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.

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OBJECTIVE -We examined changes in metabolic parameters in clinical trials of duloxetine for diabetic peripheral neuropathic pain (DPNP).RESEARCH DESIGN AND METHODS -Data were pooled from three similarly designed clinical trials. Adults with diabetes and DPNP (n ϭ 1,024) were randomized to 60 mg duloxetine q.d., 60 mg b.i.d., or placebo for 12 weeks. Subjects (n ϭ 867) were re-randomized to 60 mg duloxetine b.i.d. or routine care for an additional 52 weeks. Mean changes in plasma glucose, lipids, and weight were evaluated. Regression and subgroup analyses were used to identify relationships between metabolic measures and demographic, clinical, and electrophysiological parameters.RESULTS -Duloxetine treatment resulted in modest increases in fasting plasma glucose in short-and long-term studies (0.50 and 0.67 mmol/l, respectively). A1C did not increase in placebo-controlled studies; however, a greater increase was seen relative to routine care in long-term studies (0.52 vs. 0.19%). Short-term duloxetine treatment resulted in mean weight loss (Ϫ1.03 kg; P Ͻ 0.001 vs. placebo), whereas slight, nonsignificant weight gain was seen in both duloxetine and routine care groups with longer treatment. Between-group differences were seen for some lipid parameters, but these changes were generally small. Metabolic changes did not appear to impact improvement in pain severity seen with duloxetine, and nerve conduction was also not significantly impacted by treatment.CONCLUSIONS -Duloxetine treatment was associated with modest changes in glycemia in patients with DPNP. Other metabolic changes were limited and of uncertain significance. These changes did not impact the significant improvement in pain observed with duloxetine treatment. Diabetes Care 30:21-26, 2007N europathy is the most common diabetic microvascular complication, affecting up to 50% of all individuals with diabetes (1). Substantial morbidity is associated with diabetic peripheral neuropathy (DPN), which is the leading risk factor for diabetic foot complications and nontraumatic amputations. Though these late complications frequently occur in the insensate foot, symptomatic DPN also significantly impacts quality of life (2,3). Estimates of the prevalence of diabetic peripheral neuropathic pain (DPNP) vary from 3% to Ͼ20% (4).For many agents, the data supporting effectiveness is limited. In addition, nearly all treatments are associated with safety or tolerability issues. One category of side effects common to a number of the antidepressant and anticonvulsant drugs is related to metabolic changes. Weight gain is seen with tricyclic antidepressants (TCAs) (5) and anticonvulsants (e.g., valproate, gabapentin, pregabalin) (6). Changes in plasma glucose have also been reported with TCAs (7,8) and phenytoin (9), and dyslipidemia can be seen with carbamazepine (10).Duloxetine has demonstrated efficacy in several large clinical trials of DPNP (11-13) and is one of only two drugs to have received regulatory approval for the treatment of this condition. As a selective reupt...

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