Sodium-glucose co-transporter 2 inhibition and acute myocardial infarction: the DAPA-MI and EMPACT-MI trials

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1. Introduction

Ischemic heart disease, the leading cause of global mortality according to the World Health Organization, claims roughly 16% of lives worldwide [1]. In the United States alone, cardiovascular diseases incurred a staggering annual cost exceeding $407.3 billion (2018-2019) [1]. Fortunately, advancements in treatment strategies have shifted the focus from palliative care for acute myocardial infarction to curative interventions. This progression began with the introduction of streptokinase in 1958, followed by primary coronary intervention in 1977. To date, researchers continue the pursuit of improved treatment options with the primary objective of minimizing myocardial damage post-myocardial infarction. The promising under research novel therapies like sodium-glucose co-transporter 2 inhibitors (SGLT2i), sphingoinse-1-phosphate receptor agonists, and multiple medications for hypercholesterolemia are such examples [2,3].

Dapagliflozin and empagliflozin, the first SGLT2i medications, were initially approved for type 2 diabetes mellitus in January and August of 2014, respectively. Recent trials, however, have also highlighted their potential benefits in cardiovascular disease management. Currently, SGLT2i are indicated for patients with heart failure with reduced ejection fraction, as well as chronic kidney disease with an estimated glomerular filtration rate of ≥ 20–25 mL/min/1.73 m² in both diabetic and non-diabetic patients [4–6]. Notably, empagliflozin stands out as the sole cardiovascular medication approved for heart failure with preserved ejection fraction [7]. While dapagliflozin awaits the Food and Drug Administration approval for this specific indication in the United States, the European Union has already granted its approval based on encouraging trials data [8,9].

Observational studies have consistently demonstrated a reduction in cardiovascular events among patients taking SGLT2i, offering a compelling rationale for their use in the context of acute myocardial infarction. The SGLT2-I AMI PROTECT Registry further bolstered this rationale by revealing that SGLT2i use in type 2 diabetes mellitus patients with acute myocardial infarction correlated with a lower risk of adverse cardiovascular outcomes during hospitalization and long-term follow-up, including a reduced risk of new-onset arrhythmic events during acute myocardial infarction hospitalization [10]. Despite the promising data from observational studies and registries, questions regarding the safety and efficacy of SGLT2i in the acute post acute myocardial infarction setting remained unanswered. Two recent pivotal trials, DAPA-MI trial (Dapagliflozin Effects on Cardiometabolic Outcomes in Patients with an Acute Heart Attack) and the EMPACT-MI trial (Study to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) have shed significant light on the role of SGLT2i in this critical setting [11,12].

2. SGLT2i – a promising new frontier

SGLT channel proteins, first identified in the 1960s by Robert Crane, have emerged as potential game-changers in diabetes, heart failure and chronic kidney disease. While primarily located in the kidneys, SGLT channels are also present in various organs such as the liver, pancreas, intestines, adipose tissue, heart, lungs, thyroid, and even the central nervous system. There are two main SGLT channel types: SGLT1 and SGLT2. SGLT1 is found primarily in the proximal straight tubules (beyond the proximal convoluted tubules) and the small intestine. Conversely, SGLT2 resides in the proximal convoluted tubule, where roughly 97% of glucose reabsorption occurs [13].

SGLTi drugs are designed based on the structure of phlorizin, a natural SGLT1/2 inhibitor. Dapagliflozin and empagliflozin, both SGLT2i, exhibit minimal to no SGLT1 inhibition [14]. Notably, empagliflozin demonstrates a slight edge over dapagliflozin in terms of SGLT2 selectivity. Sotagliflozin, the sole FDA-approved dual SGLT1/2 inhibitor, remains the only medication in its class with most other SGLT1/2 inhibitors still in pre-trial stages [15,16].

Although SGLT2i exert positive effects on various organs beyond glucose control, however, it’s important to acknowledge potential organ-specific side effects, including genitourinary infections, dehydration leading to hypotension, acute kidney injury, temporary hypoglycemia, pancreatitis, euglycemic diabetic ketoacidosis, upper respiratory tract infections, bone fractures, and possible sarcopenia in specific patients [17,18]. The incidence of these side effects is generally less than one percent and it’s crucial to note that multiple confounding variables and pre-existing health conditions can contribute to these side effects [19]. A recent meta-analysis by Shi et al. encompassing 816 trials with 471,038 patients evaluated thirteen different diabetes medication classes including SGLT2i. This analysis identified a significant association between SGLT2i and genital infections (Odds Ratio [OR] 3.3 with 95% confidence interval [CI] 2.88 to 3.78), ketoacidosis (OR 1.27 with 95% CI = 1.01 to 1.61) and amputation (OR 2.05 with 95% CI = 1.44 to 2.98) [20]. While the benefits outweigh the risks for most patients, potential side effects require careful monitoring and patient education.

3. Cardioprotective effects of SGLT2 inhibitors: a multifaceted approach

The cardioprotective effects of SGLT2i extend beyond initial assumptions. It includes potential modulation of metabolic pathways within the heart, dampening of inflammatory processes in coronary arteries, and possible influence on the autonomic nervous system. Earlier hypotheses focused on SGLT2i’s ability to reduce plasma glucose levels, blood pressure, and body weight. The diuretic effect was thought to decrease interstitial volume, thereby lowering cardiac hydrostatic pressure and potentially mitigating ventricular hypertrophy. However, recent studies suggest more direct cardio-protective mechanisms. Costantino et al. and Hussain et al. shed light on metabolic molecular mechanisms within the human heart suggesting that diabetic cardiomyopathy is associated with overexpression of activator protein 1 (AP-1), JunD through peroxisome proliferator-activated receptor-γ (PPAR-γ) [21,22]. Marfella et al. provided clinical confirmation that SGLT2i may act directly on the myocardium, down regulating JunD/PPAR-γ potentially preventing diabetic heart dysfunction [23]. Similarly, Sardu et al. identified an association between the presence of fatty breast tissue, overexpression of SGLT2 and inflammatory cytokines, and downregulation of sirtuins, which inversely correlated with improvements in cardiac performance. These findings suggest that SGLT2i therapy may theoretically reverse these molecular effects, leading to improved left ventricular ejection fraction and myocardial performance index [24].

SGLT2i modulate myocardial metabolism, shifting energy production away from glucose-dependent, less efficient pathways towards the utilization of fatty acids and ketone bodies [25]. Notably, ketones also interact with sirtuin pathways, and exogenous ketone administration has been shown to independently reduce myocardial infarction size [26]. This is also supported by data in humans with type two diabetes mellitus patients that SGLT2i users have smaller myocardial infarction size as per peak troponin levels than non-SGLT2i users [27]. Furthermore, SGLT2 protein expression is found in peri-coronary fat and atherosclerotic plaque. The oxidative properties of SGLT2i may down regulate the inflammatory process within coronary arteries, potentially stabilizing fibrous cap thickness [28]. It has been demonstrated by SGLT2i (empagliflozin) treatment ameliorates myocardial ischemia-reperfusion and reduces acute myocardial infarction as per low gadolinium enhancement by magnetic resonance imaging and triphenyltetrazolium chloride-infarct size in porcine model of left anterior descending artery occlusion [26].

Additionally, SGLT2i exhibit favorable effects on lipid accumulation. In another study, Sardu et al. demonstrated that SGLT2i therapy halved the incidence of major adverse cardiovascular events (MACEs) in diabetic patients with multi-vessel non-obstructive coronary artery lesions [29]. The researchers suggested that introducing SGLT2i therapy after coronary angiography and optical coherence tomography may predict a sixty five percent risk reduction in MACEs at one year follow-up. Notably, SGLT2i use has also been associated with a reduced incidence of intra-stent restenosis events, independent of glycemic control [30]. Finally, the SCAN study suggests an intriguing new dimension to SGLT2i’s impact on the heart. It reveals a possible direct effect on the cardiac and systemic autonomic axis. The study found that SGLT2i reduced the risk of recurrent vasovagal syncope, and that cardiac denervation indexes predicted subsequent recurrence [31].

4. DAPA-MI trial: investigating dapagliflozin for acute myocardial infarction

The DAPA-MI trial included 4017 patients who presented with acute myocardial infarction and exhibited impaired left ventricular systolic function. All participants were free from pre-existing diabetes or chronic heart failure at the time of enrollment. Patients were randomly assigned to receive either dapagliflozin 10 mg once daily (n=2019) or a placebo (n=1998). The study followed participants for a period of one year. The primary endpoint of the DAPA-MI trial was a composite measure encompassing several factors: death from any cause, hospitalization for heart failure, non-fatal myocardial infarction, atrial fibrillation/flutter, new-onset type 2 diabetes mellitus, functional classification according to the New York Heart Association (NYHA) at the final visit, and a minimum body weight reduction of 5% or greater at the final visit. Originally aligned with the primary endpoints of the EMPACT-MI trial, the DAPA-MI trial initially focused on cardiovascular-related deaths and heart failure hospitalizations. However, a late endpoint modification shifted the trial’s focus to cardio-metabolic outcomes. This composite endpoint was analyzed using the win ratio method. A secondary endpoint mirrored the primary endpoint but excluded the body weight component.

While the study did not yield a statistically significant difference in the pre-defined composite endpoints of cardiovascular death or hospitalization for heart failure between the dapagliflozin and placebo groups (hazard ratio [HR] 0.95; 95% CI 0.64 to 1.40), the win ratio analysis revealed a significant advantages for dapagliflozin. Patients receiving dapagliflozin demonstrated a statistically superior outcome (win ratio 1.34; 95% CI 1.20 to 1.50; P<0.001) with regards to the broader range of cardio-metabolic factors included in the primary composite endpoints.

4.1 Critique

It is also important to acknowledge that the low number of heart failure events and deaths in the study limited the ability to draw definitive conclusions about the impact of dapagliflozin on these specific cardiovascular outcomes. This ultimately led researchers to shift their primary analysis from cardiovascular deaths and heart failure related hospitalizations to the win ratio analysis focusing on a broader range of cardio-metabolic factors. A win ratio analysis is a statistical method used in clinical trials when dealing with composite endpoints rather than just a single one. It has its own benefits and limitations depending on each case. Encouragingly, the DAPA-MI trial did not identify any significant safety concerns associated with dapagliflozin use in this patient population. A detailed comparison of the DAPA-MI and EMPACT-MI trials is presented in Table 1.

Table 1: A detailed comparison of the DAPA-MI and EMPACT-MI trials.

Trial	DAPA-MI trial	EMPACT-MI trial
Trial ID	NCT04564742	NCT04509674
Year of Publication	2023	2024
Trial design	Randomized, placebo-controlled, double blind trial	Randomized, placebo-controlled, double blind trial
Inclusion criteria	AMI with concurent impaired LVEF	Age ≥ 18 years and hospitalized within 14 days of acute MI, with either LVEF < 45% or signs/symptoms of congestion or both. + one enrichment factor (a clinical factor that was known to be associated with hospitalization for heart failure or death from any cause)
Exclusion criteria	H/o heart failure. H/o diabetes mellitus	H/o heart failure. Patients already on SGLT2 inhibitors
Sample Size (n)	4017 patients	6522 patients
Primary endpoint	Hierarchical composite (using the win ratio analysis method) of death, hospitalization for heart failure, nonfatal MI, atrial fibrillation/flutter, T2DM, NYHA functional classification at the last visit, and body weight decrease of 5% or greater at the last visit.	Composite of hospitalization for heart failure or death from any cause
Key secondary endpoint	The key secondary outcome was the same hierarchical composite excluding the body weight component.	Pre- specified hierarchical testing strategy related to hospitalizations (total number of HF/nonelective CV/nonelective for any cause/acute MI hospitalization or death from any cause.
Time of initiation of medicine	Within 1-2 weeks	Within 14 days after admission
Dose used	10 mg dapagliflozin	10 mg empagliflozin
Duration of follow up	1 year	Median 17.9 months
Conclusion	Seven level win ratio analysis showed significant wins for dapagliflozin in cardiometabolic outcomes (WR, 1.34; 95% CI, 1.20 to 1.50; P<0.001). The composite of time to cardiovascular death/hospitalization for heart failure in dapagliflozin vs placebo group (HR, 0.95; 95% CI, 0.64 to 1.40).	No significant difference in primary endpoint (hospitalization for heart failure or death from any cause) between empagliflozin and placebo (HR, 0.90; 95% CI, 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point; a. first hospitalization for heart failure (HR, 0.77; 95% CI, 0.60 to 0.98). b. death from any cause (HR, 0.96; 95% CI, 0.78 to 1.19).
Safety profile	No major differences observed between dapagliflozin and placebo groups	No major differences observed between empagliflozin and placebo groups
Limitations	Predefined primary endpoint may not have been sensitive enough, leading to a change in analysis method. Predefined primary endpoint (cardiovascular death/heart failure hospitalization) did not reach statistical significance due to low event rates.	Confidence intervals for individual components of primary endpoint (heart failure hospitalization and death from any cause) were broad

CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NYHA = New York Heart Association; T2DM = type 2 diabetes mellitus; WR = win ratio

While the trial ultimately demonstrated positive results, these were primarily driven by cardio-metabolic factors. This shift in endpoints dilutes the clinical significance of the trial’s findings. Given the pre-established efficacy of dapagliflozin on multiple cardio-metabolic endpoints, incorporating them into the primary composite outcome did not substantially enhance the trial’s clinical relevance. Consequently, we contend that the change in endpoints, rather than the statistical analysis, is the primary factor undermining the clinical importance of the DAPA-MI trial.

5. EMPACT-MI trial: unveiling the efficacy of SGLT2i in acute myocardial infarction

The EMPACT-MI trial enrolled patients aged 18 years or older who had been hospitalized within fourteen days of experiencing an acute myocardial infarction. Inclusion criteria encompassed individuals with either a left ventricular ejection fraction below forty five percent or signs and symptoms suggestive of congestion (or both). Patients with a pre-existing diagnosis of heart failure or those currently taking or planning to take SGLT2i were excluded from the study. A total of 6522 patients were randomly assigned to receive either empagliflozin 10 mg daily (n=3260) or a placebo (n=3262). The median follow-up period was 17.9 months. The primary outcome measure of the study was a composite endpoint encompassing the first occurrence of hospitalization for heart failure or death from any cause. The study demonstrated no statistically significant difference in the primary endpoint between the empagliflozin and placebo groups. The hazard ratio for the primary endpoint was 0.90 (95%CI, 0.76 to 1.06; P = 0.21). In terms of the individual components of the primary endpoints, the cardiovascular related or deaths from all causes was not reduced significantly in empagliflozin group (HR 0.89, 95% CI 0.78 to 1.19). However, the heart failure hospitalization rates were reduced significantly (HR 0.79, 95% CI 0.60 to 0.98) suggesting a 21% decrease of heart failure hospitalization in empagliflozin group. Additionally, analyses of key secondary endpoints and safety profiles of both groups revealed no major discrepancies.

6. Unveiling the full potential of SGLT2 inhibitors in acute MI

While the EMMY (Impact of Empagliflozin on Cardiac Function and Biomarkers of Heart Failure in Patients with Acute Myocardial Infarction) trial demonstrated the ability of empagliflozin to improve biomarkers and cardiac function following acute myocardial infarction, it did not evaluate clinical outcomes [32]. The DAPA-MI and EMPACT-MI trials aimed to bridge this knowledge gap by assessing the impact of SGLT2i on hospitalization, mortality, and other key clinical endpoints. These trials have significantly advanced our understanding of SGLT2 inhibitors in acute myocardial infarction patients.

However, certain design limitations may have obscured their full potential benefits. Early patient enrollment and a lower than expected primary event rate could have contributed to the lack of statistically significant effects on the primary endpoints. Additionally, the COVID-19 pandemic’s influence on hospitalization rates might have further masked potential benefits. Specifically, the EMPACT-MI trial’s design raises concerns about the lack of monitoring for outpatient heart failure symptoms and treatment adjustments, such as intravenous diuretics and medication modifications. A compelling argument can be made for initiating SGLT2i therapy later in the acute myocardial infarction trajectory, potentially after myocardial stunning resolves or even during ischemia. While both trials under consideration incorporated effective standard-of-care treatments to mitigate left ventricular remodeling and reduce the need for additional interventions, it is conceivable that the isolated evaluation of SGLT2i in these settings, absent concomitant therapies, could yield more pronounced benefits akin to those observed in early angiotensin-converting enzyme inhibitor trials in 1990s.

7. Conclusion

Despite the lack of statistically significant benefits observed in DAPA-MI and EMPACT-MI trials, the potential of SGLT2 inhibitors in acute myocardial infarction management remains promising. Future trials, meticulously designed to address the above-mentioned limitations, hold the key to unlocking the full potential of this class of medications. The ongoing exploration for novel therapeutic approaches underscores our commitment to finding effective strategies for acute myocardial infarction patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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