Lipid-modifying Therapy for Metabolic Syndrome: A Systematic Review_Chinese Journal of Evidence-Based Medicine

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Systematic review; Meta-analysis; RCT; Metabolic syndrome; Metformin; Adverse drug reactions

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10.7507/1672-2531.20080217

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Objective 　To evaluate the efficacy and safety of metformin for metabolic syndrome.
Methods 　We searched The Cochrane Library, MEDLINE, EMBASE, China Biological Medicine Database, VIP, and CMAC up to the year of 2007. Handsearches and additional searches were also conducted. Randomized controlled trials of metformin for metabolic syndrome were included. Two reviewers independently extracted data from eligible studies and evaluated the quality of included studies. Meta-analysis was performed for the results of homogeneous studies by The Cochrane Collaboration’s software RevMan 4.2.9.
Results 　Six trials involving a total of 2442 patients with metabolic syndrome were included. Meta-analysis was not performed due to the apparent heterogeneity. Metformin, compared with placebo, exhibited more favorable effects in reducing the proportion of patients with metabolic syndrome (RR 1.27, 95% CI 1.01 to 1.60), the proportion of patients with low HDL-c (RR 1.61, 95%CI 1.16 to 2.23), wide waist circumference (RR 1.64, 95%CI 1.06 to 2.55), and high FPG (RR 1.55, 95%CI 1.17 to 2.05). Metformin was also more effective in improving FPG and insulin sensitivity. The addition of metformin to atenolol plus nitrendipine was superior to atenolol plus nitrendipine alone in reducing the proportion of patients with high TG (RR 5.57, 95%CI 1.56 to 19.84), abdominal obesity (RR 14.47, 95%CI 3.34 to 62.61), and IGT (RR 16.51, 95%CI 6.06 to 45.0). Compared with low-fat diet therapy, metformin was superior in improving FPG, 2-hour postload plasma glucose, and insulin sensitivity. No differences were observed between metformin and acarbose in the reduction of TG and FPG, but metformin was less effective than acarbose in improving 2-hour postload plasma glucose. No adverse drug reactions were reported.
Conclusion 　 Metformin has beneficial effects in reducing the incidence of high FPG, IGT, and abdominal obesity. It also proved beneficial in reducing the prevalence of metabolic syndrome and increasing insulin sensitivity. The therapeutic effects of metformin on blood pressure, obesity, and lipid profile are uncertain. There is insufficient evidence to recommend the use of metformin in the treatment of metabolic syndrome due to low methodological quality, small sample size, and limited number of trials. More high quality, large-scale randomized controlled trials are required.

Citation： GOU Zhongping,LI Xiujun,WU Taixiang. Lipid-modifying Therapy for Metabolic Syndrome: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2008, 08(11): 980-987. doi: 10.7507/1672-2531.20080217 Copy

1.	Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes, 1988, 37(12): 1595-1607.
2.	Glueck CJ, Wang P, Fontaine R, et al. Metfomun-induced resumption of normal menses in 39 of 43(91%) previously a menorrheic women with the polycystic ovary syndrome. Metabolism, 1999, 48(4): 511-519.
3.	YuanL, Reinhard Z, Andreas H, et al. Metformin modulates insulin post-receptor signaling transduction in chronically insulin-treated HepG2 cells. Acta Pharrnacol Sin, 2003, 24(1): 55-64.
4.	李益明, 段文澜, 朱禧星, 等. 二甲双胍对糖尿病大鼠骨骼肌GLUT4基因表达的影响. 上海医科大学学报, 1998, 25(6): 409-414.
5.	HeG, Pedesen SB, Bruno JM, et al . Metforrnin, but not thiazolidinediones, inhibits plasminogen activator inhibitor-1 production in human adipose tissue in vitro. Horm Metab Res, 2003, 35(1): 18-27.
6.	Stefanovic V, Antic S, Mitic-Zlatkovic M, et al. Reversal of increased lymphocyte PC-1 activity in patients with type2 diabetes treated with metformin. Diabetes Metab Res Rev, 1999, 15(6): 400-409.
7.	Stolar MV. Insulin resistance, diabetes, and the adipocyte. Am J Health Syst Pharm, 2002, 59 (Suppl 9): S3-S9.
8.	Yasuda N, Inoue T, Nagakum T, et al. Enhanced secretion of glucagon like peptide-1 by biguanide compounds. Biochem Biophys Res Commun, 2002, 298(5): 779-787.
9.	Kay JP, Alemzadeh R, Iangley G, et al. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism, 2001, 50(12): 1457-1464.
10.	McNulty SJ, Ur E, Williams G, et al. A randomized trial of sibutramine in the management of obese type2 diabetic patients treated with metformin. Diabetes Care, 2003, 26(1): 125-132.
11.	Johansen K. Efficacy of metformin in the treatment of NIDDM. Meta analysis. Diabetes Care, 1999, 22(l): 33-39.
12.	Carlsen SM, Rossvoll O, Bjeve KS, et al. Metformin improves blood lipid patern in nondiabetic patients with coronary heart disease. J Intern Med, 1996, 239(3): 227- 235.
13.	邓宏明, 肖常青, 夏宁, 等. 二甲双胍治疗2型糖尿病人对血压影响的研究. 高血压杂志, 2002, 10(3): 197-10.
14.	Alberti KGMM, Zimmet PZ, WHO Consultation. Definition, diagnos is and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med, 1998, (15): 539-553.
15.	Expert Panel on Detection, Evaluation, and Treatment of High Blood cholesterol in Adults (Adult treatment Panel Ⅲ). Executive summary of the third report of the National Cholesteral Education Program (NECP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. J Am Med Assoc, 2001, 285(19): 2486-2497.
16.	Barclay L. Medscape Medical News. New definition of the metabolic syndrome: a newsmaker interview with Sir George Alberti, MA, DPhil, BMBCh. Available at: http: //www. medscape. com/ viewarticle/504382 Accessed July 8, 2005.
17.	吴泰相, 刘关键. 隐蔽分组（分配隐藏）和盲法的概念、实施与报告. 中国循证医学杂志, 2007, 7(3): 222-225.
18.	郭冀珍, 龚艳春, 章建梁, 等. 高血压病伴代谢综合征患者463例的干预治疗研究. 中华心血管病杂志, 2005, 33(21): 32-36.
19.	向群, 姚强, 熊正南, 等. 二甲双胍对代谢综合征患者血压的影响. 高血压杂志, 2005, 13(11): 687-610.
20.	齐昆青, 马丽, 樊永亮. 阿卡波糖和二甲胍治疗糖耐量异常合并代谢综合征的比较. 第四军医大学学报, 2005, 26(16): 687-688.
21.	de Aguiar LG, Bahia LR, Villela N, et al. Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance. Diabetes Care, 2006, 29(5): 1083-1089.
22.	Vitale C, Mercuro G, Cornoldi A, et al. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med, 2005, 258(3): 250-256.
23.	Orchard TJ, Temprosa M, Goldberg R, et al. A lifestyle intervention or metformin prevented or delayed the onset of the metabolic syndrome in persons at risk. Ann Intern Med, 2005, 142(8): 611-619.
24.	Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346(6): 393-403.
25.	Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care, 2001, 24(4): 683-689.
26.	Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA, 2002, 288(21): 2709-2716.
27.	Hunt KJ, Resendez RG, Williams K, et al. NCEP versus WHO metabolic syndrome in relation to all cause and cardiovascular mortality in the San Antonio Heart Study (SAHS)[abstract] . Circulation, 2004, 110(10): 1251-1257.
28.	Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med, 1996, 334(15): 952-957.
29.	Haffner SM. Epidemiology of insulin resistance and its relation to coronary artery disease. Am J Cardiol, 1999, 84(1A): 11J-14J.
30.	Deedwania PC. Metabolic syndrome and vascular disease: is nature or nurture leading the new epidemic of cardiovascular disease. Circulation, 2004, 109(1): 2-4.
31.	Kay JP, Alemzadeh R, Iangley G, et al. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism, 2001, 50(12): 1457-1467.
32.	McNulty SJ, Ur E, Williams G, et al. A randomized trial of sibutramine in the management of obese type2 diabetic patients treated with metformin. Diabetes Care, 2003, 26(1): 125-133.
33.	Despres JP. Potential contribution of metformin to the management of cardiovascular disease risk in patients with abdominal obesity, the metabolic syndrome and type 2 diabetes. Diabetes Metab, 2003, 29(4pt 2): 6S53-6S61.
34.	UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 1998, 352 (9131): 854-865.
35.	Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346(6): 393-403.

1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes, 1988, 37(12): 1595-1607.
2. Glueck CJ, Wang P, Fontaine R, et al. Metfomun-induced resumption of normal menses in 39 of 43(91%) previously a menorrheic women with the polycystic ovary syndrome. Metabolism, 1999, 48(4): 511-519.
3. YuanL, Reinhard Z, Andreas H, et al. Metformin modulates insulin post-receptor signaling transduction in chronically insulin-treated HepG2 cells. Acta Pharrnacol Sin, 2003, 24(1): 55-64.
4. 李益明, 段文澜, 朱禧星, 等. 二甲双胍对糖尿病大鼠骨骼肌GLUT4基因表达的影响. 上海医科大学学报, 1998, 25(6): 409-414.
5. HeG, Pedesen SB, Bruno JM, et al . Metforrnin, but not thiazolidinediones, inhibits plasminogen activator inhibitor-1 production in human adipose tissue in vitro. Horm Metab Res, 2003, 35(1): 18-27.
6. Stefanovic V, Antic S, Mitic-Zlatkovic M, et al. Reversal of increased lymphocyte PC-1 activity in patients with type2 diabetes treated with metformin. Diabetes Metab Res Rev, 1999, 15(6): 400-409.
7. Stolar MV. Insulin resistance, diabetes, and the adipocyte. Am J Health Syst Pharm, 2002, 59 (Suppl 9): S3-S9.
8. Yasuda N, Inoue T, Nagakum T, et al. Enhanced secretion of glucagon like peptide-1 by biguanide compounds. Biochem Biophys Res Commun, 2002, 298(5): 779-787.
9. Kay JP, Alemzadeh R, Iangley G, et al. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism, 2001, 50(12): 1457-1464.
10. McNulty SJ, Ur E, Williams G, et al. A randomized trial of sibutramine in the management of obese type2 diabetic patients treated with metformin. Diabetes Care, 2003, 26(1): 125-132.
11. Johansen K. Efficacy of metformin in the treatment of NIDDM. Meta analysis. Diabetes Care, 1999, 22(l): 33-39.
12. Carlsen SM, Rossvoll O, Bjeve KS, et al. Metformin improves blood lipid patern in nondiabetic patients with coronary heart disease. J Intern Med, 1996, 239(3): 227- 235.
13. 邓宏明, 肖常青, 夏宁, 等. 二甲双胍治疗2型糖尿病人对血压影响的研究. 高血压杂志, 2002, 10(3): 197-10.
14. Alberti KGMM, Zimmet PZ, WHO Consultation. Definition, diagnos is and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med, 1998, (15): 539-553.
15. Expert Panel on Detection, Evaluation, and Treatment of High Blood cholesterol in Adults (Adult treatment Panel Ⅲ). Executive summary of the third report of the National Cholesteral Education Program (NECP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. J Am Med Assoc, 2001, 285(19): 2486-2497.
16. Barclay L. Medscape Medical News. New definition of the metabolic syndrome: a newsmaker interview with Sir George Alberti, MA, DPhil, BMBCh. Available at: http: //www. medscape. com/ viewarticle/504382 Accessed July 8, 2005.
17. 吴泰相, 刘关键. 隐蔽分组（分配隐藏）和盲法的概念、实施与报告. 中国循证医学杂志, 2007, 7(3): 222-225.
18. 郭冀珍, 龚艳春, 章建梁, 等. 高血压病伴代谢综合征患者463例的干预治疗研究. 中华心血管病杂志, 2005, 33(21): 32-36.
19. 向群, 姚强, 熊正南, 等. 二甲双胍对代谢综合征患者血压的影响. 高血压杂志, 2005, 13(11): 687-610.
20. 齐昆青, 马丽, 樊永亮. 阿卡波糖和二甲胍治疗糖耐量异常合并代谢综合征的比较. 第四军医大学学报, 2005, 26(16): 687-688.
21. de Aguiar LG, Bahia LR, Villela N, et al. Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance. Diabetes Care, 2006, 29(5): 1083-1089.
22. Vitale C, Mercuro G, Cornoldi A, et al. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med, 2005, 258(3): 250-256.
23. Orchard TJ, Temprosa M, Goldberg R, et al. A lifestyle intervention or metformin prevented or delayed the onset of the metabolic syndrome in persons at risk. Ann Intern Med, 2005, 142(8): 611-619.
24. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346(6): 393-403.
25. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care, 2001, 24(4): 683-689.
26. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA, 2002, 288(21): 2709-2716.
27. Hunt KJ, Resendez RG, Williams K, et al. NCEP versus WHO metabolic syndrome in relation to all cause and cardiovascular mortality in the San Antonio Heart Study (SAHS)[abstract] . Circulation, 2004, 110(10): 1251-1257.
28. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med, 1996, 334(15): 952-957.
29. Haffner SM. Epidemiology of insulin resistance and its relation to coronary artery disease. Am J Cardiol, 1999, 84(1A): 11J-14J.
30. Deedwania PC. Metabolic syndrome and vascular disease: is nature or nurture leading the new epidemic of cardiovascular disease. Circulation, 2004, 109(1): 2-4.
31. Kay JP, Alemzadeh R, Iangley G, et al. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism, 2001, 50(12): 1457-1467.
32. McNulty SJ, Ur E, Williams G, et al. A randomized trial of sibutramine in the management of obese type2 diabetic patients treated with metformin. Diabetes Care, 2003, 26(1): 125-133.
33. Despres JP. Potential contribution of metformin to the management of cardiovascular disease risk in patients with abdominal obesity, the metabolic syndrome and type 2 diabetes. Diabetes Metab, 2003, 29(4pt 2): 6S53-6S61.
34. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 1998, 352 (9131): 854-865.
35. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346(6): 393-403.

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