What is the research question? Semaglutide and tirzepatide cause weight loss and blood pressure reduction. However, weight loss only partially explains the blood pressure reduction. Based on previous studies, there might be direct effects in the cardiovascular system. In forearm blood flow studies, semaglutide and tirzepatide will be infused into the brachial artery to investigate their effects on the function of blood vessels. In systemic studies, semaglutide and tirzepatide will be infused into systemic circulation to investigate their effects on heart and blood vessels.

There are three different populations being looked at for this study: participants with normal weight and normal blood pressure, participants with obesity and normal blood pressure, and participants with obesity and high blood pressure.

There are six sub-studies each with different visit schedules. The minimum participant study duration (including follow-up phone call) would be 2 days, while the maximum participant study duration would be approximately 2 - 2.5 months. The overall study duration is expected to be approximately 18 months.

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.

Inclusion Criteria:

1. Inclusion Criteria - Participants with normal weight and normal blood pressure

   • Have given written informed consent to participate
   • Aged 18 to 50 years (inclusive)
   • Females must be post/peri-menopausal or if of child-bearing potential they are required to use adequate contraception and to have a negative pregnancy test (performed at each visit)
   • Current non-smoker
   • Body mass index (BMI) in range 18.5-24.9 kg/m2
   • Clinic brachial systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg

2. Inclusion Criteria - Obese participants with normal blood pressure

   • Have given written informed consent to participate
   • Aged 18 to 50 years (inclusive)
   • Male or female
   • Females must be post/peri-menopausal or if of child-bearing potential they are required to use adequate contraception and to have negative pregnancy test (performed at each visit)
   • Current non-smoker
   • BMI ≥30 kg/m2
   • Clinic brachial systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg

3. Inclusion Criteria - Obese participants with high blood pressure

   • Have given written informed consent to participate
   • Aged 18 to 50 years (inclusive)
   • Male or female
   • Females must be post/peri-menopausal or if of child-bearing potential they are required to use adequate contraception and to have negative pregnancy test (performed at each visit)
   • Current non-smoker
   • BMI ≥30 kg/m2
   • Diagnosis of stage 1 essential hypertension

Exclusion Criteria:

• Regular use of medications with vasoactive or cardiac effects in normotensive individuals; inability or unwillingness to omit anti-hypertensive medications on the morning of the study visits in hypertensive individuals
• Hypersensitivity to any of the study drugs or excipients
• Known clinically significant valvular heart disease
• Implanted pacemaker or implantable cardioverter defibrillator (ICD)
• Known active malignancy
• Known renal impairment (creatinine >150µmol/L)
• Clinically significant neurological disease
• History of scleroderma
• Current pregnancy, breastfeeding
• Current involvement in the active treatment phase of other research studies (excluding observational/non-interventional)
• Second or third-degree AV block, sino-atrial block, sick sinus syndrome
• Known HIV, hepatitis B or C
• Needle phobia
• Participants treated with formal anticoagulant therapy such as, but not limited to, heparin or warfarin
• Diagnosis of Type 1 or Type 2 Diabetes Mellitus or current usage of insulin or other injectable drugs for the treatment of diabetes such as but not limited to GLP-1 and GIP receptor agonists
• BMI <18.5 kg/m2
• Known heart failure
• Currently taking drugs likely to have interactions with semaglutide or tirzepatide
• Family history of multiple endocrine neoplasia
• Known thyroid cancer
• Known history of pancreatitis
• History of gall stones (unless the gall bladder has been removed)
• Any other clinical reason which may preclude entry in the opinion of the investigator

Access to IPD may be granted if a prospective applicant submits a request. The request will be reviewed by the sponsor and the Chief Investigator, and access will be approved only where there are clear academic reasons to allow use of the data. An IPD sharing plan will be discussed and relevant data sharing agreements will be developed when required.