The Effect of Metformin on the Incidence of Type 2 Diabetes Mellitus and Cardiovascular Disease Risk Factors in Overweight and Obese Subjects – The Carmos Study

Abstract

We investigated whether the addition of metformin to the treatment of overweight and obese individuals further reduces the incidence of type2 diabetes mellitus (T₂DM), prediabetes and metabolic syndrome (MetS) and improves cardiovascular disease (CVD) risk factors (RFs).

Design and methods: We studied 366 adults (mean age 53.0±0.5 SE years, and mean BMI 32.3±0.2 SE Kg/m² ) without CVD. All subjects received lifestyle recommendations and drug management of CVD-RFs, whilst 95 of them were additionally given metformin. The follow-up period lasted 12 months.

Results: At the end of the study the frequency of T₂DM in the metformin and non-metformin group was 1.1 and 8.1%, respectively (risk difference=−7% with 95% CI from −12.7% to −1.4%, p=0.012). Participants with prediabetes displayed a greater reduction in the incidence of T₂DM after taking metformin compared to those who had not received this drug (risk difference=−18.5% with 95%CI from −33.1% to −3.9%, p=0.010). Metformin had a similar beneficial impact on subjects with MetS (risk difference=−12.9% with 95% from −25% to −0.7%, p=0.040) and this was attributed to the greater increase in HDL-C (p=0.046) and decrease in fasting plasma glucose levels (p=0.024). Metformin also achieved a greater reduction in total cholesterol and LDL-C levels (metformin vs. non-metformin treated subjects: −31.9 vs. −17.3 mg/dl, p=0.001, and −26.2 vs. −15.9 mg/dl, p=0.006, respectively).

Conclusions: Metformin reduces the occurrence of T₂DM in overweight and obese non-diabetic adults and decreases the rate of MetS by improving the CVD risk factor profile.

Key words

metformin - type 2 diabetes mellitus - prediabetes - metabolic syndrome

References

• 1 Kuczmarski RI, Flegal KM, Campbell SM. et al . Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991.  JAMA. 1994;  272 205
• 2 Sainaghi PP, Castello L, Bergamasco L. et al . Metabolic characteristics of glucose intolerance: the critical role of obesity.  Exp Clin Endocrinol Diabetes. 2008;  116 86-93
• 3 Alberti KG, Zimmet P, Shaw J. The metabolic syndrome: a new worldwide definition.  Lancet. 2005;  366 1059-1062
• 4 Schwarz PE, Lindstrom J, Kissimova-Scarbeck K. et al . DE-PLAN project.  Exp Clin Endocrinol Diabetes. 2008;  116 167-172
• 5 Pfeiffer AF. Adipose tissue and diabetes therapy: do we hit the target?.  Horm Metab Res. 2007;  39 734-738
• 6 The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. . Effect of rosiglitazone of the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized control trial.  Lancet. 2006;  368 1096-1105
• 7 Chiasson JL, Josse RJ, Gomis R. et al . Acarbose for prevention of type2 diabetes mellitus: the STOP-NIDDM randomized trial.  Lancet. 2002;  359 2072-2077
• 8 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;  346 393-403
• 9 Diamantopoulos EJ, Andreadis EA, Tsourous GI. et al . Metabolic syndrome and prediabetes identify overlapping but not identical populations.  Exp Clin Endocrinol Diabetes. 2006;  114 377-383
• 10 Diamantopoulos EJ, Andreadis EA, Tsourous GI. et al . Intermediate postchallenge hyperglycemia in overweight and obese subjects: a new marker of impaired glucose regulation?.  Angiology. 2006;  57 709-716
• 11 Calle EE, Thun MJ, Petrelli JM. et al . Body mass index and mortality in a prospective cohort of US adults.  N Engl J Med. 1999;  341 1097-1105
• 12 Friedwald WT, Levy RI, Fredrickson DS. Estimation of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge.  Clin Chem. 1972;  18 499-502
• 13 Hainline  Jr  A, Karon J, Lippel K. eds. Manual of Laboratory Operations, ed. 2, Lipid Research Clinics Program, Lipid and Lipoprotein Analysis. Washington, DC: US Department of Health and Human Services, Public Health Service, National Institutes of Health (updated 1983)
• 14 Multicenter study of Tina-quant Albumin in urine and β-N-acetyl-glycosaminidase (β-NAG) in urine. Workshop Munich, November 29–30, 1990.  Wien Klin Wschr. 1991;  103 ((Suppl. 189)) 1-64
• 15 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. . Follow-up report on the diagnosis of diabetes mellitus.  Diabetes Care. 2005;  28 S37-S42
• 16 The Food Guide Pyramid Washington, DC. . , Department of Agriculture, Center for Nutrition Policy and Promotion, 1996. (Home and Garden Bulletin no. 252.)
• 17 Step by step: eating to lower your high blood cholesterol . Bethesda, Md.: National Heart, Lung, and Blood Institute Information Center 1987
• 18 Third report of the 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 3143-3421
• 19 Chobanian AV, Bakris GL, Black H. et al . Seventh Report Of The Joint National Committee On Prevention, Detection, Evaluation, And Treatment Of High Blood Pressure.  Hypertension. 2003;  42 1206-1252
• 20 Palumbo PJ. Metformin: Effects on cardiovascular risk factors in patients with Non-Insulin-Dependent Diabetes Mellitus.  J Diab Complicat. 1998;  12 110-119
• 21 Maglalhaes FO, Gouveia LM, Torquato MT. et al . Metformin increases blood flow and forearm glucose uptake in a group of non-obese type 2 diabetes patients.  Horm Metab Res. 2006;  38 513-517
• 22 Kirpichnikov D, MacFarlane SI, Sowers JR. Metformin: An Update.  Ann Intern Med. 2002;  137 25-33
• 23 Giugiliano D, Acampora R, DeRosa N. et al . Metformin improves glucose lipid metabolism and reduces blood pressure in hypertensive obese women.  Diabetes Care. 1993;  16 1387-1390
• 24 Stumvoll M, Nurjahan N, Perriello G. et al . Metabolic effects of metformin in non-insulin dependent diabetes mellitus.  N Engl J Med. 1995;  333 550-554
• 25 Rains SGH, Wilson GA, Richmond W. et al . The effect of glibenclamide and metformin on serum lipoproteins in type 2 diabetes.  Diabetic Med. 1988;  5 653-658
• 26 DeFronzo RA, Goodman AM. and the Multicenter Metformin Study Group . Efficacy of metformin in patients with non-insulin dependent diabetes mellitus.  N Engl J Med. 1995;  333 541-549
• 27 Wu MS, Johnston P, Sheu WH-H. et al . Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients.  Diabetes Care. 1990;  13 1-8
• 28 Landin K, Tengborn I, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors.  J Intern Med. 1991;  229 181-187
• 29 Nathan D, Davidson BM, DeFronzo RA. et al . Impaired fasting glucose and impaired glucose tolerance. Implications for care.  Diabetes Care. 2007;  3 753-759
• 30 Xiang GD, Sun HL, Hou J. et al . Acute hyperglycemia rapidly suppresses endothelium-dependent arterial dilation in first-degree relatives of type 2 diabetic patients.  Exp Clin Endocrinol Diabetes. 2008;  116 112-117
• 31 Grant RW, Meigs JB. Prevalence and treatment of low HDL choles-terol among primary care patients with type 2 diabetes. An unmet challenge for cardiovascular risk reduction.  Diabetes Care. 2007;  30 479-484

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