Articles
Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial

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Summary

Background

Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes. We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both.

Methods

We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites in 18 countries. Eligible patients were aged at least 18 years (or at least 20 years in Japan) and diagnosed with type 2 diabetes, with insufficient glycaemic control (HbA1c 7·0–10·5% [53·0–91·0 mmol/mol]) despite stable treatment with metformin, thiazolidinediones, or both. We randomly assigned participants (2:2:1:1) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0·5 mg once weekly plus oral sitagliptin placebo once daily, subcutaneous semaglutide 1·0 mg once weekly plus oral sitagliptin placebo once daily, oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0·5 mg once weekly, or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1·0 mg once weekly. The two oral sitagliptin 100 mg groups (with semaglutide placebo 0·5 mg and 1·0 mg) were pooled for the analyses. The primary endpoint was change in HbA1c from baseline to week 56, assessed in the modified intention-to-treat population (all randomly assigned participants who received at least one dose of study drug); change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint. Safety endpoints included adverse events and hypoglycaemic episodes. This trial is registered with ClinicalTrials.gov, number NCT01930188.

Findings

Between Dec 2, 2013, and Aug 5, 2015, we randomly assigned 1231 participants; of the 1225 included in the modified intention-to-treat analysis, 409 received semaglutide 0·5 mg, 409 received semaglutide 1·0 mg, and 407 received sitagliptin 100 mg. Mean baseline HbA1c was 8·1% (SD 0·93); at week 56, HbA1c was reduced by 1·3% in the semaglutide 0·5 mg group, 1·6% in the semaglutide 1·0 mg group, and 0·5% with sitagliptin (estimated treatment difference vs sitagliptin −0·77% [95% CI −0·92 to −0·62] with semaglutide 0·5 mg and −1·06% [–1·21 to −0·91] with semaglutide 1·0 mg; p<0·0001 for non-inferiority and for superiority, for both semaglutide doses vs sitagliptin). Mean baseline bodyweight was 89·5 kg (SD 20·3); at week 56, bodyweight reduced by 4·3 kg with semaglutide 0·5 mg, 6·1 kg with semaglutide 1·0 mg, and 1·9 kg with sitagliptin (estimated treatment difference vs sitagliptin −2·35 kg [95% CI −3·06 to −1·63] with semaglutide 0·5 mg and −4·20 kg [–4·91 to −3·49] with semaglutide 1·0 mg; p<0·0001 for superiority, for both semaglutide doses vs sitagliptin). The proportion of patients who discontinued treatment because of adverse events was 33 (8%) for semaglutide 0·5 mg, 39 (10%) for semaglutide 1·0 mg, and 12 (3%) for sitagliptin. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 73 (18%) who received semaglutide 0·5 mg, 72 (18%) who received semaglutide 1·0 mg, and 30 (7%) who received placebo, and diarrhoea was reported in 54 (13%) who received semaglutide 0·5 mg, 53 (13%) who received semaglutide 1·0 mg, and 29 (7%) who received placebo. Seven (2%) patients in the semaglutide 0·5 mg group, two (<1%) in the semaglutide 1·0 mg group, and five (1%) in the sitagliptin group had blood-glucose confirmed hypoglycaemia. There were six fatal events (two in the semaglutide 0·5 mg group, one in the semaglutide 1·0 mg group, and three in the sitagliptin group); none were considered likely to be related to the trial drugs.

Interpretation

Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin, thiazolidinediones, or both, and had a similar safety profile to that of other GLP-1 receptor agonists. Semaglutide seems to be an effective add-on treatment option for this patient population.

Funding

Novo Nordisk A/S.

Introduction

Type 2 diabetes is a complex, progressive disease; despite the wide range of treatment options available,1 many patients with type 2 diabetes do not achieve recommended blood glucose concentrations2 (HbA1c <7·0% [53·0 mmol/mol];3 HbA1c ≤6·5% [48·0 mmol/mol]).4 Achievement of target blood glucose concentrations is a key goal of diabetes management because improved glycaemic control reduces the risk of associated microvascular and macrovascular complications.5 Weight reduction is also recommended in overweight patients as it is known to improve glycaemic control and cardiovascular risk factors.6

Several treatment options exist for improving glycaemic control in patients with type 2 diabetes. However, there are challenges associated with these options, including adverse events and other factors that can compromise adherence. Complex dosing regimens are known to affect adherence to therapy and might hinder achievement of glycaemic targets.7 Furthermore, many people with type 2 diabetes are overweight or obese and some drug regimens are associated with weight gain or an increased risk of hypoglycaemia.8 These drawbacks, together with regimen complexity when using several compounds, might contribute to poor adherence and reduce the proportion of patients achieving their HbA1c targets.1

Both glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can be used as second-line therapy when first-line therapy (mainly metformin) alone is insufficient for achieving glycaemic control.1 DPP-4 inhibitors and GLP-1 receptor agonists have different mechanisms of action by which they mediate their effects. DPP-4 inhibitors extend the half-life of endogenous GLP-1, whereas GLP-1 receptor agonists, resistant to DPP-4 degradation, provide supraphysiological stimulation of GLP-1 receptors.9 GLP-1 receptor agonists improve glycaemic control by stimulating insulin secretion and inhibiting the release of glucagon in a glucose-dependent manner, targeting the pathophysiological factors underlying the islet cell dysfunction associated with type 2 diabetes.10 Importantly, GLP-1 receptor agonists also reduce bodyweight, by reducing appetite and energy intake.11 DPP-4 is an enzyme known to act on various pharmacological and physiological substrates, including its inactivation of the incretin hormones GLP-1 and gastric inhibitory polypeptide, plus other hormones.12 DPP-4 is targeted by DPP-4 inhibitors, which increase insulin secretion and suppress glucagon release through the increased half-life of endogenous GLP-1. Their specific modes of action result in different efficacy and tolerability profiles from those of GLP-1 receptor agonists. Furthermore, unlike GLP-1 receptor agonists, DPP-4 inhibitors do not generally reduce bodyweight.13, 14

For first-generation GLP-1 receptor agonists, twice-daily or daily dosing is required.15 Recent efforts have focused on developing GLP-1 receptor agonists for once-weekly administration, which could improve patient adherence and health-related quality of life.16 Six GLP-1 receptor agonists have been approved for treatment of type 2 diabetes: exenatide (twice daily), lixisenatide and liraglutide (both once daily), and exenatide extended-release, albiglutide, and dulaglutide (all once weekly).10

Semaglutide, a novel GLP-1 receptor agonist with 94% structural homology to native GLP-1, is currently in development for the treatment of type 2 diabetes. It is similar in structure to liraglutide,17 but important structural modifications make semaglutide less susceptible to degradation by the enzyme DPP-4, and thus more enzymatically stable.17 These modifications also improve the specific high-affinity binding to albumin and, overall, result in a half-life of about 1 week, making semaglutide appropriate for once-weekly subcutaneous administration.17

The efficacy and safety of subcutaneous semaglutide have been assessed as part of a large phase 3 trial programme (SUSTAIN). In SUSTAIN 1, a double-blind, randomised, international trial, the efficacy and safety of once-weekly subcutaneous semaglutide monotherapy compared with placebo in treatment-naive patients with type 2 diabetes was assessed over 30 weeks. The results showed that both semaglutide 0·5 mg and 1·0 mg significantly improved HbA1c and bodyweight compared with placebo (p<0·0001 for all).18 Similarly, in the 2-year SUSTAIN 6 cardiovascular outcomes trial of semaglutide treatment in patients with type 2 diabetes at high cardiovascular risk, semaglutide was associated with improvements in HbA1c and sustained reductions in bodyweight compared with placebo, as well as reductions in the rate of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.19

Here we report the findings from SUSTAIN 2, a phase 3a clinical trial that assessed the efficacy and safety of semaglutide compared with a commonly used DPP-4 inhibitor, sitagliptin, as add-on treatment in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both.

Section snippets

Study design and participants

We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites (hospitals, clinical institutions, or private practices) in Europe (Bulgaria, Czech Republic, Hungary, Norway, Portugal, Romania, Spain, Sweden, Turkey, and Ukraine), Argentina, Hong Kong, India, Japan, Mexico, Russia, South Africa, and Thailand.

Patients were eligible for inclusion if they were aged 18 years or older (or aged 20 years

Results

Between Dec 2, 2013, and Aug 5, 2014, we randomly assigned 1231 participants to treatment; of the 1225 participants exposed to at least one dose of study drug and included in the efficacy and safety analyses, 409 received once-weekly semaglutide 0·5 mg, 409 received once-weekly semaglutide 1·0 mg, and 407 received sitagliptin 100 mg once daily (203 in the semaglutide 0·5 mg placebo group and 204 in the semaglutide 1·0 mg placebo group; figure 1). 1163 (94%) participants completed the trial,

Discussion

In this phase 3a trial, semaglutide 0·5 mg and semaglutide 1·0 mg were superior to sitagliptin in improving glycaemic control and reducing bodyweight, leading to reductions of up to three times (with semaglutide 1·0 mg) compared with sitagliptin in HbA1c and bodyweight, from baseline. The results from the primary analysis were substantiated by all sensitivity analyses. Improvements in glycaemic control and reductions in bodyweight in the semaglutide groups were associated with a low risk of

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