SGLT2 inhibitor treatment is beneficial in T2DM patients with a broad range of ejection fractions
Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus Based on Ejection Fraction – Results from the DECLARE-TIMI 58 Trial
Presented at ACC.19 by Eri Kato (Kyoto, Japan)
Introduction and methods
Type 2 diabetes (T2DM) is a well-established risk factor for development of heart failure (HF). SGLT2 inhibitors was found to reduce the composite primary endpoint of CV death and heart failure hospitalizations (HFH), which was mainly driven by reduction in HFH. The relationship between left ventricular ejection fraction (LVEF) and the clinical benefit of SGTL2 inhibition is unknow as yet.
The DECLARE-TIMI 58 randomized over 17.000 T2DM patients with established or multiple risk factors for ASCVD to the SGLT2 inhibitor dapagliflozin or placebo. The trial showed a 17% relative risk reduction of CV death and HFH, both in patients with and without a history of HF. This prespecified analysis of the DECLARE-TIMI 58 trial aimed to examine the clinical benefit of dapagliflozin in patients with and without HF with reduced EF (HFrEF), on top of evidence-based medication for HF. Not having HFrEF was defined as patients with HF without known reduced EF and patients without HF therapy. Moreover, it was assessed whether dapagliflozin’s benefits can be predicted based on LVEF, by comparing EF categories: <30%, 30-<45, 45-<55 and EF ≥55%.
- No interaction was seen of having HFrEF or non-HFrEF with the treatment effect of dapagliflozin on HFH (HFrEF: 13.5% with dapagliflozin vs. 19.0% with placebo, HR: 0.64, 95%CI: 0.43-0.95, non-HFrEF: 2.1% vs. 2.7%, HR: 0.76, 95%CI: 0.62-0.92, P-interaction=0.449).
- A significant interaction was seen of having HFrEF or non-HFrEF with the treatment effect of dapagliflozin on CV death (HFrEF: 7.2% with dapagliflozin vs. 12.4% with placebo, HR: 0.55, 95%CI: 0.34-0.90, non-HFrEF: 2.3% vs. 2.5%, HR: 1.08, 95%CI: 0.89-1.31, P-int=0.012).
- Similarly, a significant interaction was seen of having HFrEF or non-HFrEF with the treatment effect of dapagliflozin on all-cause mortality (HFrEF: 11.3% vs. 17.7 %, HR: 0.59, 95%CI: 0.40-0.88, non-HFrEF: 5.4% vs. 5.5%, HR: 0.97, 95%CI: 0.86-1.10, P-int=0.016)
- In a sensitivity analysis, no interaction for the treatment effects of HFH was seen for EF in the comparison of non-HFrEF with EF ≥45% and HFrEF (P-int: 0.615). A significant interaction was seen for the treatment effect on CV death (EF ≥45%: HR: 1.44, HFrEF: HR: 0.55, P-int: 0.011).
- Analysis comparing different EF categories showed a significant trend towards a greater treatment effect in lower EF categories for CV death/HFH (P-trend: 0.039), for CV death (P-trend: 0.049) and for all-cause death (P-trend: 0.26), but the trend analysis for HFH did not reach statistical significance (P-trend: 0.084).
- Dapagliflozin was not associated with increased rate of safety events. No significant interactions were seen for HFrEF status on the occurrence of serious adverse events (P-int: 0.754), of symptoms of volume depletion (P-int: 0.204), and of acute renal failure (P-int: 0.240).
These data show that patients with HFrEF are at the highest risk for CV events and mortality. Treatment with dapagliflozin resulted in a lower rate of hospitalization for HF as compared with placebo, in a broad spectrum of patients, including those with preserved EF. Dapagliflozin reduced CV death (NNT-4years: 19) and all-cause mortality (NNT-4years: 16) in patients with HFrEF, but not in those without HFrEF. Safety of treatment with dapagliflozin was not affected by HF status.
Discussant Valentin Fuster noted that the SGLT2 inhibitors are ‘landing nicely in the clinical arena’. Initially, it was a big question why something that lowers blood sugar in diabetes would beneficially affect heart failure. This study contributes to the understanding of these processes.
He did note that the number of HFrEF patients was rather small (671 out of 17.160), so he would call these data preliminary. Because the study was not primarily set up for this analysis, some caution should be applied when interpreting the data.
Deepak Bhatt, also present during the press conference, added that, although the data are not definitive on whether dapagliflozin can reduce mortality in HFpEF, and although most benefit is seen in HFrEF, that does not take away the importance of potential effects in HFpEF.
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