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Introduction Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear. Methods We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimated glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy or death due to kidney disease) in EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure. Results In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid and urine albumin-to-creatinine ratio mediated 79.4%, 33.2% and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%) and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis. Conclusions Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to evaluate the bidirectional relationship between kidney and cardiovascular (CV) events in trial participants with type 2 diabetes and CV disease. Methods and results: Post hoc analyses of EMPA‐REG OUTCOME using Cox regression models were performed to assess the association of baseline factors with risk of a kidney event and bidirectional associations of incident kidney events and CV events. Among placebo‐treated participants, baseline factors significantly associated with greater kidney event risk included lower baseline estimated glomerular filtration rate, albuminuria, higher uric acid, low‐density lipoprotein cholesterol levels, and prior heart failure (HF). Coronary artery disease was not associated with increased risk. In placebo‐treated participants, occurrence of an incident non‐fatal kidney event increased the subsequent risk of hospitalization for HF (HHF) but not 3‐point major adverse CV events (non‐fatal stroke, non‐fatal myocardial infarction, and CV death). Vice versa, HHF (but not myocardial infarction/stroke) increased the risk of subsequent kidney events. These associations were generally also seen in empagliflozin‐treated participants and in the overall population. Interestingly, the risk of kidney events following HHF was not significantly increased in the relatively small number of placebo‐treated participants already diagnosed with HF at baseline. Conclusions: These findings demonstrate a bidirectional inter‐relationship between HHF and kidney events. Further exploration of this relationship and strategies to optimize the use of therapies to reduce both kidney and HF outcomes is warranted. [ABSTRACT FROM AUTHOR]

Aims Sodium intake has been linked to left ventricular hypertrophy independently of blood pressure, but the underlying mechanisms remain unclear. Primary hyperaldosteronism (PHA), a condition characterized by tissue sodium overload due to aldosterone excess, causes accelerated left ventricular hypertrophy compared to blood pressure matched patients with essential hypertension. We therefore hypothesized that the myocardium constitutes a novel site capable of sodium storage explaining the missing link between sodium and left ventricular hypertrophy. Methods and results Using 23Na magnetic resonance imaging, we investigated relative sodium signal intensities (rSSI) in the heart, calf muscle, and skin in 8 PHA patients (6 male, median age 55 years) and 12 normotensive healthy controls (HC) (8 male, median age 61 years). PHA patients had a higher mean systolic 24 h ambulatory blood pressure [152 (140; 163) vs. 125 (122; 130) mmHg, P  < 0.001] and higher left ventricular mass index [71.0 (63.5; 106.8) vs. 55.0 (50.3; 66.8) g/m2, P  = 0.037] than HC. Compared to HC, PHA patients exhibited significantly higher rSSI in the myocardium [0.31 (0.26; 0.34) vs. 0.24 (0.20; 0.27); P  = 0.007], calf muscle [0.19 (0.16; 0.22) vs. 0.14 (0.13; 0.15); P  = 0.001] and skin [0.28 (0.25; 0.33) vs. 0.19 (0.17; 0.26); P  = 0.014], reflecting a difference of +27%, +38%, and +39%, respectively. Treatment of PHA resulted in significant reductions of the rSSI in the myocardium, calf muscle and skin by −13%, −27%, and −29%, respectively. Conclusion Myocardial tissue rSSI is increased in PHA patients and treatment of aldosterone excess effectively reduces rSSI, thus establishing the myocardium as a novel site of sodium storage in addition to skeletal muscle and skin. [ABSTRACT FROM AUTHOR]

Aim: Nicotinamide N-methyltransferase (NNMT) is a novel regulator of energy homeostasis in adipose tissue. NNMT expression is higher in obese mice than in lean mice, and NNMT knockdown prevents diet-induced obesity. Little is known about the regulation of enzyme activity during the development of obesity. The aim of this study was to analyze NNMT activity in tissues of mice with incipient and established obesity.Methods: A fluorescence-based, sensitive, low-volume, high-throughput method was developed to assay NNMT activity. C57BL/6 mice were fed a high-fat diet for 4 weeks (incipient obesity) and for 12 weeks (established obesity). Tissues and serum were harvested and analyzed.Results: NNMT activity was highest in subcutaneous white fat (55.0 µU/mg), followed by epididymal white fat (35.6 µU/mg), brown adipose tissue (7.8 µU/mg), liver (7.6 µU/mg), and lung (7.3 µU/mg). Little activity was detected in heart, skeletal muscle, and kidney. No activity was found in serum samples. Body weight predicted NNMT activity in white fat, but not in brown fat or any other tissue, and only in incipient obesity. With established obesity, this association was lost.Conclusions: As obesity develops, body weight predicts NNMT activity in white adipose tissue, but not in any other tissue, consistent with a specific role of adipose-tissue NNMT in the regulation of body weight. [ABSTRACT FROM AUTHOR]

Aim: Nicotinamide N-methyltransferase (NNMT) is a novel regulator of energy homeostasis in adipose tissue. NNMT expression is higher in obese mice than in lean mice, and NNMT knockdown prevents diet-induced obesity. Little is known about the regulation of enzyme activity during the development of obesity. The aim of this study was to analyze NNMT activity in tissues of mice with incipient and established obesity. Methods: A fluorescence-based, sensitive, low-volume, high-throughput method was developed to assay NNMT activity. C57BL/6 mice were fed a high-fat diet for 4 weeks (incipient obesity) and for 12 weeks (established obesity). Tissues and serum were harvested and analyzed. Results: NNMT activity was highest in subcutaneous white fat (55.0 µU/mg), followed by epididymal white fat (35.6 µU/mg), brown adipose tissue (7.8 µU/mg), liver (7.6 µU/mg), and lung (7.3 µU/mg). Little activity was detected in heart, skeletal muscle, and kidney. No activity was found in serum samples. Body weight predicted NNMT activity in white fat, but not in brown fat or any other tissue, and only in incipient obesity. With established obesity, this association was lost. Conclusions: As obesity develops, body weight predicts NNMT activity in white adipose tissue, but not in any other tissue, consistent with a specific role of adipose-tissue NNMT in the regulation of body weight. [ABSTRACT FROM AUTHOR]

Background: Diabetic kidney disease with nephrotic-range proteinuria (NRP) is commonly associated with rapid kidney function loss, increased cardiovascular risk, and premature mortality. We explored the effect of empagliflozin in patients with type 2 diabetes and cardiovascular disease, complicated by presence of this major risk factor for progressive kidney disease, in a post-hoc analysis of data from the EMPA-REG OUTCOME trial (NCT01131676)., Methods: Cox proportional hazards models were used to investigate the risk of cardiovascular and kidney outcomes in participants with and without NRP, defined by urine albumin-to-creatinine ratio (UACR) ≥2200 mg/g at baseline. Annual loss of eGFR during chronic treatment (eGFR slopes) and hypothetical time to projected end-stage kidney disease (ESKD), conditioning upon linearity of eGFR change over time if a patient did not decease before projected ESKD, were calculated using a random-intercept random-coefficient model. Safety was described based on investigator-reported adverse events., Findings: 112 participants (pooled empagliflozin, n  = 70; placebo, n  = 42; median on-treatment follow-up of 1·9 years on placebo compared with 2·3 years on empagliflozin) presented with NRP at baseline; eGFR and UACR were balanced between treatments. Empagliflozin benefits on cardiovascular death, hospitalisation for heart failure, or kidney outcomes, were consistent in participants with and without NRP (p interaction >0·1). Treatment effects of empagliflozin on adjusted annual mean eGFR slope were more pronounced in participants with NRP versus those without (p interaction 0·005). Empagliflozin was estimated to double the median hypothetical time to projected ESKD in participants with NRP. The overall safety profile of empagliflozin was comparable between participants with and without NRP at baseline., Interpretation: Our data suggests that empagliflozin might slow kidney function loss and delay the estimated onset of projected ESKD in patients with type 2 diabetes and cardiovascular disease complicated by NRP., Competing Interests: PR and GR have no conflicts to report. BJK is an employee of Boehringer Ingelheim, the University Hospital of Würzburg and has received grants from the IZKF (Interdisziplinaeres Zentrum fuer klinische Forschung) of the University of Wuerzburg, and from Boehringer Ingelheim. SI reports consulting fees and honoraria from Intarcia Therapeutics, Daiichi-Sankyo, Lexicon Pharmaceuticals, Janssen, Sanofi, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. BZ has received grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk; and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi Aventis. SH, MM, MvE, and AKW are employees of Boehringer Ingelheim. CW reports honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Mitsubishi, and MSD., (© 2021 Published by Elsevier Ltd.)

Aims: Sodium intake has been linked to left ventricular hypertrophy independently of blood pressure, but the underlying mechanisms remain unclear. Primary hyperaldosteronism (PHA), a condition characterized by tissue sodium overload due to aldosterone excess, causes accelerated left ventricular hypertrophy compared to blood pressure matched patients with essential hypertension. We therefore hypothesized that the myocardium constitutes a novel site capable of sodium storage explaining the missing link between sodium and left ventricular hypertrophy., Methods and Results: Using 23Na magnetic resonance imaging, we investigated relative sodium signal intensities (rSSI) in the heart, calf muscle, and skin in 8 PHA patients (6 male, median age 55 years) and 12 normotensive healthy controls (HC) (8 male, median age 61 years). PHA patients had a higher mean systolic 24 h ambulatory blood pressure [152 (140; 163) vs. 125 (122; 130) mmHg, P < 0.001] and higher left ventricular mass index [71.0 (63.5; 106.8) vs. 55.0 (50.3; 66.8) g/m2, P = 0.037] than HC. Compared to HC, PHA patients exhibited significantly higher rSSI in the myocardium [0.31 (0.26; 0.34) vs. 0.24 (0.20; 0.27); P = 0.007], calf muscle [0.19 (0.16; 0.22) vs. 0.14 (0.13; 0.15); P = 0.001] and skin [0.28 (0.25; 0.33) vs. 0.19 (0.17; 0.26); P = 0.014], reflecting a difference of +27%, +38%, and +39%, respectively. Treatment of PHA resulted in significant reductions of the rSSI in the myocardium, calf muscle and skin by -13%, -27%, and -29%, respectively., Conclusion: Myocardial tissue rSSI is increased in PHA patients and treatment of aldosterone excess effectively reduces rSSI, thus establishing the myocardium as a novel site of sodium storage in addition to skeletal muscle and skin., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)