Seferovic Jelena P, Solomon Scott D, Seely Ellen W
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ther Adv Endocrinol Metab. 2020 Dec 25;11:2042018820970444. doi: 10.1177/2042018820970444. eCollection 2020.
Heart failure (HF) and diabetes mellitus (DM) frequently coexist, with a prevalence of DM of 35-40% in patients with HF, independent of the level of impairment of the ejection fraction (EF). Furthermore, DM is considered a strong independent risk factor for the progression of HF with either preserved or reduced EF and is associated with poor prognosis. The ability of neprilysin inhibitors to elevate levels of biologically active natriuretic peptides has made them a potential therapeutic approach in HF. In the Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, a dual-acting angiotensin-receptor-neprilysin inhibitor, sacubitril/valsartan was superior to enalapril in reducing the risks of death and HF hospitalization in patients with HF with reduced EF. In addition, in a post-hoc analysis of this trial, among patients with DM, treatment with sacubitril/valsartan resulted in improved glycemic control compared with enalapril. Also, there are additional studies suggesting beneficial metabolic effects of this class of drugs. In this review we discuss potential mechanisms of sacubitril/valsartan effect on glycemic control. Sacubitril/valsartan concomitantly blocks the renin-angiotensin system and inhibits neprilysin, a ubiquitous enzyme responsible for the breakdown of more than 50 vasoactive peptides, including the biologically active natriuretic peptides, bradykinin, angiotensin I and II, endothelin 1, glucagon, glucagon-like peptide-1, insulin-B chain, and others. There are a number of potential mechanisms by which inhibition of neprilysin may lead to improvement in glycemic control, with most evidence suggesting modulation of neprilysin circulating substrates. Although there is some evidence suggesting the improvement of glucose metabolism by renin-angiotensin system inhibition, this effect is most likely modest. As these mechanisms are not fully understood, detailed mechanistic studies, as well as large randomized clinical trials in patients with DM, are needed to further clarify beneficial metabolic properties of sacubitril/valsartan.
心力衰竭（HF）与糖尿病（DM）常并存，在心力衰竭患者中糖尿病的患病率为35%-40%，与射血分数（EF）的受损程度无关。此外，糖尿病被认为是射血分数保留或降低的心力衰竭进展的一个强有力的独立危险因素，且与预后不良相关。中性肽链内切酶抑制剂提高生物活性利钠肽水平的能力使其成为心力衰竭的一种潜在治疗方法。在“ARNI与ACEi对心力衰竭全球死亡率和发病率影响的前瞻性比较（PARADIGM-HF）”试验中，一种双效血管紧张素受体-中性肽链内切酶抑制剂沙库巴曲/缬沙坦在降低射血分数降低的心力衰竭患者的死亡风险和心力衰竭住院风险方面优于依那普利。此外，在该试验的一项事后分析中，在糖尿病患者中，与依那普利相比，沙库巴曲/缬沙坦治疗可改善血糖控制。另外，还有其他研究表明这类药物具有有益的代谢作用。在本综述中，我们讨论沙库巴曲/缬沙坦对血糖控制作用的潜在机制。沙库巴曲/缬沙坦同时阻断肾素-血管紧张素系统并抑制中性肽链内切酶，这是一种普遍存在的酶，负责分解50多种血管活性肽，包括生物活性利钠肽、缓激肽、血管紧张素I和II、内皮素-1、胰高血糖素、胰高血糖素样肽-1、胰岛素B链等。抑制中性肽链内切酶可能通过多种潜在机制导致血糖控制改善，大多数证据表明是对中性肽链内切酶循环底物的调节。虽然有一些证据表明抑制肾素-血管紧张素系统可改善葡萄糖代谢，但这种作用很可能较小。由于这些机制尚未完全了解，需要进行详细的机制研究以及针对糖尿病患者的大型随机临床试验，以进一步阐明沙库巴曲/缬沙坦有益的代谢特性。
