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Journal of Molecular Endocrinology Oct 2023Metabolic syndrome is a group of risk factors that increase the risk of developing metabolic and cardiovascular disease (CVD) and include obesity, dyslipidemia, insulin... (Review)
Review
Metabolic syndrome is a group of risk factors that increase the risk of developing metabolic and cardiovascular disease (CVD) and include obesity, dyslipidemia, insulin resistance, atherosclerosis, hypertension, coronary artery disease, and heart failure. Recent research indicates that excessive production of aldosterone and associated activation of mineralocorticoid receptors (MR) impair insulin metabolic signaling, promote insulin resistance, and increase the risk of developing metabolic syndrome and CVD. Moreover, activation of specific epithelial sodium channels (ENaC) in endothelial cells (EnNaC), which are downstream targets of endothelial-specific MR (ECMR) signaling, are also believed to play a crucial role in the development of metabolic syndrome and CVD. These adverse effects of ECMR/EnNaC activation are mediated by increased oxidative stress, inflammation, and lipid metabolic disorders. It is worth noting that ECMR/EnNaC activation and the pathophysiology underlying metabolic syndrome and CVD appears to exhibit sexual dimorphism. Targeting ECMR/EnNaC signaling may have a beneficial effect in preventing insulin resistance, diabetes, metabolic syndrome, and related CVD. This review aims to examine our current understanding of the relationship between MR activation and increased metabolic syndrome and CVD, with particular emphasis placed on the role for endothelial-specific ECMR/EnNaC signaling in these pathological processes.
Topics: Humans; Metabolic Syndrome; Cardiovascular Diseases; Receptors, Mineralocorticoid; Insulin Resistance; Epithelial Sodium Channels; Endothelial Cells
PubMed: 37610001
DOI: 10.1530/JME-23-0066 -
PloS One 2023Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of this analysis is to compare drug treatments of DKD by means of a systemic review and a network meta-analysis.
METHODS
We searched Medline, CENTRAL and clinicaltrials.gov for randomized, controlled studies including adults with DKD treated with the following drugs of interest: single angiotensin-converting-enzyme-inhibitor or angiotensin-receptor-blocker (single ACEi/ARB), angiotensin-converting-enzyme-inhibitor and angiotensin-receptor-blocker combination (ACEi+ARB combination), aldosterone antagonists, direct renin inhibitors, non-steroidal mineralocorticoid-receptor-antagonists (nsMRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). As primary endpoints, we defined: overall mortality and end-stage kidney disease, as secondary endpoints: renal composite outcome and albuminuria and as safety endpoints: acute kidney injury, hyperkalemia and hypotension. Under the use of a random effects model, we computed the overall effect estimates using the statistic program R4.1 and the corresponding package "netmeta". Risk of bias was assessed using the RoB 2 tool and the quality of evidence of each pairwise comparison was rated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation).
RESULTS
Of initial 3489 publications, 38 clinical trials were found eligible, in total including 42346 patients. Concerning the primary endpoints overall mortality and end stage kidney disease, SGLT2i on top of single ACEi/ARB compared to single ACEi/ARB was the only intervention significantly reducing the odds of mortality (OR 0.81, 95%CI 0.70-0.95) and end-stage kidney disease (OR 0.69, 95%CI 0.54-0.88). The indirect comparison of nsMRA vs SGLT2i in our composite endpoint suggests a superiority of SGLT2i (OR 0.60, 95%CI 0.47-0.76). Concerning safety endpoints, nsMRA and SGLT2i showed benefits compared to the others.
CONCLUSIONS
As the only drug class, SGLT2i showed in our analysis beneficial effects on top of ACEi/ARB treatment regarding mortality and end stage kidney disease and by that reconfirmed its position as treatment option for diabetic kidney disease. nsMRA reduced the odds for a combined renal endpoint and did not raise any safety concerns, justifying its application.
Topics: Adult; Humans; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Angiotensin Receptor Antagonists; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors; Kidney Failure, Chronic; Angiotensins; Diabetes Mellitus
PubMed: 37917640
DOI: 10.1371/journal.pone.0293183 -
Circulation May 2024Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown.
METHODS
EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes.
RESULTS
Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; =0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; =0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all <0.05).
CONCLUSIONS
Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.
Topics: Humans; Glucosides; Benzhydryl Compounds; Heart Failure; Male; Female; Myocardial Infarction; Aged; Middle Aged; Double-Blind Method; Sodium-Glucose Transporter 2 Inhibitors; Hospitalization; Treatment Outcome; Stroke Volume
PubMed: 38581389
DOI: 10.1161/CIRCULATIONAHA.124.069217 -
Journal of Clinical Medicine Oct 2023Hypertension is a critical component of cardiovascular disease progression in patients with chronic kidney disease, and specifically diabetic kidney disease (DKD).... (Review)
Review
Hypertension is a critical component of cardiovascular disease progression in patients with chronic kidney disease, and specifically diabetic kidney disease (DKD). Causation versus correlation remains up for debate, but what has been confirmed is the delay of DKD progression when hypertension is controlled or moved to guideline drive ranges. Many medications have been studied and used in real world experience for best outcomes, and we discuss below the proven winners thus far making up the renin angiotensin aldosterone system. As well, we discuss guideline changing medications including sodium-glucose cotransporter 2 inhibitors and newer generation mineralocorticoid receptor antagonists. With the growing prevalence of diabetes and DKD in the population, newer agents are emerging in multiple drug class and will be highlighted below. Clinicians continue to search for the optimal care plans for this challenging patient population.
PubMed: 37959333
DOI: 10.3390/jcm12216868 -
JACC. Heart Failure Aug 2023Approximately 25% of patients admitted to hospitals for worsening heart failure (WHF) are readmitted within 30 days. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Approximately 25% of patients admitted to hospitals for worsening heart failure (WHF) are readmitted within 30 days.
OBJECTIVES
The authors conducted a post hoc analysis of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post-WHF) trial to evaluate the efficacy of sotagliflozin versus placebo to decrease mortality and HF-related events among patients who began study treatment on or before discharge from their index hospitalization.
METHODS
The main endpoint of interest was cardiovascular death or HF-related event (HF hospitalization or urgent care visit) occurring within 90 and 30 days after discharge for the index WHF hospitalization. Treatment comparisons were by proportional hazards models, generating HRs, 95% CIs, and P values.
RESULTS
Of 1,222 randomized patients, 596 received study drug on or before their date of discharge. Sotagliflozin reduced the main endpoint at 90 days after discharge (HR: 0.54 [95% CI: 0.35-0.82]; P = 0.004) and at 30 days (HR: 0.49 [95% CI: 0.27-0.91]; P = 0.023) and all-cause mortality at 90 days (HR: 0.39 [95% CI: 0.17-0.88]; P = 0.024). In subgroup analyses, sotagliflozin reduced the 90-day main endpoint regardless of sex, age, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, left ventricular ejection fraction, or mineralocorticoid receptor agonist use. Sotagliflozin was well-tolerated but with slightly higher rates of diarrhea and volume-related events than placebo.
CONCLUSIONS
Starting sotagliflozin before discharge in patients with type 2 diabetes hospitalized for WHF significantly decreased cardiovascular deaths and HF events through 30 and 90 days after discharge, emphasizing the importance of beginning sodium glucose cotransporter treatment before discharge.
Topics: Humans; Diabetes Mellitus, Type 2; Heart Failure; Hospitalization; Stroke Volume; Ventricular Function, Left
PubMed: 37558385
DOI: 10.1016/j.jchf.2023.05.026 -
Frontiers in Endocrinology 2023Diabetic kidney disease (DKD) is a common disorder with numerous severe clinical implications. Due to a high level of fibrosis and inflammation that contributes to renal... (Review)
Review
Diabetic kidney disease (DKD) is a common disorder with numerous severe clinical implications. Due to a high level of fibrosis and inflammation that contributes to renal and cardiovascular disease (CVD), existing treatments have not effectively mitigated residual risk for patients with DKD. Excess activation of mineralocorticoid receptors (MRs) plays a significant role in the progression of renal and CVD, mostly by stimulating fibrosis and inflammation. However, the application of traditional steroidal MR antagonists (MRAs) to DKD has been limited by adverse events. Finerenone (FIN), a third-generation non-steroidal selective MRA, has revealed anti-fibrotic and anti-inflammatory effects in pre-clinical studies. Current clinical trials, such as FIDELIO-DKD and FIGARO-DKD and their combined analysis FIDELITY, have elucidated that FIN reduces the kidney and CV composite outcomes and risk of hyperkalemia compared to traditional steroidal MRAs in patients with DKD. As a result, FIN should be regarded as one of the mainstays of treatment for patients with DKD. In this review, the safety, efficiency, and potential mechanisms of FIN treatment on the renal system in patients with DKD is reviewed.
Topics: Humans; Diabetic Nephropathies; Cardiovascular Diseases; Inflammation; Fibrosis; Diabetes Mellitus
PubMed: 38174337
DOI: 10.3389/fendo.2023.1320603 -
Journal of the American Heart... Apr 2024Aldosterone is a steroid hormone that primarily acts through activation of the mineralocorticoid receptor (MR), a nuclear receptor responsible for downstream genomic... (Review)
Review
Aldosterone is a steroid hormone that primarily acts through activation of the mineralocorticoid receptor (MR), a nuclear receptor responsible for downstream genomic regulation. Classically, activation of the MR in the renal tubular epithelium is responsible for sodium retention and volume expansion, raising systemic blood pressure. However, activation of the MR across a wide distribution of tissue types has been implicated in multiple adverse consequences for cardiovascular, cerebrovascular, renal, and metabolic disease, independent of blood pressure alone. Primary aldosteronism, heart failure, and chronic kidney disease are states of excessive aldosterone production and MR activity where targeting MR activation has had clinical benefits out of proportion to blood pressure lowering. The growing list of established and emerging therapies that target aldosterone and MR activation may provide new opportunities to improve clinical outcomes and enhance cardiovascular and renal health.
Topics: Humans; Aldosterone; Blood Pressure; Hyperaldosteronism; Receptors, Mineralocorticoid; Heart; Kidney; Mineralocorticoid Receptor Antagonists; Drug-Related Side Effects and Adverse Reactions; Hypertension
PubMed: 38497438
DOI: 10.1161/JAHA.123.030142 -
Journal of Lipid Research Nov 2023Activation of brown adipose tissue (BAT) contributes to energy dissipation and metabolic health. Although mineralocorticoid receptor (MR) antagonists have been...
Activation of brown adipose tissue (BAT) contributes to energy dissipation and metabolic health. Although mineralocorticoid receptor (MR) antagonists have been demonstrated to improve metabolism under obesity, the underlying mechanisms remain incompletely understood. We aimed to evaluate the role of BAT MR in metabolic regulation. After 8 weeks of high-fat diet (HFD) feeding, BAT MR KO (BMRKO) mice manifested significantly increased bodyweight, fat mass, serum fasting glucose, and impaired glucose homeostasis compared with littermate control (LC) mice, although insulin resistance and fasting serum insulin were not significantly changed. Metabolic cage experiments showed no change in O consumption, CO production, or energy expenditure in obese BMRKO mice. RNA sequencing analysis revealed downregulation of genes related to fatty acid metabolism in BAT of BMRKO-HFD mice compared with LC-HFD mice. Moreover, H&E and immunohistochemical staining demonstrated that BMRKO exacerbated HFD-induced macrophage infiltration and proinflammatory genes in epididymal white adipose tissue (eWAT). BMRKO-HFD mice also manifested significantly increased liver weights and hepatic lipid accumulation, an increasing trend of genes related to lipogenesis and lipid uptake, and significantly decreased genes related to lipolytic and fatty acid oxidation in the liver. Finally, the level of insulin-induced AKT phosphorylation was substantially blunted in eWAT but not liver or skeletal muscle of BMRKO-HFD mice compared with LC-HFD mice. These data suggest that BAT MR is required to maintain metabolic homeostasis, likely through its regulation of fatty acid metabolism in BAT and impacts on eWAT and liver.
Topics: Animals; Mice; Adipocytes, Brown; Adipose Tissue, Brown; Diet, High-Fat; Fatty Acids; Glucose; Insulin; Insulin Resistance; Lipids; Mice, Inbred C57BL; Mice, Obese; Receptors, Mineralocorticoid; Energy Metabolism
PubMed: 37734559
DOI: 10.1016/j.jlr.2023.100449 -
Cureus Aug 2023It is believed that 9-18% of patients with hypertension have resistant hypertension, a serious medical disease. The increased cardiovascular risk associated with this... (Review)
Review
It is believed that 9-18% of patients with hypertension have resistant hypertension, a serious medical disease. The increased cardiovascular risk associated with this illness demands appropriate diagnosis and treatment. It is necessary to conduct an in-depth investigation of the various etiologies, indicators of risk, and multiple disorders of resistant hypertension. This is crucial in order to establish the diagnosis and make the best decisions regarding therapy. Treatment should also take lifestyle changes into account in addition to medicinal and interventional therapy. When there is a suspicion of resistant hypertension, examining the medications used to treat the hypertensive patient after ruling out pseudo hypertension, improper blood pressure monitoring and control, and the white-coat effect are necessary. Resistant hypertension, according to a specific definition, is a condition that cannot be treated with more than two antihypertensive drugs, including a diuretic. An effective multidrug therapy for the treatment of resistant hypertension includes angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, diuretics, long-acting calcium channel blockers, and mineralocorticoid receptor antagonists. However, alternative, cutting-edge treatments, such as renal denervation or baroreflex activation, could develop a brand-new avenue for decreasing blood pressure. These new surgical interventions might prove out to be of immense importance in coming times. Secondary causes of resistant hypertension, such as obstructive sleep apnea, coronary artery diseases, nephropathy, or endocrinal diseases, must be checked out in order to make an accurate diagnosis of this illness. This review article briefly summarizes the epidemiology, risk factors, causes, pathogenesis, diagnosis, and treatment approaches that may help with the long-term management of resistant hypertension.
PubMed: 37719515
DOI: 10.7759/cureus.43617