Lancet:二甲双胍追加艾塞那肽效果优于追加格列美脲

费城(EGMN)——美国糖尿病学会(ADA)年会上公布的一项开放标记随机对照研究显示，对于经二甲双胍治疗失败的2型糖尿病患者，每日2次艾塞那肽预防血糖恶化的作用优于格列美脲。该研究同时发表于《柳叶刀》杂志(Lancet)(2012 June 9 [doi:10.1016/S0140-6736[12]60479-6])。

在这项研究中，维也纳Rudolfstiftung医院的Guntram Schernthaner博士及其同事从欧洲14个国家的128个中心入选1,029例2型糖尿病患者，将其随机分入艾塞那肽组(初始剂量5 mcg，每日2次，连用4周，此后为10 mcg，每日2次，直至研究结束)和格列美脲组(给药方案由医生决定)。意向治疗人群包括艾塞那肽组490例患者和格列美脲组487例患者。

患者服用二甲双胍的中位剂量为2,000 mg/d。艾塞那肽和格列美脲的平均剂量分别为17.4 mcg/d和2.0 mg/d。两组的平均疗程均约为2年。艾塞那肽组和格列美脲组的平均基线血红蛋白A_1c水平分别为7.5%和7.4%。

主要终点是至出现血糖控制不佳的时间。血糖控制不佳的定义为治疗3个月后HbA_1c水平≥9%，或治疗6个月后连续两次就诊(每次就诊之间间隔3个月)观察到HbA_1c水平≥7%。艾塞那肽组和格列美脲组分别有203例(41%)患者和262例(54%)患者达到这一终点，组间差异显著。其中，艾塞那肽组和格列美脲组分别有5例和7例患者HbA_1c≥9%，分别有198例和255例患者连续两次就诊HbA_1c均≥7%。与格列美脲组相比，艾塞那肽组血糖控制不佳的危险比(HR)为0.75。

艾塞那肽组和格列美脲组至出现HbA_1c控制不佳的中位时间分别为180周和142周。基线HbA_1c水平较高者的治疗失败风险更高，艾塞那肽组治疗失败的风险低于格列美脲组。艾塞那肽组HbA_1c≤7%(45% vs. 31%)和≤6.5%的患者比例(29% vs. 18%)均显著高于格列美脲组。艾塞那肽组治疗1年、2年和3年后的空腹血糖水平也显著低于格列美脲组。艾塞那肽组第2年和第3年的平均HbA_1c水平与格列美脲组相比存在显著差异，总体疗效较佳。艾塞那肽组患者自我监测的餐后血糖波动幅度显著小于格列美脲组。

两组各有5例患者死亡，但均与治疗无关。艾塞那肽组因不良事件停药的患者数量显著多于格列美脲组(49例 vs.17例)。然而，两组中因不良事件(主要为胃肠道不良事件)停药的患者数量仅在研究最初6个月内才有显著差异。

艾塞那肽组患者的收缩压降低，而格列美脲组未见降低，艾塞那肽组1~3年的收缩压比格列美脲组显著降低3.1 mmHg。艾塞那肽组患者的体重在基线至研究终点这段时间内降低3.32 kg，而格列美脲组患者的体重在这段时间内增加1.15 kg，差异显著。

艾塞那肽组出现低血糖的患者比例低于格列美脲组。艾塞那肽组研究期间任何类型低血糖的估计发生率平均为1.52次/年，而格列美脲组为5.32次/年。

研究者表示，对于二甲双胍控制不佳的2型糖尿病患者，常规的做法是在二甲双胍治疗基础上加用一种磺脲类药物。尽管这类药物可在短时间内快速起效，并且费用较低，但随着时间推移，可导致低血糖和血糖控制恶化。而像艾塞那肽这样的胰高血糖素样肽-1(GLP-1)受体激动剂在改善血糖控制的同时并不增加低血糖风险，并且有助于降低体重和改善心血管危险因素，因此可作为二甲双胍的追加药物。

该研究获礼来和Amylin制药公司资助。研究者声明与安进等多家公司存在联系。

 

PHILADELPHIA(EGMN)–Exenatide twice daily prevented glycemic deterioration better than did glimepiride in type 2 diabetes patients who had metformin failure in an open label, randomized, controlled trial.

Common practice for patients with type 2 diabetes who are inadequately controlled by metformin has been to add a sulphonylurea to the treatment regimen. Although these agents have a rapid short-term effect and are low cost, they are associated with hypoglycemia and worsening glycemic control over time.

Glucagonlike peptide–1 (GLP-1) receptor agonists, on the other hand, improve glycemic control with no increased risk of hypoglycemia, and are associated with weight loss and improvements in cardiovascular risk factors and can be used as alternative add-ons to metformin treatment, said Dr. Guntram Schernthaner at the annual scientific sessions of the American Diabetes Association.

“Up to now, EUREXA is the longest study undertaken with a GLP-1 receptor agonist, and could contribute substantially to decisions in clinical practice,” said Dr. Schernthaner of Rudolfstiftung Hospital in Vienna.

In this open-label, randomized, controlled European trial, 1,029 patients from 128 centers in 14 countries were randomized to exenatide twice daily (starting at 5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily for the remaining study period) or glimepiride per physician dosing practice. The intention-to-treat population comprised 490 patients in the exenatide group and 487 in the glimepiride group.

The study was simultaneously published in the Lancet (2012 June 9 [doi:10.1016/S0140-6736[12]60479-6]).

Patients were taking a median metformin dose of 2,000 mg/day. The mean exenatide dose was 17.4 mcg/day and the mean glimepiride dose was 2.0 mg/day. Average treatment time was about 2 years in both groups. Mean baseline hemoglobin A1c was 7.5% in the exenatide group and 7.4% in those randomized to glimepiride.

The primary outcome was time to inadequate glycemic control (defined as an HbA1c level greater than 9% after the first 3 months of treatment, or greater than 7% at two consecutive visits 3 months apart after the first 6 months). That end point was reached by 203 (41%) patients in the exenatide group, compared with 262 (54%) in the glimepiride group, a significant difference. These included 5 in the exenatide group and 7 in the glimepiride group who had an HbA1c of more than 9%, and 198 vs. 255 with HbA1c levels greater than 7% at two visits. The hazard ratio for inadequate glycemic control with exenatide, compared with glimepiride, was 0.75.

Median time to inadequate HbA1c control was 180 weeks with exenatide vs. 142 weeks with glimepiride. The risk of treatment failure was greater with higher baseline HbA1c, as was the reduction in risk with exenatide compared with glimepiride, Dr. Schernthaner reported.

Compared with those in the glimepiride group, significantly more patients in the exenatide group achieved HbA1c values lower than 7% (31% vs. 45%, respectively) and 6.5% or less (18% vs. 29%). Fasting glucose levels were also significantly lower in the exenatide group after year 1, year 2, and year 3 of treatment. There was an overall treatment effect in favor of the exenatide group, with significant differences between groups in mean HbA1c levels at years 2 and 3. Self-monitored postmeal excursions of blood glucose after meals were significantly lower in the exenatide group than in the glimepiride group.

Five patients in each treatment group died, but all deaths were from causes regarded as unrelated to the study treatment. Significantly more patients discontinued in the exenatide group than in the glimepiride group because of adverse events (49 vs.17). However, discontinuations due to adverse events mostly gastrointestinal were significantly different between treatments only in the first 6 months of study, Dr. Schernthaner said.

Systolic blood pressure decreased in patients in the exenatide group but not in the glimepiride group, resulting in a significant, 3.1-mm Hg difference between groups from year 1 to year 3. Body weight fell from baseline to end point in the exenatide group by 3.32 kg, while it rose by 1.15 kg in the glimepiride group, also a significant difference.

The proportion of patients reporting hypoglycemia was lower in patients in the exenatide group than in those in the glimepiride group. For hypoglycemia of any type during the study, the estimated mean rate was 1.52 episodes per year in the exenatide group, compared with 5.32 episodes per year in the glimepiride group, he reported.

Drug Has Lower Risk of Hypoglycemia

The stepwise approach to the management of type 2 diabetes starts with lifestyle interventions with the addition of one or more antidiabetic drugs, wrote Dr. Sten Madsbad in an editorial that accompanied the publication of the study findings. Most clinical guidelines indicate that metformin should be the first-line drug, but no consensus exists about additional use of other glucose-lowering drugs or insulin when glucose control deteriorates over time, he pointed out.

Therefore, physicians typically chose the second drug based on factors such as effectiveness in HbA1c reduction, safety, cost, and patient-specific factors such as effect on weight and tolerability, noted Dr. Madsbad of the department of endocrinology at the University of Copenhagen and its Hvidovre University Hospital.

With a follow-up of 3 years, the current study is so far the longest randomized trial to compare a GLP-1 receptor agonist with a commonly used treatment in type 2 diabetes. Overall, it indicates that exenatide twice daily is more effective than glimepiride in terms of several clinical parameters related to treatment of patients with type 2 diabetes, he wrote.

Strengths of the study are the long-term follow-up and the comparison between the frequently used glimepiride and a GLP-1 receptor agonist, according to Dr. Madsbad. Physicians are divided in their opinions about the safety and effectiveness of sulphonylureas, which potentiate insulin secretion and lead to a rapid improvement in glycemic control, but result in faster deterioration of glycemic control than do metformin or a glitazone. The adverse effects of sulphonylureas are predictable, with most patients gaining weight, and risk of hypoglycemia is higher than with metformin. Studies linking sulphonylureas with cardiovascular adverse effects are based on databases rather than on randomized trials, he noted.

As a drug class, GLP-1 receptor agonists improve glycemia by stimulating insulin secretion and the inhibition of glucagon release, but only when glucose concentrations are raised, thus conferring a lower risk of hypoglycemia than that noted with sulphonylureas, he wrote. Moreover, exenatide twice daily reduces postprandial glucose excursions, and the GLP-1 receptor agonist class of agents induce weight loss in most patients; however, they are associated with gastrointestinal side effects and have been linked to pancreatitis, although those data conflict.

Analyses of phase II and phase III trials with exenatide twice daily vs. placebo or insulin showed no evidence of cardiovascular harm with exenatide, and some data suggest they may be associated with a reduction in cardiovascular events. Dr. Madsbad noted that the U.S. Food and Drug Administration now requires the assessment of cardiovascular risks of new glucose-lowering drugs both before and after approval, and results of cardiovascular outcome studies for the different GLP-1 receptor agonists are expected after 2015.

EUREXA was funded by Eli Lilly and Amylin Pharmaceuticals. Dr. Schernthaner disclosed that he has been a consultant for and received honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly, Merck, Novartis, Poxel, Roche, Sanofi-Aventis, Novo Nordisk, Servier, and Takeda. Dr. Madsbad has been a consultant for, adviser to, and/or speaker for Novartis Pharma, Novo Nordisk, Merck Sharp & Dohme, Sanofi-Aventis, AstraZeneca, Johnson & Johnson, Roche, Mannkind, Boehringer-Ingelheim, Zeeland, Lilly, Intarcia Therapeutics, Schering-Plough, and Bristol-Myers Squibb.