TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Lancet. 2018 Nov 24;392(10161):2269-2279. doi: 10.1016/S0140-6736(18)32328-6. Epub 2018 Oct 4.
There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of lorcaserin on diabetes prevention and remission.
In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264.
Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0-3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3-2·9) for those with diabetes, 2·8 kg (2·5-3·2) for those with prediabetes, and 3·3 kg (2·6-4·0) for those with normoglycaemia (p<0·0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8·5%] of 2015 vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63-0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97-1·49; p=0·093). In patients with diabetes, lorcaserin resulted in a reduction of 0·33% (95% CI 0·29-0·38; p<0·0001) in HbA compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054).
Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health.
Eisai.
体重与糖尿病风险之间存在直接关系。洛卡塞嗪是一种选择性 5-羟色胺 2C 受体激动剂，可抑制食欲，已被证明可促进肥胖或超重患者的持续体重减轻。我们旨在评估洛卡塞嗪在预防和缓解糖尿病方面的长期效果。
在这项在 8 个国家进行的随机、双盲、安慰剂对照试验中，我们招募了超重或肥胖（体重指数≥27kg/m）且有或有动脉粥样硬化性血管疾病风险的患者。合格的患者年龄在 40 岁或以上；有动脉粥样硬化性血管疾病风险的患者年龄必须在 50 岁或以上，且患有糖尿病和至少另外一个风险因素。患者被随机分配接受洛卡塞嗪（每日两次，每次 10mg）或匹配的安慰剂。此外，所有患者都可以根据生活方式改变参加标准化的体重管理计划。以基线时患有糖尿病前期的患者为对象，将主要代谢疗效终点定义为新发糖尿病的时间。所有没有糖尿病的患者的新发糖尿病、患有糖尿病前期的患者达到正常血糖水平和患有糖尿病的患者糖化血红蛋白（HbA）变化的次要疗效结果是预先设定的。低血糖是预先设定的安全性结果。采用 Cox 比例风险模型进行时间到事件分析，按意向治疗进行分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT02019264。
2014 年 2 月 7 日至 2015 年 11 月 20 日期间，共有 12000 名患者被随机分配至洛卡塞嗪或安慰剂组（每组 6000 名患者），并随访中位数为 3.3 年（IQR 3.0-3.5）。基线时，6816 名患者（56.8%）患有糖尿病，3991 名（33.3%）患有糖尿病前期，1193 名（9.9%）血糖正常。在 1 年时，与安慰剂相比，服用洛卡塞嗪的患者体重减轻了 2.6kg（95%CI 2.3-2.9），患有糖尿病的患者体重减轻了 2.8kg（2.5-3.2），患有糖尿病前期的患者体重减轻了 3.3kg（2.6-4.0），血糖正常的患者体重减轻了（所有分析均 p<0.0001）。洛卡塞嗪可降低糖尿病前期患者的糖尿病发病风险 19%（2015 年 172 名[8.5%]与 1976 年 204 名[10.3%]；危险比 0.81，95%CI 0.66-0.99；p=0.038），也可降低无糖尿病患者的糖尿病发病风险 23%（2615 年 174 名[6.7%]与 2569 年 215 名[8.4%]；0.77，0.63-0.94；p=0.012）。洛卡塞嗪可使糖尿病前期患者的达标率略有升高（185 名[9.2%]与 151 名[7.6%]；1.20，0.97-1.49；p=0.093）。在患有糖尿病的患者中，与安慰剂相比，洛卡塞嗪可使 HbA 在 1 年时降低 0.33%（95%CI 0.29-0.38；p<0.0001），基线时平均 HbA 为 53mmol/mol（7.0%）。在基线时患有糖尿病的患者中，严重低血糖合并严重并发症很少见，但服用洛卡塞嗪时更常见（12 例[0.4%]与 4 例[0.1%]；p=0.054）。
洛卡塞嗪可降低肥胖和超重患者的糖尿病发病风险，诱导血糖控制正常，减少微血管并发症的发生，支持洛卡塞嗪作为生活方式改变的辅助手段，用于慢性管理体重和代谢健康。
卫材。
