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Potential Mechanisms of Beneficial Effect of Sacubitril/Valsartan On TAE0010.1177/2042018820970444Therapeutic Advances in Endocrinology and MetabolismJP Seferovic, SD Solomon 970444research-article20202020 Cardiovascular Disease and Diabetes: Special Collection Risk Factors, Prevention and Management Therapeutic Advances in Endocrinology and Metabolism Review Ther Adv Endocrinol Potential mechanisms of beneficial effect of Metab 2020, Vol. 11: 1–9 sacubitril/valsartan on glycemic control DOI:https://doi.org/10.1177/2042018820970444 10.1177/ 2042018820970444https://doi.org/10.1177/2042018820970444 © The Author(s), 2020. Jelena P. Seferovic , Scott D. Solomon and Ellen W. Seely Article reuse guidelines: sagepub.com/journals- permissions Abstract: 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. Keywords: heart failure, diabetes mellitus, sacubitril/valsartan Received: 18 April 2019; revised manuscript accepted: 12 October 2020. Correspondence to: Jelena P. Seferovic Cardiovascular Division, Brigham and Women’s Introduction Despite the fact that angiotensin-converting enzyme Hospital, Harvard Medical Heart failure (HF) and diabetes mellitus (DM) (ACE) inhibitors, angiotensin AT1 receptor School, 75 Francis Street, Boston, MA 02115, USA are frequent co-morbidities, with a prevalence of blockers (ARBs), beta-blockers, and mineralo- [email protected] DM as high as 35–40% in patients with HF, inde- corticoid receptor antagonists (MRAs) were ben- Scott D. Solomon pendent of ejection fraction (EF) impairment.1 eficial in HF (including DM), mortality in these Cardiovascular Division, Brigham and Women’s 6 Moreover, DM is considered to be a strong inde- patients still remains high. Also, they are usually Hospital, Harvard Medical pendent risk factor for the progression of HF with combined with diuretics and ivabradine. School, Boston, MA, USA 2 Ellen W. Seely either preserved or reduced EF, while presence Endocrinology, Diabetes, of both is associated with a poor subsequent prog- ACE inhibitors improved symptoms and reduced and Hypertension Division, Brigham and Women’s nosis, as shown in both observational studies and morbidity and mortality in patients with HF and Hospital, Harvard Medical clinical trials.3–5 type 2 DM, and are recommended in this group School, Boston, MA, USA journals.sagepub.com/home/tae 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Endocrinology and Metabolism 11 of patients. In the Studies Of Left Ventricular On the other hand, sodium–glucose co- transporter Dysfunction (SOLVD) trial, there was a signifi- type 2 inhibitors are novel glucose-lowering cant mortality reduction in DM patients with HF agents shown to reduce HF hospitalizations in randomized to enalapril.7 In the Assessment of CV outcome trials.23,24 Further more, two agents Treatment with Lisinopril and Survival in heart from this class have been shown to reduce the failure (ATLAS) trial high-dose lisinopril treat- combined risk of CV death or HF hospitalization ment resulted in mortality and HF hospitaliza- in patients with HF with reduced EF (HFrEF), tion risk reduction in patients with and without regardless of the presence or absence of DM, and type 2 DM.8 Meta-analysis including six studies seem to have become game changers in the treat- (2398 DM and 10,188 non-DM patients) found ment of HFrEF.25,26 Also, there is currently an that HF treatment with ACE inhibitors resulted ongoing study investigating the potential benefit in reduced mortality in both groups.9 However, of empagliflozin in patients with HF with pre- hypoglycemia has been reported with ACE inhib- served EF (HFpEF) (EMPagliflozin outcomE itors treatment in type 2 DM on glucose-lowering tRial in Patients With chrOnic heaRt Failure treatment, so glucose monitoring is necessary.10 With Preserved Ejection Fraction-EMPEROR- ARBs also have beneficial effects in patients with Preserved). HF and DM.11 In the CHARM-Alternative trial, candesartan reduced cardiovascular (CV) mor- The ability of neprilysin (NEP) inhibitors to ele- tality and morbidity in HF patients intolerant to vate levels of biologically active natriuretic peptides ACE inhibitors.12 However, as DM patients has made them a potential therapeutic approach in treated with candesartan had a 2-fold risk of HF. First NEP inhibitors ecadotril and candoxatril hyperkalemia, kidney function and potassium were initially tested in HF, but lack of efficacy and monitoring is necessary when ARBs are used in side effects led to discontinuation of their develop- this group of patients.12,13 Beta-blockers reduced ment.27 Although the dual ACE/NEP inhibitor mortality and hospital admission, and improved omapatrilat was found to be protective against symptoms in both DM and non-DM patients.14 HF,28 it was not approved for clinical use due to In a meta-analysis of six trials, beta-blockers increased frequency of angioedema29,30 reduced all-cause mortality in patients with and without type 2 DM.15 Also, in a meta-analysis of Sacubitril/valsartan (formerly known as LCZ696) CIBIS-2, MERIT-HF and COPERNICUS, is a dual-acting angiotensin-receptor–NEP inhib- patients with type 2 DM (n = 1883) had reduced itor, that contains equimolar amounts of valsar- mortality when treated with beta-blockers.9 tan, a type 1 angiotensin II receptor (AT1) Hypoglycemia has been described with non-car- blocker (ARB), and sacubitril, a prodrug that is dio-selective beta-blockade (propranolol), but hydrolyzed into the active NEP inhibitor not with beta-1-selective agents or with carve- LBQ657.30,31 The combined ARB/NEP inhibitor dilol.16,17 Treatment with MRAs was associated was developed to address two pathophysiological with improved outcomes in HF patients with and mechanisms underlying HF—activation of the without DM.18 Spironolactone and eplerenone renin–angiotensin aldosterone system (RAS) and reduced mortality in both patients with HF, decreased sensitivity to natriuretic peptides regardless of the presence or absence of type 2 (NPs). In the Prospective comparison of ARNi DM.19 Meta-analysis of four studies found that with ACEi to Determine Impact on Global MRA treatment was associated with improved Mortality and morbidity in Heart Failure clinical outcomes in patients with DM and HF. (PARADIGM-HF trial), sacubitril/valsartan was Also, eplerenone seems to have a neutral meta- superior to ACE inhibitor enalapril in reducing bolic profile.20 The most serious adverse effect of the risks of death and HF hospitalization in MRAs is hyperkalemia, so surveillance of kidney patients with HFrEF, which led to its approval by function and potassium is mandatory. Loop diu- U.S. Food and Drug Administration for the retics are recommended to reduce HF symp- reduction of HF hospitalization.32 toms, while thiazides have been shown to promote hyperglycemia.21 Also, ivabradine dem- The effect of earlier NEP inhibitors on glycemic onstrated a significant reduction in CV death or control has been investigated. Omapatrilat HF hospitalization, regardless of the presence or improved whole-body insulin-mediated glucose absence of type 2 DM.22 disposal, induced profound
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