TOPLINE:

In patients with type 2 diabetes (T2D), 6 months of empagliflozin therapy was associated with a modest increase in the fat oxidation rate during exercise of low‑to‑moderate intensity compared with sitagliptin therapy. These findings suggested that empagliflozin could potentially improve exercise capacity in patients with T2D.

METHODOLOGY:

• Researchers conducted an exploratory analysis of the EMPA-HEART trial to determine whether empagliflozin modified substrate oxidation during exercise in patients with T2D.
• They analysed data of 44 patients who were randomly assigned to receive 6 months of treatment with empagliflozin 10 mg daily (n = 22; mean age, 61.6 years; 86% men) or sitagliptin 100 mg daily (n = 22; mean age, 61.8 years; 86% men).
• Patients underwent cardiopulmonary exercise tests at baseline and after 6 months, after more than 12 hours of fasting.
• Indirect calorimetry of breath-by-breath gas exchange data was used to estimate rates of fat and glucose oxidation, identify the maximal fat oxidation (MFO) rate, and determine the exercise intensity at which MFO was reached (FATmax).
• Fasting plasma levels of beta-hydroxybutyrate and free fatty acids were measured on the same days of cardiopulmonary exercise testing.

TAKEAWAY:

• After 6 months of therapy, empagliflozin was associated with a significantly increased fat oxidation rate (+10.1 vs -3.8 mg per minute per kg of fat‑free mass) and a significantly decreased glucose oxidation rate (-10.5 vs +8.8 mg per minute per kg of fat‑free mass; P < .05 for both) compared with sitagliptin during exercise of low-to-moderate intensity.
• Treatment with empagliflozin — but not sitagliptin — was associated with increases in MFO (P for drug × time = .025) and FATmax (P for drug × time = .043).
• Fasting levels of beta-hydroxybutyrate rose with empagliflozin vs sitagliptin, and this increase correlated with improvements in both MFO and FATmax (P < .05 for both).
• In the overall population, the increases in MFO and FATmax correlated with changes in cardiopulmonary fitness measured as the rate of oxygen uptake at peak exercise, independent of cardiac output, peripheral oxygen extraction, and systolic function indices.

IN PRACTICE:

"The observed association between improvements in metabolic flexibility and peak oxygen uptake further supports the notion that enhanced substrate adaptability may translate into improved overall functional capacity, particularly in individuals with impaired baseline fitness," the authors wrote.

SOURCE:

The study was led by Lorenzo Nesti, University of Pisa in Pisa, Italy. It was published online on March 31, 2026, in Diabetes, Obesity and Metabolism.

LIMITATIONS:

Lipid metabolites were measured only at rest rather than during exercise. Physical activity levels were not formally quantified during the trial. Indirect calorimetry captures data on whole body metabolism rather than tissue-specific measurements.

DISCLOSURES:

This study was supported by an unrestricted grant from Boehringer Ingelheim covering 49% of the costs. The authors reported having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.