Overview

Hypertension is the leading risk factor for death globally, affecting approximately 30% of adults in the United Kingdom. Obesity is also a serious and ongoing epidemic, with global obesity rates having more than tripled in men and doubled in women, since 1975. In the United Kingdom, 64% of the adult population are overweight or obese. Hypertension and obesity share a well-established association, with obesity being responsible for the development of hypertension in 40-78% of cases. In young adults, this link between body size and blood pressure (BP) is much stronger that in older adults. Since overweight and obesity are among the most common and modifiable causes of high BP, weight loss induced by lifestyle-changes is recommended for overweight or obese patients with hypertension. However, lifestyle interventions, even when successful, result in only moderate weight loss, which is not maintained in the majority of cases. A meta-analysis of randomised controlled trials demonstrated that lifestyle-interventions lead to an average net weight reduction of 5.1 kg, accompanied by a significant, but modest, \~4 mmHg reduction in BP. Weight loss interventions could play a crucial role in the treatment of obesity-related hypertension in young adults.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, originally developed for the treatment of type 2 diabetes, are safe and clinically effective anti-obesity drugs. Recent data show a 10-20% placebo-adjusted reduction in body weight in overweight or obese adults without diabetes using the GLP-1 analogue semaglutide or the dual GLP-1/GIP receptor agonist tirzepatide, with the majority of weight loss achieved within the initial six months. The substantial weight loss induced by these drugs is accompanied by a significant reduction in BP. Two recent meta-analyses showed that semaglutide is associated with a \~5 mmHg placebo-adjusted reduction in clinic systolic BP (SBP). A sub-study of the SURMOUNT-1 trial reported a \~10 mmHg reduction in 24-h ambulatory SBP with tirzepatide. Most participants in these studies were normotensive or had well-controlled hypertension. Furthermore, antihypertensive medication use declined amongst those receiving anti-obesity drugs meaning the BP-lowering effect of weight loss, elicited by these drugs, is probably underestimated. These data suggest that the new anti-obesity drugs could be effective in managing overweight or obesity-related hypertension. Furthermore, it may be possible to cure hypertension in at least some young adults, removing the need for life-long antihypertensive treatment. However, the magnitude and time course of BP reduction elicited by these new anti-obesity drugs remain uncertain.

The primary aim of this feasibility study is to assess the extent and trajectory of BP reduction achieved through intensive weight loss in overweight or obese adults with stage 1 hypertension and compare this to current standard of care measures which uses anti-hypertensive medications and lifestyle advice. The study will utilise a modified trial within cohort approach, using patients based within the clinical pharmacology/hypertension service at Addenbrooke's Hospital, Cambridge.

Eligibility

Eligibility criteria for randomisation

Inclusion Criteria:

• Aged 18 to 40 years (inclusive)
• Body mass index (BMI) ≥27 kg/m2
• Clinical diagnosis of primary (essential) hypertension as per NICE guidance
• Unattended brachial SBP ≥135 and/or DBP ≥85 mmHg and \<160/100 mmHg
• Maximum of one antihypertensive medication

Exclusion Criteria:

• Anything in medical notes suggesting unsuitable in the opinion of the investigator

Eligibility criteria for participation in weight loss arm

Inclusion criteria:

• Written informed consent
• Aged 18 to 40 years (inclusive)
• Body mass index ≥27 kg/m2
• Clinical diagnosis of primary (essential) hypertension as per NICE guidance
• Unattended brachial SBP ≥135 and/or DBP ≥85 mmHg and \<160/100 mmHg
• Maximum of one antihypertensive medication

Exclusion criteria:

The presence of any of the following will preclude participant inclusion:

• Known or suspected secondary hypertension
• Hypersensitivity to any of the study drugs or excipients
• Currently taking drugs likely to have interactions with tirzepatide
• 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
• Prior or planned surgical, endoscopic and/or device-based therapy treatment for obesity
• Self-reported, intentional or unintentional, change in body weight (over \~10%) within \~three months of screening
• Known heart failure or clinically significant valvular heart disease
• Implanted pacemaker or implantable cardioverter defibrillator (ICD)
• Second or third-degree AV block, sino-atrial block, sick sinus syndrome
• Known active malignancy including thyroid cancer
• Known renal impairment (creatinine \>150µmol/L)
• Clinically significant neurological disease
• History of scleroderma
• Participants on anticoagulant therapy
• Known history of pancreatitis
• Known inflammatory bowel disease
• History of gallstones (unless previous cholecystectomy)
• Severe gastroparesis or gastric emptying abnormality
• Family history of multiple endocrine neoplasia
• Needle-phobia
• Planned pregnancy, current pregnancy, or breastfeeding
• Current involvement in the active treatment phase of other research studies
• Any other clinical reason which may preclude entry in the opinion of the investigator