Elsevier

The Lancet

Volume 391, Issue 10140, 30 June–6 July 2018, Pages 2607-2618
The Lancet

Articles
MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study

https://doi.org/10.1016/S0140-6736(18)30726-8Get rights and content

Summary

Background

Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes.

Methods

This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18–65 years with controlled type 2 diabetes (glycated haemoglobin A1c [HbA1c] levels of 6·5–8·5% at screening) and a body-mass index between 27 kg/m2 and 40 kg/m2. An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A–C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 μg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 μg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0–4 h (AUC0–4 h) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585.

Findings

Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0–4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean −32·78% [90% CI −36·98 to −28·57] vs −10·16% [–14·10 to −6·21], and the mean difference was −22·62% [–28·40 to −16·85]; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean −3·84 kg [90% CI −4·55 to −3·12] vs −1·70 kg [–2·40 to −1·01] and mean difference of 2·14 kg [–3·13 to −1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group).

Interpretation

MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes.

Funding

MedImmune.

Introduction

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.

Section snippets

Study design

This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was designed to determine the optimal dosing regimen and assess the safety and efficacy of MEDI0382 in overweight or obese individuals with type 2 diabetes. Participants were enrolled at 11 study sites (hospitals and contract research organisations) in Germany. The study was done in accordance with all local laws, the International Conference on Harmonisation Good Clinical Practice

Results

Between Dec 9, 2015, and Feb 24, 2017, 422 individuals were screened for eligibility, of whom 61 (14%) were randomly assigned to the MAD portion (42 [69%] were randomly assigned to receive MEDI0382 and 19 [31%] to receive placebo), and 51 (12%) were randomly assigned to the phase 2a portion of the study (25 [49%] were randomly assigned to receive MEDI0382 and 26 [51%] to receive placebo; figure 1). Demographic and baseline characteristics were generally well balanced between treatment groups in

Discussion

This randomised, placebo-controlled, double-blind, combined MAD and phase 2a study indicates that treatment with MEDI0382 can deliver clinically meaningful improvements in glycaemic control and bodyweight in overweight or obese patients with type 2 diabetes. Significant reductions in fasting and postprandial plasma glucose concentrations occurred rapidly (being evident after 7 days of treatment) and were sustained for up to 41 days. Treatment with MEDI0382 was associated with an acceptable

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