Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

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...