title: Metabolic complications with the use of mTOR inhibitors for cancer therapy.
abstract: BACKGROUND
  mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized.
  
  
  METHODS
  PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated.
  
  
  RESULTS
  Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control.
  
  
  CONCLUSIONS
  The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.
authors.affiliation: Hematology/Oncology Medical Specialists, Lancaster General Health, Lancaster, PA, United States.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Sivendran
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gartrell
authors.forename: Jian
authors.initials: J
authors.lastname: Ying
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boucher
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D050171:Dyslipidemias / Q000139:chemically induced / Q000453:epidemiology; D000068338:Everolimus; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced* / Q000453:epidemiology; D015994:Incidence; D009369:Neoplasms / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000903:Antibiotics, Antineoplastic; C515074:ridaforolimus; C401859:temsirolimus; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Adverse events; Cancer; Everolimus; Metabolic; Ridaforolimus; Temsirolimus; mTOR inhibitor