Obesity treatments may offer powerful bonus benefit: Lowering high blood pressure
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The disease of obesity often brings cardiometabolic consequences, including hypertension, which remains the most potent and predictive risk factor for cardiovascular disease.
As the burden of obesity rises globally, so too does the prevalence of obesity-associated hypertension. Data from the U.S. National Health and Nutrition Examination Survey show that among the estimated 35.6% of adults with obesity, 24.7% had controlled hypertension and another 22.2% had uncontrolled hypertension, despite wide availability of inexpensive and safe antihypertensive therapies. Those with obesity and controlled or uncontrolled hypertension both had markedly higher risk for all-cause mortality compared with those who were normotensive.
Image: Courtesy of Sangeeta Kashyap. Printed with permission.
“Obesity is a risk factor for all disease related to the blood vessels,” Sangeeta Kashyap, MD, assistant chief of clinical affairs in the division of endocrinology, diabetes and metabolism at NewYork-Presbyterian/Weill Cornell Medical Center and a Healio | Endocrine Today Co-editor, said during an interview. “Treating obesity not only will prevent but will also delay complications related to hypertension. That includes kidney disease, heart disease and stroke, all the major killers in our patients.”
The newest class of obesity drugs, including the GLP-1 receptor agonist semaglutide 2.4 mg (Wegovy, Novo Nordisk) and the dual agonist tirzepatide (Zepbound, Eli Lilly), have made headlines for inducing weight loss that approaches what is seen with bariatric surgery, long considered the gold standard treatment for severe obesity. Now, data demonstrate that with substantial weight loss comes a sustained reduction in blood pressure, and for some, hypertension remission.
The emerging evidence suggests that obesity treatments, whether drugs or surgery, could potentially serve as a potent tool for the growing global burden of hypertension.
“Given that estimates of up to 75% of hypertension can be attributed to overweight or obesity, the impact of excess weight on BP is becoming a bigger problem,” Michael E. Hall, MD, MSc, professor and chair of the department of medicine and director of clinical and population sciences at the Mississippi Center for Clinical and Translational Research at University of Mississippi Medical Center in Jackson, told Healio | Endocrine Today. “By treating obesity, you are treating the root cause. With hypertension, we have good, effective therapies that are inexpensive and accessible, but even so, a large proportion of people with hypertension are suboptimally treated. But if you treat the obesity — the primary cause of the hypertension — you are going to the source and treating the source. Then you not only eliminate the need for the antihypertensive medications, but also the need for lipid and diabetes medications.”
Obesity, hypertension, CVD links
The mechanisms through which obesity causes hypertension are complex and include sympathetic nervous system overactivation, stimulation of the renin-angiotensin-aldosterone system, alterations in adipose-derived cytokines, insulin resistance, and structural and functional renal changes, researchers wrote in a review published in Gland Surgery. Weight loss is the primary goal of treatment for obesity-related hypertension; however, few people are successful with lifestyle interventions alone.
“The easy way to think about this is, as your body mass increases, the arteries have to provide blood,” George L. Bakris, MD, professor of medicine and director of the American Heart Association-accredited Comprehensive Hypertension Center at the University of Chicago Medicine, told Healio | Endocrine Today. “There is expansion, and within certain limits, this is OK. However, once you get to certain level — that is a BMI of around 30 kg/m2 — then you have gone beyond the means that a typical body can handle. The older you are, the more likely it is that the body is going to generate higher pressures to be able to deal with that.”
Adding to hypertension risk, Bakris said, are the drawbacks of a typical Western diet, such as sodium-rich foods and consuming alcohol in excessive amounts.
“All of that contributes in different ways, not just via calories in, but by activating specific systems to raised blood pressures — notably, the symathetic nervous system," Bakris said.
Most of the trials assessing weight loss induced by lifestyle intervention show that, per 1 kg of weight loss, a person can expect about 1 mm Hg of BP lowering, according to Luke J. Laffin, MD, co-director of the Center for Blood Pressure Disorders at Cleveland Clinic.
“We know that obesity-associated hypertension is real,” Laffin told Healio | Endocrine Today. “It does not mean that everyone who is lean is going to have a normal BP or that everyone with obesity is going to have high BP. It really is a spectrum. However, individuals with obesity are much more likely to have diabetes, CVD and high BP.”
Laffin said data show weight loss from bariatric surgery and some newer obesity medicines can “drastically” reduce BP.
“For some of these lower-risk patients with a BMI of, say, 35 kg/m2, with slightly elevated BP, LDL cholesterol and glucose — what if we treat the obesity right off the bat instead of prescribing three different medicines we know people do not want to take?” Laffin said. “Upfront treatment of obesity could prevent downstream complications and needing two or three medicines.”
Obesity medications with CV benefits
Data from the SURMOUNT-1 study, presented in 2022, showed that nearly all participants with obesity without diabetes who received tirzepatide, an injectable GIP/GLP-1 dual incretin-based agonist, experienced at least 5% weight loss over 72 weeks compared with placebo, with at least 20% weight loss for more than half who received the 15 mg dose.
Data from a planned substudy of the SURMOUNT-1 trial, published in February, showed tirzepatide also reduced 24-hour ambulatory BP for adults with obesity-related hypertension. Researchers said the BP effects were potentially independent of weight loss.
For the prospectively planned substudy published in Hypertension, researchers analyzed data from 600 of the SURMOUNT-1 participants with a BP less than 140 mm Hg/90 mm Hg and stable antihypertensive therapy, if used, including 145 assigned tirzepatide 5 mg, 152 assigned tirzepatide 10 mg, 148 assigned tirzepatide 15 mg, and 155 assigned placebo. This subgroup underwent 24-hour ambulatory BP monitoring (ABPM) at baseline and again at 36 weeks.
The baseline mean 24-hour systolic BP was 124.6 mm Hg, with no between-group differences.
Treatment with each tirzepatide dose reduced 24-hour systolic BP at 36 weeks compared with placebo. The placebo-adjusted systolic BP change from baseline was –7.4 mm Hg (95% CI, –10 to –4.7) for the 5 mg tirzepatide dose, –10.6 mm Hg (95% CI, –13.2 to –8) for the 10 mg dose and –8 mm Hg (95% CI, –10.6 to –5.4) for the 15 mg dose. Results were consistent for both day and nighttime BP.
Participants assigned tirzepatide experienced an increase in heart rate across doses compared with placebo; at week 36, heart rate increased with tirzepatide vs. placebo by 2.1 (95% CI, 0.3-3.9), 2.3 (95% CI, 0.6-4.1) and 5.4 (95% CI, 3.6-7.1) beats per minute, with tirzepatide 5 mg, 10 mg and 15 mg, respectively.
“In this analysis, we cannot tease out: Was it just weight loss that led to a drop in BP or was it some other mechanism associated with this GLP-1/GIP?” said Laffin, a co-investigator of SURMOUNT-1. “We do not know that answer. One could make the argument that it is an academic question more than anything else. What we do know is if people are losing 20% of their body weight, which is the ballpark weight loss seen with these GLP-1s, they are going to be on fewer BP medicines. You can almost guarantee that.”
The researchers cautioned that BP was measured only at baseline and one other time point, and measurements were taken only once per hour at night to minimize participant burden. The differences did not account for changes in food intake and 24-hour urine sodium excretion, which were not assessed.
“If you go in for bariatric surgery, and have Roux-en-Y gastric bypass, within a few months, you will have a dramatic fall in your BP,” Bakris said. “The take-home message is not, ‘Wow, we’ve got drugs now that can reduce body weight and lower BP.’ ... If you cannot [lose weight], these drugs will help you do it.”
Hypertension benefits with surgery
Bariatric surgery has proved to be the most effective means of achieving substantial and sustained weight loss, and data show bariatric surgery can improve glycemic response or even induce type 2 diabetes remission. New evidence suggests bariatric surgery may also be an effective treatment for obesity-related hypertension.
Final 5-year data from the GATEWAY trial — the only randomized controlled trial to compare bariatric surgery with medical therapy for BP reduction, use of antihypertensive medications and hypertension remission in people with obesity — demonstrated adults with obesity plus hypertension used fewer BP-lowering medications and were much more likely to experience hypertension remission 5 years after undergoing bariatric surgery compared with medical therapy alone.
The study, published in February in the Journal of the American College of Cardiology, showed that 86.5% of the participants who underwent Roux-en-Y gastric bypass surgery reduced their total antihypertensive medication burden by at least 30% at 5 years, compared with just 12.5% of participants who received antihypertensive medical therapy alone. Additionally, the likelihood of hypertension remission 5 years after gastric bypass was nearly 20-fold higher than for those who received medical therapy only.
“The GATEWAY trial showed that bariatric surgery can be very effective for treatment of patients with obesity and hypertension in the long term,” Carlos Aurelio Schiavon, MD, PhD, FACS, of the Center of Obesity and Bariatric Surgery at Hospital BP in Sao Paulo and a lead investigator for the GATEWAY study, told Healio | Endocrine Today. “The most important clinical implication of this trial is that we must treat obesity to achieve success when treating patients with cardiovascular diseases such as hypertension.”
Schiavon and colleagues analyzed data from 100 adults with obesity plus hypertension prescribed at least two BP-lowering medications, who had no prior CVD (76% women; mean age, 44 years; mean BMI, 36.9 kg/m2). Researchers randomly assigned participants to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary outcome was a reduction of at least 30% of total antihypertensive medications while maintaining a BP less than 140 mm Hg/90 mm Hg at 5 years.
Compared with medical therapy, gastric bypass surgery was associated with a higher rate of BP medication reduction (80.7% vs. 13.7%), for an RR of 5.91 (95% CI, 2.58-13.52; P < .001). The mean number of antihypertensive medications was 2.97 for participants in the medical therapy group (95% CI, 2.33-3.6) and 0.8 for participants in the surgery group (95% CI, 0.51-1.09; P < .001).
The rates of hypertension remission were 2.4% in the medical therapy group and 46.9% in the surgery group, for an RR of 19.66 (95% CI, 2.74-141.09; P < .001). For those in the bariatric surgery group, the rate of apparent resistant hypertension was lower after the procedure (0% vs. 15.2%).
“To move forward, we need randomized trials comparing bariatric surgery with new anti-obesity drugs to demonstrate reduction in CV risk and mortality,” Schiavon told Healio | Endocrine Today.
Drugs vs. bariatric surgery
Among obesity therapies, bariatric surgery has the most robust long-term data. However, newer obesity medications have encouraging data and a head-to-head trial with surgery has not yet occurred. Kashyap said it is important for clinicians to find the optimal treatment strategy for patients who require weight loss beyond diet and lifestyle changes.
“With bariatrics, you have to have a very select, very compliant group of people,” Kashyap said. “They have to be psychologically sound. With [obesity] medications, that threshold is much lower. Fewer than 1% of people end up getting bariatric surgery. Most people will be treated with medications. And with medications, the earlier we get to people in the course of their disease, the greater the impact.”
Kashyap cautioned that when it comes to drugs vs. surgery, social determinants of health play an important role in what patients can access.
“If a person does not have good insurance, they will not be taking these newer, better medications,” Kashyap said. “These are expensive drugs that need to be taken chronically. If you stop, you will relapse. It is a big commitment for people to take medication. ... Things like access to appropriate providers, getting the optimal diet and exercise counseling, all of those things are an important part of management that is not always available. Without access to these things, bariatrics might be a good solution, because you have one fixed intervention. Once it is done and the patient recovers, they can sustain the benefit for 5 to 10 years, which is what we want for them.”
Weight loss reduces CV risk
In an editorial that accompanied the latest GATEWAY study, Hall and colleagues wrote that novel medical therapies and bariatric surgery are effective ways to treat obesity and related complications, such as hypertension. However, comparative studies of obesity pharmacotherapies and bariatric surgery are needed to clarify the optimal treatment pathways for a common and growing disease.
“In addition to needing clinical trials, we need to look at long-term cost-effectiveness,” Hall said. “Right now, obesity drugs are expensive. Eventually, the cost will start to come down, but we will need to look at this because more than 10% of people now have severe obesity. This is a problem that is growing. It is one thing to have effective therapies. We also need to have effective therapies that are cost-effective.”
Laffin, who said obesity pharmacotherapy as a means to treat hypertension and other comorbid conditions could be a paradigm shift, said clinicians should expect pushback due to the high cost of semaglutide and tirzepatide.
“The cost for treating hypertension or elevated glucose is low,” Laffin said. “Could we have a shift where we are treating the underlying cause for some people? There will need to be a shift where we stop thinking about these conditions as separate problems — the hypertension bucket, the diabetes bucket, the obesity bucket and the cholesterol bucket. While this does not apply to everyone, for at least a quarter to a third of these patients, you treat them with one of these mechanisms — surgery or medication — and you may eliminate the need to start BP medicines, or at least push it off as far as possible.
“It is always the combination of lifestyle, medications, plus or minus surgery as well,” Laffin said. “Sometimes people, particularly on social media, like to pit one [treatment] against the other. It is not about one vs. the other. This is about working with a specialist to figure out the best combination for any individual. These new drugs potentially give us a cure for obesity, which is exciting.”
Click here to read the Point/Counter, “Are drugs or surgery superior for obesity treatment?”
- References:
- Dankner R, et al. JAMA Netw Open. 2024;doi:10.1001/jamanetworkopen.2023.50408.
- de Lemos JA, et al. Hypertension. 2024;doi:10.1161/HYPERTENSIONAHA.123.22022
- Hall ME, et al. J Am Coll Cardiol. 2024;doi:10.1016/j.jacc.2023.11.033.
- Kong G, et al. Obesity. 2023;doi:10.1002/oby.23658.
- Schiavon CA, et al. J Am Coll Cardiol. 2024;doi:10.1016/j.jacc.2023.11.032.
- Shariq OA, et al. Gland Surg. 2020;doi:10.21037/gs.2019.12.03.
- For more information:
- George L. Bakris, MD, can be reached at gbakris@gmail.com; X (Twitter): @BakrisGeorge.
- Michael E. Hall, MD, MSc, can be reached at mehall@umc.edu; X (Twitter): @UMMC_MCCTR.
- Sangeeta Kashyap, MD, can be reached at srk4008@med.cornell.edu; X (Twitter): @CleClinicMD.
- Luke J. Laffin, MD, can be reached at laffinl@ccf.org; X (Twitter): @ljlaffin.
- Carlos Aurelio Schiavon, MD, PhD, FACS, can be reached at carlos.schiavon@bp.org.br; X (Twitter): @caschiavon.
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