After a series of trials which included individuals receiving dialysis, the benefit of statin-based therapies as eGFR declines, particularly to the point of requiring renal-replacement therapy, has been uncertain (link, link). More recent work from the Cholesterol Treatment Trialists’ collaboration found a 21% relative risk reduction per each mmol/L reduction in LDL cholesterol in a broad group of individuals defined as having CKD, but they also found, despite an absolute benefit, the relative benefit of statin therapy appeared to decrease as eGFR declined. Among individuals with CKD, the strongest single-trial supporting cardiovascular risk-lowering benefit for statin therapies was demonstrated with ezetimibe plus simvastatin compared with placebo in the Study of Heart and Renal Protection (SHARP), which demonstrated combination therapy with ezetimibe plus simvastatin was associated with primary cardiovascular risk reduction (major atherosclerotic events) for individuals with CKD, including those with severe reductions eGFR, including dialysis. Largely based on SHARP, current guidelines recommend the use of statin monotherapy or ezetimibe plus statin for nearly all individuals ≥50 years old with reduced eGFR.
However, to what extent the benefit observed in SHARP was due to the addition of ezetimibe, a cholesterol absorption inhibitor, is unknown. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated an additional benefit of ezetimibe plus simvastatin (compared with simvastatin alone) in preventing cardiovascular outcomes among individuals with known coronary artery disease.
Therefore, we conducted a secondary analysis of IMPROVE-IT to determine whether a difference in treatment effect existed across levels of eGFR reported in JASN. IMPROVE-IT did exclude individuals with CrCl less than 30ml/min due to safety reasons, so we were unable to examine differences at the most severe reductions in eGFR.
Among 18,015 individuals enrolled and followed for a median of 7 years, we observed a difference in the effect of treatment on the occurrence of the primary endpoint (death from cardiovascular disease, a major coronary event, or nonfatal stroke) across levels of kidney function (Figure). The difference in treatment was statistically significant (p=0.037) and appeared as the baseline eGFR declined to ≤75 mL/min/1.73m2. The difference in treatment was most pronounced at eGFR levels ≤60 mL/min/1.73m2. At an eGFR of 60 mL/min/1.73m2, individuals in the combination therapy arm compared with individuals in the monotherapy arm had a 12% relative risk reduction (HR 0.88, 95% CI 0.82–0.95) for the primary composite endpoint; at a baseline eGFR of 45 mL/min/1.73m2, they had a 13% relative risk reduction (HR 0.87, 95% CI 0.78–0.98) for the primary composite endpoint. We also observed few adverse events in either treatment arm across all levels of eGFR.
|Figure from Stanifer et al. JASN Online May 15, 2017|
Individuals with CKD have several risk factors for cardiovascular disease including malnutrition, chronic inflammation, increased oxidative stress, and vascular and endothelial dysfunction related to uremia and calcium and phosphorus dysregulation. Importantly, they also experience significant dyshomeostasis in lipid metabolism leading to potentially modifiable atherosclerotic risks, including poor clearance of circulating triglycerides and lipoproteins, reduced lipoprotein lipase activity, increased oxidation of LDL cholesterol, and possibly increased relative cholesterol absorption. In IMPROVE-IT, individuals randomized to combination therapy with ezetimibe plus simvastatin experienced a greater mean reduction in both LDL cholesterol and triglycerides across all levels of eGFR. Because individuals with CKD are an inherently higher-risk group, achieving the same absolute level of reduction in LDL cholesterol through both inhibition of cholesterol synthesis and cholesterol absorption may be more effective in risk mitigation; yet, on the other hand, considering the numerous mechanisms by which CKD leads to increased cardiovascular risk, the relative benefit we observed from combination therapy as eGFR declined could also suggest ezetimibe add-on therapy conferred pleiotropic effects beyond LDL cholesterol or triglyceride reduction alone.
Though important differences exist between SHARP and IMPROVE-IT (including exclusion of individuals with CrCl less than 30 ml/min, higher statin doses, and a study population with known coronary artery disease), our data support the efficacy and safety of ezetimibe added to statin for further cardiovascular benefit in individuals with coronary disease and moderately reduced eGFR.
John W. Stanifer, MD, MSc
Fellow, Duke Nephrology