Mammalian Target of Rapamycin Inhibitor Dyslipidemia in Kidney Transplant Recipients

Abstract

The incidence, pathogenesis, consequences and treatment of mammalian target of rapamycin (mTOR) inhibitor dyslipidemia are not well described. We conducted a systematic review of randomized controlled trials reporting cholesterol and triglycerides in mTOR versus non-mTOR inhibitor immunosuppressive treatment regimens in kidney transplant recipients. All but one of 17 trials reported higher levels of cholesterol and triglycerides, or an increased prevalence of treatment with lipid-lowering agents. Approximately 60% of mTOR inhibitor-treated patients received lipidlowering agents (2-fold higher than controls). There appeared to be little difference between dyslipidemias caused by sirolimus (14 trials) versus everolimus (3 trials). It was difficult to determine the extent to which declines in lipids over time posttransplant were due to lipid-lowering therapy, changes in doses and/or discontinuations of mTOR inhibitors. From the four trials that measured lipoproteins, it appeared that at least some of the increase in total cholesterol with mTOR inhibitors was due to increased low-density lipoprotein cholesterol. What direct or indirect effects mTOR inhibitors have on atherosclerotic cardiovascular disease in kidney transplant patients are unknown. However, in the absence of the necessary clinical trials, dyslipidemia should be managed, as it would be in nontransplant patients at high risk for cardiovascular disease.

Everolimus Causing Severe Hypertriglyceridemia and Acute Pancreatitis

“…9 This was also observed in patients on everolimus after other organ transplants, such as liver and lung.…”

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

“…In most clinical studies, sirolimus treatment is associated with a significant increase in LDL cholesterol (40,43,47). 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.…”

“…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).…”

“…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).…”

“…Treatment with everolimus is associated with a significant increase in plasma triglycerides in most studies (40,43,44,51,52). In the phase III trial evaluating everolimus in metastatic RCC, hypertriglyceridemia was significantly more frequent with everolimus (71%) than with placebo (30%) (3).…”