Statins To Reduce CV Risk In Patients With CKD – Do We Have A SHARPer Indication For Treatment?

The evidence regarding the benefits of statin therapy in patients with chronic kidney disease has been far from clear. There is no doubt that treatment of low density lipoprotein cholesterol (LDL-C) with statins reduces coronary events in many patient populations (average 20% reduction per 1 mmol/L LDL-C reduction or 38mg/dL).¹ But previous trials in the end stage CKD population, two in patients who were receiving dialysis,^2,3 and one in patients status post renal transplant⁴, did not show benefits in regards to cardiovascular risk reduction. Conversely, meta-analyses evaluating statins in patients with non-dialysis dependent CKD have shown an overall reduction in cardiovascular and all-cause mortality.^5,6When a patient’s estimated glomerular filtration rate (eGFR) falls below 30 ml/min/1.73m², the pathophysiology of cardiovascular disease may be somewhat different.   Vascular stiffness, aortic calcification, and increased sympathetic tone may explain the difference in response seen with statin therapy in this population.⁷  

The National Kidney Foundation and the Kidney Disease Outcomes Quality Initiative’s (NKF-KDOQ) recommend that CKD be considered a risk equivalent for cardiovascular disease and be treated to a LDL-C goal of less than 100 mg/dL, with an option target  <70 mg/dL. The NKF-KDOQI guidelines endorse statin use in all stages of CKD.8   There was no mention of ezetimibe in the NKF-KDOQI guidelines due to the lack of evidence regarding its safety and efficacy at the time of publication.8 TheStudy of Heart and Renal Protection trial (SHARP) was initiated to evaluate the benefits of statin plus cholesterol-absorption inhibitor therapy in patients with CKD and no prior cardiac disease.

Patients age forty and older with a serum creatinine greater than 1.7 mg/dL (men) or 1.5 mg/dL (women) were randomized to receive placebo, simvastatin 20 mg, or simvastatin 20 mg plus ezetimibe 10 mg for one year. After one year, the simvastatin monotherapy group was re-randomized to placebo or simvastatin plus ezetimibe. The statin monotherapy group was implemented to assess the safety of adding ezetimibe to simvastatin in renally compromised patients. After re-randomization, a total of 4650 participants received simvastatin plus ezetimibe and 4620 received placebo. The primary outcome was occurrence of major atherosclerotic events (non-fatal MI, coronary death, non-hemorrhagic stroke, or arterial revascularization).  Participants had labs drawn at 2, 6, and 12 months, then at least every 6 months thereafter for at least four years that assessed creatine kinase, liver transaminases, creatinine, and a non-fasting direct LDL-C.

Baseline demographics were similar in the groups.  The mean age was 62 years and most participants were male (63%), white (72%) and overweight (mean BMI of 27 kg/m²).  The baseline mean LDL-C was 107 mg/dL and mean eGFR was 26.6 ml/min.  Additionally, 23% of participants had diabetes, 15% had a prior history of vascular disease, and unlike previous trials, only 33% were receiving dialysis at the time of randomization.  The median duration of follow up was 4.9 years with a low discontinuation rate due to adverse effects (<10%). Of note, mean LDL-C concentrations were substantially lower in dialysis vs. non-dialysis patients (99 mg/dL vs. 110 mg/dL, p <0.0001).

The average LDL-C reduction in the treatment group was 33 mg/dL with a mean LDL-C of 74 mg/dL after 4 years of follow-up. During the treatment period, 526 (11.3%) and 619 (13.4%) subjects in the ezetimibe plus simvastatin group and placebo group, respectively, experienced a first major atherosclerotic event representing a 17% reduction in CV events in the ezetimibe/simvastatin group (p=0.0021). The number needed to treat (NNT) is 48.  When the patients initially allocated to simvastatin monotherapy were excluded, there was similar a reduction in major vascular events with ezetimibe/simvastatin (p=0.0012).  When examining individual endpoints, the differences between groups in first major coronary events, cardiac deaths, and stroke deaths were not significant (p=0.37), but there was a significant reduction in non-hemorrhagic stroke (p=0.01) and arterial revascularization (p=0.04). There were no significant differences between groups in incidence of creatine kinase elevations, transaminase elevations, rhabdomyolysis, or cancer.   

The study was not powered to detect differences in atherosclerotic events in specific subgroups such as dialysis and non-dialysis patients.  Nevertheless, patients on dialysis appeared to have a reasonably similar benefit when compared to non-dialysis patients in terms of reduction of atherosclerotic events (RR of 0.90; 95% CI 0.75-1.08).  Although dialysis patients had a lower baseline LDL-C and a smaller absolute LDL-C reduction while on treatment, the reduction in major atherosclerotic events per 1 mmol/L reduction in LDL-C was similar at each stage of CKD.  

Although the results may seem contradictory with the findings from previous studies in end-stage renal disesase patients, comparing them to the SHARP study is difficult because of the significant differences in study design.  The previous trials studied different patient populations, examined different primary endpoints, had different baseline LDL-C values, and had smaller sample sizes,^2,3

Some essential questions arise when evaluating this study.   Can the results be extrapolated to a “real world” CKD population seen in our clinics daily?  It is well documented that African-Americans have a higher incidence of CKD, yet only 3% of the study population was African-American. Similarly, this study enrolled patients without prior history of coronary disease.  A preponderance of patients seen in our clinic have concurrent coronary disease at baseline.  Adherence in this study was less than optimal.  Would improved adherence increase the benefit of statin therapy in this population … or increase the risk of adverse events?

Another issue to consider was the decision to discontinue the simvastatin monotherapy arm after one year.  Although the authors clearly state that simvastatin monotherapy was undertaken to evaluate potential safety concerns with ezetimibe only, it would have been interesting to see if simvastatin monotherapy (continued throughout the study) would have provided the same benefit in terms of reducing atherosclerotic events.  Likewise, would simvastatin 40mg, a dose shown to be safe and effective in previous studies,^9,10 provide similar or greater reductions in atherosclerotic events? Clinical trials such as ENHANCE and ARBITER-6 have shown that ezetimibe lowers LDL-C but may have no effect on outcomes (e.g. morbidity or mortality).^11,12 Continuation of the simvastatin monotherapy arm could have provided us a better understanding regarding ezetimibe’s role in lipid management.

The SHARP study does provide some valuable new evidence. Specifically, it seems to validate current guidelines that advocate aggressive LDL-C treatment in patients with CKD, regardless of the stage of disease.  However, more evidence is needed before the combination of simvastatin and ezetimibe can be recommended over statin monotherapy.  So, while we have a SHARPer indication to aggressively treat elevated LDL-C in patients with CKD, statin monotherapy should remain the first line choice.