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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiovascular Diseases
• Intervention / Treatment: Drug: semaglutide; Drug: Tirzepatide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 112
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Guneswary Thaygaraja, Msc Genomic Medicine; Phone Number: 01223 349762; Email: cuh.cambs.cardiovascular@nhs.net

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB20QQ
      • Addenbrooke's Hospital
      • Principal Investigator: Joseph Cheriyan, MBChB, MA, FRCP
      • Contact: Joseph Cheriyan, MBChB, MA, FRCP; Phone Number: 01223256653; Email: jc403@cam.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sub-study 1A; Intra-arterial infusion of semaglutide	Drug: semaglutide; Semaglutide: GLP-1 analogue
Experimental: Sub-study 1B; Intra-arterial infusion of Tirzepatide	Drug: Tirzepatide; Tirzepatide: dual GIP/GLP-1 receptor agonist
Experimental: Sub-study 1C; Intra-arterial infusion of Saline, Semaglutide and Tirzepatide	Drug: semaglutide; Semaglutide: GLP-1 analogue; Drug: Tirzepatide; Tirzepatide: dual GIP/GLP-1 receptor agonist
Experimental: Sub-study 2A; Slow intravenous bolus of Semaglutide	Drug: semaglutide; Semaglutide: GLP-1 analogue
Experimental: Sub-study 2B; Slow intravenous bolus of Tirzepatide	Drug: Tirzepatide; Tirzepatide: dual GIP/GLP-1 receptor agonist
Experimental: Sub-study 2C; Slow intravenous bolus of Semaglutide and Tirzepatide	Drug: semaglutide; Semaglutide: GLP-1 analogue; Drug: Tirzepatide; Tirzepatide: dual GIP/GLP-1 receptor agonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sub-study 1A:Change in forearm blood flow parameters after infusion of semaglutide (Ratio)	Ratio, expressed as a number (no units as this is a ratio)	2-2.5 months from screening to follow-up
Sub-study 1A:Change in forearm blood flow parameters after infusion of semaglutide (Absolute flow)	Absolute flow in the infused arm, in mL/min/100 mL	2-2.5 months from screening to follow-up
Sub-study 1A: Change in forearm blood flow parameters after infusion of semaglutide (Percentage Change)	Percentage change in the infused arm, in %	2-2.5 months from screening to follow-up
Sub-study 1B: Change in forearm blood flow parameters after infusion of tirzepatide (Absolute flow)	Absolute flow in the infused arm, in mL/min/100 mL	2-2.5 months from screening to follow-up
Sub-study 1B: Change in forearm blood flow parameters after infusion of tirzepatide (Ratio)	Ratio, expressed as a number (no units as this is a ratio)	2-2.5 months from screening to follow-up
Sub-study 1B: Change in forearm blood flow parameters after infusion of tirzepatide (Percent Change)	Percentage change in the infused arm, in %	2-2.5 months from screening to follow-up
Sub-study 1C: Change in forearm blood flow parameters after infusion of semaglutide or tirzepatide or saline (Absolute flow)	Absolute flow in the infused arm, in mL/min/100 mL	2-2.5 months from screening to follow-up
Sub-study 1C: Change in forearm blood flow parameters after infusion of semaglutide or tirzepatide or saline (Ratio)	Ratio, expressed as a number (no units as this is a ratio)	2-2.5 months from screening to follow-up
Sub-study 1C: Change in forearm blood flow parameters after infusion of semaglutide or tirzepatide or saline (Percentage change)	Percentage change in the infused arm, in %	2-2.5 months from screening to follow-up
Sub-study 2A: Changes in cardiovascular haemodynamic variables after administration of semaglutide (Blood pressure)	Blood pressure measured in mmHg	2-2.5 months from screening to follow-up
Sub-study 2A: Changes in cardiovascular haemodynamic variables after administration of semaglutide (Heart rate)	Heart rate measured in beats per minute (bpm)	2-2.5 months from screening to follow-up
Sub-study 2A: Changes in cardiovascular haemodynamic variables after administration of semaglutide (Cardiac output)	Cardiac output measured in L/min	2-2.5 months from screening to follow-up
Sub-study 2A: Changes in cardiovascular haemodynamic variables after administration of semaglutide (Vascular resistance)	Vascular resistance measured in dynes⋅sec⋅cm5	2-2.5 months from screening to follow-up
Sub-study 2B: Changes in cardiovascular haemodynamic variables after administration of tirzepatide (Blood pressure)	Blood pressure measured in mmHg	2-2.5 months from screening to follow-up
Sub-study 2B: Changes in cardiovascular haemodynamic variables ) after administration of tirzepatide (Heart rate)	Heart rate measured in beats per minute (bpm)	2-2.5 months from screening to follow-up
Sub-study 2B: Changes in cardiovascular haemodynamic variables after administration of tirzepatide (Cardiac output)	Cardiac output measured in L/min	2-2.5 months from screening to follow-up
Sub-study 2B: Changes in cardiovascular haemodynamic variables after administration of tirzepatide (Vascular resistance)	Vascular resistance measured in dynes⋅sec⋅cm5	2-2.5 months from screening to follow-up
Sub-study 2C: Changes in cardiovascular haemodynamic variables after administration of semaglutide or tirzepatide or saline (Blood pressure)	Blood pressure measured in mmHg	2-2.5 months from screening to follow-up
Sub-study 2C: Changes in cardiovascular haemodynamic variables after administration of semaglutide or tirzepatide or saline (Heart rate)	Heart rate measured in beats per minute (bpm)	2-2.5 months from screening to follow-up
Sub-study 2C: Changes in cardiovascular haemodynamic variables after administration of semaglutide or tirzepatide or saline (Cardiac output)	Cardiac output measured in L/min	2-2.5 months from screening to follow-up
Sub-study 2C: Changes in cardiovascular haemodynamic variables after administration of semaglutide or tirzepatide or saline (Vascular resistance)	Vascular resistance measured in dynes⋅sec⋅cm5	2-2.5 months from screening to follow-up

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: February 3, 2026
• First Submitted That Met QC Criteria: March 17, 2026
• First Posted (Actual): March 19, 2026

Study Record Updates

• Last Update Posted (Actual): March 19, 2026
• Last Update Submitted That Met QC Criteria: March 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Semaglutide; weight loss; Metabolic; Endocrine; tirzepatide; hypertension)
• Additional Relevant MeSH Terms: Vascular Diseases; Body Weight; Body Weight Changes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Weight Loss; Hypertension; Cardiovascular Diseases; Amino Acids, Peptides, and Proteins; Proteins; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Tirzepatide; semaglutide
• Other Study ID Numbers: DECODE (A097165)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No