Exendin-4 (1-8)

Context: Various drugs affect body weight as a side effect. Objective: We conducted this systematic review and meta-analysis to summarize the evidence about commonly prescribed drugs and their association with weight change. Data sources: MEDLINE, DARE, and the Cochrane Database of Systematic Reviews were searched to identify published systematic reviews as a source for trials. Study selection: We included randomized trials that compared an a priori selected list of drugs to placebo and measured weight change. Data extraction: We extracted data in duplicate and assessed the methodological quality using the Cochrane risk of bias tool. Results: We included 257 randomized trials (54 different drugs; 84 696 patients enrolled). Weight gain was associated with the use of amitriptyline (1.8 kg), mirtazapine (1.5 kg), olanzapine (2.4 kg), quetiapine (1.1 kg), risperidone (0.8 kg), gabapentin (2.2 kg), tolbutamide (2.8 kg), pioglitazone (2.6 kg), glimepiride (2.1 kg), gliclazide (1.8 kg), glyburide (2.6 kg), glipizide (2.2 kg), sitagliptin (0.55 kg), and nateglinide (0.3 kg). Weight loss was associated with the use of metformin (1.1 kg), acarbose (0.4 kg), miglitol (0.7 kg), pramlintide (2.3 kg), liraglutide (1.7 kg), exenatide (1.2 kg), zonisamide (7.7 kg), topiramate (3.8 kg), bupropion (1.3 kg), and fluoxetine (1.3 kg). For many other remaining drugs (including antihypertensives and antihistamines), the weight change was either statistically nonsignificant or supported by very low-quality evidence. Conclusions: Several drugs are associated with weight change of varying magnitude. Data are provided to guide the choice of drug when several options exist and institute preemptive weight loss strategies when obesogenic drugs are prescribed.

What is known and objective: In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) including once-weekly (QW) formulations have been incorporated into type 2 diabetes (T2D) clinical guidelines, making it essential that pharmacists and healthcare professionals (HCPs) have a clear understanding of their safety profiles. Currently, three QW GLP-1 RAs are approved and marketed in the United States for the treatment of T2D: dulaglutide, exenatide extended-release and semaglutide. This review provides pharmacists and HCPs with collated data related to potential safety and tolerability issues when patients use QW GLP-1 RAs, enabling patient education and treatment optimization. Methods: This is a narrative review comparing the safety and tolerability of the three QW GLP-1 RAs, using data from Phase 3 clinical trials. Extracted safety data included gastrointestinal (GI) adverse events (AEs), hypoglycaemia, injection-site reactions, pancreatitis, neoplasms, gallbladder events, and diabetic retinopathy (DR) and/or its complications (DRCs). Results and discussion: A total of 30 trials were identified for inclusion; eight were head-to-head trials involving another GLP-1 RA; of these, six compared GLP-1 RAs with different dosing regimens (QW vs once-daily or twice-daily), and two were direct QW vs QW GLP-1 RA comparisons. The most commonly reported AEs were GI events (notably nausea, vomiting and diarrhoea), but there was variation between the three QW drugs. These were generally mild-to-moderate in severity and transient. Risk of hypoglycaemia, injection-site reactions, pancreatitis, neoplasms and gallbladder events was generally low across the GLP-1 RAs investigated. Overall rates of DR or DRC were low across the trials. Only in one trial (SUSTAIN 6) there were significantly more DRC events reported in patients treated with QW semaglutide (3.0%) compared with placebo (1.8%). This was likely due to the rapid improvement in glucose control in patients with pre-existing DR enrolled within that trial. What is new and conclusion: This review puts the latest clinical data from the marketed QW GLP-1 RAs into context with results from older Phase 3 trials, to enable pharmacists and HCPs to make informed treatment decisions. Each of the three QW GLP-1 RAs has their own safety profile, which should be considered when choosing the optimal treatment for patients.

Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA1c) targets is challenging in some patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide effective reductions in HbA1c and body weight. Semaglutide is the only GLP-1RA that is available in both an injectable and oral formulation. The efficacy of once-weekly subcutaneous semaglutide and once-daily oral semaglutide has been investigated in the global SUSTAIN and PIONEER phase III clinical trial programs in a range of clinical settings, including early T2D managed with diet and exercise only, more established T2D uncontrolled on one to three oral antidiabetic drugs, and advanced disease treated with insulin. Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA1c by 1.5-1.8% after 30-56 weeks, which was significantly more than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine. Across the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA1c by 1.0-1.4%, significantly more than sitagliptin or empagliflozin, and to a similar extent as liraglutide after 26 weeks. In addition, subcutaneous semaglutide reduced body weight significantly more than all active comparators tested, while oral semaglutide reduced body weight more than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Neither formulation of semaglutide has been associated with an increased risk of hypoglycemia and both improve various measures of health-related quality of life. Semaglutide offers the benefits of a highly effective GLP-1RA in both injectable and oral formulations. Selection of the most appropriate formulation can be made on an individual basis to best suit the patient's preferences and needs.