NEW ORLEANS (EGMN) – A novel investigational insulin sensitizer improved fasting glucose levels without associated fluid retention or weight gain in a double-blind, randomized, placebo-controlled trial of 69 patients with type 2 diabetes.
The compound, INT131, is a nonthiazolidinedione (TZD) selective peroxisome proliferator-activated receptor gamma modulator (SPPARM) with glycemic effects similar to the full PPAR-gamma agonists rosiglitazone and pioglitazone, Dr. Alex M. DePaoli said at the annual scientific sessions of the American Diabetes Association.
“The fluid retentive nature of the [TZD] class of agents is probably one of the most significant concerns. If we can avoid this, as well as the weight gain associated with the TZDs, we would achieve the benefit of PPAR-gamma without the side effect profile,” said Dr. DePaoli, chief medical officer of InteKrin Therapeutics, Los Altos, California.
Study patients in the 4-week trial had type 2 diabetes, but were not taking any glucose-lowering agents. At baseline, they had hemoglobin A1c values of 6.8%-10% and fasting plasma glucose levels of 126-240 mg/dL. They were randomized to either 1-mg or 10-mg doses of INT131 or placebo. Statistically significant reductions in fasting plasma glucose were first seen at 1 week, with a reduction of 53.8 mg/dL with the 10-mg dose at 4 weeks, compared with placebo.
When plotted against data for the highest rosiglitazone dose (8 mg) compiled from a meta-analysis of 12 trials, the FPG reductions seen with 1 mg of INT131 were similar, whereas the 10-mg dose reduction was greater. Body weight changes were minimal with the 1-mg dose and similar to rosiglitazone with the 10-mg dose (a gain of 1.4 kg). Hematocrit – a proxy for fluid retention – was minimally changed with 1 mg of INT131 and dropped by 1.7% with 10 mg of INT131, compared with placebo. Again, this change in the 10-mg group is similar to that seen with the highest dose of rosiglitazone.
There were no serious adverse events and no subjects dropped out because of an adverse event.
Previously reported data on INT131 showed no changes in LDL cholesterol, but a significant dose-dependent increase in HDL cholesterol and a trend toward a reduction in triglycerides, Dr. DePaoli said.
These findings provided the rationale for the now fully enrolled 24-week randomized, double-blind, placebo-controlled phase IIb study of 360 patients on sulfonylureas alone or in combination with metformin. Doses of INT131 for this study will be 0.5, 1, 2, or 3 mg. In addition, pioglitazone 45 mg will also be included as an active comparator. Data are expected later this year, he said.
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新奥尔良(EGMN) ——一项包括69例2型糖尿病患者的双盲、随机、安慰剂对照试验显示，研究中的一种新型胰岛素增敏剂可改善空腹血糖水平，且不会导致体液潴留或体重增加。
这种复合物INT131是一种非噻唑烷二酮(TZD)类选择性过氧化物酶体增殖物激活型受体g调节剂(SPPARM)，其对血糖的影响与完全PPAR-g激动剂罗格列酮和吡格列酮相似，Alex M. DePaoli医生在美国糖尿病协会(ADA)年度学术会议上报告。
“[TZD]类药物导致体液潴留的性质可能是其应用的最大障碍之一。如果我们能够解决这一问题，同时避免TZD相关的体重增加，就可以享有PPAR-g的益处而无需再顾忌副作用，”加利福尼亚州Los Altos市InteKrin Therapeutics公司的首席医学官DePaoli医生说。
在这项为期4周的研究中，受试者均为未接受任何降糖药治疗的2型糖尿病患者。基线时糖化血红蛋白A1c介于6.8%~10%之间，空腹血糖水平为126~240 mg/dl。将这些患者随机分配到INT131 1 mg、10 mg或安慰剂治疗组。第一周时首次观察到空腹血糖的下降达到统计学意义，第4周时10 mg组空腹血糖较安慰剂组降低了53.8 mg/dl。
当与12项研究的荟萃分析中最高剂量罗格列酮(8 mg)的数据进行比照时发现，INT131 1 mg降低FPG的效果与罗格列酮8 mg相似，而10 mg剂量对FPG的降低幅度更高。1 mg剂量组的体重变化很小，10 mg剂量组体重变化(增加1.4 kg)与与罗格列酮最高剂量相似。一项体液潴留的指标——红细胞压积在INT131 1 mg组中的变化很小，在INT131 10 mg组中较安慰剂组降低了1.7%。同样，10 mg剂量组与罗格列酮最高剂量治疗的变化相似。
研究中无严重不良事件发生，且无一患者因不良事件退出研究。之前关于INT131的报告资料中显示LDL胆固醇无变化，HDL胆固醇呈显著剂量依赖性升高，甘油三酯呈降低趋势，DePaoli医生说。
这些结果为目前已完成患者入选的一项为期24周的随机、双盲、安慰剂对照的IIb期研究提供了依据，该研究中已纳入360例单纯磺脲类药物治疗或磺脲类联合二甲双胍治疗的患者。研究中INT131的剂量将为0.5、1、2或 3 mg，并且纳入吡格列酮45 mg治疗作为活性对照。其数据预期将于今年晚些时候公布，他说。
