sacubitril and Diabetes-Mellitus--Type-2

Heart failure (HF) represents a major global health and economic burden with still unacceptably high morbidity and mortality rates. In recent decades, novel therapeutic opportunities with a significant impact on HF outcomes have been introduced in addition to angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and mineralocorticoid receptor antagonists. These include drugs such as ivabradine, sacubitril-valsartan, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The availability of an extremely large pharmacological armamentarium to face this chronic global disease highlights the importance of assessing cost effectiveness to promote sustainable healthcare. In light of the recent approval of SGLT-2 inhibitors for the treatment of HF with reduced ejection fraction, including in individuals without type 2 diabetes mellitus, the aim of this review was to provide an updated comparative evaluation of the efficacy and cost effectiveness of different pharmacological treatments for the prevention (stage A) and treatment of asymptomatic (stage B) and symptomatic (stages C-D) left ventricular dysfunction.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Combinations; Heart Failure; Humans; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Tetrazoles; Treatment Outcome; Ventricular Dysfunction, Left

This review aims to investigate the blood pressure (BP)-lowering effects of emerging drugs developed to treat diabetic kidney disease and heart failure (HF). We summarize the potential pathophysiological mechanisms responsible for mitigating hypertensive target organ damage and evaluating the available clinical data on these newer drugs.. Nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists (MRAs), dual angiotensin II receptor-neprilysin inhibitors (valsartan with sacubitril), sodium-glucose cotransporter 2 inhibitors (SGLT2i), and soluble guanylate cyclase stimulators are new classes of chemical agents that have distinct mechanisms of action and have been shown to be effective for the treatment of cardiovascular (CV) disease (CVD), HF, and type 2 diabetes mellitus (T2D). These drugs can be used either alone or in combination with other antihypertensive and CV drugs. Among these, SGLT2i and valsartan with sacubitril offer new avenues to reduce CVD mortality. SGLT2i have a mild-to-moderate effect on BP lowering with a favorable effect on CV and renal hemodynamics and have been shown to produce a significant reduction in the incidence of major adverse CVD events (as monotherapy or add-on therapy) compared with controls (placebo or non-SGLT2i treatment). Most of the participants in these studies had hypertension (HTN) at baseline and were receiving antihypertensive therapy, including renin-angiotensin system blockers. The combination of valsartan with sacubitril also lowers BP in the short term and has demonstrated a striking reduction in CVD mortality and morbidity in HF patients with a reduced left ventricular ejection fraction. If widely adopted, these novel therapeutic agents hold significant promise for reducing the public health burden posed by HTN and CVD. Based on the results of several clinical trials and considering the high prevalence of HTN and T2D, these new classes of agents have emerged as powerful therapeutic tools in managing and lowering the BP of patients with diabetic kidney disease and HF.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Female; Heart Failure; Humans; Hypertension; Male; Stroke Volume; Tetrazoles; Valsartan; Ventricular Function, Left

Elevated blood pressure and hyperglycaemia frequently coexist and are both components of metabolic syndrome. Enhanced cardiovascular risk is strongly associated with diabetes and the occurrence of hypertension. Both hypertension and type 2 diabetes, if treated inappropriately, lead to serious complications, increasing the mortality of patients and generating much higher costs of health systems. This is why it is of great importance to find the missing link between hypertension and diabetes development and to simultaneously search for drugs influencing these two disorders or even drugs aimed at their pathological bases. Standard antihypertensive therapy mainly focuses on blood pressure reduction, while novel drugs also possess a wide range of pleiotropic modes of actions, such as cardio- and nephroprotective properties or body weight reduction. These properties are especially desirable in a situation when type 2 diabetes coexists with hypertension. This review describes the connections between diabetes and hypertension development and briefly summarises the current knowledge regarding attempts to define targets for the treatment of high blood pressure in diabetic patients. It also describes the standard hypotensive drugs preferred in patients with type 2 diabetes, as well as novel drugs, such as finerenone, esaxerenone, sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide-1 analogues and sacubitril/valsartan.

Topics: Aminobutyrates; Antihypertensive Agents; Biphenyl Compounds; Diabetes Mellitus, Type 2; Humans; Hypertension; Sodium-Glucose Transporter 2 Inhibitors

Despite the significant contribution of hypertension to the global burden of disease, disease control remains poor worldwide. Considering this unmet clinical need, several new antihypertensive drugs with novel mechanisms of action are under development.. The present review summarizes the recent advances in the development of emerging pharmacological agents for the management of hypertension. The latest technological innovations in the design of optimized formulations of available antihypertensive drugs and the potential role of the modification of intestinal microbiota to improve blood pressure (BP) control are also covered.. Significant efforts have been made to develop new antihypertensive agents with novel actions that target the main mechanisms involved in resistant hypertension. Sacubitril/valsartan may emerge as a potential first-line drug due to its superiority over renin angiotensin system inhibitors, and SGLT2 inhibitors can reduce BP in difficult-to-control hypertensive patients with type 2 diabetes. In addition, firibastat and aprocitentan may expand the therapeutic options for resistant hypertension by novel mechanism of actions. Since gut dysbiosis not only leads to hypertension but also causes direct target organ damage, prebiotics and probiotics could represent a potential strategy to prevent or reduce the development of hypertension and to contribute to BP control.

Topics: Aminobutyrates; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Humans; Hypertension

After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin-angiotensin-aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Diabetes Mellitus, Type 2; Heart Failure; Humans; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Tetrazoles

Pre-heart failure with preserved ejection fraction (pre-HFpEF) is common and has no specific therapy aside from cardiovascular risk factor management.. To investigate the hypothesis that sacubitril/valsartan vs valsartan would reduce left atrial volume index using volumetric cardiac magnetic resonance imaging in patients with pre-HFpEF.. The Personalized Prospective Comparison of ARNI [angiotensin receptor/neprilysin inhibitor] With ARB [angiotensin-receptor blocker] in Patients With Natriuretic Peptide Elevation (PARABLE) trial was a prospective, double-blind, double-dummy, randomized clinical trial carried out over 18 months between April 2015 and June 2021. The study was conducted at a single outpatient cardiology center in Dublin, Ireland. Of 1460 patients in the STOP-HF program or outpatient cardiology clinics, 461 met initial criteria and were approached for inclusion. Of these, 323 were screened and 250 asymptomatic patients 40 years and older with hypertension or diabetes, elevated B-type natriuretic peptide (BNP) greater than 20 pg/mL or N-terminal pro-b-type natriuretic peptide greater than 100 pg/mL, left atrial volume index greater than 28 mL/m2, and preserved ejection fraction greater than 50% were included.. Patients were randomized to angiotensin receptor neprilysin inhibitor sacubitril/valsartan titrated to 200 mg twice daily or matching angiotensin receptor blocker valsartan titrated to 160 mg twice daily.. Maximal left atrial volume index and left ventricular end diastolic volume index, ambulatory pulse pressure, N-terminal pro-BNP, and adverse cardiovascular events.. Among the 250 participants in this study, the median (IQR) age was 72.0 (68.0-77.0) years; 154 participants (61.6%) were men and 96 (38.4%) were women. Most (n = 245 [98.0%]) had hypertension and 60 (24.0%) had type 2 diabetes. Maximal left atrial volume index was increased in patients assigned to receive sacubitril/valsartan (6.9 mL/m2; 95% CI, 0.0 to 13.7) vs valsartan (0.7 mL/m2; 95% CI, -6.3 to 7.7; P < .001) despite reduced markers of filling pressure in both groups. Changes in pulse pressure and N-terminal pro-BNP were lower in the sacubitril/valsartan group (-4.2 mm Hg; 95% CI, -7.2 to -1.21 and -17.7%; 95% CI, -36.9 to 7.4, respectively; P < .001) than the valsartan group (-1.2 mm Hg; 95% CI, -4.1 to 1.7 and 9.4%; 95% CI, -15.6 to 4.9, respectively; P < .001). Major adverse cardiovascular events occurred in 6 patients (4.9%) assigned to sacubitril/valsartan and 17 (13.3%) assigned to receive valsartan (adjusted hazard ratio, 0.38; 95% CI, 0.17 to 0.89; adjusted P = .04).. In this trial of patients with pre-HFpEF, sacubitril/valsartan treatment was associated with a greater increase in left atrial volume index and improved markers of cardiovascular risk compared to valsartan. More work is needed to understand the observed increased cardiac volumes and long-term effects of sacubitril/valsartan in patients with pre-HFpEF.. ClinicalTrials.gov Identifier: NCT04687111.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Female; Heart Atria; Heart Failure; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Neprilysin; Stroke Volume; Tetrazoles; Valsartan

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).

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucagon-Like Peptide 1; Glucose Tolerance Test; Heart Failure; Humans; Hypoglycemic Agents; Male; Middle Aged; Neprilysin; Sitagliptin Phosphate; Tetrazoles; Valsartan

Sacubitril/valsartan, a novel therapy in chronic heart failure (CHF), inhibits the breakdown of various peptides. However, whether or not sacubitril/valsartan administration affects urinary C-peptide levels is unclear. We herein report a 70-year-old man with type 2 diabetes mellitus (T2DM) and hypertension coexisting with CHF and nephrotic syndrome. The patient's urinary C-peptide levels dramatically increased after sacubitril/valsartan administration and decreased after discontinuation of the drug. Furthermore, sacubitril/valsartan administration to five other patients with hypertension and T2DM markedly increased urinary C-peptide levels. Thus, the insulin secretory capacity of patients with T2DM receiving sacubitril/valsartan may be overestimated when their urinary C-peptide level is measured.

Topics: Aged; Angiotensin Receptor Antagonists; Biphenyl Compounds; C-Peptide; Diabetes Mellitus, Type 2; Drug Combinations; Heart Failure; Humans; Hypertension; Male; Stroke Volume; Tetrazoles; Valsartan

Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified.. Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2 μg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO + VAL (valsartan), and ALDO + SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid.. The ALDO + SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO + VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2, and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR.. In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability.

Topics: Aldosterone; Animals; Biphenyl Compounds; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fibrosis; Kidney; Male; Mice; Natriuretic Peptides; Renal Plasma Flow; Valsartan

This work aims to describe the clinical characteristics and therapeutic management and to determine cardiovascular outcomes after one year of follow-up in a contemporaneous population with heart failure (HF) with and without type 2 diabetes in Spain. These factors were also analyzed in the DAPA-HF-like population (patients who met most inclusion criteria of the DAPA-HF trial) and in patients treated with SGLT2 inhibitors at baseline.. This work is an observational, retrospective, population-based study using the BIG-PAC database. The index date was January 1, 2019. People aged ≥ 18 years who received care for HF in 2019 were selected. Events that occurred in 2019 were analyzed.. We identified 21,851 patients with HF (age 78.0 ± 11.3 years, 53.0% men, 50.9% with HF with reduced left ventricular ejection fraction, 44.5% in NYHA functional class II). HF prevalence was 1.88% and incidence was 2.83 per 1,000 person-years. Regarding HF treatments, 66.1% were taking renin-angiotensin system inhibitors, 69.4% beta blockers, 31.2% aldosterone antagonists, and 7.5% sacubitril/valsartan. During the year of follow-up, 29.8% had HF decompensation which led to hospitalization (mean time to first event of 120.9 ± 72.5 days), 12.3% died, and 8.1% died during hospitalization. Events were more common among patients with type 2 diabetes. Hospitalizations for HF were more common in the DAPA-HF-like population.. In Spain, the population with HF is elderly and has many comorbidities. Approximately half of patients have HF with reduced left ventricular ejection fraction. There is room for improvement in HF management, particularly through the use of drugs that reduce both HF hospitalization and mortality, in order to reduce the burden of HF.

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Male; Retrospective Studies; Spain; Stroke Volume; Treatment Outcome; Ventricular Function, Left

Comorbid heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (DM) is associated with a very high risk of HF events. Sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), and dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, improve HF outcomes in these patients, but their comparative value for money in this patient population has not yet been determined.. We aimed to compare the cost needed to treat (CNT) to avoid an HF event with each drug.. CNT was estimated by multiplying the annualized number needed to treat (NNT) to prevent one HF event by the annual cost of each therapy. HF events were defined as the first event of hospitalization for HF or cardiovascular mortality. Drug efficacy data were extracted from published secondary analyses of patients with DM in the DAPA-HF and PARADIGM-HF trials. Drug costs were estimated as 75% of the 2021 US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed on parameters that may have affected the CNT.. The annualized NNT was 24 (95% confidence interval [CI] 16-54) for dapagliflozin and 57 (95% CI 31-433) for the ARNI. At an annual cost of $US4523 and 5099, respectively, the CNT was $US108,563 (95% CI 72,375-244,267) for dapagliflozin and $US290,671 (95% CI 158,084-2,208,079) for the ARNI.. Dapagliflozin seems to offer greater value for money than the ARNI for patients with HFrEF and DM. Our results provide support for contemporary guidelines advocating the use of dapagliflozin in these patients.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Benzhydryl Compounds; Biphenyl Compounds; Diabetes Mellitus, Type 2; Drug Combinations; Glucosides; Heart Failure; Humans; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Tetrazoles; Valsartan; Ventricular Dysfunction, Left

Type 2 diabetes is associated with the upregulation of neprilysin, a peptidase capable of cleaving glucoregulatory peptides such as glucagon-like peptide-1 (GLP-1). In humans, use of the neprilysin inhibitor sacubitril in combination with an angiotensin II receptor blocker was associated with increased plasma GLP-1 levels and improved glycemic control. Whether neprilysin inhibition per se is mediating these effects remains unknown. We sought to determine whether pharmacological neprilysin inhibition on its own confers beneficial effects on glycemic status and β-cell function in a mouse model of reduced insulin secretion, and whether any such effects are dependent on GLP-1 receptor (GLP-1R) signaling. High-fat-fed male wild-type (

Topics: Aminobutyrates; Animals; Biphenyl Compounds; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Insulin; Insulin Secretion; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neprilysin

Treatment of heart failure with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improved glycemic control in individuals with type 2 diabetes. The relative contribution of neprilysin inhibition versus angiotensin II receptor antagonism to this glycemic benefit remains unknown. Thus, we sought to determine the relative effects of the neprilysin inhibitor sacubitril versus the angiotensin II receptor blocker valsartan on beta-cell function and glucose homeostasis in a mouse model of reduced first-phase insulin secretion, and whether any beneficial effects are additive/synergistic when combined in sacubitril/valsartan. High fat-fed C57BL/6J mice treated with low-dose streptozotocin (or vehicle) were followed for eight weeks on high fat diet alone or supplemented with sacubitril, valsartan or sacubitril/valsartan. Body weight and fed glucose levels were assessed weekly. At the end of the treatment period, insulin release in response to intravenous glucose, insulin sensitivity, and beta-cell mass were determined. Sacubitril and valsartan, but not sacubitril/valsartan, lowered fasting and fed glucose levels and increased insulin release in diabetic mice. None of the drugs altered insulin sensitivity or beta-cell mass, but all reduced body weight gain. Effects of the drugs on insulin release were reproduced in angiotensin II-treated islets from lean C57BL/6J mice, suggesting the insulin response to each of the drugs is due to a direct effect on islets and mechanisms therein. In summary, sacubitril and valsartan each exert beneficial insulinotropic, glycemic and weight-reducing effects in obese and/or diabetic mice when administered alone; however, when combined, mechanisms within the islet contribute to their inability to enhance insulin release.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Insulin Resistance; Insulins; Mice; Mice, Inbred C57BL; Neprilysin; Receptors, Angiotensin; Tetrazoles; Valsartan