Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diabetes Obes Metab. 2022 Oct;24(10):2017-2026. doi: 10.1111/dom.14789. Epub 2022 Jul 21.
Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.
We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.
Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.
The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.
gov (NCT03893526).
沙库巴曲缬沙坦是一种用于治疗心力衰竭的新型脑啡肽酶抑制剂/血管紧张素 II 受体阻滞剂。最近，一项为期 3 年的随机对照试验的事后分析显示，心力衰竭合并 2 型糖尿病患者使用沙库巴曲缬沙坦治疗可改善血糖控制。我们之前曾报道过，沙库巴曲缬沙坦与二肽基肽酶-4 抑制剂联合使用可增加健康个体中活性胰高血糖素样肽-1（GLP-1）的水平。我们现在假设，在 2 型糖尿病患者中，沙库巴曲缬沙坦联合或不联合二肽基肽酶-4 抑制剂治疗可通过增加活性 GLP-1 来降低餐后血糖浓度（主要结局）。
我们在 12 例肥胖合并 2 型糖尿病患者中进行了一项交叉试验。在以下 5 种干预措施后摄入混合餐：（a）单次沙库巴曲缬沙坦剂量；（b）西格列汀；（c）沙库巴曲缬沙坦+西格列汀；（d）对照（无治疗）；和（e）缬沙坦单药。测量血糖、肠道和胰腺激素的反应。
与对照相比，沙库巴曲缬沙坦治疗后餐后血浆葡萄糖增加 57%（0-240 分钟时曲线下面积的增量）（p=0.0003），峰值血浆葡萄糖增加 1.7mM（95%CI：0.6-2.9）（p=0.003），而沙库巴曲缬沙坦+西格列汀后餐后血糖水平无明显变化。沙库巴曲缬沙坦治疗后胰高血糖素、GLP-1 和 C 肽浓度增加，但胰岛素和葡萄糖依赖性胰岛素释放肽没有变化。
在心力衰竭和 2 型糖尿病患者中报告的长期沙库巴曲缬沙坦治疗的降血糖作用可能不依赖于肠胰激素的变化。脑啡肽酶抑制导致高胰高血糖素血症，这可能解释了本研究中观察到的葡萄糖耐量恶化。
gov（NCT03893526）。
