OBJECTIVECompare the efficacy and safety of monotherapy with dulaglutide, a once-weekly GLP-1 receptor agonist, to metformin-treated patients with type 2 diabetes. The primary objective compared dulaglutide 1.5 mg and metformin on change from baseline glycosylated hemoglobin A 1c (HbA 1c ) at 26 weeks. RESEARCH DESIGN AND METHODSThis 52-week double-blind study randomized patients to subcutaneous dulaglutide 1.5 mg, dulaglutide 0.75 mg, or metformin. Patients (N = 807) had HbA 1c ‡6.5% ( ‡48 mmol/mol) and £9.5% (£80 mmol/mol) with diet and exercise alone or low-dose oral antihyperglycemic medication (OAM) monotherapy; OAMs were discontinued at beginning of lead-in period. RESULTSAt 26 weeks, changes from baseline HbA 1c (least squares [LS] mean 6 SE) were: dulaglutide 1.5 mg, 20.78 6 0.06% (28.5 6 0.70 mmol/mol); dulaglutide 0.75 mg, 20.71 6 0.06% (27.8 6 0.70 mmol/mol); and metformin, 20.56 6 0.06% (26.1 6 0.70 mmol/mol). Dulaglutide 1.5 and 0.75 mg were superior to metformin (LS mean difference): 20.22% (22.4 mmol/mol) and 20.15% (21.6 mmol/mol) (one-sided P < 0.025, both comparisons), respectively. Greater percentages reached HbA 1c targets <7.0% (<53 mmol/mol) and £6.5% (£48 mmol/mol) with dulaglutide 1.5 and 0.75 mg compared with metformin (P < 0.05, all comparisons). No severe hypoglycemia was reported. Compared with metformin, decrease in weight was similar with dulaglutide 1.5 mg and smaller with dulaglutide 0.75 mg. Over 52 weeks, nausea, diarrhea, and vomiting were the most common adverse events; incidences were similar between dulaglutide and metformin. CONCLUSIONSDulaglutide improves glycemic control and is well tolerated as monotherapy in patients with early stage type 2 diabetes.Muscle and liver insulin resistance and b-cell failure represent the core pathophysiologic defects in type 2 diabetes. In addition, there is increasing evidence that the gastrointestinal (GI) tract plays an essential role in the development of carbohydrate intolerance of type 2 diabetes (1). The incretin concept suggests that ingested glucose results in a considerably larger and more sustained insulin secretion compared with glucose administered intravenously due to the release of two intestinal-derived

OBJECTIVEThis study compared the efficacy and safety of once-weekly dulaglutide, a glucagonlike peptide-1 receptor agonist, with daily insulin glargine, both combined with maximally tolerated doses of metformin and glimepiride in patients with type 2 diabetes. The primary objective was noninferiority of dulaglutide 1.5 mg to glargine in the HbA 1c change from baseline at 52 weeks. RESEARCH DESIGN AND METHODSIn this 78-week, open-label study, 810 patients were randomized to dulaglutide 1.5 mg, dulaglutide 0.75 mg, or glargine. RESULTSThe baseline mean 6 SD HbA 1c was 8.1 6 1.0% (65.5 6 10.8 mmol/mol). The least squares mean 6 SE HbA 1c change from baseline to the primary end point was 21.08 6 0.06% (211.8 6 0.7 mmol/mol) for dulaglutide 1.5 mg, 20.76 6 0.06% (28.3 6 0.7 mmol/mol) for dulaglutide 0.75 mg, and 20.63 6 0.06% (26.9 6 0.7 mmol/mol) for glargine, with an end point mean 6 SD dose of 29 6 26 units (0.33 6 0.24 units/kg), and a fasting plasma glucose (mean 6 SD) of 118 6 23 mg/dL from self-monitored plasma glucose. Statistical criteria for superiority were met with dulaglutide 1.5 mg and for noninferiority with dulaglutide 0.75 mg. More patients on dulaglutide 1.5 mg achieved HbA 1c targets <7.0% (53 mmol/mol) versus glargine (P < 0.001). Body weight decreased with dulaglutide and increased with glargine. Total hypoglycemia rates were lower with dulaglutide; severe hypoglycemia was minimal. Increases in pancreatic enzymes were observed for dulaglutide. Incidence of nausea (15.4, 7.7, and 1.5%) and diarrhea (10.6, 9.2, and 5.7%) were more common with dulaglutide 1.5 mg and 0.75 mg than with glargine. CONCLUSIONSOnce-weekly dulaglutide 1.5 mg, compared with daily insulin glargine without forced titration, demonstrated greater HbA 1c reduction and weight loss, with a higher incidence of gastrointestinal adverse events and a lower risk of hypoglycemia.

Background: Information is lacking on the potential effect of nҀ3 polyunsaturated fatty acids (PUFAs) on the adipose tissue of patients with type 2 diabetes. Objective: We evaluated whether nҀ3 PUFAs have additional effects on adiposity, insulin sensitivity, adipose tissue function (production of adipokines and inflammatory and atherogenic factors), and gene expression in type 2 diabetes. Design: Twenty-seven women with type 2 diabetes without hypertriglyceridemia were randomly allocated in a double-blind parallel design to 2 mo of 3 g/d of either fish oil (1.8 g nҀ3 PUFAs) or placebo (paraffin oil). Results: Although body weight and energy intake measured by use of a food diary were unchanged, total fat mass (P 0.019) and subcutaneous adipocyte diameter (P 0.0018) were lower in the fish oil group than in the placebo group. Insulin sensitivity was not significantly different between the 2 groups (measured by homeostasis model assessment in all patients and by euglycemichyperinsulinemic clamp in a subgroup of 5 patients per group). By contrast, atherogenic risk factors, including plasma triacylglycerol (P 0.03), the ratio of triacylglycerol to HDL cholesterol (atherogenic index, P 0.03), and plasma plasminogen activator inhibitor-1 (P 0.01), were lower in the fish oil group than in the placebo group. In addition, a subset of inflammation-related genes was reduced in subcutaneous adipose tissue after the fish oil, but not the placebo, treatment. Conclusions: A moderate dose of nҀ3 PUFAs for 2 mo reduced adiposity and atherogenic markers without deterioration of insulin sensitivity in subjects with type 2 diabetes. Some adipose tissue inflammation-related genes were also reduced. These beneficial effects could be linked to morphologic and inflammatory changes in adipose tissue. This trial was registered at clinicaltrials.gov as NCT0037.Am J Clin Nutr 2007;86:1670 -9.