Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials

Ehud Grossman1,4, Moshe Laudon2, Nava Zisapel2,31Department of Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel; 2Neurim Pharmaceuticals Ltd, Tel Aviv, Israel and 3Department of Neurobiology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; 4Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelBackground: Patients with nocturnal hypertension are at higher risk for cardiovascular complications such as myocardial infarction and cerebrovascular insult. Published studies inconsistently reported decreases in nocturnal blood pressure with melatonin.Methods: A meta-analysis of the efficacy and safety of exogenous melatonin in ameliorating nocturnal blood pressure was performed using a random effects model of all studies fitting the inclusion criteria, with subgroup analysis of fast-release versus controlled-release preparations.Results: Seven trials (three of controlled-release and four of fast-release melatonin) with 221 participants were included. Meta-analysis of all seven studies did not reveal significant effects of melatonin versus placebo on nocturnal blood pressure. However, subgroup analysis revealed that controlled-release melatonin significantly reduced nocturnal blood pressure whereas fast-release melatonin had no effect. Systolic blood pressure decreased significantly with controlled-release melatonin (-6.1 mmHg; 95% confidence interval [CI] -10.7 to -1.5; P = 0.009) but not fast-release melatonin (-0.3 mmHg; 95% CI -5.9 to 5.30; P = 0.92). Diastolic blood pressure also decreased significantly with controlled-release melatonin (-3.5 mmHg; 95% CI -6.1 to -0.9; P = 0.009) but not fast-release melatonin (-0.2 mmHg; 95% CI -3.8 to 3.3; P = 0.89). No safety concerns were raised.Conclusion: Add-on controlled-release melatonin to antihypertensive therapy is effective and safe in ameliorating nocturnal hypertension, whereas fast-release melatonin is ineffective. It is necessary that larger trials of longer duration be conducted in order to determine the long-term beneficial effects of controlled-release melatonin in patients with nocturnal hypertension.Keywords: melatonin, nocturnal blood pressure, meta-analysis&nbsp

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Uric acid variability at midlife as an independent predictor of coronary heart disease and all-cause mortality.

BackgroundSerum uric acid (SUA) has long been associated with cardiovascular disease. Variability of serum uric acid (SUA) has seldom been examined in association with long-term morbidity and mortality. Therefore, we aimed to investigate the association between SUA variability and long-term all-cause and specific-cause mortality.MethodsAmong 10,059 men, aged 40-65, tenured civil servants and municipal employees in Israel, 8822 participants who were examined in 1963, 1965 and 1968 had assessment of diabetic and coronary morbidity status and SUA levels. We conducted analysis examining whether the standard deviations (SD) of Z-scores of SUA across study visits predicted coronary heart disease (CHD) and mortality. Hazard ratios (HR) associated with the SD of SUA-Z were calculated for stroke, CHD mortality and all-cause mortality associated with quartiles of the above variability.ResultsMultivariate analysis of 18-year CHD mortality yielded a significant association with the 1963-1968 SD of SUA-Z with age adjusted HR of CHD mortality of 0.97 (95% CI, 0.8-1.19), 1.05 (95% CI, 0.87-1.28) and 1.37 (95% CI, 1.15-1.65) for quartiles 2 to 4 respectively). The results of all-cause mortality similarly and strongly indicated increasing age-adjusted mortality risk with increasing SD of SUA-Z: HR = 1.08 (95% CI, 0.97-1.21), 1.15 (1.03-1.28) and 1.37 (1.23-1.51). No association was observed between the SD of SUA-Z and stroke mortality.ConclusionIn this cohort of tenured male workers, with diverse occupations, higher variability of SUA measurement taken over 5 years was clearly predictive of 18-year CHD and all-cause mortality, above and beyond the SUA levels proper