Prevention and management of cardiovascular disease in metabolic disorders

Background. A close link exists between metabolic disorders and cardiovascular disease which is the most prevalent cause of morbidity and mortality in western countries. The contemporary epidemiological investigation of cardiovascular complications in metabolic disorders allows better risk stratification in order to optimize treatment strategies. Hypothesis. We hypothesized that clinical features and risk of cardiovascular disease may vary within subjects affected by different metabolic disorders. Aims and methods. The overall aim of this Ph.D. project was to investigate the prognostic impact of metabolic disorders and their related therapies on cardiovascular health in the current era. More specifically we aimed to: 1. Investigate causes of death and their associated risk factors in type 2 diabetes patients with or without established cardiovascular disease. To this aim, we performed a cause-of-death analysis among patients enrolled in SAVOR-TIMI 53 and used the competing-risk methodology to identify independent predictors of cardiovascular death and non-cardiovascular death. In addition, we aimed to describe features associated specifically with sudden cardiac death in diabetes. 2. Investigate the impact of metabolic disease on cardiovascular outcomes in a particular subset of patients, a contemporary cohort of subjects after an acute coronary syndrome (ACS). To this aim, we aimed to assess long-term cardiovascular risk associated with the presence of the metabolic syndrome or diabetes mellitus among patients recently hospitalized with an ACS using data from the SOLID-TIMI 52 trial. 3. Investigate the risk of thromboembolic complications in patients with atrial fibrillation and diabetes. To this aim, we explored the differential prognostic weight of diabetes on insulin therapy versus no insulin therapy on thromboembolic events in patients with AF using data from a multicenter, European AF registry called PREFER in AF. 4. Assess cardiovascular safety (a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter) of odanacatib, a cathepsin K inhibitor for the treatment of postmenopausal osteoporosis. To this aim, the anti-fracture efficacy and safety of odanacatib in postmenopausal women with osteoporosis was assessed in the Long-term Odanacatib Fracture Trial (LOFT) and its extension study (LOFT Extension). Results. Specific aim 1: this study involving more than 16,000 patients with T2D found that cardiovascular disease remains the leading cause of death in a contemporary cohort of patients with or at high risk for atherosclerotic cardiovascular disease. Approximately 1/3 of all deaths observed in the study met criteria for sudden death, regardless of whether patients did or did not have established atherosclerotic cardiovascular disease. While excess mortality is associated with older age, worse glycemic control, kidney complications including albuminuria, prior heart failure, peripheral artery disease, prior cardiovascular events (myocardial infarction or ischemic stroke) and elevated heart rate, biomarkers, especially elevated levels of NT-proBNP and hs-TnT measured in a stable population, are strongly associated with many causes of death, including non-cardiovascular death. Specific aim 2: this study demonstrates that, in patients who have recently suffered an ACS, the presence of metabolic syndrome is associated with the risk of adverse cardiovascular events but this risk appears to be primarily driven by the presence of diabetes mellitus. In contrast, a diagnosis of metabolic syndrome on its own did not provide incremental information for risk stratification in this population once diabetes history was considered; however, in patients without diabetes at baseline, the presence of metabolic syndrome was associated with nearly a 3-fold higher risk of developing new-onset diabetes mellitus during follow-up. Specific aim 3: in this analysis of individual patient data from the prospective PREFER in AF registry, patients with diabetes on insulin therapy had a significantly higher risk of stroke/systemic embolism at 1 year versus both patients without diabetes and patients with noninsulin-requiring diabetes; yet, for people with diabetes not treated with insulin, there was no significantly increased risk. These results may have implications in the assessment of thromboembolic risk in the AF population with diabetes and might have therapeutic implications. Specific aim 4: in a trial of more than 16,000 postmenopausal women with osteoporosis followed for up to 5 years, treatment with the cathepsin K inhibitor odanacatib was associated with progressive increases in bone mineral density and reductions in the incidences of vertebral, hip, and non-vertebral fractures. However, treatment also increased the risk of stroke with most events ischemic in aetiology. Further development of odanacatib as a potential treatment for patients with osteoporosis was stopped based on the overall balance between benefit and risk. Conclusions. This contemporary epidemiological investigation of cardiovascular complications in people with metabolic disorders indicates that cardiovascular disease remains the leading cause of death in this population. However, we also highlighted that subjects with metabolic disorders represent an heterogeneous group in terms of cardiovascular risk, with individuals affected by diabetes showing the highest risk, especially those treated with insulin, compared to subjects with other endocrinological disorders such as metabolic syndrome or post-menopausal osteoporosis.