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.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.

Many people with type 2 diabetes mellitus (T2DM) fail to achieve glycaemic control promptly after diagnosis and do not receive timely treatment intensification. This may be in part due to 'clinical inertia', defined as the failure of healthcare providers to initiate or intensify therapy when indicated. Physician-, patient- and healthcare-system-related factors all contribute to clinical inertia. However, decisions that appear to be clinical inertia may, in fact, be only 'apparent' clinical inertia and may reflect good clinical practice on behalf of the physician for a specific patient. Delay in treatment intensification can happen at all stages of treatment for people with T2DM, including prescription of lifestyle changes after diagnosis, introduction of pharmacological therapy, use of combination therapy where needed and initiation of insulin. Clinical inertia may contribute to people with T2DM living with suboptimal glycaemic control for many years, with dramatic consequences for the patient in terms of quality of life, morbidity and mortality, and for public health because of the huge costs associated with uncontrolled T2DM. Because multiple factors can lead to clinical inertia, potential solutions most likely require a combination of approaches involving fundamental changes in medical care. These could include the adoption of a person-centred model of care to account for the complex considerations influencing treatment decisions by patients and physicians. Better patient education about the progressive nature of T2DM and the risks inherent in long-term poor glycaemic control may also reinforce the need for regular treatment reviews, with intensification when required.

Adherence to antihyperglycemic medications is often suboptimal in patients with type 2 diabetes, and this can contribute to poor glycemic control, increased hospitalization, and the development of diabetic complications. Reported adherence rates to antihyperglycemics vary widely among studies, and this may be related to differences in methodology for measuring adherence, patient populations, and other factors. Poor adherence may occur regardless of the specific regimen used and whether therapy is oral or injectable, and can be especially common in chronic, asymptomatic conditions, such as type 2 diabetes. More convenient drug-administration regimens and advances in formulations and delivery devices are among strategies shown to improve adherence to antihyperglycemic therapy, especially for injectable therapy. This is exemplified by technological developments made in the drug class of glucagon-like peptide 1-receptor agonists, which are a focus of this narrative review. Dulaglutide, albiglutide, and prolonged-release exenatide have an extended duration of action and can be administered once weekly, whereas such agents as liraglutide require once-daily administration. The convenience of once-weekly versus once-daily administration is associated with better adherence in real-world studies involving this class of agent. Moreover, provision of a user-friendly delivery device has been shown to overcome initial resistance to injectable therapy among patients with type 2 diabetes. This suggests that recent innovations in drug formulation (eg, ready-to-use formulations) and delivery systems (eg, single-dose prefilled pens and hidden, ready-attached needles) may be instrumental in encouraging patient acceptance. For physicians who aim to improve their patients’ adherence to antihyperglycemic medications, it is thus important to consider the patient’s therapeutic experience (treatment frequency, drug formulation, delivery device). Better adherence, powered by recent technological advances in the delivery of glucagon-like peptide 1-receptor agonists, may thus lead to improved clinical outcomes in type 2 diabetes.

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Dulaglutide was associated with improvements in treatment satisfaction and a decrease in perceived frequency of hyperglycaemia.