Cardiovascular risk reduction in insulin resistant states

Introduction: Insulin resistance is the hall mark of a number of pathological conditions and is thought to play a major role in the cardiovascular risk associated with them. This thesis critically evaluates two insulin resistant conditions - polycystic ovary syndrome (PCOS) and type 2 diabetes (T2DM) - where there are many unresolved issues. During the course of these studies, the effect of weight loss and medications in modifying cardiovascular risk in these conditions was evaluated. Methods: The first studies focused on a randomised open labelled parallel study of metformin and rimonabant in obese patients with PCOS. Subsquently, an extension to this study was undertaken where patients who were on rimonabant were changed over to metformin, whereas those on metformin were continued on metformin for another 3 months. As part of this study the effect of rimonabant and metformin on incretin hormones in patients with PCOS was studied. The next studies focused on a randomised double blind placebo controlled study on the pleotrophic effect of atorvastatin in patients with PCOS. Subsequent metformin therapy after atorvastatin treatment was undertaken. This study led to the investigation of the effect of simvastatin and atorvastatin on biological variation of lipids in patients with T2DM that has got implications in treating to lipid targets. A corollary to this study was whether the biological variation of LDL calculated using Friedewald formula differed from that of direct LDL. Results: In the first series of studies, after 12 weeks of rimonabant there was a significant reduction in anthropometric and metabolic parameters as well as biochemical hyperandrogenemia in patients with PCOS. There was no change in any of these parameters in the metformin treated group. In three months extension arm to this study, metformin maintained the weight loss as well as enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone. There was a significant and reversible increase in glucose-dependent insulinotropic polypeptide (GIF) levels after 3 months of rimonabant treatment. There were no changes in GIF or glucagon-like peptide-1 (GLP-1) levels with metformin. In the second series of studies it has shown that atorvastatin was effective in reducing inflammation, biochemical hyperandrogenemia and metabolic parameters in patients with polycystic ovary syndrome after a 12 week period compared to placebo. The subsequent effect of three months metformin treatment was augmented by atorvastatin pre-treatment compared to placebo pre-treatment. In the subsequent study it was shown that the coefficient of variation (CV) of TC, LDL, HDL and TG on simvastatin was significant but comparable to atorvastatin in patients with T2DM. However, subsequent directly measured LDL cholesterol was shown to be an order of magnitude more stable when taking equivalent doses of atorvastatin rather than simvastatin. Conclusion: Both weight loss using rimonabant and atorvastatin were effective in reducing biochemical hyperandrogenemia and metabolic profile in patients with PCOS. The effect of rimonabant might be partly mediated through modulating GIF levels.EThOS - Electronic Theses Online ServiceGBUnited Kingdo