INTRODUCTION
death, glucose tolerance, cancer, diabetes mellitus, biochemically-relapsed, non-cutaneous malignancy, metabolic syndrome, type II diabetes
CANCER, DIABETES MELLITUS, SECONDARY, INSULIN RESISTANCE, PROSTATE CANCER, METABOLIC SYNDROME, INCREASED INSULIN, TYPE II DIABETES
Background: Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation.Materials and Methods: To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT. Fasting serum glucose, insulin, PSA, metformin, weight and waist circumference (WC) were measured at baseline, week 12 and 28. The primary endpoint was a group of MS metrics. Secondary endpoints include PSA response, safety, serum metformin concentrations and analysis of downstream an mTOR target, phospho-S6-kinase.Results: 36 men were randomized to either metformin or placebo. Mean age was 68.4. Mean weight, WC and insulin levels increased in both arms. At week 12 and 28, no statistical differences in weight, WC or insulin were observed in either arm. No significant difference in percentage of patients with PSA <0.2 at week 28 between metformin (45.5%) vs. placebo (46.7%). Analysis in the metformin-arm showed variable down-regulation of phospho-S6 kinase.Conclusions: In our small study, metformin added to ADT did not show a reduced risk of ADT-related MS or differences in PSA response.Prostate cancer (PC) is the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer related death in U.S. men [ADT has been shown to be associated with increased fasting glucose levels, elevated serum insulin and insulin resistance, including the diagnosis of diabetes mellitus [Metformin is an oral anti-hyperglycemic drug used in the management of type II diabetes that improves overall glucose tolerance [AMPK is involved in energy homeostasis at both the cellular and macroscopic level. Metformin activates AMPK leading to inhibition of the mTOR pathway by phosphorylating TSC2 and Raptor. Phosphorylation of TSC2 and Raptor subsequently decreases phosphorylation of S6 Kinase 1 (S6K1) resulting in decreased protein and lipid synthesis [We hypothesized that control of increased insulin uptake by overcoming resistance may lead to improved control of metabolic syndrome in PC patients through metrics such as weight, waist circumference and serum insulin levels. We also hypothesized that metformin may enhance ADT’s anti-tumor effects either directly or indirectly through improved control of metabolic syndrome. To test these hypotheses, we conducted a phase II randomized, placebo-controlled, prospective study of metformin vs. placebo in patients with advanced, castrate sensitive PC treated with ADT (NCT:01620593).