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| Name | Class |
|---|---|
| National Institute for Health Research, United Kingdom | OTHER_GOV |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tirzepatide [weight loss arm] | Experimental | 6 months of treatment with a combined GLP-1/GIP receptor agonist, tirzepatide |
|
| Lifestyle advice and anti-hypertensive medications [standard of Care arm] | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tirzepatide | Drug | 2.5mg for 4 weeks, 5mg for 4 weeks, 7.5mg for 4 weeks, 10mg for 12 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ambulatory systolic blood pressure | Change in daytime ambulatory systolic blood pressure in the weight loss arm | Baseline to week 24 |
| Measure | Description | Time Frame |
|---|---|---|
| Ambulatory diastolic blood pressure | Change in daytime ambulatory diastolic blood pressure in the weight loss arm | Baseline to week 24 |
| Clinic systolic blood pressure | Changes in clinic systolic blood pressure in the weight loss arm |
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Eligibility criteria for randomisation
Inclusion Criteria:
Exclusion Criteria:
• Anything in medical notes suggesting unsuitable in the opinion of the investigator
Eligibility criteria for participation in weight loss arm
Inclusion criteria:
Exclusion criteria:
The presence of any of the following will preclude participant inclusion:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cambridge University Hospitals NHS Foundation Trust | Recruiting | Cambridge | Cambridgeshire | CB2 0QQ | United Kingdom |
Following publication, the data that support the findings of this study will be available from the Chief Investigator/corresponding author upon reasonable request
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Following publication, the data that support the findings of this study will be available from the Chief Investigator/corresponding author upon reasonable request
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The study will utilise a modified trial within cohort (TwiC) design for patients under the hypertension/clinical pharmacology clinic. Those who meet the eligibility criteria for randomisation will be randomised to being approached for either:
(i) 6 months of treatment with a combined GLP-1/GIP receptor agonist, Tirzepatide [Group A - Weight loss arm] (ii) Standard anti-hypertensive treatment and attendance at a 6-month combined research/clinical follow-up visit [Group B - Standard of Care (SoC) arm].
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| Anti-Hypertensive medications | Drug | Anti-hypertensive drug therapy as per local and national guidelines |
|
| Baseline to week 24 |
| Clinic diastolic blood pressure | Changes in clinic diastolic blood pressure in the weight loss arm | Baseline to week 24 |
| Clinic mean arterial pressure | Changes in clinic mean arterial pressure in the weight loss arm | Baseline to week 24 |
| Unattended systolic blood pressure | Changes in unattended systolic blood pressure in the weight loss arm | Baseline to week 24 |
| Unattended diastolic blood pressure | Changes in unattended diastolic blood pressure in the weight loss arm | Baseline to week 24 |
| Unattended mean arterial pressure | Changes in unattended mean arterial pressure in the weight loss arm | Baseline to week 24 |
| Body weight | Changes in body weight in the weight loss arm | Baseline to week 24 |
| Body fat | Changes in body fat in the weight loss arm | Baseline to week 24 |
| Waist:hip ratio | Changes in waist:hip ratio in the weight loss arm | Baseline to week 24 |
| Cardiac output | Changes in cardiac output in the weight loss arm | Baseline to week 24 |
| Peripheral vascular resistance | Changes in peripheral vascular resistance in the weight loss arm | Baseline to week 24 |
| Pulse wave analysis / pulse wave velocity | Changes in markers of pulse wave analysis and pulse wave velocity in the weight loss arm | Baseline to week 24 |
| Heart rate variability | Changes in heart rate variability in the weight loss arm | Baseline to week 24 |
| Renin | Changes in plasma renin in the weight loss arm | Baseline to week 24 |
| Aldosterone | Changes in plasma aldosterone in the weight loss arm | Baseline to week 24 |
| Plasma metanephrines | Changes in plasma metanephrines in the weight loss arm | Baseline to week 24 |
| Leptin | Changes in leptin in the weight loss arm | Baseline to week 24 |
| Insulin | Changes in plasma insulin in the weight loss arm | Baseline to week 24 |
| Lipid profile | Changes in the lipid profile in the weight loss arm | Baseline to week 24 |
| HbA1C | Changes in HbA1C in the weight loss arm | Baseline to week 24 |
| Estimated glomerular filtration rate | Changes in eGFR in the weight loss arm | Baseline to week 24 |
| N-terminal pro-B-type natriuretic peptide | Changes in NT-proBNP in the weight loss arm | Baseline to week 24 |
| Urine albumin:creatinine ratio | Change in urine albumin:creatinine ratio in the weight loss arm | Baseline to week 24 |
| 24-hour urine sodium | Change in 24-hour urine sodium in the weight loss arm | Baseline to week 24 |
| 24-hour urine aldosterone | Change in 24-hour urine aldosterone in the weight loss arm | Baseline to week 24 |
| Antihypertensive medications | Change in number of antihypertensive medications | Baseline to week 24 |
| Quality of life measures | Changes in quality of life questionnaire scores in the weight loss arm | Baseline to week 24 |
| Ambulatory systolic blood pressure | Between-group comparison in ambulatory sytolic blood pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Ambulatory diastolic blood pressure | Between-group comparison in ambulatory diastolic blood pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Clinic systolic blood pressure | Between-group comparison in clinic systolic blood pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Clinic diastolic blood pressure | Between-group comparison in clinic diastolic blood pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Clinic mean arterial pressure | Between-group comparison in clinic mean arterial pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Unattended systolic blood pressure | Between-group comparison in unattended systolic blood pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Unattended diastolic blood pressure | Between-group comparison in unattended diastolic blood pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Unattended mean arterial pressure | Between-group comparison in mean arterial pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Body weight | Between-group body weight | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Body fat | Between-group comparison in body fat | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Waist:hip ratio | Between-group comparison in waist:hip ratio | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Cardiac output | Between-group comparison in cardiac output | At week 24 (weight loss arm) and 6 months (standard of care arm) |
| Peripheral vascular resistance | Between-group comparison in peripheral vascular resistance | At week 24 (weight loss arm) and 6 months (standard of care arm) |
| Pulse wave analysis / pulse wave velocity | Between-group comparison in markers of pulse wave analysis and pulse wave velocity | At week 24 (weight loss arm) and 6 months (standard of care arm) |
| Heart rate variability | Between-group comparison in heart rate variability | At week 24 (weight loss arm) and 6 months (standard of care arm) |
| Plasma renin | Between-group comparison in plasma renin | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Plasma aldosterone | Between-group comparison in plasma aldosterone | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Plasma metanephrines | Between-group comparison in plasma metanephrines | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Lipid profile | Between-group comparison in lipid profile | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| HbA1C | Between-group comparison in HbA1C | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Estimated glomerular filtration rate | Between-group comparison in eGFR | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| N-terminal pro-B-type natriuretic peptide | Between-group comparison in NT-proBNP | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Urine albumin:creatinine ratio | Between-group comparison in urine albumin:creatinine ratio | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| 24-hour urine sodium | Between-group comparison in 24-hour urine sodium | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| 24-hour urine aldosterone | Between-group comparison in 24-hour urine aldosterone | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Number of antihypertensive medications | Between-group comparison in the number of anti-hypertensive medications | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) |
| Quality of life measures | Between-group comparison in quality of life questionnaire scores | At week 24 (weight loss arm) and 6 months (standard of care arm) |
| ID | Term |
|---|---|
| D006973 | Hypertension |
| D009765 | Obesity |
| D050177 | Overweight |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000098860 | Tirzepatide |
| ID | Term |
|---|---|
| D000067757 | Glucagon-Like Peptide-1 Receptor |
| D000067756 | Glucagon-Like Peptide Receptors |
| D043562 | Receptors, G-Protein-Coupled |
| D011956 | Receptors, Cell Surface |
| D008565 | Membrane Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011964 | Receptors, Gastrointestinal Hormone |
| D018000 | Receptors, Peptide |
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