The prevalence of obesity continues to rise, now at 40.3% of U.S. adults, and doubled worldwide over the last forty years.^1,2

The evidence linking excess adiposity to a variety of cardiovascular conditions continues to mount.³ It also increases the risk of diabetes, chronic kidney disease and various cancers.^3-5 These associations highlight the important role it plays in the development and progression of chronic diseases and the need for more aggressive approaches to prevention and treatment of obesity.

The pathophysiology of many of these obesity-associated conditions is attributed to metabolic dysfunction, hemodynamic abnormalities and inflammation. Engulfment of the heart and coronary arteries by inflamed adipose tissue may contribute to increased cardiac filling and coronary atherosclerosis while infiltration of organs such as the liver and skeletal muscle lead to insulin resistance and metabolic syndrome.⁶ It imposes increased metabolic demands on the cardiovascular system, increasing total blood volume, stroke volume and cardiac output.^3,5,7 Collectively, these may lead to left ventricular dilation and hypertrophy and diastolic dysfunction.⁵

Among the effects of obesity are a strong association with heart failure with preserved ejection fraction (HFpEF),⁷ and a 180% increased risk for developing HF.⁵ Overweight is associated with an increased incidence of coronary heart disease, stroke and dementia.⁸ Cardiotoxic effects imposed by an increased neck circumference and pharyngeal soft tissue and excessive weight on the thorax and respiratory system lead to nocturnal hypoxia and hypercarbia from sleep apnea.^5,6

A multitude of adverse pathophysiological changes occur due to excess body fat. An endocrine organ, adipose is responsible for secretion of immune factors and hormones crucial for immunity responses and feeding behaviors. The intricate balance between these functions is vital to human health. An increase in adipose tissue increases levels of the energy-balancing hormone leptin. Additionally, adipocytes go through apoptosis, promoting dysregulation of macrophages through adiponectin and other immune cells, leading to secretion of proinflammatory markers and cytokines.^5,6,9 Excessive proinflammatory adipokines lead to systemic and local inflammation.⁹ Excessive adiposity leads to hydrolysis of triglycerides, which are released into plasma and other organs, leading to dyslipidemia, metabolic inflexibility and potentially atherosclerosis.⁶ Excessive storage of lipids in the liver causes steatohepatitis and eventually cirrhosis.^5,6

Approaches to Reduce Obesity-Related CV Risk

A moderate 5-10% weight loss is associated with improvements in obesity-related risk factors and co-existing diseases.⁶ Greater degrees of weight loss may produce additional benefits, particularly in the growing group of patients with severe obesity. As more studies become available on the risks of particular food groups for cardiovascular disease, dietary modification continues to be the single most important modifiable factor for achieving a healthy weight.^5,6,10,11 But, most studies of lifestyle interventions have shown relatively modest reductions in body weight and these are rarely sustained for ≥12 months.

High levels of physical activity sustained over longer durations has profound cardioprotective effects according to cross-sectional or population studies,⁵ although data are limited from prospective or long-term controlled studies. Along with helping to maintain healthy body composition and weight, additional benefits likely accrue from reducing heart rate and blood pressure, enhancing mitochondrial function, increasing vessel elasticity and improving myocardial perfusion.^6,10

Only 24.2% of adults meet the recommended minimum of 150 minutes/week of moderate-intensity aerobic physical activity, or 75 minutes/week of vigorous-intensity aerobic physical activity, or an equivalent combination of both.^12,13

Higher levels of cardiorespiratory fitness (CRF) are strongly associated with overall survival and other health outcomes.^3,5 An inverse relationship between BMI, body fat and waist circumference with CRF has been shown.¹⁴ A meta-analysis suggests that metabolically unhealthy individuals with obesity had lower levels of CRF.⁵ A decreased CRF increases risk for developing hypertension, hyperlipidemia and diabetes.^3,5,15 Thus it's no surprise a lower CRF is associated with increased mortality.¹⁵

The underutilized tool of intentional physical activity or exercise has the potential to be a low cost, widely applicable countermeasure against the epidemic of obesity-related cardiovascular disease. Cardiac rehab or physical activity has been shown to improve CRF and lower risk.³ Combining high-intensity aerobic and resistance training was shown to be associated with decreased abdominal adiposity, increased CRF and increased lean body mass.¹⁶

Unfortunately, exercise training alone generally produces very modest weight loss (≤2-3 kg).¹⁷

Anti-obesity pharmacotherapy can be considered in addition to lifestyle measures in individuals with a BMI ≥30 or 27-29 plus at least one weight-related coexisting condition.⁶ The newest and currently most effective agents are incretin agonists, including GLP-1 RAs and combined GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RAs.¹⁸

A 20% reduction in major adverse cardiovascular events with once-weekly semaglutide was shown in  those with obesity and known cardiovascular disease but without diabetes in SELECT.¹⁸ Reduced apneic episodes, hypoxic burden, systolic blood pressure and improved sleep were shown with tirzepatide, a dual GLP-1 RA/GIP RA in SURMOUNT-OSA.¹⁹ Progression to kidney disease was slowed with tirzepatide in individuals with type 2 diabetes (T2D) and high cardiovascular risk in SURPASS-4.²⁰ Both semaglutide and tirzepatide have shown efficacy in patients with obesity-related HFpEF.^21,22

Bariatric surgery is a good option for individuals unable to lose weight with lifestyle modifications or pharmacotherapy or those who need to lose more weight than usually achieved with drugs. It has traditionally been reserved for individuals with a BMI >40 or BMI >35 with comorbidities, although it has been argued these cutoffs are arbitrary and not based on evidence.

Also called metabolic surgery because of highly favorable effects on diabetes, it has been shown to reduce the inflammatory processes associated with obesity, improve biomarkers and gut flora, and improve other chronic diseases associated with obesity.⁴

After bariatric surgery, remission of diabetes and hypertension as well as significant reductions in cardiovascular endpoints and all-cause mortality have been shown.^6,23 To date, trials of incretin-based pharmacotherapy have not conclusively demonstrated reductions in cardiovascular or total mortality. Given the newness of these agents, long-term outcome data equivalent to that with bariatric surgery (up to 20 years) are lacking.

References

1. Centers for Disease Control and Prevention. Adult Obesity Prevalence Remains High. 2024. Accessed Dec. 18, 2024. Available here.
2. World Health Organization (WHO). Obesity and Overweight. 2024. Accessed Dec. 18 2024. Available here.
3. Haidar A, Horwich T. Obesity, cardiorespiratory fitness, and cardiovascular disease. Curr Cardiol Rep. 2023;25:1565-71. doi: 10.1007/s11886-023-01975-7.
4. Lin X, Li H. Obesity: epidemiology, pathophysiology, and therapeutics. Front Endocrinol. 2021;12:706978. doi: 10.3389/fendo.2021.706978.
5. Elagizi A, Kachur S, Carbone S, et al. A review of obesity, physical activity, and cardiovascular disease. Curr Obes Rep. 2020;9:571-81. doi: 10.1007/s13679-020-00403-z.
6. Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med.2017;376):254-66. doi: 10.1056/NEJMra1514009.
7. Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305-13. doi: 10.1056/NEJMoa020245.
8. Hughes TM, Tanley J, Chen H, et al. Subclinical vascular composites predict clinical cardiovascular disease, stroke, and dementia: The Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2024;392:117521. doi: 10.1016/j.atherosclerosis.2024.117521.
9. Taylor EB. The complex role of adipokines in obesity, inflammation, and autoimmunity.Clin Sci Lond Engl. 2021;135:731-52. doi: 10.1042/CS20200895.
10. Yanovski SZ, Yanovski JA. Approach to obesity treatment in primary care: A review. JAMA Intern Med. 2024;184:818-29. doi: 10.1001/jamainternmed.2023.8526.
11. Salehin S, Rasmussen P, Mai S, et al. Plant based diet and its effect on cardiovascular disease. Int J Environ Res Public Health. 2023;20:3337. doi: 10.3390/ijerph20043337.
12. Centers for Disease Control and Prevention. Adult Activity. 2023. Accessed Jan 24, 2025. here.
13. Centers for Disease Control and Prevention. Exercise or Physical Activity. 2024. Accessed Jan 24, 2025. Available here.
14. Zeiher J, Ombrellaro KJ, Perumal N, et al. Correlates and Determinants of cardiorespiratory fitness in adults: A systematic review. Sports Med Open. 2019;5:39. doi: 10.1186/s40798-019-0211-2.
15. Sloan RA. Estimated cardiorespiratory fitness and metabolic risks. Int J Environ Res Public Health. 2024;21:635. doi: 10.3390/ijerph21050635.
16. O'Donoghue G, Blake C, Cunningham C, et al. What exercise prescription is optimal to improve body composition and cardiorespiratory fitness in adults living with obesity? A network meta-analysis. Obes Rev Off J Int Assoc Study Obes. 2021;22:e13137. doi: 10.1111/obr.13137.
17. Oppert J-M, Ciangura C, Bellicha A. Physical activity and exercise for weight loss and maintenance in people living with obesity. Rev Endocr Metab Disord. 2023;24:937-49. doi: 10.1007/s11154-023-09805-5.
18. Lingvay I, Deanfield J, Kahn SE, et al. Semaglutide and cardiovascular outcomes by baseline hba1c and change in hba1c in people with overweight or obesity but without diabetes in SELECT. Diabetes Care.2024;47:1360-69. doi: 10.2337/dc24-0764.
19. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the Treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391:1193-1205. doi: 10.1056/NEJMoa2404881.
20. Heerspink HJL, Sattar N, Pavo I, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: Post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10:774-85. doi: 10.1016/S2213-8587(22)00243-1.
21. Cimino G, Vaduganathan M, Lombardi CM, et al. Obesity, heart failure with preserved ejection fraction, and the role of glucagon-like peptide-1 receptor agonists. ESC Heart Fail. 2024;11(2):649-61. doi: 10.1002/ehf2.14560.
22. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med.2025;392:427-37. doi: 10.1056/NEJMoa2410027.
23. Bellicha A, van Baak MA, Battista F, et al. Effect of exercise training before and after bariatric surgery: A systematic review and meta-analysis. Obes Rev Off J Int Assoc Study Obes. 2021;22 Suppl 4(Suppl 4):e13296; doi: 10.1111/obr.13296.

Clinical Topics: Prevention, Diet

Keywords: Cardiology Magazine, ACC Publications, Weight Loss, Diet, Risk Factors, Obesity