Navigating Heart Failure: Unveiling Sex Disparities in Guideline-Directed Medical Therapy Combinations.

Major heart failure (HF) trials remain insufficient in terms of assessing the differences in clinical characteristics, biomarkers, treatment efficacy, and safety because of the under-representation of women. The study aimed to present sex-related disparities in HF management, including differences in demographics, co-morbidities, cardiac biomarkers, prescribed medications, and treatment outcomes. The study utilized anonymized data from the Turkish Ministry of Health's National Electronic Database between January 1, 2016, and December 31, 2022. The cohort analysis included 2,501,231 adult patients with HF. Specific therapeutic combinations were analyzed using a Cox regression model to obtain relative risk reduction for all-cause death. The primary end point was all-cause mortality. In the cohort, 48.7% (n = 1,218,911) were male, whereas 51.3% (n = 1,282,320) were female. Female patients exhibited a higher median age (71 vs 68 years) and manifested higher prevalence of diabetes mellitus, anemia, atrial fibrillation, anxiety, and ischemic stroke. Male patients demonstrated higher rates of previous myocardial infarction, dyslipidemia, chronic obstructive pulmonary disease, and chronic kidney disease. Higher concentrations of natriuretic peptides were observed in female patients. Renin-angiotensin aldosterone inhibitor, ß blockers, mineralocorticoid receptor antagonists, sodium/glucose cotransporter 2 inhibitor (SGLT2i), and ivabradine were more commonly prescribed in male patients, whereas loop diuretics, digoxin, and ferric carboxymaltose were more frequent in female patients. Male patients had higher rates of cardiac resynchronization therapy and implantable cardioverter defibrillator implantation rates. All-cause mortality and hospitalization rates were higher in male patients. Compared with monotherapy, all combinations, including SGLT2i, showed a beneficial effect on all-cause mortality in both female and male patients with HF. In hospitalized patients with HF, the addition of digoxin to renin-angiotensin aldosterone inhibitor, mineralocorticoid receptor antagonists, and ß blockers was superior to monotherapy regarding all-cause mortality in female patients with HF compared with male patients with HF. In conclusion, this study highlights that sex-specific responses to HF medication combinations compared with monotherapy and differences in co-morbidities underscore the importance of tailored management strategies. Digoxin showed a contrasting effect on all-cause mortality between both sexes after hospitalization, whereas SGLT2i exhibited a consistent beneficial effect in both sexes when added to all combinations.

Angiotensin-Neprilysin inhibition in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials.

BACKGROUND: The effect of sacubitril/valsartan on patients with heart failure (HF) with preserved ejection fraction (HFpEF) is a topic of ongoing debate. METHODS: Medline was queried from inception through the last week of May 2023 for randomized studies assessing the effects of sacubitril/valsartan in patients with HFpEF. For continuous outcomes, we pooled either the geometric mean ratios (gMR) or weighted mean difference (WMD) with 95% confidence intervals (CI). For dichotomous outcomes, we pooled Risk ratios (RR) with 95% CI. RESULTS: Four trials were included (N=8,129). Compared to the control, sacubitril/valsartan was associated with a reduction in NT-proBNP levels (gMR: 0.84, 95% CI 0.80, 0.88) and improvement in KCCQ score (WMD: 0.85, 95% CI: 0.02, 1.67). We observed no differences for HF hospitalization (RR: 0.90, 95% CI: 0.79, 1.01), cardiovascular mortality (RR: 0.83, 95% CI: 0.52, 1.32), all-cause mortality (RR: 0.99, 95% CI: 0.86-1.13) and improvement (RR: 1.15, 95% CI: 0.93, 1.42) or worsening (RR: 0.92, 95% CI: 0.78, 1.09) of NYHA class between the sacubitril/valsartan and comparator group. Sacubitril/valsartan was generally safe, and patients were less likely to have a ≥50% decline in eGFR compared to control (RR: 0.60, 95% CI: 0.39, 0.92). CONCLUSION: Pooled analysis suggests that sacubitril/valsartan reduces natriuretic peptide levels and improves the quality of life in patients with HFpEF, which may translate into better clinical outcomes as observed by a numerical trend towards improvement in major HF outcomes with sacubitril/valsartan therapy.

Management of Heart Failure With Reduced Ejection Fraction in Patients With Diabetes Mellitus and Chronic Kidney Disease.

Heart failure (HF), diabetes, and chronic kidney disease (CKD) frequently coexist, with one comorbidity worsening the prognosis of another. ß-blockers, angiotensin-receptor-neprilysin inhibitors, renin-angiotensin-aldosterone system inhibitors, mineralocorticoid-receptor antagonists, and sodium-glucose cotransporter-2 inhibitors all have been shown to reduce mortality in patients with HF with reduced ejection fraction. However, their uptake in real-world clinical practice remains low, especially among patients who have multiple other comorbidities such as CKD and diabetes. The management of HF in patients with diabetes and CKD can be especially challenging because these patients typically are older, frail, and have multiple other comorbidities, and guideline-directed medical therapy used in HF potentially can affect renal function acutely and chronically. In this article, we discuss the available evidence for each of the foundational HF therapies in patients with diabetes and CKD, emphasizing the current challenges and outlining future directions to optimize the management of HF among these high-risk patients.

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management.

Importance: The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown. Objective: To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF. Design, Setting, and Participants: This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023. Main Outcomes and Measures: A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs. Results: Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%). Conclusions and Relevance: Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.

Pharmacogenetics of angiotensin modulators according to APOE-ϵ4 alleles and the ACE insertion/deletion polymorphism in Alzheimer's disease.

OBJECTIVE: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-ß by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-ß-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators. METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs. RESULTS: For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations. CONCLUSION: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

Blood pressure management and long-term outcomes in kidney transplantation: a holistic view over a 35-year period.

INTRODUCTION: Hypertension is a burden for most kidney transplant recipients. Whether respect of hypertension guidelines results in better outcomes is unknown. METHODS: In this multicenter study, office blood pressure at 12 months following transplantation (i.e., after > 20 outpatient visits), and survival were assessed over 35 years among 2004 consecutive kidney transplant recipients who received a first kidney graft from 1985 to 2019 (follow-up: 26,232 patient-years). RESULTS: Antihypertensive medications were used in 1763/2004 (88.0%) patients. Renin-angiotensin-system blockers were used in 35.6% (47.1% when proteinuria was > 0.5 g/day) and calcium-channel blockers were used in 6.0% of patients. Combined treatment including renin-angiotensin-system-blockers, calcium-channel blockers and diuretics was used in 15.4% of patients receiving ≥ 3 antihypertensive drugs. Blood pressure was controlled in 8.3%, 18.8% and 43.1%, respectively, depending on definition (BP < 120/80, < 130/80, < 140/90 mmHg, respectively) and has not improved since the year 2001. Two-thirds of patients with uncontrolled blood pressure received < 3 antihypertensive classes. Low sodium intake < 2 g/day (vs ≥ 2) was not associated with better blood pressure control. Uncontrolled blood pressure was associated with lower patient survival (in multivariable analyses) and graft survival (in univariate analyses) vs controlled hypertension or normotension. Low sodium intake and major antihypertensive classes had no influence on patient and graft survival. CONCLUSIONS: Pharmacological recommendations and sodium intake reduction are poorly respected, but even when respected, do not result in better blood pressure control, or patient or graft survival. Uncontrolled blood pressure, not the use of specific antihypertensive classes, is associated with reduced patient, and to a lesser extent, reduced graft survival, even using the 120/80 mmHg cut-off.

Risk Factors, Use of Preventive Drugs, and Cardiovascular Events in Diabetes Mellitus: The PURE Türkiye Cohort.

BACKGROUND: The risk of cardiovascular disease is correlated with the frequency and control of associated risk factors in diabetes mellitus and may vary according to country. We evaluated risk factors for cardiovascular disease, cardiovascular events, and the use of preventive medications in patients with diabetes mellitus using the Prospective Urban and Rural Epidemiological Türkiye cohort. METHODS: Patients with diabetes mellitus versus without diabetes mellitus were compared for risk factors, cardioprotective drugs (angiotensin-converting enzyme inhibitors or angiotensin-II receptor antagonists, statins, and antiplatelets), and cardiovascular events. The primary outcome was major cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, or heart failure). RESULTS: Among 4041 participants, 549 (13.6%) had diabetes mellitus. The mean age (54.8 ± 8.4 vs. 49.3 ± 9.0 years, P <.001) and proportion of women (65.4% vs. 59.9%, P =.014) were higher in diabetics compared with non-diabetics. Hypertension, history of coronary heart disease, and use of statin, antiplatelets, and angiotensin-converting enzyme inhibitors or angiotensin-II receptor antagonists were more common in diabetics; however, the use of these medications at baseline was lower than optimal even in patients with diabetes mellitus and concomitant coronary heart disease (statin 31.2%, antiplatelets 46.9%, and angiotensin-converting enzyme inhibitors or angiotensin-II receptor antagonists 54.7%). During 11.5 years of follow-up, major cardiovascular events occurred in 288 (7.1%) patients, and the risk was higher in diabetics [hazard ratio (95% confidence interval) 1.71 (1.30-2.24); P <.001]. The increase in the risk of future events was comparable for those with diabetes mellitus alone without cardiovascular disease [hazard ratio 1.62 (1.20-2.20)] versus those with cardiovascular disease alone without diabetes mellitus [hazard ratio 1.31 (0.83-2.07)] and was additive in those with both conditions [hazard ratio 2.79 (1.65-4.69)]. The risk of major coronary events (myocardial infarction, angina, percutaneous, or surgical coronary intervention) was also higher in diabetes mellitus [hazard ratio 1.64 (1.26-2.15); P <.001]. CONCLUSION: Patients with diabetes mellitus have a higher risk of major cardiovascular events, and the risk is comparable to that observed in those with cardiovascular disease but no diabetes mellitus. The use of preventive medicines for cardiovascular diseases is disturbingly low in diabetics.

Guideline-directed medical therapy for HFrEF: sequencing strategies and barriers for life-saving drug therapy.

Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials have led to the introduction of four main drug classes into the 2021 ESC guideline, namely angiotensin-receptor neprilysin inhibitors/angiotensin-converting-enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. The life-saving effect of these therapies has been shown to be additive and becomes apparent within weeks, which is why maximally tolerated or target doses of all drug classes should be strived for as quickly as possible. Recent evidence, such as the STRONG-HF trial, demonstrated that rapid drug implementation and up-titration is superior to the traditional and more gradual step-by-step approach where valuable time is lost to up-titration. Accordingly, multiple rapid drug implementation and sequencing strategies have been proposed to significantly reduce the time needed for the titration process. Such strategies are urgently needed since previous large-scale registries have shown that guideline-directed medical therapy (GDMT) implementation is a challenge. This challenge is reflected by generally low adherence rates, which can be attributed to factors considering the patient, health care system, and local hospital/health care provider. This review of the four medication classes used to treat HFrEF seeks to present a thorough overview of the data supporting current GDMT, discuss the obstacles to GDMT implementation and up-titration, and identify multiple sequencing strategies that could improve GDMT adherence. Sequencing strategies for GDMT implementation. GDMT: guideline-directed medical therapy; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNi: angiotensin receptor-neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose co-transporter 2 inhibitor.

Safety and efficacy of new potassium binders on hyperkalemia management in patients with heart failure: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hyperkalemia leads to suboptimal use of evidence-based therapies in patients with heart failure (HF). Therefore, we aimed to assess whether new potassium binders are effective and safe to promote medical optimization in patients with HF. METHODS: MEDLINE, Cochrane, and Embase were searched for randomized controlled trials (RCTs) that reported outcomes after initiation of Patiromer or Sodium Zirconium Cyclosilicate (SZC) versus placebo in patients with HF at high risk of hyperkalemia development. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random effects model. Quality assessment and risk of bias were performed according to Cochrane recommendations. RESULTS: A total of 1432 patients from 6 RCTs were included, of whom 737 (51.5%) patients received potassium binders. In patients with HF, potassium binders increased the use of renin-angiotensin-aldosterone inhibitors (RR 1.14; 95% CI 1.02-1.28; p = 0.021; I2 = 44%) and reduced the risk of hyperkalemia (RR 0.66; 95% CI 0.52-0.84; p < 0.001; I2 = 46%). The risk of hypokalemia was significantly increased in patients treated with potassium binders (RR 5.61; 95% CI 1.49-21.08; p = 0.011; I2 = 0%). There was no difference between groups in all-cause mortality rates (RR 1.13; 95% CI 0.59-2.16; p = 0.721; I2 = 0%) or in adverse events leading to drug discontinuation (RR 1.08; 95% CI 0.60-1.93; p = 0.801; I2 = 0%). CONCLUSION: The use of new potassium binders Patiromer or SZC in patients with HF at risk for hyperkalemia increased the rates of medical therapy optimization with renin-angiotensin-aldosterone inhibitors and reduced the incidence of hyperkalemia, at the cost of an increased prevalence of hypokalemia.

Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure.

BACKGROUND: U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown. OBJECTIVES: PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event. METHODS: PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP. RESULTS: In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95). CONCLUSIONS: Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634).

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

A review of current key guidelines for managing high-risk patients with diabetes and heart failure and future prospects.

We reviewed recent guidelines on the management of heart failure (HF) in patients with diabetes. Major recommendations in European and US society guidelines were scrutinized. First, sodium-glucose co-transporter 2 inhibitors are now recommended treatments for all patients with symptomatic HF (stage C and D; New York Heart Association class II-IV), irrespective of the presence of type 2 diabetes and left ventricular ejection fraction (LVEF). Second, patients with HF and reduced EF (LVEF ≤40%) should have foundational therapies from four drug classes (sodium-glucose co-transporter 2 inhibitor, angiotensin-receptor neprilysin inhibitor, beta-blocker and mineralocorticoid receptor antagonist). Third, patients with HF with mildly reduced (41%-49%) and preserved (≥50%) LVEF may also benefit from angiotensin-receptor neprilysin inhibitor, beta-blocker and mineralocorticoid receptor antagonist therapy, although evidence for these is less robust. Fourth, selected patients should be considered for other therapies such as diuretics (if congestion), anticoagulation (if atrial fibrillation) and cardiac device therapy. Fifth, glucose-lowering therapies such as thiazolidinediones and certain dipeptidyl peptidase-4 inhibitors (such as saxagliptin and alogliptin) should be avoided in patients with HF. Sixth, guidelines recommend enrolment of patients with HF into exercise rehabilitation and multidisciplinary HF management programmes. Particular attention should be paid to important comorbidities such as obesity, alongside pharmacological therapies. As diabetes and obesity are major risk factors for HF, earlier consideration of, and diagnosis of HF, followed by guideline-directed medical therapy can meaningfully improve patients' lives. Diabetes doctors would do well to understand the basics of such guidelines to help improve all aspects of HF diagnosis and care.

Candesartan, an angiotensin-II receptor blocker, ameliorates insulin resistance and hepatosteatosis by reducing intracellular calcium overload and lipid accumulation.

Insulin resistance is a major contributor to the pathogenesis of several human diseases, including type 2 diabetes, hypertension, and hyperlipidemia. Notably, insulin resistance and hypertension share common abnormalities, including increased oxidative stress, inflammation, and organelle dysfunction. Recently, we showed that excess intracellular Ca2+, a known pathogenic factor in hypertension, acts as a critical negative regulator of insulin signaling by forming Ca2+-phosphoinositides that prevent the membrane localization of AKT, a key serine/threonine kinase signaling molecule. Whether preventing intracellular Ca2+ overload improves insulin sensitivity, however, has not yet been investigated. Here, we show that the antihypertensive agent candesartan, compared with other angiotensin-II receptor blockers, has previously unrecognized beneficial effects on attenuating insulin resistance. We found that candesartan markedly reduced palmitic acid (PA)-induced intracellular Ca2+ overload and lipid accumulation by normalizing dysregulated store-operated channel (SOC)-mediated Ca2+ entry into cells, which alleviated PA-induced insulin resistance by promoting insulin-stimulated AKT membrane localization and increased the phosphorylation of AKT and its downstream substrates. As pharmacological approaches to attenuate intracellular Ca2+ overload in vivo, administering candesartan to obese mice successfully decreased insulin resistance, hepatic steatosis, dyslipidemia, and tissue inflammation by inhibiting dysregulated SOC-mediated Ca2+ entry and ectopic lipid accumulation. The resulting alterations in the phosphorylation of key signaling molecules consequently alleviate impaired insulin signaling by increasing the postprandial membrane localization and phosphorylation of AKT. Thus, our findings provide robust evidence for the pleiotropic contribution of intracellular Ca2+ overload in the pathogenesis of insulin resistance and suggest that there are viable approved drugs that can be repurposed for the treatment of insulin resistance and hypertension.

Renin-Angiotensin Inhibition and Outcomes in HFrEF and Advanced Kidney Disease.

BACKGROUND: Renin-angiotensin system inhibitors improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, less is known about their effectiveness in patients with HFrEF and advanced kidney disease. METHODS: In the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF), 1582 patients with HFrEF (ejection fraction ≤40%) had advanced kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2). Of these, 829 were not receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prior to admission, of whom 214 were initiated on these drugs prior to discharge. We calculated propensity scores for receipt of these drugs for each of the 829 patients and assembled a matched cohort of 388 patients, balanced on 47 baseline characteristics (mean age 78 years; 52% women; 10% African American; 73% receiving beta-blockers). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated comparing 2-year outcomes in 194 patients initiated on ACE inhibitors or ARBs to 194 patients not initiated on those drugs. RESULTS: The combined endpoint of heart failure readmission or all-cause mortality occurred in 79% and 84% of patients initiated and not initiated on ACE inhibitors or ARBs, respectively (HR associated with initiation, 0.79; 95% CI, 0.63-0.98). Respective HRs (95% CI) for the individual endpoints of - Respective HRs (95% CI) for the individual endpoints of all-cause mortality and heart failure readmission were 0.81 (0.63-1.03) and 0.63 (0.47-0.85). CONCLUSIONS: The findings from our study add new information to the body of cumulative evidence that suggest that renin-angiotensin system inhibitors may improve clinical outcomes in patients with HFrEF and advanced kidney disease. These hypothesis-generating findings need to be replicated in contemporary patients.

Gentisic acid protects against diabetic nephropathy in Nicotinamide-Streptozotocin administered male mice by attenuating oxidative stress and inflammation: The role of miR-200a/Keap1/Nrf2 pathway, renin-angiotensin system (RAS) and NF-кB.

Oxidative stress and inflammation play a pivotal role in the pathogenesis of diabetic nephropathy (DN). Local renin-angiotensin systems (RAS) contribute to the pathogenesis and progression of DN by exacerbating oxidative stress and inflammation.Gentisic acid (GA), a phenolic compound and also a metabolite of aspirin, is reported to possess antioxidant and anti-inflammatory properties. However, the protective effects of GA against DN remain to be elucidated. Nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg) were used to induce diabetes in male mice. Oral administration of GA once daily for 2 weeks (100 mg/kg) ameliorated diabetes-induced renal injury by reducing plasma creatinine, urea, blood urea nitrogen, and urinary albuminuria levels. Diabetic mice showed a significant increase in total oxidant status and malondialdehyde, along with decreased catalase, superoxide dismutase, and glutathione peroxidase in the kidney tissue, which was ameliorated in the GA-treated mice. Histopathological analysis showed that GA treatment reduced diabetes-induced renal injury. Furthermore, GA treatment was associated with the downregulation of miR-125b, nuclear factor kappa beta (NF-кB), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and upregulation of interleukin-10 (IL-10), miR-200a, and nuclear factor erythroid 2-related factor 2 (Nrf2) in the renal tissue. GA treatment also downregulated angiotensin-converting enzyme 1 (ACE1), angiotensin II receptor 1 (AT1R), and NADPH oxidase 2 (NOX 2) and upregulated angiotensin-converting enzyme 2 (ACE2). In conclusion, the ameliorative effects of GA against DN may be attributed to its powerful antioxidant and anti-inflammatory properties through the downregulation of NF-кB, upregulation of Nrf2, and modulation of RAS in renal tissue.

Impact of early initiation of renin-angiotensin blockade on renal function and clinical outcomes in patients with hypertensive emergency: a retrospective cohort study.

BACKGROUND: Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the renin-angiotensin-aldosterone (RAA) system is enormously activated in this disease, there are few reports that attempt to characterize the effect of early use of RAA inhibitors (RASi) on the temporal course of kidney function. METHODS: This retrospective cohort study was conducted to clarify whether the early use of RASi during hospitalization offered more favorable benefits on short-term renal function and long-term renal outcomes in patients with hypertensive emergencies. We enrolled a total of 49 patients who visited our medical center with acute severe hypertension and multiple organ dysfunction between April 2012 and August 2020. Upon admission, the patients were treated with intravenous followed by oral antihypertensive drugs, including RASi and Ca channel blockers (CCB). Kidney function as well as other laboratory and clinical parameters were compared between RASi-treated and CCB- treated group over 2 years. RESULTS: Antihypertensive treatment effectively reduced blood pressure from 222 ± 28/142 ± 21 to 141 ± 18/87 ± 14 mmHg at 2 weeks and eGFR was gradually restored from 33.2 ± 23.3 to 40.4 ± 22.5 mL/min/1.73m2 at 1 year. The renal effect of antihypertensive drugs was particularly conspicuous when RASi was started in combination with other conventional antihypertensive drugs at the early period of hospitalization (2nd day [IQR: 1-5.5]) and even in patients with moderately to severely diminished eGFR (< 30 mL/min/1.73 m2) on admission. In contrast, CCB modestly restored eGFR during the observation period. Furthermore, renal survival probabilities were progressively deteriorated in patients who had manifested reduced eGFR (< 15 mL/min/1.73 m2) or massive proteinuria (urine protein/creatinine ≥ 3.5 g/gCr) on admission. Early use of RASi was associated with a favorable 2-year renal survival probability (0.90 [95%CI: 0.77-1.0] vs. 0.63 [95%CI: 0.34-0.92] for RASi ( +) and RASi (-), respectively, p = 0.036) whereas no apparent difference in renal survival was noted for CCB. CONCLUSIONS: Early use of RASi contributes to the renal functional recovery from acute reduction in eGFR among patients with hypertensive emergencies. Furthermore, RASi offers more favorable effect on 2-year renal survival, compared with CCB.

The Role of ACE-Inhibitors and ARBs in reducing hypertrophic scarring following bilateral breast reduction.

BACKGROUND: The angiotensin-renin system (ARS) has been shown to play a role in the promotion of tissue fibrosis through angiotensin II activation of the angiotensin-receptor 1 and subsequently transforming growth factor beta-1 (TGF- ß1). Breast reduction surgery is known to have a potential complication of hypertrophic scarring. The primary objective of this study is to assess whether the use of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARBs) by patients undergoing bilateral reduction mammoplasty is correlated with a reduction in hypertrophic scarring complications post-operatively. METHODS: A retrospective chart review of all patients who received bilateral breast reduction surgery in our province over a 10-year period was performed. Patient charts were reviewed for post-operative hypertrophic scarring as well as medications being used around the time of surgery. The rate of hypertrophic scarring within patients treated with an ACEi or ARB for existing hypertension were compared with the rest of the population. RESULTS: A total of 981 patients met the inclusion criteria of the study. The overall incidence of hypertrophic scarring was 6%. Within the population, 132 (14%) of patients had a clinical diagnosis of hypertension. Of the patients who were managed with an ACEi or ARB, one (2%) patient developed hypertrophic scarring post-operatively. This was significantly less than the total population and the remainder of the population with hypertension treated with a medication other than an ACEi or ARB. CONCLUSIONS: This study investigated the impact of routine ACEi or ARB use by patients undergoing bilateral reduction mammoplasty and demonstrated a statistically significant reduction in the incidence of hypertrophic scarring. This study is one of the first to investigate ACEi or ARB use in humans to reduce rates of unsightly scarring. LEVEL OF EVIDENCE: Level III.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients.

BACKGROUND: Activities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients METHOD: A single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. RESULTS: 742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56-0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53-0.86],p = 0.002) for overall survival. CONCLUSION: In this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

Evaluating Guideline Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction Post-coronary Artery Bypass Grafting.

Background: Limited evidence regarding the use of guideline directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) undergoing coronary artery bypass grafting (CABG) is available. Objective: The purpose of this study was to characterize prescription of HFrEF GDMT use before and after CABG. Methods: A retrospective analysis of adult patients with an ejection fraction ≤40% undergoing CABG was performed. The primary objective was to evaluate patients receiving HFrEF GDMT, defined as a heart failure beta-blocker (HFBB) and a renin-angiotensin inhibitor preoperatively and postoperatively. Secondary outcomes included dosing, percent of patients on each individual therapy, mineralocorticoid receptor antagonist (MRA) use, and the combination thereof. The follow up period was 1 year. Results: Thirty-eight patients met criteria for inclusion. Prior to CABG, 52.6% of patients were receiving HFrEF GDMT. The prescribing rate of HFrEF GDMT was not significantly higher at any point within 1 year postoperatively (P = .299). The rate of renin-angiotensin inhibitors, HFBB, and aldosterone antagonists use significantly increased from 13.2% preoperatively to 36.8% at 1 year after CABG (P = .022). Doses of individual therapies were not significantly different across all time points preoperatively and postoperatively. Conclusion: HFrEF GDMT use and doses of individual therapies after CABG were not maximized. Collaborative efforts between cardiac surgeons, heart failure cardiologists, and pharmacists could be used to optimize HFrEF GDMT use and dose titration.

Risk of Acute Kidney Injury Among Older Adults With Heart Failure and With Reduced Ejection Fraction Treated With Angiotensin-Neprilysin Inhibitor vs Renin-Angiotensin System Inhibitor in Routine Clinical Care.

BACKGROUND: The acute hemodynamic effects of sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), may result in early changes in kidney function, raising concerns about acute kidney injury (AKI), particularly in those who are naïve to renin-angiotensin system inhibitors (RASis). METHODS: We conducted a cohort study using U.S. Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥ 65 years newly initiating ARNI or RASi, with no prior use of either drug class, were included. The primary outcome was hospitalization due to AKI as the primary discharge diagnosis, and the secondary outcome included AKI as a primary or secondary discharge diagnosis. AKI risks were described under an as-treated follow-up approach, with censoring on treatment discontinuation, switch, insurance disenrollment, death, or administrative censoring as well as an intent-to-treat approach. Propensity-score-based fine-stratification weighting was used to account for potential confounding by 81 pre-exposure characteristics. Cumulative incidence functions were used to report absolute risks, and Cox proportional hazards models were used to provide hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We included 27,166 patients with a mean (SD) age of 73 (7.3) years, and 4155 (15.3%) were initiating ARNI. After propensity score weighting, the 180-day cumulative incidence was 2.7% (2.4%-3.1%) among RASi initiators and 2.7% (2.2%-3.5%) among ARNI initiators for the primary outcome, and it was 6.5% (6.0%-7.1%) and 6.1% (5.2%-7.1%), respectively, for the secondary outcome under as-treated follow-up. HR (95% CI) comparing ARNI with RASi were 0.91 (95% CI: 0.72-1.16) for the primary outcome and 0.92 (95% CI: 0.79-1.08) for the secondary outcome. Similar results were observed in the intent-to-treat analysis. CONCLUSIONS: Among a large cohort of U.S. Medicare beneficiaries with HFrEF, ARNI treatment was not associated with higher rates of AKI than RASi treatment. These results provide reassurance for providers considering ARNI initiation in older patients who are RASi-naïve.