Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection.

BACKGROUND: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with chronic kidney disease (CKD), with no evidence of an excess risk of cancer or death from any non-vascular cause. However, non-randomized data have suggested that statin therapy may have effects (both adverse and beneficial) on particular non-vascular conditions that do not cause death. METHODS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to simvastatin 20 mg plus ezetimibe 10 mg (simvastatin/ezetimibe) daily versus matching placebo. Participants were followed up at least 6 monthly and all post-randomization serious adverse events (SAEs) were recorded. This supplementary analysis reports the effects of treatment on non-vascular SAEs, overall, by system of disease, by baseline characteristics, and by duration of follow-up. RESULTS: During a median of 4.9 years follow-up, similar numbers of participants in the two groups experienced at least one non-vascular SAE (3551 [76.4%] simvastatin/ezetimibe vs 3537 [76.6%] placebo; risk ratio [RR] 0.99, 95% confidence interval [CI] 0.95-1.04). There was no good evidence of any significant effect of simvastatin/ezetimibe on SAEs attributed to any particular nonvascular disease system (of 43 comparisons, only 3 yielded an uncorrected p value < 0.05, of which the smallest was p = 0.02). The relative risk of any nonvascular SAE did not vary significantly among particular prognostic subgroups or by duration of follow-up. CONCLUSIONS: In the SHARP trial, allocation to simvastatin/ezetimibe combination therapy was not associated with any significant non-vascular hazard. TRIALS REGISTRATION: SHARP was retrospectively registered after the first participant was enrolled in 2003 at ISRCTN (ISRCTN54137607 on 31 January 2005: http://www.isrctn.com/ISRCTN54137607) and ClinicalTrials.gov (NCT00125593 on 29 July 2005: https://clinicaltrials.gov/ct2/show/NCT00125593).

Cystatin C and risk of vascular and nonvascular mortality: a prospective cohort study of older men.

OBJECTIVE: To assess the relevance of cystatin C, as a marker of mild-to-moderate renal impairment, for vascular and nonvascular mortality in older people. DESIGN: Prospective cohort study. SETTING: Re-survey in 1997 to 1998 of survivors in the 1970 Whitehall study of London civil servants. SUBJECTS: Five thousand three hundred and seventy-one men (mean age at resurvey: 77 years) who took part in the resurvey and had plasma cystatin C concentration measured. MAIN OUTCOME MEASURES: Cause-specific mortality over subsequent 11 years (1997 to 2008). METHODS: Cox regression was used to estimate the associations of cystatin C with vascular and nonvascular mortality, before and after adjustment for prior disease and other risk factors (including lifetime blood pressure). RESULTS: During an 11.0-year follow-up period, there were 1171 deaths from vascular causes [26 per 1000 per year (py)] and 1615 deaths from nonvascular causes (36 per 1000 py). Compared with men with cystatin C in the bottom fifth of the distribution, men in the top 10th had about two-fold higher mortality rates from vascular and nonvascular mortality (fully adjusted P both <0.001) even after adjustment for prior disease and all measured confounders, including lifetime blood pressure. The fully adjusted relative risks per 50% higher cystatin C concentrations were 1.66 [95% CI 1.48 to 1.85] for vascular mortality, 1.92 [95% CI 1.66 to 2.22] for ischaemic heart disease mortality and 1.46 [95% CI 1.31 to 1.61] for nonvascular mortality. CONCLUSIONS: In older men, plasma concentration of cystatin C, probably as a marker of mild renal disease, is a strong independent predictor of both vascular and nonvascular mortality.