The first-in-class glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide, which was initially approved in 2005, is available in twice-daily (BID) and once-weekly (QW) formulations. Clinical trial data suggest both formulations are effective and safe for patients with type 2 diabetes (T2D), both as monotherapy and as part of combination therapy. Since exenatide was approved, several other GLP-1RAs have become available for clinical use. Areas covered: Many ongoing clinical trials involving exenatide BID and exenatide QW are investigating new indications (exenatide BID) and new end points and combination therapies (exenatide QW). This review provides an overview of the delivery and pharmacokinetics of both formulations of exenatide, reviews existing data in T2D, and summarizes ongoing investigations. Expert opinion: Exenatide BID and QW have substantial clinical benefits. Comparisons with other GLP-1RAs demonstrate some differences in efficacy and safety profiles that make assessment of benefit:risk ratios complex. Head-to-head comparisons of QW GLP-1RA formulations may assist in the ranking of GLP-1RAs according to efficacy and safety. Results on the impact of exenatide QW on cardiovascular outcomes are eagerly awaited. The potential clinical utility of exenatide BID in other indications will clarify whether exenatide holds clinical promise in diagnoses other than T2D.

AimsTreatment with liraglutide 3.0 mg has been associated with gallbladder‐related adverse events. To conduct a single‐centre, double‐blind, 12‐week trial comparing the effect of 0.6 mg liraglutide and steady‐state liraglutide 3.0 mg with placebo on gallbladder emptying in adults with body mass index (BMI) ≥27 kg/m2 and without diabetes.MethodsParticipants were randomized 1:1 to once‐daily subcutaneous liraglutide (n = 26) or placebo (n = 26), starting at 0.6 mg with 0.6‐mg weekly increments to 3.0 mg, with nutritional and physical activity counselling. A 600‐kcal (23.7 g fat) liquid meal test was performed at baseline, after the first dose and after 12 weeks. The primary endpoint was the 12‐week maximum postprandial gallbladder ejection fraction (GBEFmax), measured over 240 minutes after starting the meal.ResultsBaseline characteristics were similar between groups (mean ± SD overall age 47.6 ± 10.0 years, BMI 32.6 ±3.4 kg/m2, 50% women). Mean 12‐week GBEFmax (treatment difference −3.7%, 95% confidence interval [CI] −13.1, 5.7) and area under the GBEF curve in the first 60 minutes (−390% × min, 95% CI −919, 140) did not differ for liraglutide 3.0 mg (n = 23) vs placebo (n = 24). The median (range) time to GBEFmax was 151 (11‐240) minutes with liraglutide 3.0 mg and 77 (22‐212) minutes with placebo. Similar findings were noted after the first 0.6‐mg liraglutide dose. Gastrointestinal disorders, notably nausea and constipation, were the most frequently reported adverse events.ConclusionsTreatment with liraglutide did not affect the GBEFmax but appeared to prolong the time to GBEFmax.

Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes.Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target tissue sensitivity to GLP-1. The present article critically reviews the possible mechanisms by which metformin may affect GLP-1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose-lowering actions of metformin.antidiabetic drug, DPP-IV inhibitor, drug mechanism, GLP-1, incretin therapy, metformin | INTRODUCTIONThe biguanide metformin has been used to treat diabetes for more than half a century and is currently the preferred first-line drug used, along with lifestyle modifications, in the treatment of type 2 diabetes.Despite the extensive use of metformin, the mechanisms underlying its glucose-lowering effect remain relatively unclear. Metformin is known to reduce hepatic gluconeogenesis and it is the general belief that this action constitutes the (major) mechanism behind the blood glucose-lowering effect of metformin in patients with type 2 diabetes.1,2 Interestingly, metformin has also been shown to increase intestinal glucose utilization and reduce food intake, which may help to explain the weight reduction observed in some obese metformintreated subjects.