November 20th, 2010
SHARP Shows Benefit for Vytorin in Chronic Kidney Disease
Larry Husten, PHD
The long-awaited SHARP study has turned up positive results for Vytorin (ezetimibe and simvastatin) in a population of patients with chronic kidney disease. Results of SHARP (Study of Heart and Renal Protection) were presented on Saturday at the American Society of Nephrology meeting in Denver and were scheduled to be posted online on the trial’s website.
SHARP compared Vytorin to placebo in 9,438 patients with chronic kidney disease and found that Vytorin-treated patients had a significant (p=0.0010) 16.1% reduction in the incidence of first major vascular event (nonfatal MI or cardiac death, stroke, or revascularization). A first major vascular event occurred in 15.2% of patients in the Vytorin group compared to 17.9% of patients in the placebo group.
It should be noted that the SHARP steering committee sought to change the primary endpoint (from first major vascular event to first major atherosclerotic event) and the planned statistical analysis of the trial to avoid producing a false negative result. The trial sponsor, Merck, did not endorse their plan. However, the SHARP investigators reported a similar 16.5% reduction (p=0.0022) in the proposed new endpoint, which occurred in 13.4% of the placebo group compared to 11.3% in the Vytorin group.
It should also be noted that the primary analysis of major vascular events did not include approximately 1,000 patients who took simvastatin monotherapy for the first year of the trial before being re-randomized to either Vytorin or placebo. When this group is included in the analysis the results remain substantially the same, producing a 15.3% reduction (p=0.0012), with a major vascular event occurring in 17.6% of the placebo group versus in 15.1% of the Vytorin group.
During the first year, when compared to placebo, LDL dropped by 40% in the Vytorin group and 28% in the simvastatin group. At 2.5 years, LDL cholesterol was reduced by 30% in the Vytorin group.
About a third of patients in the trial were undergoing dialysis. Among patients not on dialysis at the start of the study, there was no difference in the progression to end-stage renal disease between Vytorin and placebo.
The investigators reported no unexpected safety issues. Cancer was reported in 9.4 % of patients in the Vytorin group versus 9.5% in the placebo group.
7 Responses to “SHARP Shows Benefit for Vytorin in Chronic Kidney Disease”
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statins have been well documented to have a benefit in prevention of progresson of CKD-so in a drug like vytorin,how can it be concluded without a head-to head comparison with a statin that the beneficial effects were from vytorin-and not just from the statin component??
Check this article out from JACC: http://content.onlinejacc.org/cgi/content/short/52/20/1679
It nicely summarizes some of the current thoughts about the role of statins in CKD.
There have been several meta analyses on this topic (including this free article: http://jasn.asnjournals.org/content/17/7/2006.full) which suggests that there is some benefit with statin with regards to slowing down the progression of kidney dysfunction and in reducing proteinuria. However, a lot of this should probably be taken with a grain of salt as it is based on observational data or post-hoc analysis of large trials.
Recently, the PLANET I and II trials prospectively looked at the renal protective effects of atorvastatin and rosuvastatin in diabetic and non-diabetic renal patients with proteinuria. It found that 80mg/day of atorvastatin significantly reduced proteinuria (15-20%), and 10mg/day or 40mg/day of rosuvastatin didn’t in both diabetic and non-diabetic populations. Atorvastatin was associated with slowing the rate of loss of kidney function also. In diabetic patients on atorvastatin, there was loss of about 1 to 2 mL/min per 1.73 m2 over 52 weeks, while diabetics on rosuvastatin 10 mg/day lost about 4 mL/min per 1.73 m2, and those on rosuvastatin 40 mg/day lost close to 8 mL/min per 1.73 m2. These were all statistically significant findings.
I don’t know everything about SHARP just yet, but I have reviewed the slides from the presentation given in Denver earlier today and see that the major findings are that there is significant reduction (17%) in atherosclerotic events associated with treatment with the combination drug in the study population (CKD patients, ~60% male, around 60yo and overweight with BMI of 27, with an average BP of 140/80; 13% smoked, 15% had vascular disease, and 23% had DM). They found these findings applied to patients on and not on dialysis. With regards to renal outcomes, there was no statistically significant finding that ESRD and dialysis could be avoided. Specifically, ESRD resulted in 33.9% of the treatment group and 34.6% of the placebo group, with p=0.97. The doubling of creatinine or incidence of death also were not different in the treatment vs placebo group.
If you want to see the presentation yourself, its available for free download here: http://www.ctsu.ox.ac.uk/~sharp/slides.htm
So the final answer to your question, in my opinion, is that the SHARP study did not find benefit from Vytorin in preventing progression of CKD. This is in concordance with the AURORA trial, and somewhat with the PLANET I and II trials. The cardiovascular benefit and reduction in atherosclerotic events in this patient population with statins alone versus statins and ezetimibe combination therapy is unclear at this time, but we will probably get an answer in the future. According to my reading, there is another arm of this study that randomized an additional 1000 patients to Simvastatin alone.
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SHARP is not designed to answer whether ezetimibe has incremental benefit over statin treatment. And, of course, that is a key question.
Until we have statin studies that demonstrate a benefit in chronic kidney disease, I think we are obligated to use vytorin in this clinical circumstance. Hopefully the NIH will quickly fund a study to compare outcomes between vytorin and simvastatin in chronic kidney disease. Until then, it looks like vytorin has a clinical indication.
The value of ezetimibe is still in doubt. Always was, and this does not change that fundamental.
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Until it will demonstrate benefits of other drugs in the evolution of chronic kidney diseases, I felt obliged to suggest atorvastatin treatment for people with this disease.
Bottom line is that patients with CKD are at risk for CV events and should be treated with a statin. This study shouldnt be interpreted as evidence for superiority of Vytorin as it was compared to placebo, not statin monotherapy.
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none