■磷酸二酯酶-5抑制剂在2型糖尿病(T2D)中发挥积极的血管和代谢作用,但对T2D患者胰岛素抵抗的影响尚不清楚.
■这是随机的,双盲,安慰剂对照,在Sahlgrenska大学医院(哥德堡,瑞典)。无明显勃起功能障碍的男性(40-70岁)和女性(55-70岁,绝经后)在3个月至10年之间诊断为T2D,纳入血红蛋白A1c(HbA1c)<60mmol/mol和体重指数(BMI)27-40kg/m2。参与者被随机分配到一次口服他达拉非20毫克,每天一次,以及一次安慰剂,持续6周。分开了8周的清洗期。安慰剂和他达拉非片剂在视觉上无法区分,并在每个参与者的两个单独的盒子中随机递送。两个治疗期都以葡萄糖钳夹结束,以及血液中身体成分和代谢标志物的测量,皮下和肌肉间质液。主要目的是评估治疗6周后全身胰岛素抵抗的差异,在两个研究组完成后确定,次要目的是研究他达拉非对T2D病理生理学的影响以及高剂量他达拉非对T2D的耐受性。对所有接受至少一剂研究药物的参与者进行完整分析集(FAS)和安全性分析的参与者进行初步分析。该试验已在ClinicalTrials.gov(NCT02601989)注册,和EudraCT(2015-000573)。
■1月22日之间,2016年1月31日,2019年,23名T2D参与者报名参加,其中18人被纳入完整的分析集。与安慰剂相比,他达拉非对胰岛素抵抗的影响是中性的。然而,他达拉非降低以HbA1c测量的血糖(平均差异-2.50mmol/mol,95%置信区间(CI),-4.20;-0.78,p=0.005),and,进一步,我们观察到内皮功能和肝脏脂肪变性和糖酵解的标志物的改善,而其他临床表型无统计学差异。肌肉疼痛,消化不良,与安慰剂组相比,高剂量他达拉非组患者的头痛发生率更高(p<0.05),但严重不良事件在治疗组之间无差异.
■高剂量他达拉非不能降低全身胰岛素抵抗,但是增加了微循环,在肝脏和中间代谢物中诱导积极作用,与以HbA1c测量的改善的代谢控制平行。高剂量他达拉非的耐受性中等,需要更大规模的试验来确定T2D的最佳治疗方案。
■瑞典研究委员会,瑞典糖尿病基金会,诺和诺德基金会,根据瑞典政府和县议会之间的协议,ALF协议,Sahlgrenska大学医院的资金,哥德堡医学学会,EliLilly&Company,美国,和礼来公司,瑞典AB.
UNASSIGNED: Phosphodiesterase-5 inhibitors exert positive vascular and metabolic effects in type 2 diabetes (T2D), but the effect on insulin resistance in T2D is unclear.
UNASSIGNED: This randomised, double blind, placebo-controlled, two-period crossover trial was conducted at Sahlgrenska University Hospital (Gothenburg, Sweden). Men without apparent erectile dysfunction (age 40-70 years) and women (age 55-70 years, post-menopause) diagnosed with T2D between 3 months and 10 years, haemoglobin A1c (HbA1c) < 60 mmol/mol and a body mass index (BMI) 27-40 kg/m2 were enrolled. Participants were randomly assigned to one period of oral tadalafil 20 mg once a day and one period of placebo for 6 weeks, separated by an 8-week wash-out period. Placebo and tadalafil tablets were made visually indistinguishable and delivered randomized in two separate boxes for each participant. Both treatment periods ended with a glucose clamp, and measurements of body composition and metabolic markers in blood, subcutaneous and muscular interstitial fluid. The primary aim was to assess difference in whole-body insulin resistance after 6-weeks of treatment, determined after completion of the two study arms, and secondary aims were to study effects of tadalafil on pathophysiology of T2D as well as tolerability of high-dose tadalafil in T2D. Primary analysis was performed in participants with full analysis set (FAS) and safety analysis in all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT02601989), and EudraCT (2015-000573).
UNASSIGNED: Between January 22nd, 2016, and January 31st, 2019, 23 participants with T2D were enrolled, of whom 18 were included in the full analysis set. The effect of tadalafil on insulin resistance was neutral compared with placebo. However, tadalafil decreased glycaemia measured as HbA1c (mean difference -2.50 mmol/mol, 95% confidence interval (CI), -4.20; -0.78, p = 0.005), and, further, we observed amelioration of endothelial function and markers of liver steatosis and glycolysis, whereas no statistically significant differences of other clinical phenotyping were shown. Muscle pain, dyspepsia, and headache were more frequent in participants on high-dose tadalafil compared with placebo (p < 0.05) but no difference between treatments appeared for serious adverse events.
UNASSIGNED: High-dose tadalafil does not decrease whole-body insulin resistance, but increases microcirculation, induces positive effects in the liver and in intermediate metabolites, in parallel with an improved metabolic control measured as HbA1c. High-dose tadalafil is moderately well tolerated, warranting larger trials to define the optimal treatment regimen in T2D.
UNASSIGNED: The Swedish Research Council, Swedish Diabetes Foundation, Novo Nordisk Foundation, the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement, Sahlgrenska University Hospital funds, Gothenburg Society of Medicine, Eli Lilly & Company, USA, and Eli Lilly & Company, Sweden AB.