利拉鲁肽辅助前驱糖尿病患者减重后的胰岛β细胞功能：一项随机、安慰剂对照研究的分析
Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study.
作者信息
Kim Sun H, Liu Alice, Ariel Danit, Abbasi Fahim, Lamendola Cindy, Grove Kaylene, Tomasso Vanessa, Reaven Gerald
机构信息
Department of Medicine, Stanford University School of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305-5103, USA,
出版信息
Diabetologia. 2014 Mar;57(3):455-62. doi: 10.1007/s00125-013-3134-3. Epub 2013 Dec 11.
AIMS/HYPOTHESIS: Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.
METHODS
This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.
RESULTS
Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.
CONCLUSIONS/INTERPRETATION: A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.
目的/假设：利拉鲁肽可通过直接刺激β细胞或间接通过减轻体重和增强胰岛素敏感性来调节胰岛素分泌。最近，我们发现，与安慰剂相比，在患有糖尿病前期（空腹血糖受损和/或糖耐量受损）的超重个体中使用利拉鲁肽治疗可导致更大程度的体重减轻（-7.7% 对 -3.9%）以及胰岛素抵抗改善。本研究评估了与单纯体重减轻相比，利拉鲁肽增强的体重减轻对β细胞功能的影响。
方法
这是一项在单一学术中心进行的平行随机研究。参与者和研究管理人员均对治疗分配不知情。年龄在40 - 70岁、超重（BMI 27 - 40 kg/m²）且患有糖尿病前期的个体通过计算机系统随机分组，接受利拉鲁肽治疗（n = 35）或匹配的安慰剂治疗（n = 33），共分析了49名参与者。所有参与者均被要求遵循能量限制饮食。主要结局是胰岛素分泌功能，通过对葡萄糖分级输注和一整天混合餐的反应进行评估。
结果
与安慰剂组（n = 25）相比，利拉鲁肽治疗组（n = 24）显著（p≤0.03）提高了胰岛素分泌率（平均变化百分比[95%CI]；21%[12, 31]对 -4%[-11, 3]）和胰腺β细胞对静脉注射葡萄糖的敏感性（229%[161, 276]对 -0.5%[-15, 14]），并降低了胰岛素清除率（-3.5%[-11, 4]对8.2[0.2, 16]）。利拉鲁肽治疗组在混合餐后一整天的血糖（-8.2%[-11, -6]对 -0.1[-3, 2]）和非酯化脂肪酸浓度（-14[-20, -8]对 -2.1[-10, 6]）也显著（p≤0.03）更低，而与安慰剂相比，一整天的胰岛素浓度无显著差异。在多变量回归分析中，安慰剂组体重减轻与胰岛素分泌率以及一整天的血糖和胰岛素浓度降低相关（p≤0.05），但利拉鲁肽组体重减轻与之无关。利拉鲁肽最常见的副作用是恶心。
结论/解读：对β细胞功能的直接刺激作用是利拉鲁肽增强体重减轻过程中的主要变化。这些变化似乎与体重减轻无关。
试验注册
ClinicalTrials.gov NCT01784965 资金来源：本研究由美国糖尿病协会资助。
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