Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial

Summary

Background

Agonists of the glucagon-like peptide-1 (GLP-1) receptor provide pharmacological levels of GLP-1 activity, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors increase concentrations of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide. We aimed to assess the efficacy and safety of the human GLP-1 analogue liraglutide versus the DPP-4 inhibitor sitagliptin, as adjunct treatments to metformin, in individuals with type 2 diabetes who did not achieve adequate glycaemic control with metformin alone.

Methods

In this parallel-group, open-label trial, participants (aged 18–80 years) with type 2 diabetes mellitus who had inadequate glycaemic control (glycosylated haemoglobin [HbA_1c] 7·5–10·0%) on metformin (≥1500 mg daily for ≥3 months) were enrolled and treated at office-based sites in Europe, the USA, and Canada. Participants were randomly allocated to receive 26 weeks' treatment with 1·2 mg (n=225) or 1·8 mg (n=221) subcutaneous liraglutide once daily, or 100 mg oral sitagliptin once daily (n=219). The primary endpoint was change in HbA_1c from baseline to week 26. The efficacy of liraglutide versus sitagliptin was assessed hierarchically by a non-inferiority comparison, with a margin of 0·4%, followed by a superiority comparison. Analyses were done on the full analysis set with missing values imputed by last observation carried forward; seven patients assigned to liraglutide did not receive treatment and thus did not meet criteria for inclusion in the full analysis set. This trial is registered with ClinicalTrials.gov, number NCT00700817.

Findings

Greater lowering of mean HbA_1c (8·5% at baseline) was achieved with 1·8 mg liraglutide (−1·50%, 95% CI −1·63 to −1·37, n=218) and 1·2 mg liraglutide (−1·24%, −1·37 to −1·11, n=221) than with sitagliptin (−0·90%, −1·03 to −0·77, n=219). Estimated mean treatment differences for liraglutide versus sitagliptin were −0·60% (95% CI −0·77 to −0·43, p<0·0001) for 1·8 mg and −0·34% (−0·51 to −0·16, p<0·0001) for 1·2 mg liraglutide. Nausea was more common with liraglutide (59 [27%] patients on 1·8 mg; 46 [21%] on 1·2 mg) than with sitagliptin (10 [5%]). Minor hypoglycaemia was recorded in about 5% of participants in each treatment group.

Interpretation

Liraglutide was superior to sitagliptin for reduction of HbA_1c, and was well tolerated with minimum risk of hypoglycaemia. These findings support the use of liraglutide as an effective GLP-1 agent to add to metformin.

Funding

Novo Nordisk.

Introduction

The health-care burden of diabetes, especially type 2 diabetes mellitus, continues to increase. An estimated 285 million people worldwide have diabetes at present, and 439 million are expected to have diabetes by 2030.¹ Vascular complications are responsible for most of the associated morbidity, mortality, and excess costs.² Although good glycaemic control can decrease the risk of microvascular, and possibly macrovascular complications,³ many people with type 2 diabetes are not achieving glycaemic goals,⁴ partly because of the low efficacy and adverse side-effects of available drugs. New treatments with improved efficacy and fewer side-effects are needed.

Therapies targeting the incretin system are important for management of type 2 diabetes. Two principal incretin hormones—glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—are rapidly released after meals.⁵ Both hormones augment glucose-dependent insulin secretion; and GLP-1, but not GIP, also suppresses glucagon secretion, delays gastric emptying, and decreases food intake.⁵ GLP-1 and GIP are inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).⁵ Incretin-based therapies consist of two drug classes: GLP-1 receptor agonists, which have biological activity similar to GLP-1, but are resistant to DPP-4; and DPP-4 inhibitors, which prevent enzymatic inactivation of endogenous GLP-1 and GIP.⁶ Both classes increase insulin secretion and decrease glucagon secretion in a glucose-dependent manner, but with differences. GLP-1 receptor agonists (eg, exenatide, and the human GLP-1 analogue liraglutide) need injection. Glycaemic benefits of native GLP-1 or a GLP-1 receptor agonist (dosed to pharmacological concentrations) are accompanied by delayed gastric emptying and weight loss, but nausea initially occurs in some people.5, 6, 7 By contrast, oral DPP-4 inhibitors (eg, sitagliptin, vildagliptin, saxagliptin) increase active endogenous GLP-1 and GIP to more modest physiological concentrations.5, 6, 7 DPP-4 inhibitors do not delay gastric emptying, promote weight loss, or typically cause nausea, presumably because of lower GLP-1 concentrations.5, 6, 7

In clinical trials, agonists of the GLP-1 receptor and DPP-4 inhibitors improve glycaemic control when given as monotherapy or added to metformin, sulphonylureas, or thiazolidinediones; the intrinsic risk of hypoglycaemia is low but increases with sulphonylureas.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 Few direct comparisons of incretin-based therapies have been published, including long-term prospective comparison of a GLP-1 analogue and DPP-4 inhibitor. We aimed to compare the efficacy and safety of treatment with liraglutide or sitagliptin for 26 weeks in individuals with type 2 diabetes who did not achieve adequate glycaemic control with metformin.