DECODE - Haemodynamic Effects Of Semaglutide and Tirzepatide - a Series of Pilot Studies

High blood pressure (hypertension) is the leading risk factor for death globally. It affects approximately 30% of adults in the United Kingdom. Obesity is also serious, ongoing epidemic. Hypertension and obesity share a well-known association, but despite extensive research, the mechanisms underlying their association are still poorly understood. Approximately 50% of all hypertensive cases are linked to obesity, with an even greater proportion in young adults. Since one of the most common causes of high blood pressure is overweight or obesity, a healthy diet and weight loss are recommended for patients with stage 1 hypertension (clinic blood pressure ranging from 140/90 mmHg to 159/99 mmHg) before initiating blood pressure-lowering medications. However, lifestyle interventions, even when successful, result in only moderate weight loss, which is not maintained in the majority of cases. Therefore, further weight loss interventions could play a crucial role in the treatment of obesity and obesity-related hypertension. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones with a variety of physiological actions. Their metabolic effects in the pancreas, stimulating glucose-dependent insulin secretion have led to the development of medications acting on these GLP-1 and GIP receptors for the treatment of type 2 diabetes mellitus, which are now well established. These new medications cause significant weight loss in adults with obesity and/or diabetes and are well tolerated. Beyond the substantial weight loss caused by these drugs, blood pressure also decreased significantly according to recent large studies. The blood pressure-lowering effect of these drugs may significantly contribute to the improved cardiovascular outcomes observed in previous large trials and analyses. Accordingly, these drugs could play a very important role in the treatment of hypertensive individuals with obesity. Whilst much of the blood pressure reduction elicited by these drugs could be mediated by the weight loss (\~70% in recent trials), it is also possible based on previous experiments performed in animal models as well as human subjects that these drugs exert direct effects on the cardiovascular system. The current study will examine the direct cardiovascular effects of the GLP-1 analogue semaglutide and the dual GIP/GLP-1 receptor agonist tirzepatide using two approaches: (i) investigation of the function of blood vessels in response to locally-acting infusions of semaglutide and tirzepatide into the forearm artery, and (ii) investigation of systemic effects \[blood pressure, heart rate, cardiac output (amount of blood pumped by the heart per minute), vascular resistance\] of semaglutide and tirzepatide in response to systemically-acting intravenous infusions.