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Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study.

ABSTRACT: AIMS:To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. METHODS:Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD-free status. RESULTS:Of 1?177?896 patients with T2D, 772?336 (66%) were CVRD-free and followed for a mean of 4.5?years. A total of 137?081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all-cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75-2.33) and HR 2.05 (95% CI 1.82-2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all-cause mortality risk: HRs 3.91 (95% CI 3.02-5.07) and 3.14 (95% CI 2.90-3.40), respectively. CONCLUSION:In a large multinational study of >750?000 CVRD-free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

SUBMITTER: Birkeland KI

PROVIDER: S-EPMC7496468 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study.

Birkeland Kåre I KI Bodegard Johan J Eriksson Jan W JW Norhammar Anna A Haller Hermann H Linssen Gerard C M GCM Banerjee Amitava A Thuresson Marcus M Okami Suguru S Garal-Pantaler Elena E Overbeek Jetty J Mamza Jil Billy JB Zhang Ruiqi R Yajima Toshitaka T Komuro Issei I Kadowaki Takashi T

Diabetes, obesity & metabolism 20200603 9

<h4>Aims</h4>To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases.<h4>Methods</h4>Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral ar ...[more]

PMID: 32363737

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Project description:Background and objectivesHeart failure is the most frequent cardiac complication of CKD. Left ventricular hypertrophy is common and develops early in CKD, but studies have not adequately evaluated the association of left ventricular mass index with heart failure incidence among men and women with CKD.Design, setting, participants, & measurementsWe evaluated echocardiograms of 2567 participants without self-reported heart failure enrolled in the Chronic Renal Insufficiency Cohort Study. Two-dimensional echocardiograms were performed at the year 1 study visit and interpreted at a central core laboratory. Left ventricular mass index was calculated using the linear method, indexed to height2.7, and analyzed using sex-specific quartiles. The primary outcomes of incident heart failure and all-cause mortality were adjudicated over a median of 6.6 (interquartile range, 5.7-7.6) years.ResultsAmong 2567 participants, 45% were women, and 54% were nonwhite race; mean (SD) age was 59±11 years old, and mean eGFR was 44±17 ml/min per 1.73 m2. During a median follow-up period of 6.6 years, 262 participants developed heart failure, and 470 participants died. Compared with participants in the first quartile of left ventricular mass index, those in the highest quartile had higher rates of incident heart failure (hazard ratio, 3.96; 95% confidence interval, 1.96 to 8.02) and mortality (hazard ratio, 1.86; 95% confidence interval, 1.22 to 2.85), even after adjustment for B-type natriuretic peptide, troponin T, mineral metabolism markers, and other cardiovascular disease risk factors. Those in the lowest quartile of ejection fraction had higher rates of incident heart failure (hazard ratio, 3.01; 95% confidence interval, 1.94 to 4.67) but similar mortality rates (hazard ratio, 1.18; 95% confidence interval, 0.89 to 1.57) compared with those in the highest quartile. Diastolic dysfunction was not significantly associated with heart failure or death.ConclusionsAmong persons with CKD and without history of cardiovascular disease, left ventricular mass index is strongly associated with incident heart failure, even after adjustment for major cardiovascular risk factors and biomarkers.

Project description:AimsSomatic mutations in haematopoietic stem cells can lead to the clonal expansion of mutated blood cells, known as clonal haematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF) ≥ 2% have been associated with atherosclerosis and chronic heart failure of ischemic origin (CHF). However, the effects of mutations in other driver genes for CH with low VAF (<2%) on CHF are still unknown.Methods and resultsTherefore, we analysed mononuclear bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality in these patients (3.95 years median follow-up). We detected 1113 mutations with a VAF ≥ 0.5% in 347 of 399 patients, and only 13% had no detectable CH. Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A (165 patients) and TET2 (107 patients), mutations in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2 were associated with increased death compared with the average death rate of all patients. To avoid confounding effects, we excluded patients with DNMT3A-related, TET2-related, and other clonal haematopoiesis of indeterminate potential (CHIP)-related mutations with a VAF ≥ 2% for further analyses. Kaplan-Meier survival analyses revealed a significantly higher mortality in patients with mutations in either of the seven genes (53 patients), combined as the CH-risk gene set for CHF. Baseline patient characteristics showed no significant differences in any parameter including patient age, confounding diseases, severity of CHF, or blood cell parameters except for a reduced number of platelets in patients with mutations in the risk gene set in comparison with patients without. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (hazard ratio, 3.1; 95% confidence interval, 1.8-5.4; P < 0.001), whereas platelet numbers did not.ConclusionsSomatic mutations with low VAF in a distinct set of genes, namely, in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2, are significantly associated with mortality in CHF, independently of the most prevalent CHIP-mutations in DNMT3A and TET2. Mutations in these genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome of CHF, potentially providing a novel tool for risk assessment in CHF.

Project description:Diabetes mellitus, heart failure (HF), and chronic kidney disease are common comorbidities, but overall use and safety of antihyperglycemic medications (AHMs) among patients with these comorbidities are poorly understood.Using Get With the Guidelines-Heart Failure and linked Medicare Part D data, we assessed AHM use within 90 days of hospital discharge among HF patients with diabetes mellitus discharged from Get With the Guidelines-Heart Failure hospitals between January 1, 2006, and October 1, 2011. We further summarized use by renal function and assessed renal contraindicated AHM use for patients with estimated glomerular filtration rate <30 mL/min/1.73m(2). Among 8791 patients meeting inclusion criteria, the median age was 77 (interquartile range 71-83), 62.3% were female, median body mass index was 29.7 (interquartile range 25.5-35.3), median hemoglobin A1c was 6.8 (interquartile range 6.2-7.8), and 34% had ejection fraction <40%. 74.9% of patients filled a prescription for an AHM, with insulin (39.5%), sulfonylureas (32.4%), and metformin (17%) being the most commonly used AHMs. Insulin use was higher and sulfonylurea/metformin use was lower among patients with lower renal function classes. Among 1512 patients with estimated glomerular filtration rate <30 mL/min/1.73m(2), 35.4% filled prescriptions for renal contraindicated AHMs per prescribing information, though there was a trend toward lower renal contraindicated AHM use over time (Cochran-Mantel-Haenszel row-mean score test P=0.048). Although use of other AHMs was low overall, thiazolidinediones were used in 6.6% of HF patients, and dipeptidyl peptidase-4 inhibitors were used in 5.1%, with trends for decreasing thiazolidinedione use and increased dipeptidyl peptidase-4 inhibitor use over time (P<0.001).Treatment of diabetes mellitus in patients with HF and chronic kidney disease is complex, and these patients are commonly treated with renal contraindicated AHMs, including over 6% receiving a thiazolidinedione, despite known concerns regarding HF. More research regarding safety and efficacy of various AHMs among HF patients is needed.

Project description:BackgroundWe have previously demonstrated an association between increased sFRP3 expression and adverse outcome in a population of HF irrespective of cause and left ventricular ejection fraction. In this study we evaluated the prognostic value of sFRP3 in older patients with chronic systolic HF of ischemic origin.MethodsWe evaluated sFRP3, by tertiles, as a risk factor for the primary endpoint (cardiovascular [CV] mortality, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV mortality, death from worsening HF (WHF), any coronary event, including sudden death, as well as hospitalizations for CV causes and WHF in 1444 patients from the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo.ResultsKaplan-Meier curves for the primary endpoint, as well as all-cause- and CV mortality revealed a markedly better survival for patients with sFRP3 levels in the middle tertile of compared to the 1st and 3rd tertile. In multivariable Cox-regression, after full adjustment including high-sensitive CRP and NT-proBNP, a lower event rate for the primary end point, all cause and CV mortality was observed for patients with tertile 2 sFRP3 levels (HR 0.57 [0.44-0.74], 0.55 [0.44-0.74] and 0.52 [0.39-0.69]; p<0.001), as well as for the number of coronary events (HR 0.62 [0.47-0.82], p = 0.001) and sudden death (HR 0.55 [0.37-0.82], p = 0.002). Applying sFRP3 values to the fully adjusted regression model resulted in highly significant continuous net reclassification improvements for the primary endpoint, all cause and CV mortality, coronary events and sudden death (range 0.24-0.31; p≤0.002 for all).ConclusionsIntermediate serum sFRP3 levels are associated with better survival and fewer CV events than low or high sFRP3 levels, independently of conventional risk factors, in older patients with chronic systolic HF of ischemic origin. Our study suggests that balanced Wnt activity might confer protective effects in a clinical HF setting.Trial registrationhttp://www.clinicaltrials.gov NCT00206310.

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Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study.

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Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study.

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