BMI and glycaemic status significantly affect CV risk in patients treated with anthracyclines

A retrospective cohort study of >11,000 Hong Kong patients who initiated anthracycline-based chemotherapy found that both body-mass index (BMI) and glycaemic status significantly affect cardiovascular (CV) risks, with the highest risk observed in those with concurrent obesity and diabetes/prediabetes.

While both obesity and hyperglycaemia may exacerbate anthracycline‐induced oxidative stress and inflammation, comprehensive studies evaluating the combined impact of BMI and glycaemic status on CV outcomes in patients with cancer treated with anthracyclines have been limited. [J Am Heart Assoc 2020;9:e015288; J Clin Oncol 2016;34:3157-3165]

“By identifying high‐risk profiles, this research seeks to contribute to the body of knowledge that informs clinical decision‐making, with the goal of mitigating cardiotoxicity risks and enhancing the quality of care for patients with cancer,” stated a team of researchers from the Nanjing Medical University, the University of Hong Kong–Shenzhen Hospital and the University of Hong Kong (HKU) Queen Mary Hospital.

MACE, CV mortality and HHF

The study included 11,393 chemotherapy‐naïve patients (mean age, 63.65 years; male, 50.02 percent) from Hong Kong who initiated anthracycline‐based chemotherapy – specifically daunorubicin, doxorubicin, epirubicin, mitoxantrone, or idarubicin – between 2000 and 2019. Over a median follow-up of 8.7 years, major adverse CV events (MACE) were reported in 985 patients (8.64 percent). [J Am Heart Assoc 2025;14:e040876]

The median age of patients who experienced MACE was significantly higher vs those who did not (73.20 vs 62.75 years; p<0.01). There was also a higher proportion of men in the group with vs without MACE (57.56 vs 49.31 percent; p<0.01). The group with MACE had a significantly greater burden of comorbidities, namely, atrial fibrillation (10.05 vs 1.39 percent), hypertension (25.58 vs 10.47 percent), and coronary artery disease (4.47 vs 1.12 percent) (p<0.01 for all), and also received higher cumulative anthracycline doses (126 vs 111 mg/m²; p=0.02).

In a model, which fully adjusted for all of the above plus estimated glomerular filtration rate, serum albumin, fasting blood glucose, neutrophil count, haemoglobin, platelet count, anthracycline type, use of angiotensin‐converting enzyme inhibitors/angiotensin‐receptor blockers, β-blockers, mineralocorticoid receptor antagonists, statins, and other classes of chemotherapy drugs, obesity (defined as BMI ≥30 kg/m²) was associated with increased MACE risk (hazard ratio [HR], 1.38; 95 percent confidence interval [CI], 1.10–1.73; p=0.01). However, overweight (BMI, 25–29.9 kg/m²) showed no significant association compared with the reference group of underweight or normal-weight individuals (HR, 1.13; 95 percent CI, 0.99–1.30; p=0.08). At the same time, diabetes (defined as HbA_1c ≥6.5 percent or fasting glucose ≥126 mg/dL) or prediabetes (HbA_1c, 5.7–6.4 percent or fasting glucose 100–125 mg/dL) was significantly associated with a higher risk of MACE (HR, 1.28; 95 percent CI, 1.10–1.50; p<0.01).

Neither overweight nor obesity significantly increased the risk of CV mortality, while diabetes/prediabetes was associated with a significantly higher risk (HR, 1.32; 95 percent CI, 1.02–1.71; p=0.03). Overweight (HR, 1.24; 95 percent CI, 1.05–1.45; p=0.01), obesity (HR, 1.61; 95 percent CI, 1.25–2.07; p<0.01), and diabetes/prediabetes (HR, 1.29; 95 percent CI, 1.08–1.54; p=0.01) were all associated with a significantly increased risk of hospitalization for heart failure (HHF).

“Obesity paradox”

Interestingly, while diabetes/prediabetes was associated with a higher risk of all‐cause mortality (HR, 1.39; 95 percent CI, 1.29–1.50; p<0.01), both overweight (HR, 0.85; 95 percent CI, 0.80–0.91; p<0.01) and obesity (HR, 0.85; 95 percent CI, 0.74–0.96; p=0.01) were associated with a lower risk in the case of all‐cause mortality vs underweight or normal weight.

“The observed protective effect of higher BMI on all‐cause mortality, despite increased CV risks, aligns with the ‘obesity paradox’ seen in other chronic conditions,” wrote the researchers. [Prog Cardiovasc Dis 2023;78:2-10] “This may reflect greater nutritional reserves, metabolic adaptability, and improved tolerance to chemotherapy in patients with overweight or obesity, potentially mitigating the catabolic effects of cancer and its treatment. However, this does not negate the long‐term risks of obesity, such as inflammation and metabolic dysfunction, which contribute to CV morbidity,” they warned.

“Although BMI remains a practical metric, incorporating visceral adiposity measures [eg, waist‐to‐hip ratio] may refine risk stratification and personalize cardio‐oncology care in this population,” they suggested.

Joint effect of obesity and hyperglycaemia

The joint analysis of BMI category and diabetes status among patients with cancer treated with anthracyclines revealed that, compared with patients who were underweight or of normal weight and normoglycaemic, those with obesity plus diabetes/prediabetes had the highest risks of MACE (HR, 1.74; 95 percent CI, 1.28–2.37; p<0.01) and HHF (HR, 1.99; 95 percent CI, 1.41–2.81; p<0.01), but no significant increase in risk of CV mortality or all‐cause mortality.

“This study is the first to demonstrate that the combination of obesity and diabetes/prediabetes synergistically amplifies CV risk in patients with cancer receiving anthracyclines, surpassing the individual effects of either factor alone,” noted the researchers.

Recommendation

“It is crucial for healthcare providers to adopt a multidisciplinary approach that considers both oncologic and metabolic factors when managing patients with cancer receiving anthracycline therapy,” recommended the researchers. “Pretreatment screening for BMI, along with more refined measures of obesity, should be standard practice, followed by individualized monitoring and intervention strategies. For patients with obesity, especially those with prediabetes or diabetes, more aggressive CV protective measures may be warranted to mitigate the elevated risk of CV outcomes.”