The use of SGLT2 inhibitors was associated with significant reduction in CV outcomes in patients with and without diabetes who had pre-existing CV disease or CV risk factors [1-2]. In addition, SGLT2 inhibitors exert reno-protective effects in patients with broad spectrum of underlying kidney disease and renal function at baseline [3]. However, one large category of patients in whom SGLT2 inhibitors were not adequately studied was the setting of AMI. Unfortunately, subjects with recent MI within 6 months were excluded from trials of SGLT2 inhibitors [4,5]. In fact, despite marked progress that was achieved in management of AMI, there was still unmet need to find an effective and safe therapy for prevention of its complications, including mortality [5]. Two recent randomized trials, the DAPA-MI and EMPACT-MI, were designed to examine the effects of dapagliflozin and empagliflozin, respectively on CV events and mortality if initiated shortly (within days) after AMI [6,7]. The main purpose of this article is to provide an appraisal of early use of dapagliflozin and empagliflozin after an AMI.

The DAPA-MI Trial  

The DAPA-MI was a randomized, double-blind, placebo-controlled trial conducted in Sweden and UK [6]. Patients presenting with AMI were randomized to dapagliflozin 10 mg/d (n=2,019) or matching placebo (n=1,998) on top of standard care within a median time of 3 days from hospital admission [6]. Patients’ characteristics are depicted in table 1. All patients should have evidence of impaired left ventricular systolic function (LVSF) either by imaging or by presence of Q wave MI on an electrocardiogram [6]. Most patients (73%) had left ventricular ejection fraction (LVEF) < 50% on admission and 72% had ST-elevation MI [6]. Importantly, patients with diabetes were excluded from the DAPA-MI trial [6].  Using the win ratio analysis approach, the primary outcome was the hierarchical composite of the following 7 outcomes: death, HHF, nonfatal MI, atrial fibrillation/flutter, type 2 diabetes, NYHAFC at the last visit, and reduction in body weight of ≥5% [6]. The key secondary outcome was the same as the primary outcome after exclusion of the body weight component [6]. After a median duration of follow-up of 11.6 months, there were 32.9% wins for dapagliflozin versus 24.6% wins for placebo yielding a win ratio of 1.34 (95% CI, 1.20 to 1.50, P< 0.001) [6]. The amelioration in the primary outcome was primarily driven by the benefits achieved in weight loss, incident type 2 diabetes, and to a lesser extent by NYHA functional status [6]. Thus, compared with placebo, in the dapagliflozin arm, there was weight loss of -1.65 kg (95% CI, -2.12 to -1.18) and reduction of incident type 2 diabetes by 47% (HR 0.53, 95% CI, 0.36 to 0.77) [6]. Furthermore, there was a trend towards decrease frequency of adjudicated HHF; HR 0.83 (95% CI, 0.50 to 1.39), stroke; HR 0.61 (95% CI, 0.28 to 1.34), and atrial fibrillation/flutter; HR 0.88 (95% CI 0.36-0.77) with dapagliflozin [6]. However, in the dapagliflozin group, there was also a trend toward increased all-cause death (HR 1.22, 95% CI, 0.77 to 1.92), CV death (HR 1.15, 95% CI, 0.66 to 2.01), all-cause hospitalization (HR 1.12, 95% CI, 0.98 to 1.29), and non-fatal MI (HR 1.11, 95% CI, 0.72 to 1.71) [6]. Regarding the key secondary outcome, after excluding the outcome of weight loss, the win ratio in favor of dapagliflozin was attenuated but still statistically significant at 1.20 (95% CI, 1.04 to 1.40; P =0.015) [6]. The above results remained unchanged in various patients’ subgroups classified by age, gender, weight, baseline LVEF and troponin levels, ST-elevation versus non-ST-elevation MI, and other possible pertinent factors (e.g. type of background therapy) [6].

The EMPACT-MI trial

The most recent and largest randomized trial that examined the effects of SGLT2 inhibitor on CV outcomes after AMI was the EMPACT-MI trial [7]. The latter included 6,522 hospitalized patients for AMI within 14 days prior to randomization and had either of a new LVEF <45% and/or congestion symptoms (e.g. dyspnea) or signs (e.g. pulmonary rales on auscultation) [7]. Patients’ characteristics are depicted in table 1. Patients were randomized into 2 groups to receive empagliflozin 10 mg qd (n=3,260) or matching placebo (n=3,262) [7]. The primary outcome of the EMPACT-MI trial was a composite of first HHF or death from any cause. After a median follow-up of 17.9 months, there was no significant difference in the primary outcome between the empagliflozin group and placebo group, 8.2% and 9.2%, respectively (HR 0.90; 95% CI, 0.76 to 1.06, P=0.21) [7]. Patients randomized to empagliflozin had lower rates of the first HHF; HR 0.77 (95% CI, 0.60-0.98), and total number of HHF (i.e. first and recurrent); rate ratio 0.67 (95% CI, 0.51 to 0.89) [7]. Yet, there was no significant effect of empagliflozin on the second component of the primary outcome which was all-cause death; HR 0.96 (95% CI, 0.78 to 1.19) [7]. Likewise, empagliflozin did not decrease CV death (a secondary outcome); HR 1.03 (95% CI, 0.81 to 1.31) [7]. Results were consistent in different subgroups classified by age, gender, diabetes status, baseline LVEF, median time from index MI to randomization (≤5 days vs >5 days), use of diuretics and angiotensin-receptor antagonists [7]. 

Safety of SGLT2 inhibitors after acute myocardial infarction

In both the DAPA-MI and EMPACT-MI trials, the SGLT2 inhibitors were mostly initiated in the hospital with no unexpected adverse effects [6,7]. During the duration of both trials, there was no increased incidence of ketoacidosis, acute and contrast-induced renal injury, worsening renal function, hypovolemia, or hypoglycemia with dapagliflozin or empagliflozin [6,7].  Rates of drug discontinuation due to adverse effects were not increased with empagliflozin compared with placebo (3.8% in each group) [7]. Meanwhile, in the DAPA-MI trial, 2.6% of patients discontinued dapagliflozin due to adverse effects compared with 1.8% who discontinued placebo [6].

Comparison of the DAPA-MI and EMPACT-MI trials

As seen in table 1, compared with the DAPA-MI trial, the EMPACT-MI trial is larger, longer-term, and included patients with higher CV risk at baseline.  In fact, patients in the EMPACT-MI trial had to have at least one additional clinical risk factor, termed enrichment factor that was known to be associated with HHF or death. Such enrichment factor included age ≥ 65 years, new LVEF <35%, type 2 diabetes, a history of myocardial infarction, atrial fibrillation, three-vessel coronary artery disease or peripheral vascular disease [7]. Moreover, while patients with diabetes were excluded from the DAPA-MI study, 31.7% of patients in the EMPACT-MI had type 2 diabetes [7]. Therefore, the number of events was much higher in the EMPACT-MI trial than the DAPA-MI trial.

Clinical implications of DAPA-MI and EMPACT-IM trials

The DAPA-MI trial showed that the major benefits of using dapagliflozin after AMI were the decrease incidence of type 2 diabetes by 47% and weight reduction by 1.65 kg. However, there was a concerning tendency toward increase in all-cause death and CV death, and non-fatal MI with dapagliflozin [6]. Moreover, dapagliflozin did not significantly decrease HHF as previously demonstrated in patients with type 2 diabetes and high CV risk or patients with heart failure with and without diabetes [8-10]. In patients with higher CV risk, empagliflozin in the EMPACT-MI trial was shown to decrease HHF but failed to decrease all-cause and CV mortality. Accordingly, until more data become available, in patients with AMI, the use of dapagliflozin should be avoided, whereas empagliflozin may be used in the high-risk group of patients such as those with diabetes, or those presenting with congestion. 

Available data suggests that dapagliflozin if initiated within median time of 3 days after AMI significantly decreased incident diabetes by 47% and mean weight by 1.6 kg compared with placebo. However, there was a trend towards increase in all-cause death, CV death, or non-fatal MI with dapagliflozin [6]. Empagliflozin, initiated within 14 days after acute MI did not significantly decrease the composite outcome of first HHF or death from any cause [7]. However, empagliflozin decreased the first HHF and total number of HHF by 23% and 33%, respectively. No tendency towards increase in CV events were shown with empagliflozin. Based on the above, dapagliflozin should be avoided in the setting of acute MI. Meanwhile, empagliflozin may be used shortly after AMI to decrease HHF. Further studies are needed to help define the best candidates for empagliflozin as well as the optimum timing to start this SGLT2 inhibitor following an AMI.

Conflict of Interest

The author does not have any conflict of care to report.

Table 1: Comparison of DAPA-MI and EMPACT-MI trials.

Abbreviations: LVEF: left ventricular ejection fraction, STEMI: ST-elevation myocardial infarction, NSTEMI: non-ST elevation myocardial infarction, SGLT2: sodium-glucose co-transporter 2, HHF: hospitalization for heart failure, MI: myocardial infarction, CV cardiovascular.

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