Cardiovascular effects of the treatments for diabetes mellitus: the effect of SIRT-1 activation on markers of endothelial function, arterial stiffness and thrombosis; and the effect of hypoglycaemia on myocardial perfusion and biomarkers of ischaemia.

Abstract

Background. Both type 1 and type 2 diabetes mellitus are increasing in incidence and prevalence. Cardiovascular disease remains the number one cause of co-morbidity and mortality in this group of individuals. Intensive glucose control has been shown to be beneficial to cardiovascular outcomes in people with type 1 diabetes, but low blood sugar remains a problematic limiting factor. Intensive glucose control in people with type 2 diabetes and cardiovascular disease may cause harm, but the exact mechanism which mediates the poorer outcomes is unknown. Tight glycaemic control is associated with increased risk of hypoglycaemia. This increased risk of hypoglycaemia may have various effects on the blood supply to the heart, and the myocardium. Various treatments of diabetes also have complex effects on the heart, the vascular tree, and markers of thrombosis. The aim of this thesis was to firstly examine the cardiometabolic effects of a novel oral agent for the treatment of diabetes. Secondly, the thesis examines whether hypoglycaemia, a common side effect of insulin therapy, exerts an effect on myocardial perfusion and to markers of myocardial damage. Methods. Studies 1, 2 and 3 were conducted as Phase 1 cross-over randomised controlled trials of people with type 2 diabetes (n=15; Study 1) and people without diabetes but a cardiovascular risk factor (otherwise healthy smokers, n=24; Study 2), examining the effect of a novel sirtuin agonist on endothelial function, platelet-monocyte aggregation, and metabolic markers. In the cohort of patients with type 2 diabetes, the markers of glucose control were measured. The volunteers underwent 28 days of treatment with the novel agent SIRT2104 and crossed-over to 28 days of placebo, or vice versa. Three venous-occlusion plethysmography studies were performed at baseline, day 28 and day 56, and similarly platelet-monocyte aggregation studies. Serum triglycerides and cholesterol were measured in both cohorts. In Study 3, the effect of the novel agent treatment on markers of arterial stiffness (pulse wave velocity and pulse wave analysis) was assessed in both the diabetes and smoker cohorts. Finally, in Study 4, 17 individuals with type 1 diabetes mellitus and 10 controls without diabetes underwent experimentally-induced hypoglycaemia, using the hyperinsulinaemic glucose clamp method. Coronary flow reserve was measured non-invasively via transthoracic echocardiography and adenosine induced coronary vasodilation. The marker of myocardial injury, highly sensitive troponin I, was also measured during a euglycaemic clamp and hypoglycaemic clamp Results: In Study 1, SRT2104 had an inconsistent, predominantly neutral effect on endothelial function and platelet-monocyte aggregation studies. It had an unexpected effect in increasing markers of glucose control, and decreasing weight by approximately 1 kilogram over 28 days. Study 2 found that SRT2104 had a neutral effect on endothelial function and platelet-monocyte aggregation studies. A statistically significant reduction in total cholesterol, low density lipoproteins and triglycerides was observed after 28 days of SRT2104. Study 3 found that SRT2104 improved markers of arterial stiffness, with no discernible change to systolic and diastolic blood pressure. Finally, Study 4 found that hypoglycaemia did not have any effect on markers of myocardial injury. Coronary flow reserve was lowest during hypoglycaemia in people with type 1 diabetes, although this trend did not reach statistical significance. Conclusions. SRT2104 was a well-tolerated agent. There is a signal toward benefit in terms of lipids and markers of arterial stiffness. In people with type 2 diabetes, SRT2104 may induce weight loss at a cost of short-term loss of glycaemic control. Although the use of SRT2104 as an anti-diabetes agent may be problematic, its effect of weight and lipids merit further assessment and may provide vital clues to important molecular pathways underpinning lipid metabolism, weight, and cardiovascular disease. Hypoglycaemia in people with type 1 diabetes did not cause direct myocardial injury, but appeared to be associated with a low coronary flow reserve. This may prompt clinicians to screen for problematic hypoglycaemia during treatment, and to proceed with caution in cohorts of people with diabetes and known cardiovascular disease.