No abstract

The 4D (Die Deutsche Diabetes Dialyse) Study was a randomized, double-blind trial comparing 4 years of treatment with atorvastatin to placebo in 1255 hemodialysis patients with type 2 diabetes. The primary end point of cardiovascular events (cardiac death, myocardial infarction, and stroke) was non-significantly reduced by 8%. However, long-term effects remained uncertain. Therefore, surviving patients were invited to a follow-up survey done by questionnaire. Post-trial statin therapy was at nephrologist discretion, and outcomes were centrally adjudicated and analyzed by intention to treat and time to first event in the original treatment groups. Median overall follow-up was 11.5 years. Post-trial statin use and low-density lipoprotein cholesterol levels did not differ between groups. Statin treatment non-significantly affected the former primary outcome (relative risk, 0.91; 95% confidence interval, 0.78-1.07). The risk of all cardiac events combined and the risk of cardiac death were significantly lower in the original statin group compared to placebo (0.83, 0.70-0.97, and 0.80, 0.66-0.97). No significant effect was detected on cerebrovascular events, fatal stroke, fatal cancer, non-vascular, or all-cause death. No rhabdomyolysis was reported. Thus, after 4 years of atorvastatin treatment in diabetic hemodialysis patients, similar effects on outcomes were found after 11.5 years of follow-up as were found at the end of the original study. There was no evidence of emerging hazards in the long term, confirming current clinical practice guidelines.

Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.

Background: Data concerning long-term mortality predictors among large, purely diabetic hemodialysis collectives are scarce. Methods: We used data from a multicenter, prospective, randomized trial among 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) and its observational follow-up study. The association of 10 baseline candidate variables with mortality was assessed by Cox proportional hazards regression. Results: Overall, 103 participants survived the median follow-up of 11.5 years. Significant predictors of mortality were age (hazard ratio [HR] 1.03, 95% CI 1.02–1.04), cardiovascular (HR 1.42, 95% CI 1.25–1.62) and peripheral vascular disease (HR 1.55, 95% CI 1.36–1.76), higher hemoglobin A1c (HbA1c; HR 1.08, 95% CI 1.03–1.14), and loss of self-dependency (HR 1.20, 95% CI 1.03–1.39). Higher albumin (HR 0.72, 95% CI 0.59–0.89) and body mass index (BMI; HR 0.98, 95% CI 0.96–0.99) had protective associations. There was no significant association with sex, diabetes duration, and cerebrovascular diseases. Subgroup analyses by age and diabetes duration showed stronger associations of cardiovascular disease, HbA1c, albumin, BMI, and loss of self-dependency in younger patients and/or shorter diabetes duration. Loss of self-dependency and energy resources (albumin, BMI) increased mortality more severely in women, whilst the impact of cardiovascular and peripheral vascular diseases was more pronounced in men. Conclusion: Long-term mortality risk in patients with T2DM on hemodialysis was associated with higher age, vascular diseases, HbA1c, loss of self-dependency, and low energy resources. Interestingly, it does not vary between sexes. Further individualized prognosis estimation and therapy should strongly depend on age, diabetes duration, and gender.