Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure

Abstract

Objective: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis.

Research and design methods: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping.

Results: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/10⁶ cells, P = 0.0497 vs. - 5.2 pmole/min/10⁶ cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups.

Gov registration: NCT03782259.

Keywords: CMRI; Cardiac fibrosis; IL-1B; Inflammation; PBMC respiration; SGLT2 inhibitor; Type 2 diabetes.

Fig. 1

Trial CONSORT Flow Diagram. MR, magnetic resonance; DM, diabetes mellites

Fig. 2

(A) Representative CMRI quantitative maps of T2D patient scanned at the baseline and 1-year follow up. (B) Example of region of interest (ROI) placement to the left ventricle of the post-contrast T₁ map for evaluation the parametric mapping values. The C-shape ROI included the whole circumference of the left ventricle. The ROI was placed at about 1 mm away from the LV edges to exclude signal contamination from blood and surrounding tissues

Fig. 3

Dapagliflozin reduces systemic inflammation. Levels of pre- and post- 12-months treatment of placebo or dapagliflozin: A-H, Plasma IL-1B, TNFα, IL-6, and IL-10; I-J, Plasma ketones (acetoacetate + β hydroxybutyrate); K-L, PBMC maximal oxygen consumption rate (OCR). P-value determined by paired two-tailed T-test. Parametric t-test is used if distribution passes normality tests, otherwise non-parametric t-test is used. For plasma cytokines (IL-1B, TNFα, IL-6, and IL-10) and ketone, statistical significance set to P  ≤  0.0083 (0.05/6) with Bonferroni correction