Effects of Sirolimus on Lipids in Renal Allograft Recipients: An Analysis Using the Framingham Risk Model

Abstract

This report describes the effects of sirolimus on plasma lipids, and uses the Framingham risk model to assess the clinical importance of these effects. Lipid data from two large controlled studies of 1295 renal transplant patients were analyzed retrospectively. Sirolimus 2 mg/day and 5 mg/day were compared with placebo or azathioprine, and administered concomitantly with steroids and cyclosporine over 12 months. Hypercholesterolemia and hypertriglyceridemia occurred in all treatment groups and were maximal at 2-3 months. The sirolimus groups evidenced higher lipid levels than the controls, but the elevations diminished over time. At 1 year, the patients given sirolimus 2 mg/ day had a mean cholesterol level 17 mg/dL greater and a mean triglyceride level 59 mg/dL greater than the controls. Among the patients given sirolimus 5 mg/day, mean cholesterol was 30 mg/dL greater and mean triglycerides were 103 mg/dL greater than the controls. Treatment with statins and fibrates was effective in reducing cholesterol and triglyceride levels, respectively, in the sirolimus-treated patients. The Framingham risk model predicted that the 17 mg/dL elevation in cholesterol would increase the incidence of coronary heart disease (CHD) by 1.5 new cases per 1000 persons per year and CHD death by 0.7 events per 1000 persons per year. Lipid elevations observed in the sirolimus-treated patients were manageable, improved over time, and responded to lipid-lowering therapy. Based on the Framingham risk model, the CHD risks associated with these cholesterol elevations are small compared with the baseline risks of the transplant population.

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“…The hyperlipidemic effect of sirolimus is observed in the absence (50) and in the presence of ciclosporin (48,49). In addition, data from the clinical studies indicate that the hyperlipidemic effect of sirolimus is dose-dependent (41,49).…”

“…It has also been reported that treatment with sirolimus is associated with a dramatic increase in plasma triglycerides ranging from 65 to 100% (41,42,43,44,45,47). Patients receiving sirolimus 2 or 5 mg/day have been shown to have plasma triglycerides respectively 59 or 103 mg/dl greater than that of controls (41). In a multivariate analysis, sirolimus treatment was an independent factor associated with hypertriglyceridemia (43).…”

“…In the study performed by Spinelli et al (43), sirolimus treatment was an independent factor associated with plasma LDL cholesterol levels above 121 mg/dl. It has also been reported that treatment with sirolimus is associated with a dramatic increase in plasma triglycerides ranging from 65 to 100% (41,42,43,44,45,47). Patients receiving sirolimus 2 or 5 mg/day have been shown to have plasma triglycerides respectively 59 or 103 mg/dl greater than that of controls (41).…”

“…Sirolimus (rapamycin) " A significant increase in total cholesterol ranging from 25 to 55% has been observed with sirolimus (40,41,43,44,45,46,47,48). In most clinical studies, sirolimus treatment is associated with a significant increase in LDL cholesterol (40,43,47).…”

“…Indeed, a review of 17 randomized controlled trials shows an increase in total cholesterol and/or triglycerides in all but three trials (40). Among those three trials reporting no difference in lipids between groups, the percentage of mTOR inhibitor-treated patients on lipid lowering therapy were increased in two of them, indicating that mTOR inhibitors might have induced dyslipidemia (41,42). In a study performed on 474 kidney transplant recipients, it was noted that dyslipidemia is frequent 1 year after transplantation and, in multivariate analysis, that treatment by mTOR inhibitors (sirolimus or everolimus) is an independent factor associated with dyslipidemia (43).…”