Benefit of Ezetimibe Added to Simvastatin in Reduced Kidney Function

Abstract

Efficacy of statin-based therapies in reducing cardiovascular mortality in individuals with CKD seems to diminish as eGFR declines. The strongest evidence supporting the cardiovascular benefit of statins in individuals with CKD was shown with ezetimibe plus simvastatin versus placebo. However, whether combination therapy or statin alone resulted in cardiovascular benefit is uncertain. Therefore, we estimated GFR in 18,015 individuals from the IMPROVE-IT (ezetimibe plus simvastatin versus simvastatin alone in individuals with cardiovascular disease and creatinine clearance >30 ml/min) and examined post hoc the relationship of eGFR with end points across treatment arms. For the primary end point of cardiovascular death, major coronary event, or nonfatal stroke, the relative risk reduction of combination therapy compared with monotherapy differed by eGFR (P=0.04). The difference in treatment effect was observed at eGFR≤75 ml/min per 1.73 m² and most apparent at levels ≤60 ml/min per 1.73 m² Compared with individuals receiving monotherapy, individuals receiving combination therapy with a baseline eGFR of 60 ml/min per 1.73 m² experienced a 12% risk reduction (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.82 to 0.95); those with a baseline eGFR of 45 ml/min per 1.73 m² had a 13% risk reduction (HR, 0.87; 95% CI, 0.78 to 0.98). In stabilized individuals within 10 days of acute coronary syndrome, combination therapy seemed to be more effective than monotherapy in individuals with moderately reduced eGFR (30-60 ml/min per 1.73 m²). Further studies examining potential benefits of combination lipid-lowering therapy in individuals with CKD are needed.

Keywords: cardiovascular; chronic kidney disease; lipids; statins.

Figure 1.

Relationship between level of eGFR and event rate for primary composite end point of death from cardiovascular disease, a major coronary event, or nonfatal stroke. Kaplan-Meier curves show the primary composite end point during the 7-year study period stratified by (A) eGFR≥90 ml/min per 1.73 m², (B) eGFR=60–89 ml/min per 1.73 m², (C) eGFR=45–59 ml/min per 1.73 m², and (D) eGFR<45 ml/min per 1.73 m². EzSimva, ezetimibe and simvastatin; Simva, simvastatin.

Figure 2.

Effect of treatment on the occurrence of the primary end point across levels of kidney function. Cox proportional hazards model shows predicted event rates for the primary end point of death from cardiovascular disease, a major coronary event, or nonfatal stroke by level of eGFR.