There Is No Interaction Between BMI and SGLT2 Inhibitor Efficacy in HF, Review Finds

Body mass index (BMI) does not alter the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with heart failure (HF), according to a systematic review published in Internal and Emergency Medicine.¹

This was found to be true for both HF with preserved (HFpEF) and reduced ejection fraction (HFrEF), as well as for patients with or without diabetes.

The authors of the systematic review first identified 1461 articles for potential inclusion, considered 19 articles eligible for full-text screening, and ultimately included 3 articles in the meta-analysis: insights from the EMPEROR-Reduced trial by Anker et al, a study on obesity and stroke by Akyea et al, and a paper on obesity in cardiovascular disease by Wolfram Doehner, MD, PhD, DIC, FESC, FHFA.^2-4 These 3 articles included 14,737 total patients, with a third being women; 7367 individuals were randomized to an SGLT2 inhibitor—either dapaglifozin or empaglifozin—and 7370 were randomized to placebo.

Sodium-glucose cotransporter-2 inhibitors empaglifozin and dapaglifozin were efficacious for patients with heart failure regardless of body mass index.

Image credit: Olivier Le Moal – stock.adobe.com

BMI was classified according to the WHO classification into 4 categories:

• Under/normal weight (BMI < 25 kg/m2)
• Overweight (BMI: 25-29.9 kg/m2)
• Obesity class I (BMI: 30-34.9 kg/m2)
• Obesity classes II/III (BMI ≥ 35 kg/m2)

The review authors found significantly fewer hospitalizations for HF, cardiovascular deaths, and all-cause deaths among patients taking SGLT2 inhibitors compared with those taking placebo. Specifically, there was a 30% odds reduction in hospitalization for HF (OR, 0.70; 95% CI, 0.64-0.76) among those taking an SGLT2 inhibitor, without any interaction with BMI (test for subgroup differences: x2 = 0.86, P = .83) even after inverse-variance weighted regression analysis (P = .23).

For cardiovascular mortality, the review authors found a smaller but still significant 14% odds reduction for the SGLT2 inhibitor group (OR, 0.86; 95% CI, 0.77-0.97) compared with placebo. Again, there was no interaction with BMI (test for subgroup differences: x2 = 0.16, P = .98) including after inverse-variance weighted regression analysis (P = .63). Finally, patients taking an SGLT2 inhibitor saw a 10% odds reduction in all-cause mortality (OR, 0.90; 95% CI, 0.82-0.98) compared with patients taking placebo, again without any interaction with BMI (test for subgroup differences: x2 = 0.34, P = .95) including after inverse-variance weighted regression analysis (P = .57).

Additional analysis was conducted independently in 2 trials involving patients with HFrEF. Among the 8474 participants from the DAPA-HF and EMPEROR-reduced trials, no significant interaction with BMI was detected concerning cardiovascular mortality (test for subgroup differences: x2 = 1.53, P = .67).

According to the authors, these findings demonstrate a consistent beneficial effect of empaglifozin and dapaglifozin on these 3 outcomes across BMI range.

“Τhis observation is consistent with the results of clinical trials of SGLT2 inhibitors in other populations such as those with chronic renal disease or type II diabetes mellitus, in which there was no interaction between the effect and BMI,” the authors said. “The totality of this evidence in all three therapeutic areas of SGLT2 inhibitors indicates that there is no reason to consider BMI as a treatment-modifying factor in the decision to start dapaglifozin or empaglifozin in an eligible patient, regardless of the underlying indication.”

Based on the subgroup analyses, there was no significant interaction among various BMI groups concerning the investigated outcomes. Anastasia Adamou, MD, clinical research fellow at the University of Thessaly and lead author of the study, told The American Journal of Managed Care® (AJMC®) that it remains uncertain whether the advantages of SGLT2 inhibitors are more prominent in specific patient groups, as subgroup analyses do not offer definitive conclusions in this regard.

“Even though it seems that in each group there is an advantage of the SGLT2 inhibitors, the sample size that was used in each subgroup differs from the properly calculated number of participants by the design of this study,” Adamou said. “The two conclusions driven by these results are first that there is no interaction between the different subgroups studied, as the P-value for interaction in each studied outcome was < .05, and that SGLT2 inhibitors provide a beneficial effect in the total number of participants in each of the three outcomes studied.”

SGLT2 inhibitors are linked to a modest decrease in body weight, but they should not be relied upon as a primary tool for weight loss management in individuals with high or very high BMI, as the weight reduction observed is typically less than 5%. Interestingly, this weight reduction tends to be more pronounced in individuals with higher BMI. In patients with HFrEF, weight loss associated with empaglifozin treatment, particularly if unintentional, has been linked to an increased risk of all-cause mortality, aligning with the obesity paradox observed in HF and other cardiovascular conditions.

However, according to the authors, this association is observed even in placebo-treated patients, suggesting that the weight loss seen with SGLT2 inhibitors is not solely responsible for the obesity paradox. Further research is needed to explore the relationship between cardiovascular outcomes and obesity in patients with cardiovascular disease, with emerging evidence suggesting the potential utility of alternative anthropometric indices like waist-to-height ratio, which may offer better insights into ectopic fat distribution.

According to Adamou, the study's findings suggest that physicians should consider treating both HFpEF and HFrEF with SGLT2 inhibitors irrespective of patients' BMI, as there was no observed interaction between different BMI categories concerning cardiovascular mortality, HF hospitalization, and all-cause mortality incidence.

“SGLT2 inhibitors belong to a class of drugs that affect the body weight and body weight reduction could worsen heart failure patients’ prognosis,” Adamou told AJMC. “As a result, a physician, especially in primary care, might be hesitant to prescribe a SGLT2 inhibitor. This hypothesis was not confirmed in our analysis, so the BMI should not be a burden when considering the treatment with SGLT2 inhibitors in heart failure.”

While the review encompassed more than 14,000 patients collectively, the analysis is limited by the inclusion of only 3 studies. Another limitation the authors noted is the reliance on study-level data rather than individual patient data, which could have provided more precise results, particularly in analyzing BMI as a continuous covariate. Additionally, the study's scope is constrained by its inability to analyze specific high-risk populations, such as those with hypertension or diabetes, and some BMI subgroups were combined for clarity in reporting. Further, the analysis couldn't explore alternative obesity indices like waist circumference or skinfold thickness, which might offer deeper insights into body fat distribution.

References

1. Adamou A, Chlorogiannis DD, Kyriakoulis IG, et al. Sodium-glucose cotransporter-2 inhibitors in heart failure patients across the range of body mass index: a systematic review and meta-analysis of randomized controlled trials. Intern Emerg Med. Published online February 14, 2024. doi:10.1007/s11739-024-03532-8
2. Anker SD, Khan MS, Butler J, et al. Weight change and clinical outcomes in heart failure with reduced ejection fraction: insights from EMPEROR-Reduced [published correction appears in Eur J Heart Fail. 2023 Jun;25(6):924]. Eur J Heart Fail. 2023;25(1):117-127. doi:10.1002/ejhf.2728
3. Akyea RK, Doehner W, Iyen B, Weng SF, Qureshi N, Ntaios G. Obesity and long-term outcomes after incident stroke: a prospective population-based cohort study. J Cachexia Sarcopenia Muscle. 2021;12(6):2111-2121. doi:10.1002/jcsm.12818
4. Doehner W. Critical appraisal of the obesity paradox in cardiovascular disease: how to manage patients with overweight in heart failure?. Heart Fail Rev. 2014;19(5):637-644. doi:10.1007/s10741-014-9425-z