title: Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus.
abstract: BACKGROUND
  We investigated whether metformin hydrochloride has sustained beneficial metabolic and (cardio) vascular effects in patients with type 2 diabetes mellitus (DM2).
  
  
  METHODS
  We studied 390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy. The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality, as separate aggregate scores. In addition, effects on hemoglobin A(1c) (HbA(1c)), insulin requirement, lipid levels, blood pressure, body weight, and body mass index were analyzed.
  
  
  RESULTS
  Metformin treatment prevented weight gain (mean weight gain, -3.07 kg [range, -3.85 to -2.28 kg]; P < .001), improved glycemic control (mean reduction in HbA(1c) level, 0.4% percentage point [95% CI, 0.55-0.25]; P < .001) (where CI indicates confidence interval), despite the aim of similar glycemic control in both groups, and reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P < .001). Metformin was not associated with an improvement in the primary end point. It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P = .02), which was partly explained by the difference in weight. The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6).
  
  
  CONCLUSIONS
  Metformin, added to insulin in patients with DM2, improved body weight, glycemic control, and insulin requirements but did not improve the primary end point. Metformin did, however, reduce the risk of macrovascular disease after a follow-up period of 4.3 years. These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated. Trial Registration ClinicalTrials.gov Identifier: NCT00375388.
authors.affiliation: Department of Internal Medicine and Bethesda Diabetes Research Center, RA Hoogeveen, the Netherlands. kooy.a@bethesda.nl
authors.forename: Adriaan
authors.initials: A
authors.lastname: Kooy
authors.forename: Jolien
authors.initials: J
authors.lastname: de Jager
authors.forename: Philippe
authors.initials: P
authors.lastname: Lehert
authors.forename: Daniël
authors.initials: D
authors.lastname: Bets
authors.forename: Michiel G
authors.initials: MG
authors.lastname: Wulffelé
authors.forename: Ab J M
authors.initials: AJ
authors.lastname: Donker
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D015430:Weight Gain / Q000187:drug effects
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D008687:Metformin