Is 'Metabolically Healthy Obesity' Actually Healthy?

Quick Takes

  • There is controversy whether obesity in an otherwise metabolically healthy person is a benign condition.
  • Metabolically healthy obese adults have a higher risk for heart failure than those who are metabolically healthy normal weight.
  • Routine screening of high-sensitivity cardiac troponin-T (hs-cTnT) among metabolically healthy overweight and obese groups identifies those who are at a higher risk for CVD, especially CHD and HF.

Introduction
Obesity affects 40% of United States (US) adult population1 and is associated with a number of metabolic abnormalities.2,3 One-third of this population does not have major cardiovascular risk factors and is considered "metabolically healthy". Whether metabolically healthy obesity is a high-risk state, or a benign condition is controversial.3-11 Small elevations in high sensitivity cardiac troponin (hs-cTnT) predict incident heart failure (HF), left ventricular failure (LVH), coronary artery disease (CAD), cardiovascular disease (CVD), and all-cause mortality in the general population.12-14 Hs-cTnT reflects subclinical myocardial damage, reflecting micro-vascular damage to heart.14,15 However, the association of hs-cTnT with overall CVD risk and CVD subtypes according to obesity phenotypes has not been examined.

Several epidemiological studies supported "cardioprotection" in metabolically healthy obese adults in comparison with metabolically unhealthy adults and a meta-analysis confirmed a positive association between metabolically healthy obesity with stroke.16 However, studies to date have not used hs-cTnT to further characterize CVD risk in the entire spectrum of obesity phenotypes in addition to the metabolic health status.

Modified National Cholesterol Education Program – Adult Treatment Panel (NCEP-ATP) III Criteria17 defines an unhealthy adult with two or more of the following: triglyceride level >150 mg/dl or treated for dyslipidemia, HDL <40 mg/dL (men) and <50 mg/dL (women), systolic blood pressure (SBP) ≥130 mm Hg or diastolic blood pressure (DBP) ≥85 mm Hg or use of antihypertensive drugs.

The authors of a recent paper in Diabetes Care, "High burden of subclinical and cardiovascular disease risk in adults with metabolically healthy obesity: the Atherosclerosis Risk in Communities (ARIC) study"18 examined cross-sectional and prospective associations of obesity phenotypes with subclinical myocardial damage and future risk of CVD, and CVD and HF.

Study Design
The authors performed a cross-sectional and prospective analyses of 9,477 participants followed for an average of about 27 years. At baseline, 56% of the participants were female, and 23% identified as black. Metabolically healthy obesity was the least common (7%), metabolically unhealthy overweight (23%) and obese (19%) were the most common obesity phenotypes.

The study population was subdivided into six different phenotypes using body mass index (BMI) criteria (normal weight, <25 kg/m^2; overweight, 25 to <30 kg/m^2, or obese, ≥30 kg/m^2) and according to metabolically health using modified NCEP-ATP III Criteria.17

Hs-cTnT was used to characterize the presence of subclinical cardiac damage; it was categorized as "undetectable" (<6 ng/L), "detectable" (≥ 6 ng/L <14 ng/L) and "elevated" (≥14 ng/L).

The primary outcome was composite incident CVD, defined as an adjudicated fatal or fatal coronary heart disease (CHD), coronary artery vascularization, silent and unrecognized myocardial infarction (MI), fatal or nonfatal ischemic stroke or hemorrhagic stroke on imaging or HF hospitalization or death from HF. Secondary outcomes were CHD and HF.

Cross sectional associations of obesity phenotypes with hs-cTnT categories were examined as well as the combined associations of obesity phenotypes and detectable hs-cTnT with incident CVD.

Results
The prevalence of subclinical myocardial damage, defined as hs-cTnT ≥14 ng/L, was more common in metabolically healthy obese phenotype as compared to people in the metabolically healthy normal weight category (prevalence ratio 2.29, 95% confidence interval [CI] 1.23- 4.32). Elevated hs-cTnT was associated with an excess risk of clinical CVD in between metabolically healthy normal weight and metabolically unhealthy obese individuals.

Prospective analyses of obesity phenotypes and incident CVD showed that when compared to metabolically healthy normal weight adults, metabolically healthy obese adults were likely to have more incident CVD (hazard ratio [HR] 1.38, 95% CI 1.15–1.67) and the metabolically unhealthy obese had about a two-fold higher risk of CVD (HR 2.14, 95% CI 1.88–2.44). The metabolically healthy obese group had higher risk of HF, but the risk was not significant for CHD.

Cross categories of obesity phenotypes and hs-cTnT with incident CVD showed obese individuals with detectable hs-cTnT, even though classified as metabolically healthy, had significantly elevated risk of both CHD and HF.

Discussion
Incidence of CVD and subclinical myocardial damage have been studied in populations with risk factors for CVD and stroke. However, early detection of subclinical CVD in individuals without traditional CVD risk factors can be valuable in primordial prevention and intensification of medical therapy and lifestyle interventions. The use of hs-cTnT can 'unmask' a subgroup of adults at high risk for CVD who would otherwise be considered "metabolically healthy" obese individuals. In this study, the use of hs-cTnT improved characterization of CVD risk across the full spectrum of obesity phenotypes; hs-cTnT was an early indicator of subclinical cardiac injury and mortality regardless of the metabolic health status.

These results have important clinical implications. Clinical CVD is preceded by decades of subclinical disease. Evaluation of cardiometabolic health with hs-cTnT in overweight or obese individuals without clinical CVD could lead to early detection, diagnosis, and treatment of subclinical CVD by intensive lifestyle modification.

Association of metabolically healthy obesity with future risk of HF has been demonstrated in several studies.19-21 This present study further demonstrates that hs-cTnT provides prognostic information about future HF and CHD risk, even among those classified as "metabolically healthy."

Future Directions
Routine screening with hs-cTnT in obese adults, even in the absence of other CVD risk factors, can identify individuals at high CVD risk and may provide an opportunity to institute lifestyle modification and/or pharmacotherapy to prevent subsequent CVD. Further studies are needed to validate this concept.

References

  1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2015-2016. NCHS Data Brief 2017;288:1-8.
  2. Blüher M. The distinction of metabolically 'healthy' from 'unhealthy' obese individuals. Curr Opin Lipidol 2010;21:38-43.
  3. Stefan N, Häring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol 2013;1:152-62.
  4. Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions? A systematic review and meta-analysis. Ann Intern Med 2013;159:758-69.
  5. Fan J, Song Y, Chen Y, Hui R, Zhang W. Combined effect of obesity and cardio-metabolic abnormality on the risk of cardiovascular disease: a meta-analysis of prospective cohort studies. Int J Cardiol 2013;168:4761-68.
  6. Eckel N, Meidtner K, Kalle-Uhlmann T, Stefan N, Schulze MB. Metabolically healthy obesity and cardiovascular events: a systematic review and meta-analysis. Eur J Prev Cardiol 2016;23:956-66.
  7. Zheng R, Zhou D, Zhu Y. The long-term prognosis of cardiovascular disease and all-cause mortality for metabolically healthy obesity: a systematic review and meta-analysis. J Epidemiol Community Health 2016;70:1024-31.
  8. Eckel N, Li Y, Kuxhaus O, Stefan N, Hu FB, Schulze MB. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30-year follow-up from a prospective cohort study. Lancet Diabetes Endocrinol 2018;6:714-24.
  9. Mongraw-Chaffin M, Foster MC, Anderson CAM, et al. Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol 2018;71:1857-65.
  10. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med 2008;168:1617-24.
  11. Benjamin EJ, Muntner P, Alonso A, et al. Heart Disease and Stroke Statistics-2019 Update: a report from the American Heart Association. Circulation 2019;139:e56-e528.
  12. Saunders JT, Nambi V, de Lemos JA, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation 2011;123:1367-76.
  13. Ndumele CE, Coresh J, Lazo M, et al. Obesity, subclinical myocardial injury, and incident heart failure. JACC Heart Fail 2014;2:600-07.
  14. deFilippi CR, de Lemos JA, Christenson RH, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA 2010;304:2494-2502.
  15. Body R, Carley S, McDowell G, et al. Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay. J Am Coll Cardiol 2011;58:1332-39.
  16. Ma LZ, Sun FR, Wang ZT, et al. Metabolically healthy obesity, and risk of stroke: a meta-analysis of prospective cohort studies. Ann Transl Med 2021;9:197.
  17. ATP III Guidelines At-A-Glance Quick Desk Reference (NHLBI/NIH website). 2001. Available at: https://www.nhlbi.nih.gov/files/docs/guidelines/atglance.pdf. Accessed 06/01/2021.
  18. Commodore-Mensah Y, Lazo M, Tang O, et al. High burden of subclinical and cardiovascular disease risk in adults with metabolically healthy obesity: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care 2021;May 5:[Epub ahead of print].
  19. Caleyachetty R, Thomas GN, Toulis KA, et al. Metabolically healthy obese and incident cardiovascular disease events among 3.5 million men and women. J Am Coll Cardiol 2017;70:1429-37.
  20. Mørkedal B, Vatten LJ, Romundstad PR, Laugsand LE, Janszky I. Risk of myocardial infarction and heart failure among metabolically healthy but obese individuals: HUNT (Nord-Trøndelag Health Study), Norway. J Am Coll Cardiol 2014;63:1071-78.
  21. Ndumele CE, Matsushita K, Lazo M, et al. Obesity and subtypes of incident cardiovascular disease. J Am Heart Assoc 2016;5:e003921.

Keywords: Dyslipidemias, Metabolic Syndrome, Heart Failure, Primary Prevention, Secondary Prevention, Body Mass Index, Cardiovascular Diseases, Antihypertensive Agents, Obesity, Coronary Artery Disease, Blood Pressure, Prognosis, Cross-Sectional Studies, African Americans, Prospective Studies, Brain Ischemia, Confidence Intervals, Risk Factors, Stroke, Diabetes Mellitus, Myocardial Infarction, Atherosclerosis, Hospitalization, Cholesterol, Life Style, Health Status, Phenotype, Triglycerides, Troponin, Adenosine Triphosphate


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