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

A systematic review of the sex differences in risk factors for knee osteoarthritis

OBJECTIVES: Previous systematic reviews focused on the evidence of common risk factors for knee OA (KOA); however, the effect and strength of association between risk factors and KOA might be different between the two sexes. The aim of the present systematic review was to determine the current evidence on sex differences in the association between risk factors and KOA and their prevalence. METHODS: We searched the following electronic bibliographic databases: MEDLINE (PubMed), EMBASE and Web of Science. A methodological quality assessment was conducted independently by two researchers according to an adapted version of the standardized set of criteria known as the Newcastle-Ottawa Quality Assessment Scale (NOS). The NOS, a star system, was converted to three categories of quality. RESULTS: In total, 27 studies reported sex-specific risk estimates on several risk factors for KOA. Out of the 22 longitudinal cohort studies (except one nested case-control), 12 were of good quality and 10 were of fair quality. The five cross-sectional studies consisted of one of good, three of fair and one of poor quality. There was an indication of sex differences in risk factors leading to higher risk of KOA: high BMI, alcohol consumption, atherosclerosis and high vitamin E levels in women, and high physical activity, soft drink consumption and abdominal obesity in men. Knee injury, high blood pressure and low step rate seem to affect both women and men. CONCLUSION: More good quality studies are needed to assess sex differences in risk factors for KOA, especially for symptomatic/clinical OA

Towards sex-specific osteoarthritis risk models: evaluation of risk factors for knee osteoarthritis in males and females

OBJECTIVES: The aim of this study was to identify sex-specific prevalence and strength of risk factors for the incidence of radiographic knee OA (incRKOA). METHODS: Our study population consisted of 10 958 Rotterdam Study participants free of knee OA in one or both knees at baseline. One thousand and sixty-four participants developed RKOA after a median follow-up time of 9.6 years. We estimated the association between each available risk factor and incRKOA using sex stratified multivariate regression models with generalized estimating equations. Subsequently, we statistically tested sex differences between risk estimates and calculated the population attributable fractions (PAFs) for modifiable risk factors. RESULTS: The prevalence of the investigated risk factors was, in general, higher in women compared with men, except that alcohol intake and smoking were higher in men and high BMI showed equal prevalence. We found significantly different risk estimates between men and women: high level of physical activity [relative risk (RR) 1.76 (95% CI: 1.29-2.40)] or a Kellgren and Lawrence score 1 at baseline [RR 5.48 (95% CI: 4.51-6.65)] was higher in men. Among borderline significantly different risk estimates was BMI ≥27, associated with higher risk for incRKOA in women [RR 2.00 (95% CI: 1.74-2.31)]. The PAF for higher BMI was 25.6% in women and 19.3% in men. CONCLUSION: We found sex-specific differences in both presence and relative risk of several risk factors for incRKOA. Especially BMI, a modifiable risk factor, impacts women more strongly than men. These risk factors can be used in the development of personalized prevention strategies and in building sex-specific prediction tools to identify high risk profile patients

Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression

OBJECTIVES: The aim of this study was to identify biomarkers for radiographic osteoarthritis severity and progression acting within the inflammation and metabolic pathways. METHODS: For 3,517 Rotterdam Study participants, 184 plasma protein levels were measured using Olink inflammation and cardiometabolic panels. We studied associations with severity and progression of knee, hip, hand osteoarthritis, and a composite overall OA burden-score by multivariable regression models, adjusting for age, sex, cell counts and BMI. RESULTS: We found 18 significantly associated proteins for overall osteoarthritis burden, of which 5 stayed significant after multiple testing correction: circulating Cartilage acidic protein 1 (CRTAC1), Cartilage oligomeric matrix protein (COMP), Thrombospondin 4 (THBS4), Interleukin 18 receptor 1 (IL18R1) and Tumor necrosis factor ligand superfamily member 14 (TNFSF14). These proteins were also associated with progression of knee OA, with the exception of IL18R1. The strongest association was found for the level of CRTAC1 with 1 SD increase in protein level resulting in an increase of 0.09 (95%CI : 0.06-0.12) in overall osteoarthritis KLsum-score (p= 2.9x10-8), in the model adjusted for age, sex, BMI and cell counts. This association was also present with severity of osteoarthritis in all three joints, progression of knee osteoarthritis and was independent of BMI. We observed a stronger association for CRTAC1 with osteoarthritis than for the well-known osteoarthritis-biomarker COMP. CONCLUSION: We identified several compelling biomarkers reflecting overall osteoarthritis burden and increased risk for osteoarthritis progression. CRTAC1 was the most compelling and robust biomarker for osteoarthritis severity and progression. Such a biomarker may be used for disease monitoring