Clinicians looking after patients at risk of cardiovascular disease (CVD, the leading cause of deaths worldwide) often have to manage co-existing chronic diseases, such as endocrine and metabolic conditions. This Thesis submitted to the University of Geneva for the degree of Privat-Docent summarizes a line of clinical research to better understand the endocrine and metabolic disorders associated with CVD.

The thyroid function is tightly regulated at the central level and ensures that all tissues receive the right amount of peripheral thyroid hormones for their function. Subclinical thyroid disorders, where the peripheral thyroid hormones are in the lab reference range, but the central hormone thyrotropin is out of range, are defined based on lab results, however their clinical impact is less clear. As part of the Thyroid Studies Collaboration, we managed to explore in much depth the clinical outcomes of subclinical hypo-and hyperthyroidism, including CVD, stroke, atrial fibrillation, heart failure, bone markers, and cognitive decline. Following these observational data, an international collaboration was set up to launch the largest randomized clinical trial on this topic. The TRUST trial did not show any major benefit of levothyroxine on symptoms of elderly patients with moderate subclinical hypothyroidism, but the trial was underpowered for a definite answer on CVD outcomes. In this Thesis we explore other endocrine disorders such as hypogonadism in the elderly, which has been associated with CVD in some studies. In our latest analysis of the MrOS study, we could not find any association of lower levels of endogenous testosterone with CVD.

Energy metabolism is tightly regulated at the hypothalamic level. While increased food intake and the lack of physical activity contribute to obesity, the disrupted central regulation of appetite and food intake underlies most genetic forms of obesity. The most frequent form is due to melanocortin 4 receptor (MC4R) deficiency. We reviewed all published MC4R mutations of the past 2 decades and tested the in vitro activity of the agonist setmelanotide. This promising compound targeting the leptin-melanocortin pathway will soon be available. Energy metabolism is also linked with sleep/wake cycles and circadian rhythms which explains the strong interest in novel forms of nutritional interventions. We recently tested a time-restricted eating (TRE) intervention and are now devising personalized TRE for certain conditions and the underlying chronotype of patients. This extended line of research will lead to new personalized interventions on nutrition and lifestyle for the years to come.