Fibroblast Growth Factor 23 and Risk of New Onset Heart Failure With Preserved or Reduced Ejection Fraction: The PREVEND Study.

Background The role of fibroblast growth factor 23 (FGF23) in the development of new-onset heart failure (HF) with reduced (HFrEF) or preserved ejection fraction (HFpEF) in the general population is unknown. Therefore, we set out to investigate associations of C-terminal FGF23 with development of new-onset HF and, more specifically, with HFrEF or HFpEF in a large, prospective, population-based cohort. Methods and Results We studied 6830 participants (aged 53.8±12.1 years; 49.7% men; estimated glomerular filtration rate, 93.1±15.7 mL/min per 1.73 m2) in the community-based PREVEND (Prevention of Renal and Vascular End-Stage Disease) study who were free of HF at baseline. Cross-sectional multivariable linear regression analysis showed that ferritin (standardized ß, -0.24; P<0.001) and estimated glomerular filtration rate (standardized ß, -0.13; P<0.001) were the strongest independent correlates of FGF23. Multivariable Cox proportional hazard regression was used to study the association between baseline FGF23 and incident HF, HFrEF (ejection fraction ≤40%) or HFpEF (ejection fraction ≥50%). After median follow-up of 7.4 [IQR 6.9-7.9] years, 227 individuals (3.3%) developed new-onset HF, of whom 132 had HFrEF and 88 had HFpEF. A higher FGF23 level was associated with an increased risk of incident HF (fully adjusted hazard ratio, 1.29 [95% CI, 1.06-1.57]) and with an increased risk of incident HFrEF (fully adjusted hazard ratio, 1.31 [95% CI, 1.01-1.69]). The association between FGF23 and incident HFpEF lost statistical significance after multivariable adjustment (hazard ratio, 1.22 [95% CI, 0.87-1.71]). Conclusions Higher FGF23 is independently associated with new-onset HFrEF in analyses fully adjusted for cardiovascular risk factors and other potential confounders. The association between FGF23 and incident HFpEF lost statistical significance upon multivariable adjustment.

Serum free sulfhydryl status associates with new-onset chronic kidney disease in the general population.

BACKGROUND: Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status in health and disease. As oxidation of R-SH occurs rapidly by reactive oxygen species (ROS), oxidative stress is accompanied by reduced levels of free thiols. Oxidative stress has been implicated in the pathophysiology of chronic kidney disease (CKD), in which redox imbalance may precede the onset of CKD. Therefore, we aimed to investigate associations between serum free thiols and the risk of incident CKD as defined by renal function decline and albuminuria in a population-based cohort study. METHODS: Subjects without CKD (n = 4,745) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, urinary 24-h albumin excretion (UAE) > 30 mg/24-h, or both. RESULTS: Median level of protein-adjusted serum free thiols at baseline was 5.14 µmol/g of protein (interquartile range [IQR]: 4.50-5.75 µmol/g) and median eGFR was 96 mL/min/1.73 m2 [IQR: 85-106]. Protein-adjusted serum free thiols were significantly associated with incident CKD (hazard ratio [HR] per doubling 0.42 [95% confidence interval [CI]: 0.36-0.52, P < 0.001), even after adjustment for traditional risk factors (HR 0.67 [95% CI: 0.47-0.94], P=0.022). In secondary analyses, the highest tertile of protein-adjusted serum free thiols was inversely associated with incident UAE >30 mg/24-h after full adjustment for confounding factors (HR per doubling 0.70 [95% CI: 0.51-0.96], P=0.028). CONCLUSION: Higher levels of serum R-SH, reflecting less oxidative stress, are associated with a decreased risk of developing CKD in subjects from the general population. This association is primarily driven by incident CKD as defined by UAE.

Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population.

Background The cause of heart failure with preserved ejection fraction (HFpEF) is poorly understood, and specific therapies are lacking. Previous studies suggested that inflammation plays a role in the development of HFpEF. Herein, we aimed to investigate in community-dwelling individuals whether a higher plasma interleukin 6 (IL-6) level is associated with an increased risk of developing new-onset heart failure (HF) over time, and specifically HFpEF. Methods and Results We performed a case-cohort study based on the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective general population-based cohort study. We included 961 participants, comprising 200 participants who developed HF and a random group of 761 controls. HF with reduced ejection fraction or HFpEF was defined on the basis of the left ventricular ejection fraction of ≤40% or >40%, respectively. In Cox proportional hazard regression analyses, IL-6 levels were statistically significantly associated with the development of HF (hazard ratio [HR], 1.28; 95% CI, 1.02-1.61; P=0.03) after adjustment for key risk factors. Specifically, IL-6 levels were significantly associated with the development of HFpEF (HR, 1.59; 95% CI, 1.16-2.19; P=0.004), whereas the association with HF with reduced ejection fraction was nonsignificant (HR, 1.05; 95% CI, 0.75-1.47; P=0.77). In sensitivity analyses, defining HFpEF as left ventricular ejection fraction ≥50%, IL-6 levels were also significantly associated with the development of HFpEF (HR, 1.47; 95% CI, 1.04-2.06; P=0.03) after adjustment for key risk factors. Conclusions IL-6 is associated with new-onset HFpEF in community-dwelling individuals, independent of potential confounders. Our findings warrant further research to investigate whether IL-6 might be a novel treatment target to prevent HFpEF.

Impact of Moderate Sodium Restriction and Hydrochlorothiazide on Iodine Excretion in Diabetic Kidney Disease: Data from a Randomized Cross-Over Trial.

Sodium restriction may potentially reduce iodine intake. This study aimed to determine the effect of sodium restriction (dietary counseling) on 24-h urinary iodine excretion. Diuretics provide an alternative to sodium restriction and are frequently added to sodium restriction, so the effects of hydrochlorothiazide (50 mg daily) and combined therapy were also studied. We performed a post-hoc analysis of a Dutch multi-center, randomized cross-over trial in 45 patients with diabetic kidney disease with a mean age of 65 ± 9 years, mean eGFR of 65 ± 27 mL/min/1.73 m2, median albuminuria of 648 [230-2008] mg/24 h and 84% were male. During regular sodium intake with placebo, mean 24 h urinary sodium and iodine excretion were 224 ± 76 mmol/24 h and 252 ± 94 ug/24 h, respectively (r = 0.52, p < 0.001). Mean iodine excretion did not change significantly if sodium restriction and hydrochlorothiazide were applied separately; mean difference -8 ug/day (95% CI -38, 22; p = 0.6) and 14 ug/day (95% CI -24, 52; p = 0.5), respectively. Combined therapy induced a significant decrease in mean iodine excretion (-37 ug/day; 95% CI -67, -7; p = 0.02), yet this was not seen to a clinically meaningful level. The number of patients with an estimated intake below recommended daily allowances did not differ significantly between the four treatment periods (p = 0.3). These findings show that sodium restriction is not a risk factor for iodine deficiency.

Fibroblast Growth Factor 23 and Mortality in Patients With Type 2 Diabetes and Normal or Mildly Impaired Kidney Function.

OBJECTIVE: To study whether fibroblast growth factor 23 (FGF23) is associated with adverse outcomes in patients with type 2 diabetes and normal or mildly impaired kidney function. RESEARCH DESIGN AND METHODS: We analyzed C-terminal FGF23 levels in 310 patients with type 2 diabetes and estimated glomerular filtration rate ≥60 mL/min/1.73 m2. Associations of FGF23 with all-cause mortality and major adverse cardiovascular events (MACE) were studied by Cox regression. RESULTS: During a follow-up of 5.8 years (3.3-6.5), 47 patients developed MACE and 28 patients died. FGF23 was associated with an increased risk of all-cause mortality (age- and sex-adjusted hazard ratio 2.78 [95% CI 1.76-4.40]) and MACE (1.67 [1.12-2.49]). Results were similar after additional adjustment for other potential confounders and were consistent upon replication in an independent cohort. CONCLUSIONS: In patients with type 2 diabetes and normal or mildly impaired kidney function, FGF23 is associated with an increased risk of cardiovascular events and mortality.

Body weight course in the DIAbetes and LifEstyle Cohort Twente (DIALECT-1)-A 20-year observational study.

BACKGROUND: Although weight gain increases risk of type 2 diabetes, real-life data on the weight course in patients with established type 2 diabetes are scarce. We assessed weight course in a real-life diabetes secondary care setting and analyzed its association with patient characteristics, lifestyle habits and initiation of insulin, glucagon like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i). METHODS: Data on weight, insulin, GLP-1 RA and SGLT-2i use were collected retrospectively (12 years) and prospectively (8 years) from patients included in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1, n = 450, age 63 ± 9 years, 58% men, diabetes duration [7-18] years). Lifestyle habits were assessed using validated questionnaires. The association of clinical parameters with body mass index (BMI) course was determined using linear mixed models. Patients who underwent bariatric surgery (n = 19) had a distinct BMI course and were excluded from the study. RESULTS: Baseline BMI was 31.3 (0.3) and was higher in women, patients aged <60 years and patients with unfavorable lifestyle habits. BMI increased to 32.5 (0.3) after 12 years (P<0.001), and thereafter decreased to 31.5 (0.3) after 20 years, resulting in a similar BMI as the baseline BMI (P = 0.96, compared to baseline). Clinical parameters or initiation of insulin or SGLT-2i were not associated with BMI course. Patients who initiated GLP-1 RA declined in BMI compared to non-users (Pinteraction = 0.003). CONCLUSIONS: High BMI that real-life patients with type 2 diabetes gained earlier in life, remained stable in the following decades. Weight loss interventions should remain a priority, and GLP-1 RA might be considered to support weight loss.

High Dietary Intake of Vegetable Protein Is Associated With Lower Prevalence of Renal Function Impairment: Results of the Dutch DIALECT-1 Cohort.

INTRODUCTION: Dietary protein intake may influence development of renal function impairment in diabetes mellitus type 2 (T2DM). We assessed the association between sources of protein and prevalence of renal function impairment. METHODS: Cross-sectional analyses were performed in baseline data of 420 patients of the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1) study. Protein intake was assessed using a Food Frequency Questionnaire, modified for accurate assessment of protein intake, including types and sources of protein. Renal function impairment was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration formula). RESULTS: Among 420 patients with T2DM, 99 renal function impairment cases were identified. Multivariate Cox proportional hazard models were used and adjusted for the main lifestyle and dietary factors. The prevalence ratios in the fully adjusted model were 1 (reference), 0.74 (95% confidence interval [CI]: 0.44-1.27; P = 0.28) and 0.47 (95% CI: 0.23-0.98; P = 0.04) according to increasing tertiles of vegetable protein intake. For animal protein intake the prevalence ratios were 1 (reference), 1.10 (95% CI: 0.64-1.88; P = 0.74) and 1.06 (95% CI: 0.56-1.99; P = 0.87) according to increasing tertiles of intake. Theoretical replacement models showed that replacing 3 energy percent from animal protein by vegetable protein lowered the prevalence ratio for the association with renal function impairment to 0.20 (95% CI: 0.06-0.63; P = 0.01). CONCLUSION: In conclusion, we found that higher intake of vegetable protein was associated with a lower prevalence of renal function impairment, and theoretical replacement of animal protein with vegetable protein was inversely associated with renal function impairment among patients with T2DM.

Glycaemic control in the diabetes and Lifestyle Cohort Twente: A cross-sectional assessment of lifestyle and pharmacological management on Hba1c target achievement.

The majority of patients with type 2 diabetes do not reach target levels of glycated haemoglobin (HbA1c < 7%). We investigated the prevalence of HbA1c-target achievement and opportunities afforded by lifestyle and pharmacological treatment to increase target achievement. We performed cross-sectional analyses of baseline data from the Diabetes and Lifestyle Cohort Twente-1 (DIALECT-1). Patients were divided according to (1) HbA1c <53 and ≥53 mmol/mol (<7%) and (2) non-insulin treatment and tertiles of daily insulin use. We found that 161 (36%) patients achieved the target HbA1c level. Patients with HbA1c ≥53 mmol/mol had a longer duration of diabetes (13 [8-20] vs 9 [4-14] years; P < .001) and more frequently were insulin-users (76% vs 41%, P < .001). Patients in the highest tertile of insulin use had a higher body mass index than those in the lowest tertile (35.8 ± 5.5 vs 29.8 ± 5.5 kg/m2 ; P < .001). Achievement of target HbA1c is low in this type 2 diabetes population. High resistance to pharmacological treatment, paralleled with high body mass index, illustrates that increasing insulin sensitivity through lifestyle intervention is the best opportunity to improve HbA1c target achievement in this real-life population.

Real-life achievement of lipid-lowering treatment targets in the DIAbetes and LifEstyle Cohort Twente: systemic assessment of pharmacological and nutritional factors.

BACKGROUND/OBJECTIVES: Lowering low-density lipoprotein cholesterol (LDLc) in type 2 diabetes mellitus is of paramount importance in preventing cardiovascular disease. However, treatment targets for LDLc are often not reached. We studied the prevalence of LDLc target achievement in a real-life population of type 2 diabetes mellitus patients in secondary care, and investigated whether in those not on target, there is room for intensifying pharmacological and lifestyle management according to current treatment guidelines. SUBJECTS/METHODS: We performed a cross-sectional analysis in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1; n = 450, age 63 ± 9 years, 58% men, diabetes duration 11 (7-18) years). At baseline, we determined plasma LDLc concentration, pharmacological treatment (i.e., statin use), and lifestyle (physical activity and dietary intake). Patients were divided according to LDLc < 1.8, LDLc 1.8-2.5, and LDLc > 2.5 mmol/l. Dietary intake was collected from a validated Food Frequency Questionnaire (177 items) and we determined guideline adherence for different food groups. Physical activity was assessed with the Short Questionnaire to ASsess Health enhancing behavior. RESULTS: LDLc data were available in 428 type 2 diabetes mellitus patients. LDLc ≤ 2.5 mmol/l was achieved in 317 patients (76%). In total, 76% of patients used statins, in those with LDLc > 2.5 mmol/l, this was 44%. Adherence to lifestyle guidelines was not different between the LDLc groups and was as follows: body mass index 6%, physical activity 59%, vegetables 7%, fruit 28%, legumes 59%, nuts 14%, dairy 19%, fish 36%, tea 8%, fats 66%, red meat 12%, processed meat 2%, alcohol 71%, sweetened beverages 34%, and sodium 12%. CONCLUSIONS: In type 2 diabetes mellitus patients in secondary health care, the target LDLc is achieved by three quarters of patients. Increasing statin treatment could be a first step to improve LDLc. In addition, there are ample opportunities for lifestyle management through increasing adherence to lifestyle guidelines.

Higher Dietary Magnesium Intake and Higher Magnesium Status Are Associated with Lower Prevalence of Coronary Heart Disease in Patients with Type 2 Diabetes.

In type 2 diabetes mellitus (T2D), the handling of magnesium is disturbed. Magnesium deficiency may be associated with a higher risk of coronary heart disease (CHD). We investigated the associations between (1) dietary magnesium intake; (2) 24 h urinary magnesium excretion; and (3) plasma magnesium concentration with prevalent CHD in T2D patients. This cross-sectional analysis was performed on baseline data from the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1, n = 450, age 63 ± 9 years, 57% men, and diabetes duration of 11 (7-18) years). Prevalence ratios (95% CI) of CHD by sex-specific quartiles of magnesium indicators, as well as by magnesium intake per dietary source, were determined using multivariable Cox proportional hazard models. CHD was present in 100 (22%) subjects. Adjusted CHD prevalence ratios for the highest compared to the lowest quartiles were 0.40 (0.20, 0.79) for magnesium intake, 0.63 (0.32, 1.26) for 24 h urinary magnesium excretion, and 0.62 (0.32, 1.20) for plasma magnesium concentration. For every 10 mg increase of magnesium intake from vegetables, the prevalence of CHD was, statistically non-significantly, lower (0.75 (0.52, 1.08)). In this T2D cohort, higher magnesium intake, higher 24 h urinary magnesium excretion, and higher plasma magnesium concentration are associated with a lower prevalence of CHD.

Integrated Assessment of Pharmacological and Nutritional Cardiovascular Risk Management: Blood Pressure Control in the DIAbetes and LifEstyle Cohort Twente (DIALECT).

Cardiovascular risk management is an integral part of treatment in Type 2 Diabetes Mellitus (T2DM), and requires pharmacological as well as nutritional management. We hypothesize that a systematic assessment of both pharmacological and nutritional management can identify targets for the improvement of treatment quality. Therefore, we analysed blood pressure (BP) management in the DIAbetes and LifEstyle Cohort Twente (DIALECT). DIALECT is an observational cohort from routine diabetes care, performed at the ZGT Hospital (Almelo and Hengelo, The Netherlands). BP was measured for 15 minutes with one minute intervals. Sodium and potassium intake was derived from 24-hour urinary excretion. We determined the adherence to pharmacological and non-pharmacological guidelines in patients with BP on target (BP-OT) and BP not on target (BP-NOT). In total, 450 patients were included from August 2009 until January 2016. The mean age was 63 ± 9 years, and the majority was male (58%). In total, 53% had BP-OT. In those with BP-NOT, pharmacological management was suboptimal (zero to two antihypertensive drugs) in 62% of patients, and nutritional guideline adherence was suboptimal in 100% of patients (only 8% had a sodium intake on target, 66% had a potassium intake on target, 3% had a sodium-to-potassium ratio on target, and body mass index was <30 kg/m² in 35%). These data show pharmacological undertreatment and a low adherence to nutritional guidelines. Uncontrolled BP is common in T2DM, and our data show a window of opportunity for improving BP control, especially in nutritional management. To improve treatment quality, we advocate to incorporate the integrated monitoring of nutritional management in quality improvement cycles in routine care.

Biomarkers of Renal Function: Towards Clinical Actionability.

This review provides an overview of the clinical value of the most relevant renal biomarkers, focusing on two main clinical conditions: acute kidney injury and chronic kidney disease. We categorize biomarkers according to their actionability, in terms of a documented response to treatment in relation to outcomes. Furthermore, we introduce a new category of renal biomarkers, metabolic biomarkers, and underscore their capacity to be highly actionable.

Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy: a randomised clinical trial.

BACKGROUND: Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy. METHODS: In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366. FINDINGS: Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest extent by their combination (306 mg per day [203-461], p<0·0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred. INTERPRETATION: We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy. FUNDING: None.