DISCUSSION
metabolic syndrome, diabetes
NON-SMALL CELL LUNG CANCER, RECURRENCE, MULTIPLE CANCER, ADVERSE EVENT, INSULIN RESISTANCE, METABOLIC SYNDROME, DIABETES
The results presented are after empiric therapy with metformin compared to placebo to measure its effects on the development of metabolic syndrome in patients with PC on ADT. We caveat that all results in are study are underpowered due to changes in the standard of care as described in Results which limits the generalizability of any conclusions. However, although metformin reduces serum insulin and may have chemoprevention properties, in our small study we found no impact of the addition of metformin to ADT therapy on risk of metabolic syndrome associated with castration therapy and no additional anti-tumor effects.Multiple studies have demonstrated that markers of metabolic syndrome including weight, WC, BMI and fasting glucose increase shortly after receiving androgen deprivation therapy [We present a phase II prospective study which randomized patients receiving androgen deprivation therapy to receive metformin compared to placebo and the data (albeit limited by sample size due to explanation in Results) did not show a statistically significant difference in mean markers of metabolic syndrome. We noted a trend towards increase in all categories regardless of randomization to placebo or metformin groups. We expect that serum fasting insulin concentrations would rise in the setting of metabolic syndrome due to insulin resistance and therefore these insulin concentrations were monitored. There was an increase in serum insulin concentrations across both groups but without statistical significance. We investigated delta change in markers of metabolic syndrome and again did not demonstrate statistically significant difference.As was first described by Matthews et al., we investigated homeostatic modeling in our patient population to quantify insulin resistance and beta-cell function [Additionally, serum fasting insulin concentration means remained without significant change upon exclusion of patients with serum metformin concentration of 0. Metformin is excreted renally and does not undergo hepatic metabolism nor biliary excretion. Following oral administration, about 90% of metformin is excreted renally in 24 hours. Lack of proper absorption could lead to decreased concentration of metformin in the setting of reported compliance.The data in this analysis contrasts with previous studies. A randomized pilot study of ADT and metformin vs. ADT alone, 20 patients in each arm suggested significant improvements in abdominal girth, weight, body mass index and blood pressure was observed, although this study again did not detect changes in biomarkers of insulin resistance between cohorts [Larger studies have demonstrated the potential chemo-preventative effects of metformin on multiple cancers [Recent research has shown that metformin combined with chemotherapy drugs can significantly decrease local recurrence in patients with diabetes and non-small cell lung cancer [Despite evidence that metformin activates AMPK leading to inhibition of the mTOR pathway and decreases in phosphorylation of S6 Kinase 1 (pS6K1) [PSA was monitored at all intervals of patients in our study of both cohorts, metformin and placebo. Each patient received ADT and patients were started on metformin at the start of ADT. Approximately the same proportion of patients in both the metformin and placebo cohorts achieved PSA <0.02 by week 28. The difference between the two groups was marginal and statistically not significant (Adverse events overall were increased in the metformin cohort by comparison to placebo (