Comparative Benefit of Ezetimibe plus Simvastatin in Individuals with Moderately Reduced eGFR

Stanifer et al. JASN May 15, 2017

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

 

Scratching the Surface of Kidney Disease in Sub-Sahara Africa

"John Stanifer is currently a 4th year resident in the Global Health Pathway of the Internal Medicine Residency at Duke and will be joining the Nephrology Fellowship this year. He is interested in first understanding the prevalence of chronic kidney disease (CKD) in Tanzania and then exploring the unique risk factors at play. I asked him to share his thoughts about this region of the world here on RFN so that others can learn from his unique experiences." -Matt Sparks 

I first traveled to Tanzania in 2012 where I realized the enormous need for increased clinical awareness of chronic diseases such as CKD. Global health nephrology may be a new idea for many people, but after practicing medicine and living in Tanzania, the idea has become second nature. It is known that acute kidney injury (AKI) and CKD account for a great deal of morbidity and mortality in this region. As in the developed world, this is not just related to kidney outcomes but importantly impact cardiovascular risk and outcomes. While we do have the capacity for peritoneal dialysis here at the hospital where I work in Tanzania, cost, training, and staff substantially limit its use. The biggest difficulty may actually be in pre-dialysis care. This applies not only to early- to mid-stage CKD but also in the non-dialysis management of AKI. We still have a lot to learn about the nature and impact of kidney disease in developing regions of the world such as Tanzania. We, as a nephrology community, can make a huge impact into helping people cope and potentially prevent kidney disease in a region where little research has been performed.

The United Nations adopted a resolution in 2011 acknowledging the growing global risk of non-communicable diseases such as CKD. In fact, CKD as a cause of death has doubled worldwide since 1990. As such, CKD continues to be an under-recognized burden worldwide. Our recent article in the Lancet Global Health, “The Epidemiology of Chronic Kidney Disease in Sub-Saharan Africa: A Systematic Review and Meta-Analysis” highlights how poor the state of renal research and care is in many low-income countries, and our efforts here in Tanzania are beginning to highlight the disparity between the dearth of data pertaining to renal disease and the magnitude of the problem.

First, we are beginning to understand practice patterns and healthcare utilization among patients with chronic disease such as CKD. Besides cost and access, there are numerous reasons that lead to failure of care for chronic diseases the most important of which may be the lack of understanding of ‘chronic disease’ itself. In a region where untreated malaria is considered the paradigm for ‘chronic disease’, informing patients that their diseases are lifelong and chronic (which often translates as incurable) most commonly results in isolation, fear, and treatment failure.

Secondly, CKD is unique in that it is related to both communicable and non-communicable disease: a point which is especially important in global health nephrology. The well-known and traditional risk factors such as diabetes, hypertension, and HIV are still apparent in this region. However, CKD in this part of the world is also associated with schistosomiasis, tuberculosis, untreated streptococcal infections (structural heart disease from Rheumatic Fever is exceedingly common), environmental contaminates such as lead and arsenic. The most troubling cause of CKD in this region is the pervasive use of traditional or herbal remedies, and one of the goals of our research is to catalogue the remedies that are nephrotoxic and education locals about them.

Third, our preliminary data suggest that the burden of CKD is likely to be as substantial (if not greater) than that of the US and Europe. Alarmingly, we are finding similar prevalence estimates for diabetes, hypertension, and obesity. Crude estimates indicate that the prevalence of CKD is about 12-16% and that diabetes is prevalent in 14-18% of the adult population. In light of these findings, the importance of CKD in the spectrum of non-communicable diseases must be stressed especially in the context of it as a cardiovascular risk factor and in context of the uniform fatality of ESRD in almost all low-income countries. CKD should no longer be viewed as a disease exclusive to the developed world.

After establishing the epidemiology of CKD in the region, our next steps will be to validate measures of renal function, study the genetics of CKD in Eastern Africa, and to establish chronic disease treatment and prevention programs.

John W Stanifer