Decoding the coronary paradox of obesity: not all fat is equal!

The burden of cardiovascular complications in patients with diabetes continues to pose a major clinical and public health challenge worldwide. Despite significant advances in pharmacotherapy, lifestyle interventions, and technological innovations, the incidence of adverse cardiovascular events among individuals with type 2 diabetes remains high [[1], [2], [3]], underscoring the critical importance of ongoing research aimed at identifying modifiable risk factors, optimizing prevention strategies, and refining clinical management pathways.

Over the past two decades, a robust body of evidence has elucidated the intricate interplay between glycemic control, comorbidities, and cardiovascular outcomes. Landmark clinical trials such as UKPDS [4], ACCORD [5], ADVANCE [6], and EMPA-REG [7] have shaped current practice by highlighting not only the benefits but also the limitations of intensive glycemic management and newer cardioprotective agents [8]. Against this backdrop, in the current issue of IJC Heart & Vasculature, Ozcan and collaborators provide valuable insights into the association between glycemic variability and cardiovascular outcomes in patients with diabetes [9], a topic that has increasingly attracted attention as continuous glucose monitoring becomes more widespread in clinical care [10].

A total of 226 patients were studied, stratified by body mass index (BMI) into four groups: normal weight, overweight, obese, and morbidly obese. Myocardial blood flow at rest and during hyperemia was measured, calculating myocardial flow reserve (MFR) using ¹³N-ammonia PET/CT. Left ventricular mass (LVM), early diastolic flow (E) and relaxation (e’) velocities, and global longitudinal strain (GLS) were assessed via echocardiography. Strikingly, MFR decreased progressively from normal weight to obese, then rebounded in morbid obesity to levels comparable with normal weight [9]. In obese and morbidly obese patients, MFR was inversely associated with E velocity, and in obese patients also with LVM and GLS. GLS, E velocity, and LVM were identified as independent predictors of MFR [9].

These findings suggest that glycemic variability exerts an independent impact on cardiovascular outcomes beyond mean HbA1c levels. By leveraging a robust statistical modeling, the study contributes to the ongoing discussion of whether traditional glycemic indices are sufficient markers of risk stratification, or if a broader range of metrics should be considered in routine practice. The analysis is thorough, with careful adjustment for key confounders, and the results are both biologically plausible and clinically relevant.

An interesting aspect highlighted by the study is the so-called obesity paradox, wherein morbidly obese patients exhibited a rebound in MFR comparable to that of normal-weight individuals, despite higher overall cardiovascular risk profiles. This paradoxical phenomenon, observed in multiple cardiovascular and metabolic studies [11,12], indicates that in certain contexts, higher BMI may confer unexpected protective effects on specific functional or survival outcomes. The mechanisms remain incompletely understood, but potential explanations include differences in myocardial energy substrate utilization, favorable hemodynamic adaptations, or selection bias in observational cohorts (Table 1). In the present study, the obesity paradox underscores the complex and non-linear relationship between adiposity, cardiac structure and function, and cardiovascular risk, highlighting the need for nuanced interpretation of BMI and metabolic parameters in risk stratification.

Table 1.

Potential mechanisms underlying the U-shaped relationship between obesity severity and coronary vasodilator capacity.

Category	Mechanism	Key Features / Effects
Adipose Tissue Distribution	Shift from visceral to subcutaneous adiposity	Subcutaneous fat predominates in morbid obesity, associated with lower lipolysis, higher insulin sensitivity, and less atherogenic lipid profiles.
Adipocytokine & Hormonal Adaptations	Leptin elevation	In morbid obesity, high leptin levels may promote endothelial nitric oxide release, supporting vasodilator capacity despite hypertrophic effects.
	Adiponectin release	Enhanced secretion from subcutaneous depots exerts anti-inflammatory and vasculo-protective effects.
	Endocannabinoid shifts	Altered signaling may favor vascular tone regulation and reduced inflammation.
Inflammatory Microenvironment	Remodeling of immune signaling	Transition from visceral-driven proinflammatory state in obesity to partially attenuated inflammation in morbid obesity may protect vasculature.
	Progenitor cell mobilization	Low-level inflammation may enhance mobilization of endothelial progenitor cells that promote vascular repair and regeneration.
Progenitor Cell & Repair Pathways	Bone marrow–derived progenitor cells	Increased numbers in morbid obesity may aid endothelial integrity via direct incorporation or paracrine effects.
Hemodynamic & Metabolic Compensation	Hemodynamic adjustments	Increased blood volume and altered vascular compliance may normalize vasodilator responses.
	Depot-specific insulin sensitivity	Mesenteric/round ligament adipose tissue displays higher insulin sensitivity, reducing lipotoxic stress and improving metabolic profile.
Cardiac Remodeling Interactions	Coupling vs uncoupling of LV mass and vasodilator function	In moderate obesity, higher LV mass and impaired relaxation correlate with reduced MFR; in morbid obesity, this association weakens, suggesting divergent remodeling mechanisms.
Other Possible Explanations	Genetic/adaptive factors	Genetic predispositions, adaptive vascular remodeling, or survival bias may explain preserved coronary vasodilator function in some morbidly obese individuals.

This work has several notable strengths. First, it addresses an area of growing interest where clinical evidence is still relatively limited. Second, the study design and sample size enhance the reliability of the conclusions. Third, the emphasis on clinical outcomes, rather than surrogate endpoints alone, increases the translational value of the findings. However, limitations must also be acknowledged. The observational design precludes definitive causal inference, and residual confounding cannot be fully excluded. Furthermore, the absence of mechanistic insights limits the ability to fully explain the biological underpinnings of the observed associations. Nevertheless, these findings represent an important step forward, highlighting the need to move beyond a sole reliance on HbA1c as the gold standard of glycemic control and to incorporate more dynamic measures of glucose exposure in clinical practice. From a clinical perspective, these data suggest that managing glycemic variability may be as important as lowering average glucose levels, particularly in patients at elevated cardiovascular risk [13]. This aspect raises practical questions for clinicians: Should continuous glucose monitoring metrics be routinely incorporated into risk stratification algorithms? Could therapeutic strategies aimed specifically at stabilizing glucose fluctuations reduce cardiovascular events?

Future directions in this field should include prospective interventional trials designed to test whether reducing glycemic variability translates into improved cardiovascular outcomes in obese and morbidly obese patients. Integrating digital health technologies, artificial intelligence, and personalized therapeutic strategies will be crucial in this regard [14]. Moreover, mechanistic studies are warranted to elucidate the biological pathways linking glycemic oscillations to vascular injury, inflammation, and thrombosis [15].

In conclusion, Ozcan and co-workers provide timely and clinically relevant evidence on the prognostic significance of glycemic variability in diabetes. By drawing attention to a dimension of glucose control that is often overlooked in routine care, new avenues for research and patient management have been opened, suggesting that a paradigm shift in the assessment and treatment of glycemic control may be on the horizon, with significant implications for reducing the cardiovascular burden in diabetes.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.