Results Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of −19% (95% confidence interval −24% to −14%; P<0.001) and in folate concentration of −5% (95% CI −10% to −0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI −1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l (95% CI 18.8 to 30.0 µmol/l), compared with a mean homocysteine level of 18

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.

Objective. Metformin is a key treatment option in type 2 diabetes. However, metformin may decrease vitamin B12 levels and increase levels of homocysteine, a cardiovascular risk factor. We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with insulin. Design. Placebo-controlled, randomized trial. Measurements: at baseline and 16 weeks later. Setting. This trial was conducted in the outpatient clinics of three general hospitals in The Netherlands. Subjects. A total of 745 patients with type 2 diabetes, treated with insulin and not known with a contraindication for the use of metformin, were approached; 390 gave informed consent and entered the study. Thirty-seven subjects dropped out (12 placebo and 25 metformin users). Intervention. Addition of metformin or placebo to insulin therapy. Primary outcome parameters. Serum homocysteine, folate, vitamin B12, indices of glycaemic control and body weight. Results. Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% (0.2 to 8; P ¼ 0.039) and with decreases in folate [)7% ()1.4 to )13); P ¼ 0.024] and vitamin B12 [)14% ()4.2 to )24); P < 0.0001]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12. Conclusion. In patients with type 2 diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in homocysteine. The clinical significance of these findings remains to be investigated.

Objectives. The UK Prospective Diabetes Study (UKPDS) showed that treatment with metformin decreases macrovascular morbidity and mortality independent of glycaemic control. We hypothesized that metformin may achieve this by improving endothelial function and chronic, low-grade inflammation. Data on this issue are scarce and we therefore tested, in the setting of a randomized, placebo-controlled trial, whether metformin can affect endothelial function and low-grade inflammation. Design. The Hyperinsulinaemia the Outcome of its Metabolic Effects (HOME) trial is a double-blind trial, in which all patients were randomized to receive either metformin or placebo in addition to insulin therapy. At the beginning and the end of a 16-week treatment period fasting blood samples were drawn and a physical examination was carried out. Setting. The trial was conducted in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden; the Netherlands).Subjects. Patients were included if they were between 30 and 80 years of age; had received a diagnosis of diabetes after the age of 25; had never had an episode of ketoacidosis; and their blood glucose-lowering treatment previously consisted of oral agents but now only consisted of either insulin (n ¼ 345) or insulin and metformin (n ¼ 45). We excluded pregnant women and women trying to become pregnant, patients with a Cockroft-Gault-estimated creatinine clearance <50 mL min )1 , or low plasma cholinesterase (reference value <3.5 units L )1 ), patients with congestive heart failure (New York Heart Association class III/IV), or patients with other serious medical or psychiatric disease. A total of 745 eligible patients were approached; 390 gave informed consent and were randomized (196 metformin, 194 placebo). About 353 patients completed 16 weeks of treatment (171 metformin, 182 placebo). Main outcome measures. The HOME trial was designed to study the metabolic and cardiovascular effects of metformin during a follow-up of 4 years. Presented here are the results of an interim analysis after 16 weeks of treatment. Results. When compared with placebo, metformin treatment was associated with an increase in urinary albumin excretion of 21% ()1 to +48; P ¼ 0.06); a decrease in plasma von Willebrand factor of 6% ()10 to )2; P ¼ 0.0007); a decrease in soluble vascular cell adhesion molecule-1 of 4% ()7 to )2; P ¼ 0.0002); a decrease in soluble E-selectin of 6% ()10 to )2; P ¼ 0.008); a decrease in tissue-type plasminogen activator of 16% ()20 to )12; P < 0.0001); and a decrease in plasminogen activator inhibitor-1 of 20% ()27 to )10; P ¼ 0.0001). These changes could not be explained by metformin-associated changes in glycaemic control, body weight or insulin dose. Markers of inflammation, i.e. C-reactive protein and soluble intercellular adhesion molecule-1, did not change with metformin treatment. Conclusions. In patients with type 2 diabetes treated with insulin, metformin treatment was associated with improvement of endothelial function, which was largely unr...

OBJECTIVE -To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin.RESEARCH DESIGN AND METHODS -Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment.The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured.RESULTS -Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P ϭ 0.006; mean GHb 6.9 vs. 7.6%, P Ͻ 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P Ͻ 0.0001); reduced weight gain (Ϫ0.4 vs. ϩ1.2 kg, P Ͻ 0.01); and decreased plasma LDL cholesterol (Ϫ0.21 vs. Ϫ0.02 mmol/l, P Ͻ 0.01). Risk of hypoglycemia was similar in both groups.CONCLUSIONS -In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less.