减肥药物对糖尿病靶点三连击

休斯敦——内分泌学会年会上公布的随机双盲Ⅲ期CONQUER试验(Lancet 2011;377:1341-52)的亚组分析结果显示，在接受苯丁胺/托吡酯缓释复方制剂治疗1年的肥胖2型糖尿病患者中，约有1/3达到以下糖尿病管理严格复合终点：体重相对基线减轻10%以上，HbA1c水平＜6.5%，收缩压＜130 mmHg。此外，在接受该复方制剂全剂量治疗的患者中，有40%达到严格程度次之的复合终点：体重减轻5%以上，HbA1c和收缩压靶值同前。

在这项亚组分析中，美国路易斯安那州彭宁顿生物医学研究中心的Donna H. Ryan博士及其同事对CONQUER试验2500例肥胖患者中的388例合并2型糖尿病者进行了分析。与CONQUER试验的所有患者一样，糖尿病患者也接受一个名为LEARN(生活方式、运动、态度、关系、营养)的结构化生活方式/行为调节方案，对体重进行管理。此外，他们还被随机分入3组，接受每日1次治疗：苯丁胺7.5 mg/托吡酯46 mg组(小剂量+生活方式组)、苯丁胺15 mg/托吡酯92 mg组(全剂量+生活方式组)、安慰剂组(单纯生活方式调节组)。这些患者的糖尿病控制相对较好，基线时使用的唯一抗糖尿病药物为二甲双胍。

Donna H. Ryan博士

56周时，安慰剂组、小剂量组和全剂量组分别有12%、27%和39%的患者达到以下复合终点：体重相对基线降低5%以上，HbA1c水平＜6.5%，收缩压＜130 mm Hg；分别有4%、14%和31%的患者达到体重降低10%以上的更为严格的复合终点，表明该复方制剂联合生活方式调节的有效性是单纯生活方式调节的8倍。3组患者的体重相对基线分别平均降低2%、7%和9%。为了达到复合终点，3组分别有12%、2%和0.6%的患者需要净增加抗糖尿病药物。

苯丁胺和托吡酯均已上市多年，在CONQUER糖尿病亚组中未观察到新的副作用。口干和感觉异常在小剂量组中的发生率均为8%，便秘发生率为15%。由于副作用与剂量相关，因此如果苯丁胺/托吡酯复方制剂获批上市，建议的初始剂量很可能为苯丁胺7.5 mg/托吡酯46 mg。托吡酯是一种已知的致畸药物，妊娠期间每1,000例暴露可能发生4~5例腭裂，因此苯丁胺/托吡酯复方制剂将被列为X类药。Ryan博士表示，基于来自美国食品药品管理局(FDA)的良好反馈，预期该复方制剂(商品名Qnexa)将在年底前或最快7月中旬获准上市，适用于体重指数(BMI)≥30 kg/m2的患者或BMI≥27 kg/m2且具有合并症(如2型糖尿病)的患者。

Ryan 博士是开发Qnexa的Vivus公司的科学顾问，但不持有该公司股权。

爱思唯尔  版权所有

By: BRUCE JANCIN, Clinical Endocrinology News Digital Network

HOUSTON – Nearly one-third of obese patients who had type 2 diabetes and were randomized to an extended-release formulation of phentermine plus topiramate for 1 year achieved a rigorous composite diabetes management end point comprising greater-than-10% weight loss, an HbA1c level lower than 6.5%, and systolic blood pressure lower than 130 mm Hg.

Moreover, almost 40% of patients who were randomized to the full dose of the drug combo achieved a less-rigorous trifecta consisting of the same blood pressure and HbA1c targets, plus a greater-than-5% weight loss, Dr. Donna H. Ryan reported at the annual meeting of the Endocrine Society.

Based upon favorable feedback from the Food and Drug Administration, she expects the combination drug (brand name, Qnexa) will receive marketing approval before year’s end and perhaps as early as mid-July.

The approved indication will be for medical weight loss in the treatment of obesity in patients with either a body mass index of at least 30 kg/m2, or a BMI of 27 plus a comorbid condition, such as type 2 diabetes, according to Dr. Ryan of the Pennington Biomedical Research Center in Baton Rouge, La.

If approved, Qnexa would join lorcaserin (Belviq), which was approved by the FDA in late June and which also is indicated for patients with either a BMI of at least 30, or a BMI of at least 27 plus weight-related comorbidities.

More than 25 million Americans have type 2 diabetes, and most of them are obese.

Because both the FDA and Vivus Inc. (Qnexa’s developer) want to avoid the widespread abuse that often has been a problem with diet medications, the drug will be subject to a risk-management program. It will be available only through certified mail-order pharmacies that will collect patient data.

"This won’t be something you can get over the Internet. Patients won’t be able to go to a doc-in-a-box and say, ‘I want a diet drug; give me a prescription for this drug I read about in the newspaper.’ It won’t be like that," she said.

Dr. Ryan presented a secondary analysis from the randomized, double-blind, phase III CONQUER trial that involved roughly 2,500 obese patients (Lancet 2011;377:1341-52).

Her new substudy focused on the 388 CONQUER participants with type 2 diabetes. Like all participants in CONQUER, the diabetic patients were placed on a well-known, structured, lifestyle/behavioral modification program known as the LEARN (lifestyle, exercise, attitudes, relationships, nutrition) program for weight management. In addition, they were randomized to phentermine 7.5 mg/topiramate 46 mg, to phentermine 15 mg/topiramate 92 mg, or to placebo once daily. The subjects had relatively well-controlled diabetes and were on metformin as their sole antidiabetic medication at baseline.

At 56 weeks, the composite goal of a greater-than-5% weight loss from baseline, an HbA1c level lower than 6.5%, and a systolic blood pressure lower than 130 mm Hg was met by 12% of patients on lifestyle modification plus placebo, by 27% of those on the lifestyle program and the lower dose, and by 39% of those on the full dose. The tougher goal, which involved a greater-than-10% weight loss, was achieved in 4% of controls, 14% on the lower dose, and 31% on the full dose, which suggests that the drug plus lifestyle modification was roughly eightfold more effective than lifestyle modification alone.

The mean weight loss from baseline was 2% in controls, 7% in patients on the lower dose, and 9% in those on full-dose therapy.

To reach the composite goals, 12% of control subjects required a net increase in antidiabetic medications, as did 2% of those on the low dose and 0.6% of those on the full dose.

Both phentermine and topiramate have been on the market as individual drugs for many years, and their side effects in the CONQUER diabetic subgroup were the familiar ones associated with those agents. Dry mouth and paresthesia each occurred in about 8% of patients on the lower dose, and constipation occurred in 15%. Because the side effects are dose related, it’s quite likely that phentermine 7.5 mg/topiramate 46 mg will be the recommended starting dose, according to Dr. Ryan.

Topiramate is a known teratogen with a risk of four or five cases of cleft palate per 1,000 exposures during pregnancy. For this reason, the combination drug will be a category X drug.

In an interview, Dr. Ryan said that she could see physicians setting up contracts with their patients to take the drug for at least a year, then stopping it in order to see if lifestyle modification efforts enable them to avoid weight regain. If the pounds start piling up, they’ll restart the drug.

Dr. Ryan reported serving as a scientific advisor to Vivus but holds no equity interest in the company.