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Eri Toda Kato, Koh Ono, Basil S Lewis, SGLT2 inhibitors in acute myocardial infarction: what can we learn from the DAPA-MI trial? More news from American Heart Association Scientific Meeting, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 10, Issue 2, March 2024, Pages 95–97, https://doi.org/10.1093/ehjcvp/pvad099
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DAPA-MI, a registry-based randomized trial presented at AHA 2023, examined the question regarding use of Sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with acute myocardial infarction (MI).
SGLT2 inhibitors: pioneering change in treatment paradigms
SGLT2 inhibitors, initially developed as anti-diabetes drugs, have emerged as key Class 1 drugs in the management of patients with heart failure (HF) over a broad spectrum of left ventricular ejection fraction (EF).1–3 A sub-analysis of the DECLARE-TIMI 58 trial showed that dapagliflozin reduces major adverse cardiac events (MACE) and the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) and a history of MI,4,5 which prompted further investigation into the potential benefits of dapagliflozin in a wider group of patients with acute MI.
The DAPA-MI trial
DAPA-MI was a multicentre, parallel-group, registry-based, randomized, double-blind, placebo-controlled phase 3 trial in patients without known T2DM or established HF, presenting with ST elevation myocardial infarction (STEMI) or non-STEMI, and with imaging evidence of any degree of impaired regional or global left ventricular (LV) systolic function during their index hospitalization, or Q-wave MI. The trial evaluated the effect of dapagliflozin 10 mg initiated within 10 days of the index MI event vs. placebo, given once daily in addition to standard-of-care therapy.6
The trial was conducted across 103 sites in Sweden and the United Kingdom, employing a novel registry-based randomized controlled trial framework. Initially, the primary endpoint was to assess the impact of dapagliflozin vs. placebo on the time to CV death or hospitalization for HF (HHF). However, the unexpectedly low number of primary composite outcome events led to a modification of the trial design to examine a 7-point hierarchical composite outcome of death, HHF, non-fatal MI, atrial fibrillation/flutter, new onset of T2DM, HF symptoms, and body weight decrease, all included based on prior studies suggesting that dapagliflozin had positive effects on these domains.
Over approximately 22 months of follow-up, the dapagliflozin-treated group demonstrated an improvement in this primary hierarchical composite outcome compared to the placebo group (32.9% vs. 24.6%), resulting in a win ratio of 1.34 (95% CI 1.20–1.50). The observed benefit was driven primarily by a reduction in the incidence of new-onset T2DM among patients treated with dapagliflozin. Although this is noteworthy, the absence of benefit regarding CV death or HHF contrasts with the results of prior subgroup studies (19% risk reduction in DECLARE-TIMI 58,5 22% in DAPA-HF7).
Delving into sources of discordance
The differences between DAPA-MI, DECLARE-TIMI 58, and DAPA-HF are summarized in the Table 1. The DAPA-MI trial enrolled low-risk stable patients, excluding patients with diabetes and patients with a history of HF events, who had an absolute indication for treatment with SGLT2 inhibitors and therefore could not be randomized. The event rate was low (2.6% in the placebo group), and the follow-up duration was short (approximately 1 year). Current MI diagnosis based on troponin levels allows the detection of patients with minor myocardial damage and a low risk of HF development. In the era of coronary revascularization, an initially noted change in LV function may have been reversible.
| Trials . | DAPA-MI . | DECLARE-TIMI 58 . | DAPA-HF . |
|---|---|---|---|
| Target population | AMI | ASCVD + DM | HF |
| Subgroup | Placebo | Previous MI | Ischaemic origin |
| Number of patents in the subgroup | 1998 | 3584 | 2674 |
| Demographics | |||
| Age (year) | 63 | 62 | 68 |
| Male sex (%) | 79 | 76.4 | 79.9 |
| Europe (%) | 100 | 49.8 | 52.5 |
| Weight (kg) | 85.5 | 91 | NA |
| eGFR (mL/min/1.73 m2) | 83.4 | 88 | 63.7 |
| HbA1c (%) | 5.7 | 8 | NA |
| Medical history | |||
| Myocardial infarction (%) | 9.5 | 100 | 72.5 |
| Stroke (%) | 2.5 | 6.1 | 10.7 |
| Diabetes (%) | NA | 100 | 49.9 |
| Heart failure (%) | NA | 21.5 | 46.1 |
| Baseline medication | |||
| ACE inhibitor/ARB use (%) | 91.8 | 84.1 | 84.6 |
| Beta-blockers use (%) | 89.9 | 82.2 | 96 |
| Statins use (%) | 94.9 | 91.1 | 83.5 |
| Outcomesa | |||
| Follow-up duration (year) | 1 | 4.2 | 1.5 |
| CV death/hospitalization for HF (%) | 2.6 | 10.5 | 20.9 |
| MACE (%) | 3.6 | 17.8 | NA |
| CV death (%) | 1.2 | 5.3 | 12.5 |
| All cause death (%) | 1.7 | 10.3 | 15.2 |
| Hospitalization for HF | 1.6 | 6.3 | 12.7 |
| Trials . | DAPA-MI . | DECLARE-TIMI 58 . | DAPA-HF . |
|---|---|---|---|
| Target population | AMI | ASCVD + DM | HF |
| Subgroup | Placebo | Previous MI | Ischaemic origin |
| Number of patents in the subgroup | 1998 | 3584 | 2674 |
| Demographics | |||
| Age (year) | 63 | 62 | 68 |
| Male sex (%) | 79 | 76.4 | 79.9 |
| Europe (%) | 100 | 49.8 | 52.5 |
| Weight (kg) | 85.5 | 91 | NA |
| eGFR (mL/min/1.73 m2) | 83.4 | 88 | 63.7 |
| HbA1c (%) | 5.7 | 8 | NA |
| Medical history | |||
| Myocardial infarction (%) | 9.5 | 100 | 72.5 |
| Stroke (%) | 2.5 | 6.1 | 10.7 |
| Diabetes (%) | NA | 100 | 49.9 |
| Heart failure (%) | NA | 21.5 | 46.1 |
| Baseline medication | |||
| ACE inhibitor/ARB use (%) | 91.8 | 84.1 | 84.6 |
| Beta-blockers use (%) | 89.9 | 82.2 | 96 |
| Statins use (%) | 94.9 | 91.1 | 83.5 |
| Outcomesa | |||
| Follow-up duration (year) | 1 | 4.2 | 1.5 |
| CV death/hospitalization for HF (%) | 2.6 | 10.5 | 20.9 |
| MACE (%) | 3.6 | 17.8 | NA |
| CV death (%) | 1.2 | 5.3 | 12.5 |
| All cause death (%) | 1.7 | 10.3 | 15.2 |
| Hospitalization for HF | 1.6 | 6.3 | 12.7 |
aTo ensure maximum comparability with the DAPA-MI placebo group, the event rates reported above in the DECLARE-TIMI 58 and DAPA-HF are derived from the placebo groups of each respective subgroup.
| Trials . | DAPA-MI . | DECLARE-TIMI 58 . | DAPA-HF . |
|---|---|---|---|
| Target population | AMI | ASCVD + DM | HF |
| Subgroup | Placebo | Previous MI | Ischaemic origin |
| Number of patents in the subgroup | 1998 | 3584 | 2674 |
| Demographics | |||
| Age (year) | 63 | 62 | 68 |
| Male sex (%) | 79 | 76.4 | 79.9 |
| Europe (%) | 100 | 49.8 | 52.5 |
| Weight (kg) | 85.5 | 91 | NA |
| eGFR (mL/min/1.73 m2) | 83.4 | 88 | 63.7 |
| HbA1c (%) | 5.7 | 8 | NA |
| Medical history | |||
| Myocardial infarction (%) | 9.5 | 100 | 72.5 |
| Stroke (%) | 2.5 | 6.1 | 10.7 |
| Diabetes (%) | NA | 100 | 49.9 |
| Heart failure (%) | NA | 21.5 | 46.1 |
| Baseline medication | |||
| ACE inhibitor/ARB use (%) | 91.8 | 84.1 | 84.6 |
| Beta-blockers use (%) | 89.9 | 82.2 | 96 |
| Statins use (%) | 94.9 | 91.1 | 83.5 |
| Outcomesa | |||
| Follow-up duration (year) | 1 | 4.2 | 1.5 |
| CV death/hospitalization for HF (%) | 2.6 | 10.5 | 20.9 |
| MACE (%) | 3.6 | 17.8 | NA |
| CV death (%) | 1.2 | 5.3 | 12.5 |
| All cause death (%) | 1.7 | 10.3 | 15.2 |
| Hospitalization for HF | 1.6 | 6.3 | 12.7 |
| Trials . | DAPA-MI . | DECLARE-TIMI 58 . | DAPA-HF . |
|---|---|---|---|
| Target population | AMI | ASCVD + DM | HF |
| Subgroup | Placebo | Previous MI | Ischaemic origin |
| Number of patents in the subgroup | 1998 | 3584 | 2674 |
| Demographics | |||
| Age (year) | 63 | 62 | 68 |
| Male sex (%) | 79 | 76.4 | 79.9 |
| Europe (%) | 100 | 49.8 | 52.5 |
| Weight (kg) | 85.5 | 91 | NA |
| eGFR (mL/min/1.73 m2) | 83.4 | 88 | 63.7 |
| HbA1c (%) | 5.7 | 8 | NA |
| Medical history | |||
| Myocardial infarction (%) | 9.5 | 100 | 72.5 |
| Stroke (%) | 2.5 | 6.1 | 10.7 |
| Diabetes (%) | NA | 100 | 49.9 |
| Heart failure (%) | NA | 21.5 | 46.1 |
| Baseline medication | |||
| ACE inhibitor/ARB use (%) | 91.8 | 84.1 | 84.6 |
| Beta-blockers use (%) | 89.9 | 82.2 | 96 |
| Statins use (%) | 94.9 | 91.1 | 83.5 |
| Outcomesa | |||
| Follow-up duration (year) | 1 | 4.2 | 1.5 |
| CV death/hospitalization for HF (%) | 2.6 | 10.5 | 20.9 |
| MACE (%) | 3.6 | 17.8 | NA |
| CV death (%) | 1.2 | 5.3 | 12.5 |
| All cause death (%) | 1.7 | 10.3 | 15.2 |
| Hospitalization for HF | 1.6 | 6.3 | 12.7 |
aTo ensure maximum comparability with the DAPA-MI placebo group, the event rates reported above in the DECLARE-TIMI 58 and DAPA-HF are derived from the placebo groups of each respective subgroup.
Summary
The DAPA-MI trial was an important study. The results did not show a benefit of early initiation of SGLT2 inhibitors on MACE or HHF in low-risk MI patients without T2DM or known HF. However, the trial did affirm the safety of an SGLT2 inhibitor, dapagliflozin, in the MI population and its positive role in improving cardiometabolic health. Therefore, dapagliflozin could be an effective early treatment option for patients with pre-diabetes or those facing weight management challenges. The ongoing EMPACT-MI trial of empagliflozin, which will include higher-risk MI patients with T2DM and with clinical signs of incipient HF, may help further define the role of SGLT2 inhibitors in the MI arena.
Conflict of interest: E.T.K. reports receiving lecture fees from Astellas, AstraZeneca, Boehringer Ingelheim, Eli-Lilly, Kowa Co. Ltd, Ono Pharmaceutical and Tanabe-Mitsubishi, and research fund (outside of the current work) from Ono Pharmaceutical and Tanabe-Mitsubishi. K.O. reports receiving research funds from Boehringer Ingelheim and lecture fees from Astellas, AstraZeneca, Tanabe-Mitsubishi, Kowa, Daiichi Sankyo, and Boehringer Ingelheim. B.S.L. reports consulting fees from Janssen R&D, Idorsia, and CSL Behring.
Data availability
No new data were generated or analysed in support of this article.
