842.
Jang Y, Lincoff AM, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol. 1994;24:1591–1601.
Evangelista V, Totani L, Rotondo S, et al. Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin. Thromb Haemost. 2005;93:8–16.
Kaul K, Hodgkinson A, Tarr JM, Kohner EM, Chibber R. Is inflammation a common retinal-renal-nerve pathogenic link in diabetes? Curr Diabetes Rev. 2010;6:294–303.
Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009;94:3171–3182.
Varo N, Vicent D, Libby P, et al. Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones. Circulation. 2003;107:2664–2669.
Akbiyik F, Ray DM, Gettings KF, Blumberg N, Francis CW, Phipps RP. Human bone marrow megakaryocytes and platelets express PPARgamma, and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes. Blood. 2004;104:1361–1368.
Hsueh WA, Law RE. PPARgamma and atherosclerosis: effects on cell growth and movement. Arterioscler Thromb Vasc Biol. 2001;21:1891–1895.
Bagi Z, Koller A, Kaley G. PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Am J Physiol Heart Circ Physiol. 2004;286:H742–H748.
Ceriello A. Thiazolidinediones as anti-inflammatory and anti-atherogenic agents. Diabetes Metab Res Rev. 2008;24:14–26.
Isa SH, Najihah I, Nazaimoon WM, et al. Improvement in C-reactive protein and advanced glycosylation end-products in poorly controlled diabetics is independent of glucose control. Diabetes Res Clin Pract. 2006;72:48–52.
Goldstein BJ, Weissman PN, Wooddell MJ, Waterhouse BR, Cobitz AR. Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study. Curr Med Res Opin. 2006;22:1715–1723.
Davidson JA, McMorn SO, Waterhouse BR, Cobitz AR. A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and tolerability of combination therapy with rosiglitazone and sulfonylurea in African American and Hispanic American patients with type 2 diabetes inadequately controlled with sulfonylurea monotherapy. Clin Ther. 2007;29:1900–1914.
Kahn SE, Haffner SM, Viberti G, et al. Rosiglitazone decreases C-reactive protein to a greater extent relative to glyburide and metformin over 4 years despite greater weight gain: observations from a Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2010;33:177–183.
Mattoo V, Eckland D, Widel M, et al. Metabolic effects of pioglitazone in combination with insulin in patients with type 2 diabetes mellitus whose disease is not adequately controlled with insulin therapy: results of a six-month, randomized, double-blind, prospective, multicenter, parallel-group study. Clin Ther. 2005;27:554–567.
Derosa G, Cicero AF, Fogari E, D’Angelo A, Bianchi L, Maffioli P. Pioglitazone compared to glibenclamide on lipid profile and inflammation markers in type 2 diabetic patients during an oral fat load. Horm Metab Res. 2011;43:505–512.
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183–1197.
Chu NV, Kong AP, Kim DD, et al. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care. 2002;25:542–549.
Saito I, Folsom AR, Brancati FL, Duncan BB, Chambless LE, McGovern PG. Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Intern Med. 2000;133:81–91.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–334.
Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–1182.
Morrow DA, de Lemos JA, Sabatine MS, et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006;114:281–288.
Marx N, Schönbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res. 1998;83:1097–1103.
Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA. 2006;296:2572–2581.
Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561–1573.
Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–1289.
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–1188.
Mannucci E, Monami M, Lamanna C, Gensini GF, Marchionni N. Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2008;10:1221–1238.
Karagiannis E, Pfützner A, Forst T, et al. The IRIS V study: pioglitazone improves systemic chronic inflammation in patients with type 2 diabetes under daily routine conditions. Diabetes Technol Ther. 2008;10:206–212.
De Jager J, Kooy A, Lehert P, et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2005;257:100–109.
Monami M, Vitale V, Ambrosio ML, et al. Effects on lipid profile of dipeptidyl peptidase 4 inhibitors, pioglitazone, acarbose, and sulfonylureas: meta-analysis of placebo-controlled trials. Adv Ther. 2012;29:736–746.
Deeg MA, Buse JB, Goldberg RB, et al. GLAI Study Investigators. Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2007;30:2458–2464.
Ferrannini E, Betteridge DJ, Dormandy JA, et al. High-density lipoprotein-cholesterol and not HbA1c was directly related to cardiovascular outcome in PROactive. Diabetes Obes Metab. 2011;13:759–764.
Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012;55:885–904.
Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2008;31:173–175.
National Collaborating Centre for Chronic Conditions (UK). National Institute for Health and Clinical Excellence: Guidance. Type 2 Diabetes: National Clinical Guideline for Management in Primary and Secondary Care (Update). London: Royal College of Physicians (UK); 2008.
Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(Suppl. 2):1–53.
IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes: recommendations for standard, comprehensive, and minimal care. Diabet Med. 2006;23:579–593.
Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA. 2012;308:788–795.
Morgan CL, Poole CD, Evans M, Barnett AH, Jenkins-Jones S, Currie CJ. What next after metformin? A retrospective evaluation of the outcome of second-line, glucose-lowering therapies in people with type 2 diabetes. J Clin Endocrinol Metab. 2012;97:4605–4612.
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On behalf of the PRISCA Study Group.
Australian New Zealand Clinical Trials Registry: ACTRN12608000534381.
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Genovese, S., De Berardis, G., Nicolucci, A. et al. Effect of Pioglitazone Versus Metformin on Cardiovascular Risk Markers in Type 2 Diabetes. Adv Therapy 30, 190–202 (2013). https://doi.org/10.1007/s12325-013-0003-x
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DOI: https://doi.org/10.1007/s12325-013-0003-x