Elsevier

The Lancet

Volume 375, Issue 9733, 26 June–2 July 2010, Pages 2223-2233
The Lancet

Articles
Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(10)60407-2Get rights and content

Summary

Background

Correction of hyperglycaemia and prevention of glucotoxicity are important objectives in the management of type 2 diabetes. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces renal glucose reabsorption in an insulin-independent manner. We assessed the efficacy and safety of dapagliflozin in patients who have inadequate glycaemic control with metformin.

Methods

In this phase 3, multicentre, double-blind, parallel-group, placebo-controlled trial, 546 adults with type 2 diabetes who were receiving daily metformin (≥1500 mg per day) and had inadequate glycaemic control were randomly assigned to receive one of three doses of dapagliflozin (2·5 mg, n=137; 5 mg, n=137; or 10 mg, n=135) or placebo (n=137) orally once daily. Randomisation was computer generated and stratified by site, implemented with a central, telephone-based interactive voice response system. Patients continued to receive their pre-study metformin dosing. The primary outcome was change from baseline in haemoglobin A1c(HbA1c) at 24 weeks. All randomised patients who received at least one dose of double-blind study medication and who had both a baseline and at least one post-baseline measurement (last observation carried forward) were included in the analysis. Data were analysed by use of ANCOVA models. This trial is registered with ClinicalTrials.gov, number NCT00528879.

Findings

534 patients were included in analysis of the primary endpoint (dapagliflozin 2·5 mg, n=135; dapagliflozin 5 mg, n=133; dapagliflozin 10 mg, n=132; placebo, n=134). At week 24, mean HbA1c had decreased by −0·30% (95% CI −0·44 to −0·16) in the placebo group, compared with −0·67% (−0·81 to −0·53, p=0·0002) in the dapagliflozin 2·5 mg group, −0·70% (−0·85 to −0·56, p<0·0001) in the dapagliflozin 5 mg group, and −0·84% (−0·98 to −0·70, p<0·0001) in the dapagliflozin 10 mg group. Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin (2–4%) and placebo groups (3%). Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (2·5 mg, 11 patients [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) than in the placebo group (seven [5%]). 17 patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group).

Interpretation

Addition of dapagliflozin to metformin provides a new therapeutic option for treatment of type 2 diabetes in patients who have inadequate glycaemic control with metformin alone.

Funding

Bristol-Myers Squibb and AstraZeneca.

Introduction

From 2000 to 2010, the estimated prevalence of diabetes increased from 121 million to 285 million people, representing 6·4% of the global adult population.1 Type 2 diabetes, which accounts for more than 90% of all diabetes, is a complex progressive metabolic derangement associated with comorbidities such as obesity, hypertension, and hyperlipidaemia.2 Strategies for selection of antidiabetic agents aim to balance effectiveness, safety, tolerability, and non-glycaemic effects that can reduce long-term complications, notably microvascular and premature macrovascular disease. Despite efforts to intensify management, many adult patients with type 2 diabetes do not achieve glycaemic control.3, 4, 5, 6

Pharmacological treatment usually begins with metformin, which together with lifestyle management is a validated first-step approach.7, 8 Although metformin is often initially effective as monotherapy, the progressive nature of diabetes frequently requires additional therapies.9 As β-cell function deteriorates further, selection of agents and management of their side-effects become increasingly more difficult. For example, sulphonylureas and insulin cause weight gain and hypoglycaemia; thiazolidinediones cause weight gain and are contraindicated in patients with heart failure; and use of α-glucosidase inhibitors is limited by gastrointestinal side-effects. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are not associated with weight gain or hypoglycaemia, but assessment of long-term use is needed. There is also a necessity for additional treatments that avoid side-effects and address some of the broader metabolic issues of diabetes without dependency on β-cell function.10, 11

As part of the quest for new agents, research has expanded into new targets of glycaemic control that are not directly focused on insulin-dependent mechanisms. Sodium-glucose cotransporter 2 (SGLT2), located mainly in segment S1 of the proximal tubule of the kidney nephron, reabsorbs most glucose filtered by the glomerulus.12 Dapagliflozin is a stable and highly selective inhibitor of SGLT2.13, 14 Binding of dapagliflozin to SGLT2 inhibits renal glucose reabsorption, promotes urinary glucose excretion, and thereby lowers hyperglycaemia by an insulin-independent mechanism.15, 16, 17, 18 Since the glucotoxicity caused by chronic hyperglycaemia is a major source of microvascular complications and contributes to macrovascular disease, glycaemia per se is a very legitimate therapeutic target for treatment of type 2 diabetes.

This study assessed the efficacy and safety of dapagliflozin when added to metformin in adult patients with type 2 diabetes who are not adequately controlled with metformin alone. We report the results of 24 weeks of treatment.

Section snippets

Study design and patients

This phase 3, randomised, double-blind, parallel-group, placebo-controlled trial was undertaken at 80 sites (30 in the USA, 21 in Canada, 11 in Argentina, ten in Mexico, and eight in Brazil). Patients were accrued from Sept 18, 2007, to April 10, 2008. The study complied with the Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by institutional review boards and independent ethics committees for participating centres. All participants provided written informed

Results

Figure 1 shows the trial profile. The 24-week data cutoff date was Nov 4, 2008. Table 1 shows demographic and baseline characteristics of study participants. All randomised patients took at least one dose of study medication. 88% of randomised patients completed the trial: the most common reasons for discontinuation during the double-blind period were withdrawal of consent and loss to follow-up (figure 1).

Reductions in HbA1c percentage after 24 weeks were significantly greater in the

Discussion

Dapagliflozin offers a novel insulin-independent approach to lowering hyperglycaemia and improving metabolic control of type 2 diabetes: it reduces renal glucose reabsorption by inhibition of SGLT2 transporters in the proximal tubule of the kidney, resulting in urinary glucose excretion. Since SGLT2 inhibition is independent of β-cell function or insulin sensitivity, this treatment approach could have applications throughout the natural history of diabetes.

Patients in this trial did not have

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