Fasting glucose and triglycerides as biomarkers of mTOR inhibition, evidence of a categorical response.

Abstract

3091 Background: Hyperglycemia and hypertriglyceridemia are mechanism-based toxicities of mammalian target of rapamycin (mTOR) inhibitors, but have not been intensively studied as potential pharmacodynamic biomarkers. Methods: Changes in fasting serum glucose and triglyceride concentrations were determined in 127 patients (pts) before, and 4 weeks after treatment with the mTOR inhibitor sirolimus/rapamycin (S). Pts were enrolled in three different trials of S administered to achieve AUC of 1,000-6,000 ng-hr/ml. Results: Of these pts (67 male; 60 female; median age 62 y [range of 27-82], 72 had fasting measures for both glucose and triglycerides. Twelve pts had Type II diabetes. Mean/median change: in glucose = 17/8 mg/dL (SD=32, 95% CI 10-25, p< 0.0001), in triglycerides = 51/31 mg/dL (SD= 76, 95% CI 33-69, p< 0.0001) (p values for paired T-test). Changes were not associated with sex, S dose, baseline triglycerides, or use of lipid lowering agents. Change in glucose was significantly associated with a history of diabetes (larger increases in pts with a history, p<0.001) and baseline glucose levels (smaller increases in pts with higher baseline levels, p= 0.002). The Table features a striking observation. Of 72 pts, only 7 had no increase in glucose or triglyceride concentrations, and 9 had S- related increases in both glucose(>20 mg/dL) and triglycerides(>50 mg/dL). Meanwhile, 17 pts increased triglycerides of >50 mg/dL and 14 increased glucose of > 20 mg/dL without a change in the other marker. There was no evidence for association between changes in glucose and triglycerides (p = 0.72 by McNemar's test). Conclusions: Fasting blood glucose and triglyceride changes might be independent effects of mTOR inhibition. This would explain the absence of correlation between glucose and triglyceride changes and, excepting history of diabetes and changes in glucose, lack of association with clinically relevant covariates. These data suggest a new approach for developing these inexpensive validated laboratory measurements for qualification as clinically useful pharmacodynamic markers of mTOR inhibition. Δ glucose≤ 20 mg/dL Δglucose>20 mg/dL Δtriglycerides ≤ 50 mg/dL 32 14 Δtriglycerides > 50 mg/dL 17 9 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Amgen, Astellas Pharma, Biomarin, Daiichi Sankyo, Gilead, Millennium, Novartis, Pfizer, Takeda, Wyeth Actelion, Bayer, Bristol-Myers Squibb, EMD Serono, Genentech, Gilead, Lilly, Novartis, Pfizer, Roche patent pending for use of sorafenib in pulmonary hypertension