Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study

Summary

Background

The evolving epidemic of type 2 diabetes has challenged health-care providers to assess the safety and efficacy of various diabetes prevention strategies. The CANOE (CAnadian Normoglycemia Outcomes Evaluation) trial investigated whether low-dose combination therapy would affect development of type 2 diabetes.

Methods

In this double-blind, randomised controlled trial undertaken in clinics in Canadian centres, 207 patients with impaired glucose tolerance were randomly assigned to receive combination rosiglitazone (2 mg) and metformin (500 mg) twice daily or matching placebo for a median of 3·9 years (IQR 3·0–4·6). Randomisation was computer-generated in blocks of four, with both participants and investigators masked to treatment allocation. The primary outcome was time to development of diabetes, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7·0 mmol/L or greater. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00116932.

Findings

103 participants were assigned to rosiglitazone and metformin, and 104 to placebo; all were analysed. Vital status was obtained in 198 (96%) participants, and medication compliance (taking at least 80% of assigned medication) was 78% (n=77) in the metformin and rosiglitazone group and 81% (n=80) in the placebo group. Incident diabetes occurred in significantly fewer individuals in the active treatment group (n=14 [14%]) than in the placebo group (n=41 [39%]; p<0·0001). The relative risk reduction was 66% (95% CI 41–80) and the absolute risk reduction was 26% (14–37), yielding a number needed to treat of 4 (2·70–7·14). 70 (80%) patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group (p=0·0002). Insulin sensitivity decreased by study end in the placebo group (median −1·24, IQR −2·38 to −0·08) and remained unchanged with rosiglitazone and metformin treatment (−0·39, −1·30 to 0·84; p=0·0006 between groups). The change in β-cell function, as measured by the insulin secretion-sensitivity index-2, did not differ between groups (placebo −252·3, −382·2 to −58·0 vs rosiglitazone and metformin −221·8, −330·4 to −87·8; p=0·28). We recorded an increase in diarrhoea in participants in the active treatment group compared with the placebo group (16 [16%] vs 6 [6%]; p=0·0253).

Interpretation

Low-dose combination therapy with rosiglitazone and metformin was highly effective in prevention of type 2 diabetes in patients with impaired glucose tolerance, with little effect on the clinically relevant adverse events of these two drugs.

Funding

GlaxoSmithKline.

Introduction

Several studies have conclusively shown that lifestyle changes1, b, 3, 4 and some pharmacological interventions1, 4, 5, 6, 7, 8 can substantially reduce the development of type 2 diabetes mellitus in individuals with impaired glucose tolerance (IGT; fasting glucose <7 mmol/L and postload glucose 7·8–11·0 mmol/L) or impaired fasting glucose (IFG; fasting glucose 6·1–6·9 mmol/L), or both. However, not all drug-based interventions are effective⁹ and, most recently, the use of the β-cell secretagogue nateglinide did not show any beneficial effect on the development of type 2 diabetes.¹⁰ Despite these largely positive findings, screening of at-risk populations with the implementation of either programmed lifestyle interventions or pharmacological therapies has not been widely embraced. Screening has not been adopted for many reasons, including unclear health economic benefits, difficulties in implementation of the lifestyle interventions in clinical practice, and the potential for adverse effects from the pharmacological interventions that have been shown to be effective.

The pathophysiology of type 2 diabetes is complex and involves at least two major abnormalities—namely, insulin resistance and impaired β-cell function.¹¹ In this context, interest has grown in use of combination therapies early in the management of diabetes to effectively target the underlying abnormalities that cause this common metabolic disorder. At the same time, the implementation of low-dose combination therapy in patients with type 2 diabetes could reduce the undesirable adverse effects associated with many oral antidiabetic agents.¹² These principles and considerations probably also apply to individuals who have not yet developed diabetes but have either IGT or IFG. However, until now there have been no studies assessing low-dose combination therapies for the prevention of type 2 diabetes.

The thiazolidinedione rosiglitazone, studied in the DREAM trial,⁶ effectively reduces the progression from IGT, IFG, or combined IGT and IFG to type 2 diabetes (60% relative risk reduction), and has durability (ADOPT study) in the context of monotherapy for recent onset (within 3 years) type 2 diabetes.¹³ A post-hoc analysis from the DREAM trial has indicated that this effect of rosiglitazone is probably secondary to improvement of β-cell function.¹⁴ However, at the recommended maximum doses, which were used in the DREAM and ADOPT studies, rosiglitazone was associated with an increased risk of undesirable outcomes—namely, weight gain, fluid retention, increased risk of heart failure, and bone fractures.6, 13 Metformin is a commonly used oral hypoglycaemic agent and is generally recommended as first-line therapy in most clinical practice guidelines for type 2 diabetes.¹⁵ However, metformin is associated with significant gastrointestinal side-effects, particularly when it is used at maximum recommended doses. In the Diabetes Prevention Program (DPP), metformin at a dose of 850 mg twice daily was moderately effective in prevention of progression to type 2 diabetes (31% relative risk reduction compared with placebo) but was associated with an increased rate of gastrointestinal side-effects compared with placebo (77·8 vs 30·7 events per 100 person-years).¹ This rate of gastrointestinal side-effects with metformin seems to be higher than that which is generally recorded in clinical practice.

Because thiazolidinediones and metformin have different mechanisms of action (increasing insulin sensitivity and reducing hepatic glucose production, respectively) and have both been shown to reduce the development of diabetes in patients with IGT, to establish whether this combination at half the maximum dose would provide a robust effect on diabetes prevention, while minimising undesirable side-effects, would be of interest. The CAnadian Normoglycemia Outcomes Evaluation (CANOE) trial assessed whether combination therapy with half the maximum dose of rosiglitazone and metformin on a background of a structured lifestyle intervention would prevent type 2 diabetes in individuals with IGT.