CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1

Abstract

BACKGROUND:

Fixed-dose combination of semaglutide/cagrilintide (CagriSema 2.4 mg/2.4 mg) has demonstrated significant and clinically relevant body weight reductions in adults with overweight or obesity compared with placebo.

METHODS:

The phase 3a, 68-week REDEFINE 1 trial randomized adults without diabetes with body mass index ≥30 kg/m², or ≥27 kg/m² with ≥1 obesity-related complication, to once-weekly CagriSema 2.4 mg/2.4 mg, semaglutide 2.4 mg, cagrilintide 2.4 mg, or placebo, plus lifestyle intervention. Secondary and post hoc analyses evaluated the antihypertensive effect from REDEFINE 1, focusing on CagriSema and placebo groups, by subgroup/category, including baseline body mass index, the presence of hypertension or resistant hypertension at baseline, and concomitant changes in the use of antihypertensive medications.

RESULTS:

Overall, 3417 participants underwent randomization; CagriSema: n=2108, semaglutide: n=302, cagrilintide: n=302, and placebo: n=705. Changes from baseline to week 68 in blood pressure (BP) were greater with CagriSema versus placebo (systolic BP: –10.9 versus –2.8 mm Hg; diastolic BP: –5.4 versus –1.7 mm Hg, respectively). The proportion of participants reaching BP targets at week 68 was 63.0% and 32.0% for CagriSema and placebo, respectively. The proportion of participants with resistant hypertension at baseline (n=167) that reached BP targets at week 68 was 42.0% and 29.3% for CagriSema and placebo, respectively (odds ratio, 1.7 [95% CI, 0.7–4.4]). Among participants who used antihypertensive medication during the study, 39.6% in the CagriSema group decreased or stopped treatment from week 0 to week 68 versus 18.8% with placebo.

CONCLUSIONS:

CagriSema presents clinically relevant reductions in BP across a wide range of participant subgroups, including those with resistant hypertension.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT05567796.

NOVELTY AND RELEVANCE.

What Is New?

Treatment with cagrilintide/semaglutide 2.4 mg/2.4 mg led to clinically relevant reductions in blood pressure across a wide range of participant subgroups and resulted in a greater proportion of participants able to decrease or stop treatment with antihypertensive medications compared with placebo and other monotherapies.

What Is Relevant?

The antihypertensive effects of cagrilintide/semaglutide were assessed in a wide range of participant subgroups, including those with hypertension and resistant hypertension, who are often unresponsive to blood pressure–lowering treatments.

Clinical/Pathophysiological Implications?

The substantial reductions in blood pressure observed following treatment with cagrilintide/semaglutide are likely to lead to a reduced risk of developing cardiovascular disease–related illnesses and represent an important advance for patients with obesity-related hypertension.

Obesity represents a significant public health concern with serious consequences, including increased morbidity and reduced life expectancy.¹ The global prevalence of adults living with overweight and obesity is expected to rise substantially over the coming years to 50% by 2030.² Excess accumulation of adipose tissue can lead to a wide range of obesity-related morbidities, including increased risk of developing cardiovascular disease and metabolic complications, such as type 2 diabetes, hypertension, and dyslipidemia.³

Individuals with obesity are prone to developing arterial hypertension and, despite intensive antihypertensive regimens, blood pressure (BP) control in people living with obesity remains suboptimal, particularly when compared with those with a body mass index (BMI) in the normal range.⁴ Hypertension is a key risk factor in developing morbidities associated with cardiovascular disease, including heart failure, chronic kidney disease, heart disease, and stroke.⁵ The mechanisms linking obesity to hypertension include overactivation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, fatty kidney, sleep apnea, and inflammation.^6–8 Obesity is also recognized as a contributing factor in developing treatment-resistant arterial hypertension, defined as the failure to reach the target BP despite the use of 3 antihypertensive drugs from different classes, one of them being a diuretic.⁹ The addition of more antihypertensive agents to treat patients with resistant hypertension may not be effective, and patients may require substantial and sustained weight loss to achieve the BP target.⁹

The GLP-1RA (glucagon-like peptide-1 receptor agonist), semaglutide, is approved at a dose of 2.4 mg once weekly, administered subcutaneously, for long-term weight management and cardiovascular risk reduction.^10,11 Semaglutide is also associated with considerable weight loss,¹² beneficial effects on kidney outcomes in patients with type 2 diabetes,^13,14 and a reduced need for, or discontinuation of, antihypertensive medications.¹⁵ Cagrilintide, a long-acting human amylin analogue, impacts appetite regulation through direct effects in the brain and has been assessed as a weight management treatment option in combination with semaglutide.¹⁶ Combining therapies with complementary but distinct mechanisms of action may lead to greater weight loss and improvements in associated risk factors compared with individual medications.¹⁶

The REDEFINE 1 trial demonstrated that once-weekly subcutaneous cagrilintide/semaglutide (CagriSema) 2.4 mg/2.4 mg for 68 weeks resulted in weight loss of 22.7% compared with 16.1% with semaglutide 2.4 mg, 11.8% with cagrilintide 2.4 mg, and 2.3% with placebo in adults with overweight or obesity, without diabetes.¹⁶ Statistical superiority of CagriSema versus placebo was also reported for confirmatory secondary end points, including a 10.9-mm Hg reduction in systolic BP (SBP; trial-product estimand).¹⁶

In these secondary and post hoc analyses, we examined in detail the antihypertensive effects of CagriSema from the REDEFINE 1 study in specific participant subgroups and concomitant changes in the use of antihypertensive medications in this population.

Methods

Trial Design

REDEFINE 1 (NCT05567796) was a phase 3, double-blind, placebo-controlled, and active-controlled multicenter trial conducted in 22 countries from November 1, 2022, to June 28, 2023; full methodology has been published.¹⁶ Adults with a BMI ≥30 kg/m², or ≥27 kg/m² with ≥1 obesity-related complication, without diabetes, were included. Participants were randomized 21:3:3:7 to CagriSema 2.4 mg/2.4 mg, semaglutide 2.4 mg, cagrilintide 2.4 mg, or placebo, and lifestyle intervention in all study groups for 68 weeks. Vital signs, comprising SBP, diastolic BP (DBP), and pulse rate, were measured at 13 timepoints (from week 0 to week 68). BP and pulse rate measurements were preceded by ≥5 minutes of rest and performed in sitting participants using an automated device. Manual techniques were only used if an automated device was not available. Three SBP and DBP measurements were taken, with intervals of at least 1 to 2 minutes. An additional fourth BP measurement was performed if the first 2 readings on SBP or DBP differed by >10 mm Hg. No more than 4 measurements were performed. The last 2 SBP and last 2 DBP measurements were recorded in the electronic case report form, and the mean was calculated.

All medications that participants were receiving at the time of the first visit or received during the study were documented, along with the trade name or generic name, indication, dates of administration including start and stop dates, and dose for antihypertensive medications. Laboratory assessment of lipids was performed at weeks 0, 20, 36, 52, and 68.

Efficacy Outcomes

In REDEFINE 1, the change in SBP from baseline to week 68 for CagriSema versus placebo was a secondary confirmatory efficacy end point. Change in DBP for CagriSema versus placebo was a secondary supportive efficacy end point. Exploratory end points included change from baseline to week 68 in the number of participants taking antihypertensive medication (increase, no change, decrease, or stop) for CagriSema versus placebo as evaluated by the investigator following review of all available relevant information.

Post hoc assessments included change in SBP and DBP from week 0 to week 68 for cagrilintide and semaglutide groups versus placebo and by baseline hypertension (yes/no) in each treatment group. Hypertension at baseline was determined based on the principal investigator’s discretion. Changes in SBP and DBP from week 0 to week 68 were also assessed by baseline BP groups, as per American College of Cardiology (ACC)/American Heart Association (AHA) guidelines,¹⁷ and proportion of participants in each treatment group achieving ACC/AHA BP targets (<130/80 mm Hg),¹⁷ and in individuals with/without resistant hypertension at baseline, defined as participants who were receiving ≥3 antihypertensive agents where at least 1 is a diuretic, at baseline.⁹

Additional post hoc assessment included change in SBP and DBP from week 0 to week 68 in CagriSema and placebo groups assessed in the following subgroups/categories: sex (male and female), ethnicity (Hispanic/Latino and not Hispanic/Latino), race (Asian/White), body weight at baseline (<90, 90–<100, 100–<115, and ≥115 kg), BMI at baseline (<35 and ≥35 kg/m²), waist circumference at baseline (<100, 100–<120, and ≥120 cm), waist-to-height ratio at baseline (<0.6 and ≥0.6), weight loss category from baseline to end of treatment (<10%, 10%–<15%, 15%–20%, and ≥20%), baseline antihypertensive medication use (yes/no) as determined by the investigator, and baseline estimated glomerular filtration rate (cutoffs: normal [≥90 mL/min per 1.73 m²] and mild-to-moderate impairment [30–<90 mL/min per 1.73 m²]). Atherosclerotic cardiovascular disease risk scores were calculated for participants aged 40 to 79 years without a history of atherosclerotic cardiovascular disease and who did not develop atherosclerotic cardiovascular disease during the trial using the ACC/AHA algorithm.¹⁸

Statistical Analysis

Two observation periods were defined for the efficacy end points; the in-trial period was defined as the time from randomization to the last contact with the trial site, regardless of discontinuation of the active drug or placebo or receipt of rescue intervention. The on-treatment period was defined as the time from the first administration of the active drug or placebo to the first discontinuation (ie, the date when no trial product had been administered for 14 days) without rescue intervention (ie, other obesity medication or bariatric surgery). The treatment-policy estimand was used to assess effects regardless of discontinuation of the drug or placebo or receipt of rescue intervention and was based on data from the in-trial period, consistent with the intention-to-treat principle. The trial-product estimand was used to assess the effects if the trial products were taken as intended (including any of the approved doses) and was based on data from the on-treatment period. Safety data in the safety analysis population (all the participants who underwent randomization and received ≥1 dose of an active drug or placebo) were assessed for the on-treatment period.¹⁶

For changes in BP from baseline to week 68 by subgroup/categories, measures from the on-treatment period without rescue medication are included in a mixed model for repeated measures analysis using data from the full analysis set. To allow unstructured covariance among measures, initial estimates of the covariance parameters were obtained by minimum variance quadratic unbiased estimation and used in the subsequent maximum likelihood estimation of the model parameters. The change from baseline was modeled with the baseline included as a covariate. Fixed effect terms included the interaction between study visit and the following: treatment, subgroup, and the treatment by subgroup interaction. A mixed model for repeated measures analysis of patients in the target (ie, those achieving <130/80 mm Hg), including interactions with baseline BP and visit, and treatment and visit, was estimated using a restricted pseudolikelihood method as per Dmitrienko et al.¹⁹

To explore whether there was an effect of CagriSema on SBP independent of weight loss, a mediation analysis incorporating repeated measures was performed,²⁰ yielding an estimate of the proportion mediated at week 68. The analysis assumed that proportions mediated depended on treatment group although, in the case of no evidence for heterogeneity, a common proportion was subsequently assumed. The model was adjusted for sex, age, and baseline values of the mediator and BP. All data were analyzed using SAS, version 9.4.

Results

In the REDEFINE 1 trial, 3417 participants were randomized to CagriSema (n=2108), semaglutide (n=302), cagrilintide (n=302), or placebo (n=705), and lifestyle intervention, for 68 weeks. At baseline, mean (SD) age was 47.0 (11.8) years; 67.6% of participants were female, 72.0% were White, and 13.3% were current smokers. Mean (SD) BMI was 37.9 (6.7), and total and HDL (high-density lipoprotein) cholesterols were 5.0 and 1.3 mmol/L. Mean baseline SBP was 127.1 (14.2) mm Hg, and DBP was 82.1 (9.2) mm Hg; 36.3% of participants had hypertension as determined by the investigator. Overall, 31.2% of participants received antihypertensive medication during the study; of these participants, the vast majority received renin-angiotensin medications (82.2%).

Baseline characteristics were balanced between participants receiving CagriSema or placebo by the presence or absence of hypertension subgroups at baseline (Table). No differences in BMI and waist-to-height ratio were observed between hypertensive groups. Participants with hypertension at baseline presented higher BP, waist circumference (a marker of visceral adiposity), atherosclerotic cardiovascular disease risk scores, and a higher proportion of participants with mild or moderate renal impairment than those without hypertension at baseline (Table). Baseline characteristics by the presence or absence of hypertension at baseline for CagriSema treatment groups are shown in Table S1.

Table.

Baseline Demographics by the Presence/Absence of Hypertension at Baseline

Change in BP

Changes from baseline to week 68 in SBP were greater with CagriSema (–10.9 mm Hg) versus placebo (–2.8 mm Hg; estimated treatment difference [ETD],–8.2 [95% CI, –9.3 to –7.1] mm Hg). Changes from baseline to week 68 in SBP for semaglutide only and cagrilintide only versus placebo were –8.5 mm Hg (ETD,–5.8 [95% CI, –7.4 to –4.1] mm Hg) and –5.2 mm Hg (ETD,–2.4 [95% CI, –4.1 to –0.8] mm Hg), respectively (Figure 1A). Reductions in DBP were also greater with CagriSema (–5.4 mm Hg; ETD,–3.8 [95% CI,–4.5 to –3.0] mm Hg), semaglutide only (–4.9 mm Hg; ETD,–3.2 [95% CI,–4.4 to –2.1] mm Hg), and cagrilintide only (–2.9 mm Hg; ETD, –1.3 [95% CI, –2.4 to –0.1] mm Hg) versus placebo (–1.7 mm Hg; Figure 1B).

Figure 1.

Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Change in SBP and DBP from baseline to week 68 by treatment group in the overall study population (A and B) and by body mass index (BMI) subgroup at baseline (C and D). Data are for the trial-product estimand, which assessed the effects if the trial products were taken as intended (including any of the approved doses) and was based on data from the on-treatment period. ETD indicates estimated treatment difference.

Change in BP by Category/Subgroup at Baseline

Changes in SBP and DBP from baseline to week 68 by BMI subgroup at baseline for all treatment groups are shown in Figure 1C and 1D, respectively. The magnitude of difference in SBP and DBP change observed in CagriSema and comparators was consistent across baseline BMI subgroups (<35 and ≥35 kg/m²). Figure 2 presents the changes in SBP and DBP for CagriSema and placebo groups from baseline to week 68 by subgroup. Reductions in BP were less pronounced in participants using antihypertensive medications at baseline versus those who were not, for both SBP (ETD, −5.7 [95% CI, −7.5 to −3.9] versus −9.4 [95% CI, −10.7 to −8.1]) and DBP (ETD, −1.7 [95% CI, −3.0 to −0.4] versus −4.8 [95% CI, −5.7 to −3.9]), respectively.

Figure 2.

Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by subgroup. Change in SBP (A) and DBP (B) from baseline to week 68 by subgroup. Data are for the trial-product estimand. Estimates of change in blood pressure obtained from a mixed model for repeated measures. Measures from the on-treatment period without rescue medication are included. N is the number of patients available for the analysis. Change represents the change from baseline to week 68. BMI indicates body mass index; eGFR, estimated glomerular filtration rate; ETD, estimated treatment difference; HbA_1c, glycated hemoglobin; and HOMA IR, Homeostatic Model Assessment for Insulin Resistance.

Change in BP by Weight Loss Category From Baseline to Week 68

The change in SBP and DBP by category of weight loss from baseline to week 68 is shown in Figure 3, demonstrating a clear association between increased weight loss (by category) and a reduction in BP, for both SBP and DBP. The proportion of participants achieving ≥20% weight loss was higher in those receiving CagriSema (61.5%) compared with semaglutide (29.5%) or cagrilintide (15.2%).

Figure 3.

Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by weight loss category. Change in SBP (A) and DBP (B) by category of weight loss from baseline to week 68. Estimates of change in blood pressure obtained from a mixed model for repeated measures. Measures from the on-treatment period without rescue medication are included. N is the number of patients available for the analysis. Change represents the change from baseline to week 68. Limited numbers for the placebo group preclude inclusion of data for this group (<10%, n=236; 10%–<15%, n=36; 15%–<20%, n=18%; and ≥20%, n=11).

Change in SBP According to a Mediation Analysis

A mediation analysis, assessing the possible contribution of factors to the reduction in SBP at week 68, revealed that change in body weight was the primary driver (72% [95% CI, 54–91]). Change in HbA_1c (glycated hemoglobin; 10% [95% CI, 0–22]) and estimated glomerular filtration rate (2% [95% CI, 0–4]) also contributed to a lesser degree.

Proportion of Participants Achieving ACC/AHA BP Targets

At week 68, the proportion of participants reaching BP targets was 63.0% and 32.0% for CagriSema and placebo groups, respectively, with a corresponding odds ratio of 3.6 (95% CI, 2.9–4.6) for CagriSema versus placebo. At baseline, 36.2% of participants receiving CagriSema (763/2106) and 38.0% (268/705) on placebo presented with hypertension, and the proportion of these participants reaching BP targets at week 68 was 40.7% and 24.1% for CagriSema and placebo groups, respectively (odds ratio, 2.2 [95% CI, 1.5–3.1]).

Change in BP in Participants With Resistant Hypertension at Baseline

One hundred sixty-seven participants were classified as having resistant hypertension at baseline (CagriSema: n=98, semaglutide: n=13, cagrilintide: n=12, and placebo: n=44). Differences in SBP and DBP from baseline to week 68 in participants classified as having resistant hypertension are shown in Figure 4. In participants with resistant hypertension, the mean reductions in SBP and DBP for CagriSema versus placebo were −8.6 (95% CI, −11.4 to −5.9) versus −4.9 (95% CI, −9.2 to −0.7) mm Hg and −3.1 (95% CI, −4.7 to −1.5) versus −0.9 (95% CI, −3.4 to 1.5) mm Hg, respectively. At week 68, the proportion of participants with resistant hypertension at baseline reaching BP targets was 42.0% and 29.3% for CagriSema and placebo groups, respectively (odds ratio, 1.7 [95% CI, 0.7–4.4]).

Figure 4.

Change in blood pressure from baseline to week 68 in participants classified with resistant hypertension at baseline receiving cagrilintide/semaglutide (CagriSema; n=98) or placebo (n=44). Participants were receiving ≥3 antihypertensive agents where at least 1 is a diuretic, at baseline. Estimates of change in blood pressure obtained from a mixed model for repeated measures. Measures from the on-treatment period without rescue medication are included. N is the number of patients available for the analysis. Change represents the change from baseline to week 68. DBP indicates diastolic blood pressure; ETD, estimated treatment difference; and SBP, systolic blood pressure.

Change in Participants Taking Antihypertensive Medications During the Study

The medications used by participants with or without hypertension at baseline for the CagriSema and placebo groups are presented in Table S2. Among participants receiving antihypertensive medication at baseline who received any antihypertensive medication during the study, 39.6% in the CagriSema group had decreased or stopped treatment from week 0 to week 68 compared with 27.4% with semaglutide, 27.6% with cagrilintide, and 18.8% with placebo (Figure 5). The proportion of participants in each treatment group who increased their use of antihypertensive medications was 8.4%, 15.1%, 17.1%, and 19.6% for CagriSema, semaglutide, cagrilintide, and placebo, respectively (Figure 5).

Figure 5.

Change in hypertension medications from baseline to week 68 in participants receiving hypertension medication during the trial. Data are for the treatment-policy estimand from the in-trial period for participants receiving antihypertensive medication between baseline to week 68 with data available at the end of the on-treatment period.

Safety

Adverse events related to hypotension and hypertension by treatment group are presented in Table S3. Hypotension was reported in 38 (1.8%) and 3 (0.4%) participants who received CagriSema or placebo, respectively. Overall, the reporting of events was slightly higher in the CagriSema group compared with the other treatment groups but generally low across all treatment groups.

Discussion

In these secondary and post hoc analyses of the REDEFINE 1 trial, CagriSema 2.4 mg/2.4 mg led to clinically relevant reductions in BP in participants with overweight or obesity, irrespective of whether baseline BMI was > or <35 kg/m². Reductions in BP occurred despite a reduction in the use of antihypertensive medication.

Effective BP management, particularly when initiated in individuals aged 50 to 60 years, can meaningfully improve long-term cardiovascular outcomes.^17,21 Significant reductions in BP as a consequence of weight loss also allow health care providers to manage hypertension more effectively, potentially decreasing the need for multiple antihypertensive medications; this could improve tolerability and, therefore, have a positive impact on quality of life as side effects such as fatigue, headaches, or dizziness associated with treatment become less frequent.^9,22 Recently published ACC/AHA guidelines on the prevention, detection, evaluation, and management of high BP now include specific details on obesity treatment, recommending the use of GLP-1RAs as adjunct therapies to standard of care.¹⁷

Weight loss remains a key strategy for reducing BP in individuals with obesity.²³ The biological mechanisms underpinning weight loss–mediated reductions in BP are well-established, with decreased body fat, notably visceral adipose tissue, associated with numerous antihypertensive effects, including a reduction in arterial stiffness, improved insulin sensitivity, and reduced inflammation.^24,25 Reductions in renal sodium reabsorption seem central to initiating the decrease in BP associated with weight loss.⁶ Such improvements in natriuresis are linked to reduced sympathetic tone associated with a decrease in leptin signaling, a reduction in renin-angiotensin-aldosterone system activation, and possibly, reduced physical compression of the kidneys due to decreased visceral, retroperitoneal, and renal sinus fat.²⁶ In addition, pleiotropic effects of GLP-1 and amylin may play a role in the BP-lowering effects of CagriSema.^27–29

In REDEFINE 1, reductions in BP from baseline to week 68 with CagriSema were greater than those reported for both mono components.¹⁶ In participants who received CagriSema, a reduction in SBP of 10.9 mm Hg occurred despite a high number of these participants reducing their antihypertensive treatment use. Furthermore, 19.6% of participants in the placebo group increased their antihypertensive treatment (compared with 8.4% with CagriSema), which may have impacted the ETD in BP between these groups. Observed reductions in BP after 68 weeks of CagriSema treatment versus placebo were greater than those previously observed over the same time frame for semaglutide 2.4 mg in participants with overweight or obesity in the Semaglutide Treatment Effect in People with Obesity (STEP) 1, STEP 3, and STEP 4 trials, with an overall reduction in SBP versus placebo across the 3 trials of −5.0 (95% CI, −5.9 to −4.1) mm Hg.³⁰ In REDEFINE 1, CagriSema-induced reductions in BP generally occurred within the first 20 weeks of the trial, prior to when maximum weight loss had been achieved, and were sustained through week 68.¹⁶ The magnitude of BP reductions induced by CagriSema were consistent across various participant subgroups at baseline, including BMI, body weight, waist circumference, and waist-to-height ratio, indicating the efficacy of CagriSema across a spectrum of overweight, obesity, and adiposity. Assessment of changes in BP by weight loss category revealed that reductions in DBP seem more pronounced in participants who received semaglutide compared with other treatments. However, the proportion of participants achieving ≥20% weight loss, and the concomitant reductions in BP, was notably higher in individuals receiving CagriSema compared with other treatments. Further studies are warranted to explore these effects. A mediation analysis revealed that while a change in body weight was the primary contributing factor (72%) to the reduction in SBP, other factors, including estimated glomerular filtration rate and HbA_1c, were also involved to a lesser degree.

Intensive treatment to lower BP has previously been shown to significantly lower the risk of all-cause and cardiovascular death in patients with resistant hypertension versus standard treatment.³¹ Here, in participants with resistant hypertension at baseline, treatment with CagriSema 2.4 mg/2.4 mg led to greater reductions in BP compared with placebo. The magnitude of these changes, −8.6mm Hg for SBP and −3.1 mm Hg for DBP, represents a clinically relevant reduction in a patient population which is considered difficult to treat.⁹ Furthermore, in participants receiving antihypertensive medication at baseline, CagriSema led to a greater proportion of participants able to decrease or stop treatment with antihypertensive medications compared with placebo and other monotherapies.

A relatively small difference was observed between the CagriSema and placebo groups in the proportion of participants with resistant hypertension achieving BP targets at week 68 (42.0% and 29.3%, respectively). However, the high proportion observed in the placebo group is likely to have been impacted by the increased use of antihypertensive medications, and fewer participants were able to stop/reduce antihypertensive medication. Overall, these data reveal a marked antihypertensive benefit of CagriSema and represent an important advance for patients with obesity-related hypertension, which often remains refractory and is a leading driver of cardiovascular disease worldwide.⁸

Strengths of the study include the large sample size, the flexible dosing regimen, and the high percentage of participants who completed the trial. Limitations include a predominantly female and White population. Furthermore, the cuff size was not specified, and group circumference was not measured, both of which can affect the measurement of BP. A reduction in dietary sodium intake following the decreased caloric intake underpinning the substantial weight loss observed with CagriSema is a potential mechanistic component of the reductions observed in BP. However, given the double-blind nature of this study, participants in each treatment group received the same counseling from physicians regarding diet and exercise. Future studies that collect detailed information on caloric intake and ambulatory BP are required to determine the specific contribution of a reduction in dietary sodium to changes in BP. Sleep apnea is associated with the development of resistant hypertension,³² and its treatment can lead to reductions in BP.³³ Other than collecting participants’ baseline medical history for this important determinant, the lack of assessment of sleep apnea over the course of the study represents a limitation. In addition, changes in the dosing of antihypertensive medications during the study, and the potential impact this may have on BP, were not recorded. The determination of hypertension and awareness of antihypertensive medication at baseline were based on the principal investigator’s discretion and, as such, may represent a further limitation. Dedicated randomized controlled trials to further assess the antihypertensive effects of CagriSema are warranted.

Perspectives

The results of this study add to the existing evidence on the overall cardiometabolic benefits of CagriSema 2.4 mg/2.4 mg as a treatment option for adults with overweight or obesity. After 68 weeks of treatment, CagriSema 2.4 mg/2.4 mg led to a clinically relevant reduction in SBP of 10.9 mm Hg. CagriSema 2.4 mg/2.4 mg also led to consistent reductions in BP across a wide range of participant subgroups, including individuals with resistant hypertension who are often unresponsive to BP-lowering treatments. In addition, CagriSema led to a greater proportion of participants able to decrease or stop treatment with antihypertensive medications compared with placebo and other monotherapies.

The substantial reductions in BP observed following treatment with CagriSema 2.4 mg/2.4 mg are likely to lead to a reduced risk of developing cardiovascular disease–related illnesses, such as heart failure, stroke, and chronic kidney disease, and represent an important advance for patients with obesity-related hypertension. The results of this study indicate that future randomized control trials should be performed to further assess the antihypertensive effects of CagriSema and determine the precise nature of the physiological mechanisms that underpin them.

ARTICLE INFORMATION

Acknowledgments

This trial was sponsored by Novo Nordisk and is registered with ClinicalTrials.gov (NCT05567796). The authors thank the trial participants, the investigators, and the trial site staff who conducted the trial. The authors thank Stine-Mathilde Dalskov for their assistance in the interpretation of efficacy and safety data. Medical writing support was provided by James Parkinson, PhD, CMPP, of Apollo, OPEN Health Communications, and was funded by Novo Nordisk A/S in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). Data will be shared with bona fide researchers who submit a research proposal approved by the independent review board. Individual patient data will be shared in data sets in a deidentified and anonymized format. Data will be made available after research completion and approval of the product and product use in the European Union and the United States. Information about data access request proposals can be found at novonordisk-trials.com.

Author Contributions

S. Verma contributed to data interpretation. M. Böttcher was responsible for the analysis and interpretation of data. P. Brown was responsible for data handling, analysis, and interpretation. D. Dicker contributed to the interpretation of the study data. D. Rubino, P. Sbraccia, A.M. Sharma, L. Smedegaard, and R. Sørrig contributed to data interpretation. W.T. Garvey was involved in data acquisition, analysis, and interpretation. All authors were involved in the drafting, critical review, revision, and final approval of the manuscript.

Sources of Funding

This study was funded by Novo Nordisk; REDEFINE 1 (https://www.clinicaltrials.gov; Unique identifier: NCT05567796).

Disclosures

S. Verma reports holding a Tier 1 Canada Research Chair in Cardiovascular Surgery and receiving grants, research support, and speaking honoraria from and acting as an advisor for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, the Canadian Heart Research Centre, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management, Inc, Sanofi, and Sun Pharma. M. Böttcher reports advisory board participation for AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Sanofi. D. Dicker reports having received research grants from Boehringer Ingelheim, Eli Lilly, Graviton, and Novo Nordisk; payment or honoraria for speaker/advisory boards from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hoffman-La Roche, and Novo Nordisk; support for attending meetings and travel from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and unpaid executive committee roles for the European Federation of Internal Medicine and the European Association for the Study of Obesity. D. Rubino reports research grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Cytoki Pharma, Eli Lilly, Kallyope, Neurocrine Biosciences, Inc, Nod Thera, Novo Nordisk, Pfizer, Regeneron Pharmaceuticals, Inc, Shionogi, Inc, and Terns Pharmaceuticals. P. Sbraccia received payment of honoraria from Amryt Pharma (Chiesi), Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, and Roche, and as a member of advisory boards and payment of honoraria for lectures from Amryt Pharma (Chiesi), Eli Lilly and Novo Nordisk. A.M. Sharma received honoraria for consulting and speaking from AbbVie, Allurion, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Oviva. W.T. Garvey has been a consultant on advisory boards for AbbVie, Allurion, Alnylam Pharmaceuticals, Boehringer Ingelheim, Carmot/Roche, Corcept, Eli Lilly, Fractyl Health, Gan & Lee, Inogen, Keros Therapeutics, MetSera, Neurocrine, Novo Nordisk, Pfizer, Regeneron, Terns Pharmaceuticals, and Zealand. He has also served as a site principal investigator for multicentered clinical trials sponsored by his university and funded by Carmot/Roche, Eli Lilly, Epitomee, Neurovalens, Novo Nordisk, Terns Pharmaceuticals, Viking Therapeutics, and Zealand.

P. Brown, L. Smedegaard, and R. Sørrig are employees and shareholders with Novo Nordisk A/S.

Supplemental Material

Tables S1–S3