Non-adherence to cardiometabolic medication as assessed by LC-MS/MS in urine and its association with kidney and cardiovascular outcomes in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine-a non-invasive, direct and objective measure-to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes. METHODS: This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes. RESULTS: Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12-6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86]). CONCLUSIONS/INTERPRETATION: This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes.

Identification of endophenotypes supporting outcome prediction in hemodialysis patients based on mechanistic markers of statin treatment.

Background: Statins are widely used to reduce the risk of cardiovascular disease (CVD). Patients with end-stage renal disease (ESRD) on hemodialysis have significantly increased risk of developing CVD. Statin treatment in these patients however did not show a statistically significant benefit in large trials on a patient cohort level. Methods: We generated gene expression profiles for statins to investigate the impact on cellular programs in human renal proximal tubular cells and mesangial cells in-vitro. We subsequently selected biomarkers from key statin-affected molecular pathways and assessed these biomarkers in plasma samples from the AURORA cohort, a double-blind, randomized, multi-center study of patients on hemodialysis or hemofiltration that have been treated with rosuvastatin. Patient clusters (phenotypes) were created based on the identified biomarkers using Latent Class Model clustering and the associations with outcome for the generated phenotypes were assessed using Cox proportional hazards regression models. The multivariable models were adjusted for clinical and biological covariates based on previously published data in AURORA. Results: The impact of statin treatment on mesangial cells was larger as compared with tubular cells with a large overlap of differentially expressed genes identified for atorvastatin and rosuvastatin indicating a predominant drug class effect. Affected molecular pathways included TGFB-, TNF-, and MAPK-signaling and focal adhesion among others. Four patient clusters were identified based on the baseline plasma concentrations of the eight biomarkers. Phenotype 1 was characterized by low to medium levels of the hepatocyte growth factor (HGF) and high levels of interleukin 6 (IL6) or matrix metalloproteinase 2 (MMP2) and it was significantly associated with outcome showing increased risk of developing major adverse cardiovascular events (MACE) or cardiovascular death. Phenotype 2 had high HGF but low Fas cell surface death receptor (FAS) levels and it was associated with significantly better outcome at 1 year. Conclusions: In this translational study, we identified patient subgroups based on mechanistic markers of statin therapy that are associated with disease outcome in patients on hemodialysis.

Exercise-Induced Fluid Retention, Cardiac Volume Overload, and Peripheral Edema in Ultra-Distance Cyclists.

Introduction: Ultracyclists expose themselves to extreme physical challenges. This study aimed to elucidate the effects of ultracycling on electrolyte and fluid balance and investigate the potential occurrence of peripheral edema. Methods: A total of 4 clinical visits were performed before, during, and after a 6-day bicycle ride in 13 ultracyclists (5 female, 8 male) including serial laboratory analyses of blood and urine, bioelectrical impedance, and echocardiography. Throughout the ride, participants continuously tracked fluid intake, measured extremity circumferences daily, and self-tested urinary electrolytes using a point-of-care testing device. Portrait photos were judged by 20 physicians for occurrence of facial and eyelid edema. Results: Participants covered a mean distance of 1205 km and 19,417 vertical meters. From baseline to day 6, body weight remained stable (P = 0.479); however, body composition changed with increasing total body water (TBW) (+1.98 l ± 1.37, P = 0.003) and plasma volume (+18.86 % ± 10.7, P < 0.001). A significant increase in N-terminal pro brain natriuretic peptide (NT-proBNP) (+297.99 ng/l ± 190.42, P < 0.001) until day 6 indicates concomitant cardiac volume overload. Swelling of face and eyelids peaked on day 5 (both P ≤ 0.033). On recovery, changes partly resolved. Although urinary sodium concentration showed a nadir on day 4 (-32.18 mmol/l ± 23.88, P = 0.022), plasma osmolality (+5.69 mmosmol/kg ± 5.88, P = 0.004) and copeptin (+38.28 pg/ml ± 18.90, P < 0.001) increased steadily until day 6. Conclusion: Ultracycling over multiple days induces extracellular volume expansion, peripheral edema, and cardiac volume overload. Renal sodium and water retention is likely contributing to this condition.