Dapagliflozin significantly reduced hemoglobin A1c levels compared with placebo in a phase III, multicenter, randomized, double-blind, placebo-controlled trial involving 534 patients with type 2 diabetes inadequately controlled with metformin alone.
The study, reported online in The Lancet on June 24, was funded by dapagliflozin codevelopers Bristol-Myers Squibb and AstraZeneca. The drug is a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2), which is located in the proximal tubule of the kidney nephron and functions to reabsorb most of the glucose filtered by the glomerulus. By binding to SGLT2 and inhibiting renal glucose reabsorption, dapagliflozin promotes urinary glucose excretion and reduces blood glucose levels independently of beta cell function or insulin sensitivity, Dr. Clifford J. Bailey and his associates explained (Lancet 2010;375:2223-33).
A total of 546 patients were randomized to either 2.5-mg, 5.0-mg, or 10.0-mg once-daily doses of dapagliflozin or placebo for 24 weeks, in addition to their usual metformin doses. Among the 534 who completed the trial, reductions in HbA1c were significantly greater in the dapagliflozin groups, with mean reductions from baseline of 0.67, 0.70, and 0.84 percentage points with the 2.5-, 5.0-, and 10.0-mg doses, respectively, compared with 0.30 for placebo.
More patients in the dapagliflozin groups achieved an HbA1c value of less than 7.0% at week 24 than did those in the placebo group, with the difference reaching statistical significance for the 5.0- and 10.0-mg doses (37.5% and 40.6%, respectively, vs. 25.9% for placebo). Differences in plasma fasting glucose concentrations were notable by week 1 in the dapagliflozin groups, and by week 24 were significant for all three doses (reductions of 18-23 mg/dL compared with 6 mg/dL with placebo).
Weight loss was also greater with dapagliflozin, compared with those assigned to placebo. At week 24, the 2.5-, 5.0-, and 10.0-mg groups had lost 2.2, 3.0, and 2.9 kg, respectively, compared with 0.9 kg for placebo patients. This reduction is potentially attributable to the loss of excess energy through glucose excretion in the urine, said Dr. Bailey, of Aston University, Birmingham, U.K., and his associates.
Urinary glucose excretion increased in all of the dapagliflozin groups, whereas creatinine remained constant, the investigators noted.
There were no deaths during the study, and overall adverse events leading to discontinuation were less frequent with dapagliflozin than placebo. There were no major hypoglycemic events.
Signs, symptoms, and other reports suggestive of urinary tract infections were not increased with dapagliflozin, but reports of those suggesting genital infections were: These were reported by 8%-13% in the dapagliflozin groups compared with 5% in the placebo group. The increased rate occurred in both men and women. All were of mild or moderate intensity and resolved with treatment, and none led to study discontinuation. Genital infections are not uncommon in patients with diabetes and can be appropriately managed with better appreciation of those at higher risk, Dr. Bailey and his associates pointed out.
Serious adverse events were not associated with any particular group. No clinically meaningful changes in serum electrolytes occurred in any of the groups, and abnormalities in serum sodium and serum potassium were rare and transient. No alterations were seen in measures of renal function, including serum creatinine. No apparent changes occurred in fasting lipid profiles with dapagliflozin other than greater mean HDL cholesterol and lower triglycerides compared with placebo, they noted.
In an accompanying editorial, Dr. Markolf Hanefeld and Dr. Thomas Forst pointed out that while dapagliflozin was “only moderately effective as an add-on drug in reducing glycemic load” in this patient population, “the only relevant adverse effect was a minor increase in genital infections.”
Dr. Hanefeld and Dr. Forst, of Technical University Dresden and Mainz Institute for Clinical Research and Development, Mainz, Germany, concluded that “the net balance of this novel group of oral antidiabetic drugs look promising.” Long-term trials should be designed with careful monitoring of urogenital infections on the basis of comparisons with established oral antidiabetic drugs, they recommended.
Aside from BMS and AZ, Dr. Bailey also has consulted for Merck Sharp & Dohme, Novo Nordisk, GlaxoSmithKline, and Takeda and has received research grants from Sanofi-Aventis. Three other study authors are employees of BMS, while BMS was the only disclosure for the fifth investigator. Dr. Hanefeld was a member of the steering committee for the RECORD trial, funded by GSK, and the ORIGIN trial, funded by Sanofi-Aventis. He has also received honoraria from several other companies that manufacture diabetes products, as has Dr. Forst.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
一项多中心、随机、双盲、安慰剂对照、III期试验表明，在经二甲双胍单药治疗后血糖控制不佳的534例2型糖尿病患者中，达格列嗪(dapagliflozin)较安慰剂可显著降低患者的血红蛋白A1c (HbA1c)水平。
6月24日，《柳叶刀》(The Lancet) 在线发表了这项试验的结果，该试验是由达格列嗪的合作开发商百时美-施贵宝(BMS)和阿斯利康(AZ)共同资助的。Clifford J. Bailey 博士及其同事解释道，达格列嗪是一种选择性钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂，SGLT2位于肾单位近端小管中，其功能是重吸收经肾小球滤过的大部分葡萄糖。达格列嗪通过与SGLT2结合并抑制肾脏对葡萄糖的重吸收，从而促进葡萄糖经尿液排泄并降低血糖水平，并且该作用与β细胞功能或胰岛素敏感性无关(Lancet 2010;375:2223-33)。
该试验将总共546例患者随机分组，在其常用二甲双胍剂量的基础上分别接受2.5 mg、5.0 mg或10.0 mg(每日1次)的达格列嗪或安慰剂，连续服用24周。在完成了试验的534例患者中，所有达格列嗪治疗组的HbA1c下降幅度均显著大于安慰剂组，2.5 mg、5.0 mg和10.0 mg剂量组的HbA1c相对于基线分别平均下降了0.67、0.70和0.84个百分点，而安慰剂组只下降了0.30个百分点。
在所有达格列嗪治疗组中，第24周达到HbA1c测值<7.0%这一目标的患者人数均多于安慰剂组，5.0 mg和10.0 mg剂量组与安慰剂组相比的差异达到了统计学显著性水平(分别为37.5%和40.6% 对安慰剂组的25.9%)。第1周达格列嗪治疗组较安慰剂组在血浆空腹葡萄糖浓度方面出现差异，第24周所有3个剂量组均表现出显著差异(下降18~23 mg/dl，而安慰剂组仅下降6 mg/dl)。
较之安慰剂组，接受了达格列嗪治疗的患者其体重的下降幅度也更加明显。第24周，2.5 mg、5.0 mg和10.0 mg剂量组患者的体重分别下降了2.2 kg、3.0 kg 和2.9 kg，而安慰剂组仅下降了0.9 kg。英国伯明翰阿斯顿大学的Bailey 博士及其同事说，这可能归因于多余的能量通过葡萄糖经尿液排泄而丢失了。
研究者指出，所有达格列嗪治疗组经尿液排泄的葡萄糖均有所增加，而肌酐则维持不变。
试验期间，没有出现任何死亡病例，并且达格列嗪治疗组导致了试验终止的总不良事件发生率也低于安慰剂组。没有出现任何重大低血糖事件。
在达格列嗪治疗组中，提示尿路感染的体征、症状以及其他报告并无增加，但提示生殖器感染的报告有所增加：达格列嗪治疗组有8%~13%的患者报告了生殖器感染事件，而安慰剂组仅5%。无论男女，生殖器感染的发生率均有所增加。但所有事件的强度均为轻度或中度，经治疗后均已痊愈，并且均未导致试验终止。Bailey 博士及其同事指出，在糖尿病患者中，生殖器感染并不少见，并且只要重视对高危患者的评价，这是可以得到恰当处理的。
研究者指出，所有治疗组均与严重不良事件无关。也没有任何一个组的血清电解质出现任何有临床意义的变化，血清钠和血清钾出现异常的情况很少见，并且也是一过性的。包括血清肌酐在内的肾功能指标无改变。在接受了达格列嗪治疗的患者中，空腹血脂指标无明显改变，并且平均高密度脂蛋白(HDL)胆固醇水平高于安慰剂组，甘油三酯水平低于安慰剂组。
Markolf Hanefeld博士和Thomas Forst博士在随刊编者按中指出，虽然达格列嗪对于这个患者人群“只是在作为添加药物时在降低血糖负荷方面有一定的效果，但唯一与之相关的不良反应只有生殖器感染的发生率略有增加。”
德国美因茨德累斯顿工业大学和美因茨临床研发研究院的Hanefeld博士和Forst博士总结道：“从权衡利弊来看，这一类新型口服降糖药看似前景光明。”他们建议，将来还应设计开展长期试验，将其与已经确立的口服降糖药对照，并在此基础上对生殖器感染进行密切监测。
除BMS和AZ外，Bailey博士还为默沙东、诺和诺德、葛兰素史克(GSK)和日本武田制药提供咨询服务，并接受了赛诺菲-安万特提供的研究经费。另外3名作者为BMS员工，而第5名研究者声明只与BMS存在关系。Hanefeld博士是GSK资助的RECORD试验以及赛诺菲-安万特资助的ORIGIN试验的指导委员会成员之一。Hanefeld博士和Forst博士接受了生产糖尿病产品的其他数家企业提供的酬金。
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