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.

中文翻译：

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二甲双胍控制不足的2型糖尿病患者中加入吡格列酮和磺脲类药物对心血管事件发生率的影响：一项随机，多中心试验

背景

对于仅使用二甲双胍治疗无法获得足够的血糖控制的2型糖尿病患者，最佳治疗方案存在争议。我们的目的是比较吡格列酮与磺脲类药物（除二甲双胍外）对2型糖尿病患者心血管事件的长期影响。

方法

TOSCA.IT是一项多中心，随机，实用的临床试验，从意大利的57家糖尿病诊所招募了50-75岁的2型糖尿病患者，二甲双胍单药治疗（每天2–3 g）治疗不足。通过置换组随机分配（区组大小10），按部位和既往心血管事件分层将患者随机分配（1：1），追加吡格列酮（15–45 mg）或磺酰脲类药物（5–15 mg格列本脲，2）根据当地惯例，应使用–6 mg格列美脲或30–120 mg格列齐特）。该试验没有盲目性，但事件裁决者并未意识到治疗的分配。使用Cox比例风险模型评估的主要结局是首次全因死亡，非致命性心肌梗塞，非致命性中风或紧急冠状动脉血运重建，在经过修改的意向性治疗人群中进行评估（所有随机分配的参与者均具有可用的基线数据，并且在纳入或排除标准方面未违反任何协议）。该研究已向ClinicalTrials.gov，编号NCT00700856。

发现

在2008年9月18日至2014年1月15日之间，随机分配了3028例患者并纳入分析。吡格列酮为1535，磺脲类药物为1493（格列本脲24 [2％]，格列美脲723 [48％]，格列齐特745 [50％]）。基线时，有335名（11％）参与者曾有过心血管事件。在中位随访57·3个月后，根据无效性分析，该研究提前终止。主要结果发生在接受吡格列酮治疗的105例患者（每100人年中1·5）和接受磺脲类药物的108例患者（每100人年中1·5）（危险比0·96，95％CI 0·74） –1·26，p = 0·79）。吡格列酮组的低血糖患者少于磺酰脲类患者（148 [10％] vs508 [34％]，p ＜0·0001）。两组均出现中等体重增加（平均少于2公斤）。治疗组之间心力衰竭，膀胱癌和骨折的发生率无显着差异。

解释

在这项长期的，实用的试验中，心血管事件的发生率与磺脲类药物（主要是格列美脲和格列齐特）和吡格列酮作为二甲双胍的附加治疗药物相似。尽管吡格列酮与较少的低血糖事件相关，但就疗效和不良事件而言，这两种广泛使用且负担得起的治疗方法都是合适的选择。

资金

意大利药品管理局，糖尿病患者赖斯卡和意大利糖尿病学会。