Elsevier

The Lancet

Volume 380, Issue 9840, 4–10 August 2012, Pages 475-483
The Lancet

Articles
2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial

https://doi.org/10.1016/S0140-6736(12)60691-6Get rights and content

Summary

Background

Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride).

Methods

In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycated haemoglobin A1c (HbA1c) 6·5–10·0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1–4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA1c from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA1c measurement, and had at least one on-treatment HbA1c measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284.

Findings

777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA1c (baseline 7·69% [SE 0·03] in both groups) were similar in the linagliptin (–0·16% [SE 0·03]) and glimepiride groups (–0·36% [0·03]; difference 0·20%, 97·5% CI 0·09–0·30), meeting the predefined non-inferiority criterion of 0·35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p<0·0001) or severe hypoglycaemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs 26 patients; relative risk 0·46, 95% CI 0·23–0·91, p=0·0213).

Interpretation

The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative effectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The findings could improve decision making for clinical treatment when metformin alone is insufficient.

Funding

Boehringer Ingelheim.

Introduction

Diabetes mellitus, mainly the type 2 form, is a major public health issue globally and affected about 347 million individuals worldwide in 2008 (almost 10% of adults).1 Afflicting 138 million people in China and India alone, diabetes exerts a substantial morbidity burden in developing countries as well as industrialised nations, and ageing and population growth is likely to intensify this burden.1 Metformin is widely accepted as the first-line oral agent in the treatment of type 2 diabetes.2 However, many patients on metformin monotherapy are unable to achieve or maintain long-term glycaemic control, mostly because of a progressive loss of insulin secretory function.3 When metformin alone is insufficient, the choice of second-line treatment is challenging and there is no clear consensus on the optimum approach, although algorithms provide some guidance.2, 4 Efforts are ongoing to address this comparative-evidence gap—notably, the planned GRADE trial, although this study will not produce results for about 8 years.

At present, the most common next step in treatment when a patient is not reaching their glycated haemoglobin A1c (HbA1c) target is to add a sulphonylurea.2 This combination treatment offers improvements in glycaemic control, but is associated with hypoglycaemia and weight gain, both of which can have a potentially negative effect on cardiovascular risk, quality of life, and treatment adherence.5, 6, 7 Until evidence emerges from long-term studies, short-term head-to-head trials of sulphonylureas versus other individual antihyperglycaemic agents could provide data to inform treatment decisions. Linagliptin is an oral, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor licensed in 2011 that improves glycaemic control by preventing the rapid degradation of incretin hormones, with a resulting glucose-dependent increase in stimulation of insulin secretion and inhibition of glucagon secretion. HbA1c reductions, ranging from 0·6% to 0·9%, with a low risk of hypoglycaemia and no weight gain, were reported when linagliptin was given either alone8 or in combination with metformin9 in patients with type 2 diabetes.

The aim of this hypothesis-driven study was to assess the long-term efficacy and safety of linagliptin compared with a commonly used sulphonylurea (glimepiride) as second-line treatment in participants with type 2 diabetes inadequately controlled on metformin. Additionally, as part of a large phase 3 programme, this study prospectively assessed cardiovascular safety.

Section snippets

Study design and patients

This randomised, double-blind, parallel-group, active-controlled, non-inferiority trial was undertaken at 209 sites that included primary and secondary care centres in 16 countries (Bulgaria, Denmark, France, Germany, Hong Kong, Hungary, India, Ireland, Italy, Netherlands, Norway, Poland, South Africa, Sweden, the UK, and the USA). The study consisted of a 2-week run-in with or without a previous 6-week washout period, followed by 104-week double-blind treatment, and 1-week follow-up.

Study

Results

The trial took place between Feb 12, 2008, and Dec 21, 2010. 1552 participants were randomly assigned to receive either linagliptin (n=777) or glimepiride (n=775) in addition to metformin (figure 1). Of 1551 patients who received study drug, 1191 (77%) completed the 2-year study (587 [76%] of 777 on linagliptin vs 604 [78%] of 775 on glimepiride). The primary reasons for discontinuation were adverse events and lack of therapeutic effect. Loss to follow-up was similarly low in both treatment

Discussion

This long-term study showed that in patients with type 2 diabetes inadequately controlled on metformin, linagliptin was non-inferior to glimepiride in lowering HbA1c (treatment difference within the prespecified non-inferiority margin of 0·35%), but was associated with significantly less hypoglycaemia and weight loss. Linagliptin was also associated with significantly fewer cardiovascular events compared with glimepiride (panel).

Much evidence strongly suggests a beneficial effect of good

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