Obesity Is a Magnifier for Cardiovascular Disease: Potential Future Implications of Treatment

Obesity is a magnifier of all other cardiovascular risk factors. The INTERHEART study¹ showed that cardiovascular risk factors of smoking, diabetes mellitus, and hypertension had similar odds ratios for the development of a myocardial infarction. Still, if you add obesity, there is a 10-fold increase over the individual risk factors and a ≥60% increase over the aggregate triple risks.¹ Obesity also increases the risk of heart failure, coronary artery disease, and stroke.² Obesity, as measured by BMI, has a J-shaped association with overall mortality and most specific causes of death.³ Furthermore, persons with a BMI >40 have a –9.1-year reduction in life expectancy for men and –7.7-year reduction in life expectancy for women.³

Is it possible to counteract the decline in life expectancy among individuals with obesity?

Schauer and colleagues observed in a 2017 The New England Journal of Medicine article, “Five-year outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia.”⁴ Study results also showed a major reduction in hemoglobin A1c.

In exploring diverse treatment avenues to understand how to mitigate the reductions in life expectancy, researchers conducted an observational study of 287,438 adult patients with diabetes between 1998 to 2017, among whom 2,287 patients who underwent metabolic surgery as a therapeutic option.⁵ Compared to nonsurgical management controls, metabolic surgery (25% body weight loss) was associated with a significantly lower risk of the first occurrence of 6 primary end-points of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation (hazard ratio [HR]: 0.62 [95% confidence interval (CI): 0.55-0.69]).5 Furthermore, major adverse cardiac events (MACE), defined as myocardial infarction (MI), ischemic stroke, and mortality, were statistically significant in favor of metabolic surgery (HR: 0.62 [95% CI: 0.53-0.72]). The average weight loss was 64.1 lb in the metabolic surgery group and 19.2 lb in the nonsurgical group.

Can metabolic surgery outcomes vs nonsurgical management be reproduced with GLP-1 inhibitors?

Of 17,500 patients with established cardiovascular disease, semaglutide (GLP-1 inhibitor), reduced MACE (nonfatal MI, nonfatal stroke, and cardiovascular death) outcomes by 20%.⁶ This study targeted GLP-1, but what about other targets, such as GIP and glucagon? Tirzepatide is an unbalanced dual integrin inhibitor of GLP-1 and GIP but with more potency at the GIP receptor.⁷ The SURMOUNT-1 study, a randomized controlled clinical study of tirzepatide in 2,539 adults with BMI of ≥30, showed a mean reduction in weight of −33 lb (95% CI: −15.9 to −14.2) or 22.5% of study entry body weight.⁸

Can this weight loss result in a reduction in cardiovascular outcomes?

The SURMOUNT MNO study is currently in progress, with a primary endpoint composite of all-cause mortality, nonfatal MI, nonfatal stroke, coronary revascularization, and heart failure–related hospitalization and urgent visits.⁹ There is a triple integrin agonist called retatrutide being researched for weight loss, more potent at the GIP receptor than at the GLP-1 or glucagon receptors, with a 24.2% weight loss at 48 weeks.¹⁰ GLP-1 inhibitors are all weekly dosage injectables. Given the weight loss seen with these single, dual, and triple integrin agonist agents, which is similar to the weight loss and subsequent beneficial cardiovascular outcomes published in the STAMPEDE study, the future of reducing cardiovascular disease is within our grasp.

Over the past 10 years, I have had the privilege of contributing to Pharmacy Learning Network, covering issues ranging from community pharmacy to physical health, pharmacy legal issues to cardiovascular disease, and a myriad of other topics. Many of you have been faithful readers of these contributions and provided constructive criticism and commented positively. I appreciate all of your feedback.

I believe the future of pharmacy is a bright one. We are making inroads to instituting community practice hybrid models with our retail partners. We continue to focus on becoming a more cohesive advocate voice for pharmacy across the country. Through partnerships and professional cohesiveness, we can realize the necessary changes for pharmacy practice settings to evolve. The benefit of these changes will be improved patient therapeutics and drug safety.

I want to extend my appreciation to the Pharmacy Learning Network for providing me this platform, and I look forward to seeing how the pharmacy field develops in the future.

References

1. Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937-952. doi:10.1016/s0140-6736(04)17018-9
2. Ndumele CE, Matsushita K, Lazo M, et al. Obesity and subtypes of incident cardiovascular disease. JAHA. 2016;5(8). doi:10.1161/jaha.116.003921
3. Bhaskaran K, dos-Santos-Silva I, et al. Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3·6 million adults in the UK. Lancet Diabetes & Endocrinology. 2018;6(12):944-953. doi:10.1016/s2213-8587(18)30288-2
4. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes — 5-year outcomes. NEJM. 2017;376(7):641-651. doi:10.1056/nejmoa1600869
5. Aminian A, Zajichek A, Arterburn DE, et al. Association of metabolic surgery with major adverse cardiovascular outcomes in patients with type 2 diabetes and obesity. JAMA. 2019;322(13):1271. doi:10.1001/jama.2019.14231
6. Novo Nordisk A/S: Semaglutide 2.4 mg reduces the risk of major adverse cardiovascular events by 20% in adults with overweight or obesity in the SELECT trial. Novo Nordisk. Published August 8, 2023. Accessed October 30, 2023. https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=166301
7. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Molecular Metabolism. 2018;18:3-14. doi:10.1016/j.molmet.2018.09.009
8. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. NEJM. 2022;387:205-216. doi:10.1056/nejmoa2206038
9. FuturePulse. The Research Division of Cardiology Assoc. of Fairfield County. Accessed October 30, 2023. https://futurepulse.org/surmount-mmo
10. Jastreboff AM, Kaplan LM, Frias JP, et al. Triple–hormone-receptor agonist retatrutide for obesity — A phase 2 trial. NEJM. 2023;389:514-526. doi:10.1056/nejmoa2301972