Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus

      Abstract

      In light of the conflicting results of the recent United Kingdom Prospective Study (UKPDS), where diabetic patients on metformin monotherapy had lower all-cause mortality and the addition of metformin in sulfonylurea-treated patients was associated with an increased risk of diabetes-related death, we sought to compare the effects on cardiovascular disease (CVD) risk factors of metformin monotherapy with metformin treatment when added to a sulfonylurea compound in patients with type 2 diabetes. Thirty-one volunteers with type 2 diabetes mellitus, 16 on dietary therapy and 15 on sulfonylurea monotherapy (SU), were treated with metformin for 12 weeks. Measurements were made of (1) fasting plasma glucose, hemoglobin A1c (HbA1c), lipid, remnant lipoprotein cholesterol (RLP-C) levels, and low-density lipoprotein (LDL) particle size; (2) daylong plasma glucose, insulin, free fatty acid (FFA), triglyceride (TG), and RLP-C concentrations; and (3) fasting levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin). Fasting plasma glucose concentrations decreased to a similar degree after treatment with metformin in both the metformin monotherapy group (12.45 ± 0.48 v 9.46 ± 0.47 mmol/L, P < .001) and the combined SU and metformin therapy group (14.09 ± 0.51 v 10.57 ± 0.85 mmol/L, P = .001). Fasting plasma lipid concentrations and LDL particle size did not significantly change in either treatment group, whereas fasting RLP-C concentrations were significantly lower in the metformin monotherapy group (0.43 ± 0.09 v 0.34 ± 0.07 mmol/L, P = .02). Daylong concentrations of plasma glucose, FFA, TG, and RLP-C were lower to a similar degree in both treatment groups, whereas daylong plasma insulin concentrations were unchanged. Fasting plasma sVCAM-1 levels were significantly lower in both the metformin monotherapy group (484 ± 19 v 446 ± 18 ng/mL, P = .02) and the combined SU and metformin therapy group (496 ± 29 v 456 ± 31 ng/mL, P = .05), whereas fasting plasma sICAM-1 and sE-selectin levels were essentially unchanged. Administration of metformin, either as monotherapy or in combination with a sulfonylurea drug, improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2 diabetes.
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      References

        • 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: 854-865
        • Olsson J.
        • Lindberg G.
        • Gottsater M.
        • et al.
        Increased mortality in type II diabetic patients using sulphonylurea and metformin in combination.
        Diabetologia. 2000; 43: 558-560
        • Fisman E.Z.
        • Tenenbaum A.
        • Boyko V.
        • et al.
        Oral anti-diabetic treatment in patients with coronary artery disease.
        Clin Cardiol. 2001; 24: 151-158
        • Reaven G.M.
        • Johnston P.
        • Hollenbeck C.B.
        • et al.
        Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control.
        J Clin Endocrinol Metab. 1992; 74: 1020-1026
        • Hermann L.S.
        • Schersten B.
        • Bitzen P.O.
        • et al.
        Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study.
        Diabetes Care. 1994; 17: 1100-1109
        • DeFronzo R.A.
        • Goodman A.M.
        Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group.
        N Engl J Med. 1995; 333: 541-549
        • Abbasi F.
        • Kamath V.
        • Rizvi A.A.
        • et al.
        Results of a placebo-controlled study of the metabolic effects of the addition of metformin to sulfonylurea-treated patients. Evidence for a central role of adipose tissue.
        Diabetes Care. 1997; 20: 1863-1869
        • UK Prospective Diabetes Study (UKPDS) Group
        Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35).
        BMJ. 2000; 321: 405-412
        • Krauss R.M.
        • Burke D.J.
        Identification of multiple subclasses of plasma low density lipoproteins in normal humans.
        J Lipid Res. 1982; 23: 97-104
        • Leary E.T.
        • Wang T.
        • Baker D.J.
        • et al.
        Evaluation of an immunoseparation method for quantitative measurement of remnant-like particle-cholesterol in serum and plasma.
        Clin Chem. 1988; 44: 2490-2498
        • Ai M.
        • Tanaka A.
        • Ogita K.
        • et al.
        Relationship between hyperinsulinemia and remnant lipoprotein concentrations in patients with impaired glucose tolerance.
        J Clin Endocrinol Metab. 2000; 85: 3557-3560
        • Abbasi F.
        • McLaughlin T.
        • Lamendola C.
        • et al.
        Fasting remnant lipoprotein cholesterol and triglyceride concentrations are elevated in nondiabetic, insulin-resistant, female volunteers.
        J Clin Endocrinol Metab. 1999; 84: 3903-3906
        • Chen N.G.
        • Holmes M.
        • Reaven G.M.
        Relationship between insulin resistance, soluble adhesion molecules, and mononuclear cell binding in healthy volunteers.
        J Clin Endocrinol Metab. 1999; 84: 3485-3489
        • Haffner S.M.
        • Lehto S.
        • Rönnemaa T.
        • et al.
        Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
        N Engl J Med. 1998; 339: 229-234
        • Turner R.C.
        • Millns H.
        • Neil H.A.
        • et al.
        Risk factors for coronary heart disease in non-insulin dependent diabetes mellitus.
        BMJ. 1998; 316: 823-828
        • Hayden J.M.
        • Reaven P.D.
        Cardiovascular disease in diabetes mellitus type 2.
        Curr Opin Lipidol. 2000; 11: 519-528
        • Zilversmit D.B.
        Atherogenesis.
        Circulation. 1979; 60: 473-485
        • Jeppesen J.
        • Zhou M.Y.
        • Chen Y.D.
        • et al.
        Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM.
        Diabetes Care. 1994; 17: 1093-1099
        • Cappuccio F.P.
        • Miller M.A.
        Soluble adhesion molecules and coronary heart disease.
        Lancet. 2002; 359: 526-527
        • Hwang S.J.
        • Ballantyne C.M.
        • Sharrett A.R.
        • et al.
        Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases.
        Circulation. 1997; 96: 4219-4225
        • Ridker P.M.
        • Hennekens C.H.
        • Roitman-Johnson B.
        • et al.
        Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men.
        Lancet. 1998; 351: 88-92
        • Matsumoto K.
        • Sera Y.
        • Nakamura H.
        • et al.
        Serum concentrations of soluble adhesion molecules are related to degree of hyperglycemia and insulin resistance in patients with type 2 diabetes mellitus.
        Diabetes Res Clin Pract. 2002; 55: 131-138
        • Lim S.C.
        • Caballero A.E.
        • Smakowski P.
        • et al.
        Soluble intercellular adhesion molecule, vascular cell adhesion molecule, and impaired microvascular reactivity are early markers of vasculopathy in type 2 diabetic individuals without microalbuminuria.
        Diabetes Care. 1999; 22: 1865-1870
        • Ryysy L.
        • Yki-Jarvinen H.
        Improvement of glycemic control by 1 year of insulin therapy leads to a sustained decrease in sE-selectin concentrations in type 2 diabetes.
        Diabetes Care. 2001; 24: 549-554
        • Kuusisto J.
        • Lempiainen P.
        • Mykkanen L.
        • et al.
        Insulin resistance syndrome predicts coronary heart disease events in elderly type 2 diabetic men.
        Diabetes Care. 2001; 24: 1629-1633
        • Pirro M.
        • Mauriege P.
        • Tchernof A.
        • et al.
        Plasma free fatty acid levels and the risk of ischemic heart disease in men.
        Atherosclerosis. 2002; 160: 377-384
        • Paolisso G.
        • Howard B.V.
        Role of non-esterified fatty acids in the pathogenesis of type 2 diabetes mellitus.
        Diabet Med. 1998; 15: 360-366
        • Mather K.J.
        • Verma S.
        • Anderson T.J.
        Improved endothelial function with metformin in type 2 diabetes mellitus.
        J Am Coll Cardiol. 2001; 37: 1344-1350
        • Asagami T.
        • Abbasi F.
        • Stuelinger M.
        • et al.
        Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes.
        Metabolism. 2002; 51: 843-846