Type 2 diabetes is a chronic metabolic disorder characterised by hyperglycaemia, insulin resistance, and progressive impairment of insulin secretion.1 On the basis of evidence from large-scale interventional studies, such as the UK Prospective Diabetes Studies,2, 3 treatment of type 2 diabetes has historically focused on lowering glucose concentrations.4 There has been growing recognition of the imperative role of weight regulation in improving outcomes in overweight or obese patients with type 2 diabetes.5, 6 Specifically, sustained and moderate weight loss of more than 5% of initial bodyweight can improve glycaemic control and cardiovascular risk markers.3, 7, 8, 9
Research in context
Evidence before this study
A PubMed search done on Jan 17, 2018, using the terms “type 2 diabetes”, [AND] “obesity”, [AND] “glucagon-like peptide-1” (GLP-1), [AND] “glucagon”, filtered for “clinical trials”, yielded 107 results. No publication date or language restrictions were applied. Only 20 of these publications assessed the clinical utility of GLP-1 receptor agonists in obese patients with type 2 diabetes. No publications related to glucagon receptor agonists or dual GLP-1 and glucagon receptor agonists in obese patients with type 2 diabetes were identified.
Added value of this study
To our knowledge, this clinical trial is the first to test the efficacy of a GLP-1 and glucagon receptor dual agonist, MEDI0382, in patients with type 2 diabetes. The results from this study support further clinical development of MEDI0382 in obese or overweight patients with type 2 diabetes, as evidenced by the treatment effects of decreased bodyweight and improved glycaemic control. Moreover, the safety and pharmacokinetic profiles of MEDI0382 support daily dosing.
Implications of all the available evidence
There has been increasing recognition of the imperative role of weight reduction in effectively treating type 2 diabetes and improving long-term outcomes. Bariatric surgery remains the most effective therapeutic option for obesity management in type 2 diabetes; however, the associated risks and eligibility criteria negate this procedure in many patients. The GLP-1 receptor agonist liraglutide is approved as an antihyperglycaemic agent in patients with type 2 diabetes. Liraglutide is also approved by the US Food and Drug Administration and the European Medicines Agency for weight management in obese, non-diabetic individuals, although mean weight loss at week 56 is much less compared with surgical interventions at around 8% versus baseline. There is an unmet need for pharmacological therapies that target both obesity and hyperglycaemia in obese or overweight patients with type 2 diabetes. Over the course of 42 days of therapy, MEDI0382 has achieved a highly significant reduction in blood glucose, with a magnitude of weight loss that is greater than that seen for any pharmacological interventions in obesity so far, over the same time period. This finding suggests that for the first time, a pharmacological therapy might be able to meet treatment goals in type 2 diabetes of both durable glycaemic control and weight loss of a magnitude that will have a considerable impact on clinical outcomes. This phase 2a study supports further development of MEDI0382 for a type 2 diabetes indication. A phase 2b trial is ongoing.
In the past decade, the repertoire of therapies for type 2 diabetes has improved with scope for insulin-sparing and more personalised treatment regimens.1 Despite these advances, 50% of patients require insulin therapy within 10 years of diagnosis,10 which often leads to additional weight gain.11 The newest classes of drugs for treating type 2 diabetes, including dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists, are either weight neutral or promote a modest degree of weight loss.12, 13 None of these newer therapies, however, achieves similar outcomes to bariatric surgery.14 Bariatric surgery has been shown to restore normoglycaemia in more than 80% of patients, obviating the need for diabetes medications in up to 45% of patients after 60 months.15 Marked improvements in glyacemic control are typically observed within a few days of surgery, and often occur before clinically meaningful weight loss.15 With additional effects on visceral and liver fat stores and modification of long-term cardiovascular risk factors,16, 17 bariatric surgery delivers apparent remission for some patients with type 2 diabetes. However, as a result of costs and the associated risks and adverse effects of the intervention, bariatric surgery is not a viable option for most patients.18, 19
Although very-low-calorie diets have been shown to promote apparent reversal of type 2 diabetes in the short term,20 the profound effects of bariatric surgery, in particular Roux-en-Y gastric bypass surgery, are not wholly related to weight loss alone. Bariatric surgery is associated with a favourable hormonal milieu after reconfiguration of the gut. Specifically, suppression of ghrelin, a hormone known to drive appetite, and increases in incretin hormones (such as GLP-1 and oxyntomodulin) that promote weight loss have been reported.21, 22 GLP-1 induces glucose-dependent insulin secretion, improves postprandial glucose concentration through a delay in gastric emptying, and promotes weight loss via central effects on appetite and satiety.23 Oxyntomodulin, a peptide with GLP-1 and glucagon receptor dual agonist activity, also drives weight loss via effects on appetite and satiety, but acts through an additional alternative mechanism of increasing energy expenditure.24 Despite the known action of glucagon to mobilise hepatic glucose, oxyntomodulin is thought to promote normoglycaemia through the equipoise of GLP-1 and glucagon receptor agonist activity.25 Synthetic dual agonists of GLP-1 and glucagon receptor have also been shown to promote weight loss in animal models.26, 27
MEDI0382 (Bachem; Bubendorf, Switzerland) is a synthetic linear peptide with natural aminoacids, a palmitic acid side chain, and balanced dual GLP-1 and glucagon receptor agonist activity.28 MEDI0382 has been developed for treatment of type 2 diabetes and obesity. Treatment with MEDI0382 is predicted to improve glucose control through insulinotropic effects and drive disease-modifying weight loss through combined effects on appetite and energy expenditure. The predicted effects of MEDI0382 on weight loss are thought to be due to its ability to partially mimic the hormonal environment after bariatric surgery. In preclinical studies, MEDI0382 promoted considerable and sustained weight loss and induced normoglycaemia.28 The observed weight loss with MEDI0382 was greater than that observed with GLP-1 receptor agonism alone.28 A single-ascending-dose study (1 day)29 with MEDI0382 in healthy individuals with a body-mass index (BMI) range of 22–30 kg/m2 showed some improvements in postprandial glucose levels and an acceptable safety profile, but also highlighted the need for slower dose up-titration to improve tolerability. The aims of this study were to assess the efficacy, tolerability, and safety of longer-term treatment with MEDI0382 in overweight or obese patients with type 2 diabetes.