Articles
Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial

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Summary

Background

The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes.

Methods

TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856.

Findings

Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups.

Interpretation

In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events.

Funding

Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.

Introduction

Cardiovascular disease is the most common cause of morbidity and mortality in patients with diabetes.1 Findings from the UK Prospective Diabetes Study (UKPDS) have shown that good glycaemic control established at the time of diagnosis can reduce the incidence of cardiovascular events and microvascular complications in patients with type 2 diabetes.2, 3 However, maintaining appropriate glucose control over time is difficult. In UKPDS, only 50% of patients had attained satisfactory glucose control with monotherapy (metformin, sulfonylurea, or insulin) 3 years after diagnosis, the proportion decreasing to 25% after 9 years.4

Research in context

Evidence before this study

We searched PubMed, ScienceDirect, and the Cochrane Library for articles published in English between Jan 1, 1997, and Dec 31, 2007, with search terms “type 2 diabetes”, “metformin”, “pioglitazone”, “sulfonylureas”, and “cardiovascular events”, or “cardiovascular disease” or “cardiovascular mortality”, or “glycated haemoglobin”, or “treatment failure” or “heart failure”. In patients with type 2 diabetes, metformin is the recommended first-line drug treatment, but there is considerable uncertainty as to the best add-on treatment in patients whose glycaemia is inadequately controlled with metformin alone. Sulfonylureas are the most widely used choice, but their cardiovascular safety is uncertain. Pioglitazone could represent a suitable alternative, in view of the evidence supporting its protective effect on ischaemic cardiovascular disease, although concerns remain about possible clinically relevant side-effects. The cardiovascular effects, glycaemic effects, and safety of these therapeutic approaches have not previously been compared in a long-term, head-to-head trial.

Added value of this study

The TOSCA.IT trial provides a direct comparison of two widely available and affordable second-line treatment regimens for patients with type 2 diabetes. The patients enrolled represent an almost primary prevention population that is usually neglected in trials done to investigate the cardiovascular effects of glucose-lowering drugs. The results showed that, if used appropriately, in terms of patient selection and dose, both pioglitazone and a sulfonylurea (glimepiride or gliclazide) as add-on to metformin are associated with similarly low rates of cardiovascular events and few clinically relevant side-effects. Our findings also suggest that pioglitazone could be advantageous compared with sulfonylureas in terms of durability of glycaemic control and frequency of hypoglycaemia.

Implications of all the available evidence

Our results lend support to current treatment guidelines for type 2 diabetes, particularly in relation to patients with a low cardiovascular risk, by suggesting that both pioglitazone and sulfonylureas (glimepiride or gliclazide) are suitable alternatives as add-on treatment when metformin alone fails to provide adequate glycaemic control.

The progressive nature of type 2 diabetes requires a stepwise therapeutic approach combining different antihyperglycaemic drugs. Currently, metformin is the recommended first-line drug, but there is considerable uncertainty about the best therapeutic option in patients whose glycaemia is inadequately controlled with metformin alone.5, 6 Sulfonylureas are very effective glucose-lowering drugs, which are still largely used in combination with metformin,7 despite their well-documented side-effects, particularly hypoglycaemia and weight gain. Because the cardiovascular safety of sulfonylureas has been questioned,8, 9 assessment of the cardiovascular effects of this drug class (as well as its long-term effect on glucose control and general safety) compared with other treatment strategies is needed.

Thiazolidinediones (glitazones) are glucose-lowering drugs that are associated with a minimal risk of hypoglycaemia and can ameliorate insulin resistance and cardiovascular risk factors; therefore, they have great potential for cardiovascular protection. Although rosiglitazone has been dismissed because of a purported increase in cardiovascular risk, pioglitazone has been shown to reduce ischaemic cardiovascular events in placebo-controlled studies of individuals with and without diabetes,10, 11 although concerns remain about its potential side-effects.12, 13, 14, 15

We undertook a pragmatic trial to compare, in usual clinical practice conditions, the long-term effects of a sulfonylurea or pioglitazone as add-on therapy to metformin in the treatment of patients with type 2 diabetes inadequately controlled with metformin monotherapy. The aim of the study was to compare the long-term effect of these two therapeutic options with respect to incidence of cardiovascular events, as well as their effects on glucose control and safety.

Section snippets

Study design and participants

The Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) was a pragmatic, multicentre, randomised, parallel-group, clinical trial done at 57 diabetes clinics in Italy. We used a multicentre prospective, randomised, open label, blinded endpoint (PROBE) study design. The ethics committees of the coordinating centre (Federico II University of Naples, Italy) and of each trial site approved the study protocol and all participants provided written informed

Results

Between Sept 18, 2008, and Jan 15, 2014, 4956 patients were screened and 3041 were randomly assigned to a treatment group although 13 of these patients were excluded because of protocol violation or because they had no baseline data. Therefore, 3028 patients were included in the intention-to-treat analysis (figure 1), with 1535 patients in the metformin plus pioglitazone group and 1493 in the metformin plus sulfonylureas group. In the metformin plus sulfonylureas group, 24 (2%) patients were

Discussion

In this long-term pragmatic trial, the incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) or pioglitazone as add-on to metformin in patients with type 2 diabetes inadequately controlled with metformin alone. Both treatments were effective overall and were not associated with high risk of clinically relevant side-effects; however, patients given pioglitazone had better durability of glycaemia control, less frequent hypoglycaemia, and higher

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