二甲双胍已经作为II型糖尿病的治疗药物使用了接近60年，现在已经成为新诊断糖尿病病人的一线治疗药物，但是关于二甲双胍的争议一直不断，争议的主要内容在于二甲双胍究竟如何发挥平稳血糖的功能。
最近，来自美国北卡罗来纳大学医学院的研究人员在国际学术期刊Diabetes care上发表了一项最新研究进展，他们在研究中发现二甲双胍的作用效应主要发生在肠，而非血液中。他们还在文章中描述了处于临床申请阶段的延迟释放型二甲双胍的I期和II期临床研究结果。
在I期研究中，研究人员给予健康志愿者单剂量的延迟释放型二甲双胍，速释型二甲双胍以及缓释型二甲双胍，随后对血液中的二甲双胍进行检测，结果发现给予延迟释放型二甲双胍的志愿者其血液中的二甲双胍含量仅是另外两种药物的一半左右。
在II期研究中，研究人员给予II型糖尿病患者不同剂量的延迟释放型二甲双胍，并以服用安慰剂和缓释型二甲双胍的患者作对照。结果表明与缓释型二甲双胍相比，延迟释放型二甲双胍的作用效果呈现出40%的增加。而在长达12周的时间内，相比于安慰剂组，服用延迟释放型二甲双胍的病人其空腹血糖水平保持下降，并具有显著的统计学差异。
研究人员指出，这项研究发现二甲双胍主要作用于小肠部位，与半个世纪以来的传统观点相反，目前有大约40%的糖尿病病人不能服用一线治疗药物，而这一研究开发的二甲双胍治疗药物将为这些病人的糖尿病治疗提供新的契机。
The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation. Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies
John B. Buse1, Ralph A. DeFronzo2, Julio Rosenstock3, Terri Kim4, Colleen Burns4, Sharon Skare4, Alain Baron4 and Mark Fineman
OBJECTIVE Delayed-release metformin (Met DR) is formulated to deliver drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediate-release metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks.
RESEARCH DESIGN AND METHODS Study 1 was a Phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, Phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblinded Met XR 1,000 or 2,000 mg (reference).
RESULTS The bioavailability of 1,000 mg Met DR bid was ?50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR qd produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ?40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/Glucophage XR prescribing information.
ConCLUSIONS Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action.