Skip to main content
Top
Published in: American Journal of Cardiovascular Drugs 3/2007

01-05-2007 | Original Research Article

Effects of Simvastatin and Metformin on Inflammation and Insulin Resistance in Individuals with Mild Metabolic Syndrome

Authors: Dr Caroline Bulcão, Fernando Flexa Ribeiro-Filho, Adriana Sañudo, Sandra G. Roberta Ferreira

Published in: American Journal of Cardiovascular Drugs | Issue 3/2007

Login to get access

Abstract

Background

In addition to lipid-lowering and insulin-sensitizing actions, statins (HMG-CoA reductase inhibitors) and metformin may have pleiotropic effects.

Objective

To study the effect of simvastatin and metformin on insulin sensitivity and inflammatory markers.

Methods

Forty-one subjects with body mass index (BMI) 25–39.9 kg/m2 and impaired glucose tolerance were randomized to receive simvastatin or metformin for 16 weeks. Blood samples were obtained for measurement of metabolic and inflammatory parameters before and after each treatment.

Results

As expected, when compared with simvastatin, metformin therapy resulted in significant reductions in mean BMI, fasting plasma glucose, and homeostasis model assessment-insulin resistance (HOMA-IR), whereas simvastatin treatment resulted in significantly reduced total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and apolipoprotein B levels. Independently of the medication used, significant decreases in C-reactive protein (CRP) and interleukin (IL)-6 were detected from baseline to treatment end. CRP showed a mean reduction of 0.12 ± 0.04 mg/dL (p = 0.002) over the 16-week intervention period and IL-6 a mean reduction was 0.35 ± 0.17 pg/mL (p = 0.046). No change was observed in the tumor necrosis factor-α levels. Baseline values of CRP and IL-6 and their percentage declines were correlated (r = 0.71 and r = 0.67, respectively; p < 0.001). In simvastatin recipients, no correlation was detected between reductions in CRP or IL-6 and lipids, whereas in metformin recipients, reductions in inflammatory markers were not correlated to BMI and HOMA-IR. Conclusion: Our findings suggest that both metformin and simvastatin have similar beneficial effects on low-grade inflammation, in addition to their classical effects on glucose and lipid metabolism. Moreover, they confirm the importance of treating at-risk individuals even before the precipitation of overt diabetes mellitus or full-blown metabolic syndrome.
Footnotes
1
The use of trade names is for product identification purposes only and does not imply endorsement.
 
Literature
2.
go back to reference Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third national health and nutrition examination survey. JAMA 2002; 287: 356–9.PubMedCrossRef Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third national health and nutrition examination survey. JAMA 2002; 287: 356–9.PubMedCrossRef
3.
go back to reference Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 2004; 15: 2792–800.PubMedCrossRef Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 2004; 15: 2792–800.PubMedCrossRef
4.
go back to reference Bulcão C, Ferreira SRG, Giuffrida FMA, et al. The new adipose tissue and adipocytokines. Curr Diabetes Rev 2006; 2: 19–28.PubMedCrossRef Bulcão C, Ferreira SRG, Giuffrida FMA, et al. The new adipose tissue and adipocytokines. Curr Diabetes Rev 2006; 2: 19–28.PubMedCrossRef
5.
go back to reference Yudkin JS, Kumari M, Humphries SE, et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000; 148: 209–14.PubMedCrossRef Yudkin JS, Kumari M, Humphries SE, et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000; 148: 209–14.PubMedCrossRef
6.
go back to reference Peraldi P, Xu M, Spiegelman BM. Thiazolidinediones block tumor necrosis factor-α-induced inhibition of insulin signaling. J Clin Invest 1997; 100: 1863–9.PubMedCrossRef Peraldi P, Xu M, Spiegelman BM. Thiazolidinediones block tumor necrosis factor-α-induced inhibition of insulin signaling. J Clin Invest 1997; 100: 1863–9.PubMedCrossRef
7.
go back to reference Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of interleukin 6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767–72.PubMedCrossRef Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of interleukin 6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767–72.PubMedCrossRef
8.
go back to reference Miles PD, Romeo OM, Higo K, et al. TNF-a-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes 1997; 46: 1678–83.PubMedCrossRef Miles PD, Romeo OM, Higo K, et al. TNF-a-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes 1997; 46: 1678–83.PubMedCrossRef
9.
go back to reference Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med 1999; 130: 933–7.PubMed Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med 1999; 130: 933–7.PubMed
10.
go back to reference Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–9.PubMedCrossRef Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–9.PubMedCrossRef
11.
go back to reference Fonseca V, Desouza C, Asnani S, et al. Nontraditional risk factors for cardiovascular disease in diabetes. Endocr Rev 2004; 25 (1): 153–75.PubMedCrossRef Fonseca V, Desouza C, Asnani S, et al. Nontraditional risk factors for cardiovascular disease in diabetes. Endocr Rev 2004; 25 (1): 153–75.PubMedCrossRef
12.
go back to reference Grundy SM, Hansen B, Smith Jr SC, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 2004; 109: 551–6.PubMedCrossRef Grundy SM, Hansen B, Smith Jr SC, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 2004; 109: 551–6.PubMedCrossRef
13.
go back to reference National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002; 106: 3143–421. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002; 106: 3143–421.
14.
go back to reference United Kingdom Prospective Diabetes Study Group: effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65. United Kingdom Prospective Diabetes Study Group: effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65.
15.
go back to reference Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998; 98: 839–44.PubMedCrossRef Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998; 98: 839–44.PubMedCrossRef
16.
go back to reference Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzime a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001; 103: 1933–5.PubMedCrossRef Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzime a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001; 103: 1933–5.PubMedCrossRef
17.
go back to reference Haffner S, Temprosa M, Crandall J, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 2005; 54: 1566–72.PubMedCrossRef Haffner S, Temprosa M, Crandall J, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 2005; 54: 1566–72.PubMedCrossRef
18.
go back to reference Akbar DH. Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome. Endocrine 2003; 20: 215–8.PubMedCrossRef Akbar DH. Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome. Endocrine 2003; 20: 215–8.PubMedCrossRef
19.
go back to reference Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 4649–54.PubMedCrossRef Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 4649–54.PubMedCrossRef
20.
go back to reference 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: 100–9.PubMedCrossRef 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: 100–9.PubMedCrossRef
21.
go back to reference Caballero AE, Delgado A, Aguilar-Salinas CA, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2004; 89: 3943–8.PubMedCrossRef Caballero AE, Delgado A, Aguilar-Salinas CA, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2004; 89: 3943–8.PubMedCrossRef
22.
go back to reference American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2006; 29 Suppl. 1: S43–8. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2006; 29 Suppl. 1: S43–8.
23.
go back to reference Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association. Circulation 2003; 107: 499–511.PubMedCrossRef Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association. Circulation 2003; 107: 499–511.PubMedCrossRef
24.
go back to reference Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and B-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–9.PubMedCrossRef Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and B-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–9.PubMedCrossRef
25.
go back to reference Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327–34.PubMedCrossRef Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327–34.PubMedCrossRef
26.
go back to reference Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 4649–54.PubMedCrossRef Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 4649–54.PubMedCrossRef
27.
go back to reference Haffner S, Temprosa M, Crandall J, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 2005; 54: 1566–72.PubMedCrossRef Haffner S, Temprosa M, Crandall J, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 2005; 54: 1566–72.PubMedCrossRef
28.
go back to reference Carter AM, Bennett CE, Bostock JA, et al. Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with type 2 diabetes mellitus. Diabet Med 2005; 22: 1282–4.PubMedCrossRef Carter AM, Bennett CE, Bostock JA, et al. Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with type 2 diabetes mellitus. Diabet Med 2005; 22: 1282–4.PubMedCrossRef
29.
go back to reference 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: 100–9.PubMedCrossRef 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: 100–9.PubMedCrossRef
30.
go back to reference Caballero AE, Delgado A, Aguilar-Salinas CA, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2004; 89: 3943–8.PubMedCrossRef Caballero AE, Delgado A, Aguilar-Salinas CA, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2004; 89: 3943–8.PubMedCrossRef
31.
go back to reference Muhlestein JB, Anderson JL, Horne BD, et al. Early effects of statins in patients with coronary artery disease and high C-reactive protein. Am J Cardiol 2004; 94: 1107–12.PubMedCrossRef Muhlestein JB, Anderson JL, Horne BD, et al. Early effects of statins in patients with coronary artery disease and high C-reactive protein. Am J Cardiol 2004; 94: 1107–12.PubMedCrossRef
32.
go back to reference Luo Y, Jiang D, Wen D, et al. Changes in serum interleukin-6 and high-sensitivity C-reactive protein levels in patients with acute coronary syndrome and their responses to simvastatin. Heart Vessels 2004; 19: 257–62.PubMedCrossRef Luo Y, Jiang D, Wen D, et al. Changes in serum interleukin-6 and high-sensitivity C-reactive protein levels in patients with acute coronary syndrome and their responses to simvastatin. Heart Vessels 2004; 19: 257–62.PubMedCrossRef
33.
go back to reference Ascer E, Bertolami MC, Venturinelli ML, et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis 2004; 177: 161–6.PubMedCrossRef Ascer E, Bertolami MC, Venturinelli ML, et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis 2004; 177: 161–6.PubMedCrossRef
34.
go back to reference Keech A, Colquhoun D, Best J, et al. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003; 26: 2713–21.PubMedCrossRef Keech A, Colquhoun D, Best J, et al. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003; 26: 2713–21.PubMedCrossRef
35.
go back to reference Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352: 29–38.PubMedCrossRef Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352: 29–38.PubMedCrossRef
36.
go back to reference Chan KY, Boucher ES, Gandhi PJ, et al. HMG-CoA reductase inhibitors for lowering elevated levels of C-reactive protein. Am J Health Syst Pharm 2004; 61: 1676–81.PubMed Chan KY, Boucher ES, Gandhi PJ, et al. HMG-CoA reductase inhibitors for lowering elevated levels of C-reactive protein. Am J Health Syst Pharm 2004; 61: 1676–81.PubMed
37.
go back to reference Gupta S. Does aggressive statin therapy offer improved cholesterol-independent benefits compared to conventional statin treatment? Int J Cardiol 2004; 96: 131–9.PubMedCrossRef Gupta S. Does aggressive statin therapy offer improved cholesterol-independent benefits compared to conventional statin treatment? Int J Cardiol 2004; 96: 131–9.PubMedCrossRef
Metadata
Title
Effects of Simvastatin and Metformin on Inflammation and Insulin Resistance in Individuals with Mild Metabolic Syndrome
Authors
Dr Caroline Bulcão
Fernando Flexa Ribeiro-Filho
Adriana Sañudo
Sandra G. Roberta Ferreira
Publication date
01-05-2007
Publisher
Springer International Publishing
Published in
American Journal of Cardiovascular Drugs / Issue 3/2007
Print ISSN: 1175-3277
Electronic ISSN: 1179-187X
DOI
https://doi.org/10.2165/00129784-200707030-00007

Other articles of this Issue 3/2007

American Journal of Cardiovascular Drugs 3/2007 Go to the issue

Commentary

Clopidogrel