Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial

Summary

Background

Semaglutide is a once-weekly glucagon-like peptide-1 (GLP-1) analogue for type 2 diabetes. Few clinical trials have reported on the concomitant use of GLP-1 receptor agonists with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We aimed to investigate the efficacy and safety of semaglutide when added to SGLT-2 inhibitor therapy in patients with inadequately controlled type 2 diabetes.

Methods

The SUSTAIN 9 double-blind, parallel-group trial was done at 61 centres in six countries (Austria, Canada, Japan, Norway, Russia, and the USA). Adults with type 2 diabetes and HbA_1c 7·0–10·0% (53–86 mmol/mol), despite at least 90 days of treatment with an SGLT-2 inhibitor, were randomly assigned (1:1) to receive subcutaneous semaglutide 1·0 mg or volume-matched placebo once weekly for 30 weeks, after a dose-escalation schedule of 4 weeks of 0·25 mg semaglutide or placebo and 4 weeks of 0·5 mg semaglutide or placebo. Existing antidiabetic medications, including SGLT-2 inhibitor treatment, were continued for the duration of the trial. Rescue medication, defined as intensification of background antidiabetic treatment or the initiation of new glucose-lowering medications, could be given to patients meeting specific criteria at the discretion of the investigator. The primary outcome was change in HbA_1c from baseline at week 30, assessed in the full analysis set (all patients randomly allocated to treatment) using on-treatment data collected before rescue medication was started. The confirmatory secondary outcome was change in bodyweight from baseline to week 30. Safety was also assessed in the safety analysis set (all patients who received at least one dose of treatment). The trial was registered with ClinicalTrials.gov (NCT03086330).

Findings

Between March 15, and Dec 4, 2017, 302 patients were enrolled and randomly assigned to receive semaglutide 1·0 mg or placebo (full analysis set), of whom 301 received at least one dose of treatment (safety analysis set). One patient was assigned to semaglutide but was not treated (reason unknown). 294 (97·4%) patients completed the trial and 267 (88·4%) completed treatment. Baseline characteristics were generally comparable between groups. In addition to randomised medication and SGLT-2 inhibitor, 216 (71·5%) patients were taking metformin and 39 (12·9%) were taking sulphonylurea. Patients given semaglutide had greater reductions in HbA_1c (estimated treatment difference −1·42% [95% CI −1·61 to −1·24]; −15·55 mmol/mol [–17·54 to −13·56]) and bodyweight (−3·81 kg [–4·70 to −2·93]) versus those randomised to placebo (both p<0·0001). 356 adverse events were reported by 104 (69·3%) patients in the semaglutide group, and 247 adverse events were reported by 91 (60·3%) patients in the placebo group. Gastrointestinal adverse events were most common and were reported in 56 (37·3%) patients in the semaglutide group and 20 (13·2%) in the placebo group. Serious adverse events occurred in seven (4·7%) patients in the semaglutide group and six (4·0%) in the placebo group. Severe or blood glucose-confirmed hypoglycaemic events were reported in four patients on semaglutide (2·7%). 16 patients stopped treatment early because of an adverse event, 13 of whom were in the semaglutide group. There were no deaths during the trial.

Interpretation

Adding semaglutide to SGLT-2 inhibitor therapy significantly improves glycaemic control and reduces bodyweight in patients with inadequately controlled type 2 diabetes, and is generally well tolerated.

Funding

Novo Nordisk.

Introduction

The 2018 report on the management of type 2 diabetes from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD),¹ and the 2019 ADA Standards of Care treatment guidelines² emphasise the use of treatment regimens that take patients' characteristics into account. Notably, this report and guidelines highlight glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors as preferred agents after metformin in patients with type 2 diabetes and established cardiovascular disease.1, 2 In addition to improving glycaemic control, some drugs in each of these classes lower the risk of major cardiovascular events, reduce the progression of chronic kidney disease, minimise the risk of hypoglycaemia, and reduce bodyweight.3, 4, 5, 6, 7, 8 GLP-1 receptor agonists and SGLT-2 inhibitors are increasingly used for the treatment of type 2 diabetes, but there is scarce information from clinical trials on the efficacy and safety of their concomitant use.

Research in context

Evidence before this study

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been highlighted in the 2018 American Diabetes Association/European Association for the Study of Diabetes consensus report as preferred agents after metformin in patients with established cardiovascular disease. However, to date, few data from clinical trials are available to help physicians and patients to make informed decisions about the concomitant use of these drugs.

Added value of this study

The results of the SUSTAIN 9 trial show that the addition of subcutaneous semaglutide, a once-weekly GLP-1 analogue, to existing SGLT-2 inhibitor therapy significantly improves glycaemic control and reduces bodyweight. Additionally, the trial shows that most patients tolerate concomitant treatment well.

Implications of all the available evidence

SUSTAIN 9 is the second clinical trial to show that the concomitant use of GLP-1 receptor agonists and SGLT-2 inhibitors is effective and generally well tolerated in patients with type 2 diabetes. Combining the distinct modes of action of these two drug classes has beneficial effects on glucose and weight outcomes. Specifically, the findings of the SUSTAIN 9 trial show that the addition of semaglutide 1·0 mg appears to be an effective, well tolerated treatment option for patients who have not reached their therapeutic goals, despite treatment with an SGLT-2 inhibitor.

Semaglutide is a long-acting GLP-1 analogue approved for once-weekly treatment of type 2 diabetes.9, 10 The efficacy and safety of semaglutide have been established in the SUSTAIN clinical trial programme across the continuum of care in patients with type 2 diabetes.

During the SUSTAIN programme, semaglutide has been directly compared with various antidiabetic drugs, and has been studied both as monotherapy and in combination with other agents. Semaglutide has consistently shown superior HbA_1c and bodyweight reductions versus placebo11, 12 and a range of active comparators,13, 14, 15, 16 and has a safety profile similar to that of other GLP-1 receptor agonists.13, 15, 16 Furthermore, in SUSTAIN 6,³ semaglutide significantly reduced the risk of major adverse cardiovascular events compared with placebo, in patients with type 2 diabetes and high cardiovascular risk. The benefits of semaglutide have also been shown when used in addition to various combinations of oral antidiabetic drugs (eg, metformin, with or without sulphonylureas or thiazolidinediones).3, 13, 14, 15, 16 Semaglutide has also shown superiority over placebo when used in combination with basal insulin (with or without metformin), in terms of effects on both HbA_1c and bodyweight.¹²

As changes to international guidelines begin to be implemented at national and local levels, it is likely that concomitant treatment with GLP-1 receptor agonists and SGLT-2 inhibitors will become more common. However, at present, there are only scarce data from randomised controlled trials to inform such concomitant use,17, 18 and even less evidence relating to the specific clinical situation in which a GLP-1 receptor agonist is added to existing SGLT-2 inhibitor treatment.¹⁷

The SUSTAIN 9 trial aimed to investigate the efficacy and safety of semaglutide in patients with type 2 diabetes who were inadequately controlled on SGLT-2 inhibitor-based treatment.