Lancet: 加用甘精胰岛素改善血糖控制效果优于西他列汀

费城(EGMN)——美国糖尿病学会(ADA)年会上公布的一项为期24周的多中心开放标记研究显示，对于二甲双胍控制不佳的2型糖尿病患者，加用基础甘精胰岛素改善血糖控制的效果优于加用西他列汀。然而，甘精胰岛素组患者的体重增幅较大且低血糖发生率显著增高，不过重度低血糖发生率极低。该研究同时在线发表于《柳叶刀》杂志(Lancet 2012 June 9 [doi:10.1016/S0140-6736(12)60439-5])。

这项随机研究首次在真实临床条件下既往未接受过胰岛素治疗的患者中，对甘精胰岛素和西他列汀这两种通常被视为二甲双胍二线追加治疗的降糖药物进行了比较。该研究由哥伦比亚哈维里亚那大学的Pablo J. Aschner博士及其同事进行，纳入年龄35~70岁、2型糖尿病病程6个月以上、经二甲双胍治疗后血红蛋白A1c水平仍为7%~11%的患者。250例患者随机接受甘精胰岛素治疗，初始剂量为0.2 U/kg体重，晚餐时或睡前用预填充注射笔注射，允许根据自我监测的血糖水平调节剂量。265例患者接受西他列汀治疗，每天早上口服固定剂量100 mg，研究期间不允许改变剂量。

两组的基线HbA1c水平均为8.5%。在研究期间，甘精胰岛素组和西他列汀组的HbA1c水平分别平均降低1.72%和1.13%，差异显著。24周时，甘精胰岛素组HbA1c水平≤7%的患者比例高于西他列汀组(68% vs. 42%)，HbA1c水平≤6.5%的患者比例也高于西他列汀组(40% vs. 17%)。此外，甘精胰岛素组患者自我监测的空腹血糖的降幅显著大于西他列汀组，校正后的平均组间差值为41.2 mg/dl。

研究期间，甘精胰岛素的剂量不断增加，基线时为0.19 U/kg，12周时增至0.45 U/kg，24周时增至0.5 U/kg，平均剂量为41.4 U/d。甘精胰岛素组患者的体重增加0.44 kg，西他列汀组体重降低1.08 kg，差异显著。甘精胰岛素组发生≥1次症状性低血糖的患者比例高于西他列汀组(54% vs. 46%)。甘精胰岛素组的低血糖事件发生率是西他列汀组的8.45倍(4.21起事件/病人-年 vs. 0.5起事件/病人-年)。虽然重度低血糖在两组中均罕见，但甘精胰岛素组重度低血糖的发生率是西他列汀组的3.4倍(1% vs. ＜1%)。其他治疗中出现的不良事件的发生率无组间差异。

研究者表示，总体而言，这些结果表明，通过平均追加0.5 U/kg剂量的甘精胰岛素可以达到血糖控制目标，并且体重增加不超过0.5 kg。该研究结果与既往同类研究结果一致。为了避免低血糖相关不良反应(如心血管疾病和相关死亡)，在进行强化降糖治疗的同时，还应定期自我血糖监测，病程长的高危患者更应如此。鉴于胰岛素优化血糖控制的效果较佳，早期使用较小剂量的胰岛素进行强化降糖治疗，可在减少低血糖风险的同时达到最佳的血糖控制，可能也有助于患者获得良好的远期预后。

在随刊述评中，阿姆斯特丹VU大学医学中心的Michaela Diamant博士指出，目前既不清楚在2型糖尿病早期使用基础胰岛素是否有助于改善远期预后，也不清楚早期使用胰岛素的疗效最终是否会被进行性体重增加和过多的低血糖事件所抵消，后两者可导致心血管风险增加、治疗费用增加及生活质量下降。

该研究获赛诺菲公司资助。Aschner博士为阿斯利康等多家公司担任顾问和讲师。Diamant博士为雅培等多家公司担任顾问和讲师。在Diamant博士牵头下，阿姆斯特丹VU大学医学中心从Amylin/礼来等公司获得研究资金，但Diamant博士本人未从这些活动中获得任何个人报酬。报酬均被转入一家机构研究基金会。

PHILADELPHIA (EGMN) – Introduction of basal insulin glargine for patients with type 2 diabetes who were uncontrolled on metformin was associated with improved glycemic control compared with the addition of sitagliptin in a 24-week, multicenter, open-label trial of more than 500 patients.

However, glargine was associated with a greater degree of weight gain and significantly greater rates of hypoglycemia, although severe hypoglycemia rates were rare, Dr. Pablo J. Aschner reported.

The study, funded by Sanofi, is the first randomized trial to compare two glucose-lowering treatment options that are often considered as second-line add-on treatment to metformin, in real-world conditions. “The results of this study support the option of introduction of basal insulin in patients with type 2 diabetes inadequately controlled by metformin, with the potential for long-term benefits arising from the achievement of optimum glycemic control early in the course of the disease,” said Dr. Aschner, an endocrinologist and clinical epidemiologist, and professor of endocrinology and director of research at Javeriana University Hospital, Bogotá, Colombia.

The findings were simultaneously published online (Lancet 2012 June 9 [doi:10.1016/S0140-6736(12)60439-5]).

In the Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-Naive Patients (EASIE) study, 250 patients were randomized to glargine in doses starting at 0.2 units per kg of body weight injected at dinner or bedtime with a prefilled pen, and titrated up or down based on self-monitored blood glucose levels. The 265 patients in the sitagliptin group received a fixed oral dose of 100 mg once daily taken in the morning and no changes in dose were allowed during the trial. The patients, 480 of whom completed the trial (227 glargine/253 sitagliptin), were aged 35-70 years, diagnosed with type 2 diabetes for at least 6 months, and had hemoglobin A1c values between 7% and 11% while on metformin therapy.

HbA1c, 8.5% for both groups at baseline, was reduced to a significantly greater extent with insulin glargine than with sitagliptin throughout the study, with mean reductions of 1.72 versus 1.13 percentage points. At 24 weeks, more patients in the glargine group had achieved A1c levels below 7% (68% versus 42%) compared with those in the sitagliptin group. The story was similar for HbA1c levels of less than 6.5% (40% vs. 17%). Patients in the glargine group also had significantly greater reductions in self-monitored fasting plasma glucose, with an adjusted mean difference between groups of 41.2 mg/dL, Dr. Aschner reported.

Glargine doses increased throughout the study, from 0.19 units/kg at baseline to 0.45 units/kg at 12 weeks and then leveling off to 0.5 units/kg at 24 weeks, at which point patients were taking an average of 41.4 units/day.

Body weight increased by 0.44 kg in the insulin glargine group and decreased by 1.08 kg in the sitagliptin group, a significant difference. More patients in the glargine group had one or more episodes of symptomatic hypoglycemia (46% vs. 54%). Glargine was associated with 8.45 times more hypoglycemic events per patient-year than was sitagliptin (4.21 vs. 0.5 events/patient-year). Severe hypoglycemia was 3.4-fold more common with glargine, although it was rare in both groups (1% with glargine and less than 1% with sitagliptin). The incidence of other treatment-emergent adverse events did not differ between the groups.

In all, Dr. Aschner noted, these findings suggest that glycemic control can be achieved with an average supplementary dose of 0.5 units per kg of insulin glargine and a weight gain of less than 0.5 kg. The results of this study are in general agreement with previous results for both insulin glargine and sitagliptin, he added.

Intensive lowering of blood glucose should be accompanied by structured self-monitoring of blood glucose, especially in high-risk people with long disease duration, in an attempt to avoid hypoglycemia-related adverse effects such as cardiovascular disease and related death, Dr. Aschner advised.

“In view of the possible long-term benefits of intensive lowering of blood glucose and the superior efficacy of insulin to optimize glycemic control, strong arguments could be made to use insulin early when the dose is expected to be fairly low, with a reduced risk of hypoglycemia,” he concluded.

This study was funded by Sanofi. Dr. Aschner has served on advisory boards for AstraZeneca, Eli Lilly & Co, GlaxoSmithKline, Janssen, Merck, Sharpe & Dohme, Novartis, and Sanofi and on speakers’ bureaus for AstraZeneca, Eli Lilly & Co, Merck, Sharpe & Dohme, Novartis, and Sanofi.

Long-Term Advantage of Early Insulin Still Unproven

In type 2 diabetes, progressive decline of beta-cell function leads to deterioration of glycemic control, necessitating intensification of blood glucose–lowering therapy during the course of the disease, said Dr. Michaela Diamant of the Diabetes Centre, VU University Medical Centre, Amsterdam. Existing treatment algorithms advocate stepwise escalation of therapy, starting with metformin and subsequently adding other oral agents or insulin when glycated hemoglobin A1c exceeds the treatment target. To date, however, there is insufficient evidence to guide clinicians in choice of the second agent after metformin, she said
An early start of insulin in type 2 diabetes has been advocated, because intensive insulin therapy immediately after diagnosis was shown to normalize blood glucose, preserve beta-cell function, and induce disease remission. In clinical practice, however, insulin treatment is often postponed because of barriers perceived by patients and health care providers to initiation of insulin. In these cases, various combinations of oral agents are prescribed, often at the cost of good glycemic control, Dr. Diamant noted.

Since sulphonylurea use is associated with early treatment failure, weight gain, and hypoglycemia risk, dipeptidyl peptidase-4 (DPP-4) inhibitors are increasingly used. Presently, whether these agents can sustain glycemic control in the long term and improve outcomes in patients with type 2 diabetes is unknown, she said.

In the current trial, insulin glargine resulted in a greater HbA1c reduction than did sitagliptin, with a mean adjusted difference of –0·59%. Significantly more patients in the insulin glargine group reached the prespecified HbA1c targets of both 7% and 6.5% than in the sitagliptin group.

A small increase in body weight was noted with insulin glargine use, whereas sitagliptin decreased body weight. The number of symptomatic as well as severe hypoglycemic episodes was greater with insulin glargine than with sitagliptin treatment, she noted.

With its very short duration and design, this study can only confirm the observations by others showing that addition of basal insulin, when dosed properly, to ongoing metformin monotherapy is more efficacious in lowering HbA1c than is any currently available oral agent, Dr. Diamant said.

Most patients and caregivers prefer to postpone insulin treatment as long as possible. At present, it is unclear whether initiation of basal insulin in the early stage of type 2 diabetes translates into longer term outcome benefits or whether its early use is ultimately offset by progressive weight gain and more hypoglycemic events, both of which could result in increased cardiovascular risk, higher cost, and poor quality of life.

The anticipated results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, comparing insulin glargine treatment in patients with dysglycemia and early type 2 diabetes with usual care for more than 7 years, will hopefully provide some answers to these questions, she said.

Dr. Diamant disclosed that she serves on advisory boards for Abbott, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk, and Poxel Pharma, is a consultant for Sanofi, and is a speaker for Eli Lilly, MSD, and Novo Nordisk. Through her, VU University Medical Centre receives research grants from Amylin/Eli Lilly, MSD, Novo Nordisk, and Sanofi, but she has received no personal payments in connection with any of these activities. The payments are transferred to an institutional research foundation.