SGLT2 inhibitors block sodium and glucose reabsorption in the proximal tubule, causing glucosuria and natriuresis. This osmotic diuresis lowers plasma and interstitial fluid volume, thereby reducing cardiac preload [10]. For example, empagliflozin reduced blood and plasma volume by about a few percent within two weeks [10]. Dapagliflozin also causes a transient rise in urine sodium and volume, especially in the first few days of therapy [10, 11]. Importantly, these drugs preferentially remove interstitial fluid without sharply depleting intravascular volume [10]. In other words, SGLT2 inhibition may reduce tissue congestion while preserving arterial filling.

Volume reduction with SGLT2 inhibition does not trigger a sympathetic or renin–angiotensin system activation [10, 11]. In animal models, SGLT2 inhibitors even suppress sympathetic nerve activity [11]. The lowered blood pressure with SGLT2i does not raise heart rate [11]. In HF trials, for instance, empagliflozin lowered SBP modestly without causing hypotension or tachycardia [10, 11]. This results in mild unloading of the heart. Cardiac Magnetic resonance imaging (MRI) studies confirm reduced left ventricular end-diastolic volume after SGLT2 therapy, implying lower preload [10]. Thus, SGLT2 inhibitors produce a gentle diuresis and natriuresis that offloads the heart without the usual neurohormonal stress of traditional diuretics [10, 11].

Another consequence is a “diuretic-sparing” synergy when SGLT2i are combined with loop diuretics. Adding an SGLT2 inhibitor in HF patients already on loop diuretics boosts natriuresis beyond either drug alone [11]. This means lower loop doses may achieve similar decongestion, potentially reducing side effects.

In addition, volume effects, SGLT2 inhibitors exert direct metabolic and cellular actions on the heart. One key hypothesis is inhibition of the myocardial Na⁺/H⁺ exchanger (NHE-1). Experimental data show that empagliflozin suppresses cardiomyocyte NHE-1 activity, thus lowering cytosolic Na⁺ and Ca²⁺ concentrations [12]. High intracellular Na⁺ in failing hearts drives calcium overload and impaired relaxation, so SGLT2mediated NHE-1 blockade can improve ion homeostasis. Lower cytosolic Ca²⁺ reduces energy expenditure on ion pumps, while increased mitochondrial Ca²⁺ boosts adenosine triphosphate (ATP) production [12]. In effect, SGLT2 inhibitors may unload the cardiomyocyte energy burden via NHE-1 modulation.

Another major effect is a shift in cardiac fuel utilization toward ketone bodies. SGLT2 inhibitors raise circulating ketone levels by promoting lipolysis and altering the insulin/glucagon ratio [13]. In practice, $\beta$-hydroxybutyrate and other ketones double from baseline during sustained SGLT2 therapy [13]. The failing heart can readily oxidize ketones. Indeed, ketone bodies have been termed a “super-fuel” because they produce more ATP per unit oxygen than free fatty acids [13].

The combination of NHE-1 inhibition and increased ketone availability yields a potent energetic benefit. SGLT2 blockade appears to improve mitochondrial function and ATP generation in cardiomyocytes [14, 15, 16]. In one mitochondrial study, SGLT2i elevated coenzyme Q oxidation and enhanced the thermodynamics of ATP hydrolysis [14]. Thus, the heart muscle becomes more efficient. These adaptations may improve cardiac output and myocardial energetics in the acute post-infarction setting [12, 13].

In the kidney, SGLT2 inhibitors trigger TGF that rapidly alters glomerular hemodynamics [17]. By blocking glucose and sodium reabsorption in the proximal tubule, more sodium is delivered to the macula densa [11]. This signals the afferent arteriole to constrict. The net effect is lower intraglomerular pressure and reduced single-nephron glomerular filtration rate (GFR) [7, 11].

Clinically, this mechanism produces a small but immediate estimated glomerular filtration rate (eGFR) decline after starting SGLT2 inhibition. Trials report an average eGFR fall of ~3–6 mL/min/1.73 m² within the first 1–4 weeks [7]. This change is hemodynamic, not nephrotoxic; it reflects the afferent vasoconstriction of TGF. Importantly, once patients are on therapy, GFR stabilizes or even declines more slowly than expected. Long-term, SGLT2 inhibitors slow the rate of kidney function loss, likely by protecting glomeruli from chronic hyperfiltration stress [7].

So, the initial eGFR drop is a reversible adjustment. As pressure inside the glomerulus normalizes, filtration equilibrates. In the context of STEMI and volume management, understanding TGF helps distinguish a harmless SGLT2i-mediated dip from true contrast nephropathy. Overall, TGF explains why SGLT2 inhibitors cause a predictable eGFR dip that usually recovers or stabilizes [7, 11].

To summarize, SGLT2 inhibitors unload the heart by diuresis without reflex neurohormonal activation, reprogram myocardial metabolism for higher efficiency via NHE1 inhibition and ketones, and favorably reset renal hemodynamics through TGF. These mechanisms support early SGLT2i use post-MI by reducing congestion and protecting the kidney and myocardium [7, 10, 12].

The Dapagliflozin in Myocardial Infarction (DAPA-MI) trial (n = 4017, 2 countries) assessed dapagliflozin in STEMI patients with impaired LV function or Q-wave MI, without diabetes. Patients with eGFR 20 mL/min/1.73 m² or Chronic HF were excluded. Over a median follow-up of 11.6 months, safety was evaluated through serious adverse events leading to hospitalization or treatment discontinuation. Dapagliflozin did not increase rates of adverse events compared with placebo, with particular reassurance regarding hemodynamic stability, renal function, and infections [4].

The Empagliflozin after Acute Myocardial Infarction (EMPACT-MI) trial (n = 6522, 22 countries) tested empagliflozin in patients at high risk of HF after MI. Exclusion criteria included eGFR 20 mL/min/1.73 m² and SBP 100 mmHg, while inclusion of those with eGFR 20–60 mL/min/1.73 m² was added as an enrichment factor along with others. Over a median 17.9-month follow-up, adverse events were assessed broadly, with prespecified interest in AKI, volume depletion, and hypotension. Empagliflozin was well tolerated, with adverse event rates similar to placebo and no signal for renal or hemodynamic instability [5].

The Empagliflozin to prevent worsening of left ventricular volumes and systolic function after myocardial infarction (EMPRESS-MI) trial (n = 105, Austria) studied empagliflozin initiated within 72 h of PCI in STEMI patients. Patients with severe renal dysfunction (eGFR 20 mL/min/1.73 m²) or hypotension were excluded. With a median follow-up of 5.5 months, the safety evaluation included prespecified renal and hemodynamic endpoints, as well as adverse events of special interest. No excess in creatinine doubling, AKI, or hypotension was observed compared with placebo, underscoring the renal and hemodynamic safety of early empagliflozin initiation in acute STEMI care [18].

The Empagliflozin in Acute Myocardial Infarction (EMMY) trial (n = 476, UK) also evaluated empagliflozin initiated within 72 h post-PCI in STEMI patients, excluding those with eGFR 45 mL/min/1.73 m² or BP 110/70 mmHg. Over a median follow-up of 6 months, safety endpoints included adverse events leading to discontinuation, renal function decline, and hemodynamic complications. Empagliflozin was associated with no increase in adverse events, with renal and hemodynamic parameters stable relative to placebo [19].

The Empagliflozin Effects in Patients with ST-Elevation Myocardial Infarction (EMI-STEMI) trial (n = 101, single-center, Iran) compared empagliflozin with placebo in STEMI patients without diabetes. Patients with SBP 100 mmHg or eGFR 30 mL/min/1.73 m² were excluded. Over 6 months, adverse events were rare, with no significant differences between treatment groups, suggesting the short-term safety of empagliflozin in this lower-powered study [20]. Summary of these trials is given in Table 1 (Ref. [4, 5, 18, 19, 20]).

Taken together, these five randomized trials consistently demonstrate the safety of initiating SGLT2 inhibitors in the acute and subacute STEMI setting. Across multinational mega-trials (DAPA-MI, EMPACT-MI) and smaller studies (EMPRESS-MI, EMMY, EMI-STEMI), adverse event rates were comparable to placebo. Importantly, renal and hemodynamic outcomes showed no excess risk, even when therapy was initiated within 72 h of PCI. Events such as AKI, hypotension, or volume depletion were infrequent and not significantly different between groups. Infectious complications, including urinary tract or genital infections, were uncommon and did not exceed placebo rates. Similarly, metabolic adverse events such as ketoacidosis or hypoglycemia were not observed in excess. Mortality outcomes were comparable across arms, reinforcing the neutral-to-reassuring safety profile. Collectively, these findings suggest that early use of SGLT2 inhibitors post-STEMI is feasible and well tolerated in carefully selected patients. Nevertheless, the exclusion of those with severely impaired renal function or significant hemodynamic instability indicates that results should not be generalized to the most vulnerable post-MI populations. In summary, the uniformity of safety signals across trials strengthens confidence in therapeutic use and directs attention toward evaluating efficacy in diverse, real-world patient groups.

A key prerequisite for starting SGLT2 inhibitors during STEMI is ensuring hemodynamic stability. Key eligibility criteria include a SBP of at least 100 mmHg and a Killip class $\le$II, with no ongoing escalation of inotropes or vasopressors, as these indicate underlying instability. In patients with borderline SBP (e.g., 90–100 mmHg), initiation should not be automatically pursued or abandoned; instead, temporary withholding or dose reduction of loop diuretics may be considered to minimize volume-related hypotension, with reassessment after 12–24 h once hemodynamic parameters have stabilized. Before initiation, the absence of orthostatic hypotension or postural symptoms should be confirmed. Avoiding hypotensive episodes after starting therapy is critical, as even transient drops in blood pressure in the setting of an infarcted myocardium may exacerbate ischemia or delay recovery [12, 21, 22, 23].

An early and well-recognized effect of SGLT2 inhibitor therapy is the initial decline in eGFR, typically within 10–20% of baseline, occurring within days of initiation. This change is predominantly hemodynamically mediated via TGF, whereby afferent arteriolar vasoconstriction decreases intraglomerular pressure and mitigates hyperfiltration [12, 24]. The initial decline is considered benign, as it usually stabilizes within 1–2 weeks, and is usually unaccompanied by structural renal injury [21], and is followed by long-term preservation of renal function, with evidence suggesting that SGLT2 inhibitors slow the progression of CKD [21, 22]. Interestingly, this initial decline does not predict long-term renal function loss. Nevertheless, in patients with suspected or evolving AKI, especially those meeting Kidney Disease: Improving Global Outcomes (KDIGO) stage 1 or higher, initiation should be deferred until renal function has stabilized. Furthermore, therapy should be temporarily withheld if serum creatinine rises by more than 30% from baseline within the first week or if there is ongoing volume depletion, such as from vomiting, diarrhea, or excessive diuresis [23].

Many common precipitants of AKI have no direct mechanistic relationship to SGLT2 inhibitor therapy, including conditions such as sepsis, non-obstructive post-renal causes, or anaphylaxis. In contrast, certain AKI risk factors may be favorably influenced by SGLT2 inhibition—through improvements in CKD progression, HF status, and glycemic control—while others may be exacerbated, particularly volume depletion or ketoacidosis. Accordingly, initiation of SGLT2 inhibitors in patients with markedly reduced GFRs is generally discouraged because of the anticipated early decline in GFR. Moreover, temporary cessation of therapy is advised during episodes of acute renal dysfunction, hypovolemia, or hemodynamic instability to minimize potential renal risk.

PCI and diagnostic angiography expose patients to contrast media, which is a known contributor to contrast-associated AKI (CA-AKI). It is also worth mentioning that SGLT2 inhibitors may confer nephroprotection against contrast-induced acute kidney injury (CI-AKI), a major complication of iodinated contrast exposure [25]. Systematic reviews and meta-analyses have shown that chronic SGLT2 inhibitor use is associated with a significant reduction in the incidence of CI-AKI, with reported risk reductions up to approximately 48–63% compared with non-use in type 2 diabetes cohorts undergoing coronary angiography or PCI [25]. This protective effect is thought to derive from favorable hemodynamic modulation—including reduced glomerular hyperfiltration, lowered intraglomerular pressure, improved renal perfusion, and anti-inflammatory/antioxidant actions—which together mitigate tubular stress and oxidative injury following contrast administration [25, 26]. Although these findings are promising, the evidence base remains largely observational, and prospective RCTs are needed to confirm efficacy, clarify optimal timing/duration, and establish these agents within CI-AKI preventive strategies.

To reduce the risk of contrast-associated AKI, SGLT2 inhibitor initiation should ideally be delayed for at least 24–48 h following PCI, particularly in patients with borderline renal function or those who have undergone multiple contrast exposures. Adequate pre- and post-procedural hydration, preferably with isotonic saline, is essential to maintain renal perfusion [27]. Furthermore, concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and nephrotoxic antimicrobials should be avoided to further reduce renal injury risk [25, 28].

SGLT2 inhibitors have been associated with euglycemic diabetic ketoacidosis (euDKA), a rare but potentially life-threatening complication that can develop in the peri-infarct period or during prolonged fasting. Risk factors for euDKA include type 1 diabetes mellitus, where SGLT2 is contraindicated, recent fasting or compliance to ketogenic diets, perioperative stress, and insulin deficiency or omission. At discharge, patients should be counselled on sick-day rules, including the need to withhold SGLT2i during episodes of acute illness, vomiting, or reduced oral intake, and to seek immediate medical attention if symptoms suggestive of DKA occur. Another recognized adverse effect of SGLT2 inhibitors is genital mycotic infection—a consequence of glucosuria creating a favorable environment for pathogenic fungal growth [29]. Clinical data indicate that the risk of genital infections increases approximately 2- to 6-fold among SGLT2i users compared to those not using these agents [29]. Fortunately, most of these infections are mild to moderate in severity and respond well to standard antifungal therapy; routine discontinuation of SGLT2i is not typically required [30].

For inclusion, the patient was required to have an SBP of at least 100 mmHg, ideally measured in both the lying and standing positions. The Killip class was limited to I or II, indicating the absence of pulmonary edema or overt HF. There should have been no escalation in the use of inotropes or vasopressors within the preceding 12–24 h. Additionally, patients were required to maintain an oxygen saturation of $\ge$92% on room air or remain stable on low-flow oxygen support. The ability to tolerate oral medications was also a prerequisite [22].

The renal (tubular reserve) criteria required an eGFR of at least 25 mL/min/1.73 m². Creatinine trends were reviewed, with stability over 24–48 h considered indicative of adequate renal reserve. Initiation was deferred in the presence of a creatinine rise of $\ge$0.3 mg/dL, KDIGO stage 1 or higher AKI, or recent contrast exposure associated with renal deterioration. Patients with known CKD stage 3b were still considered eligible; however, they required close monitoring [22, 33].

Metabolic stability was confirmed by ensuring the absence of ongoing acidosis, defined as a serum bicarbonate level of $\ge$22 mmol/L, a normal anion gap, and no significant urinary or serum ketones. Use was avoided in patients adhering to ketogenic diets or undergoing prolonged fasting, as well as in those with a recent history of diabetic ketoacidosis (DKA) or poorly controlled glycemia [34].

Contraindications to in-hospital initiation included type 1 diabetes mellitus, recent DKA (within the past three months), and a perioperative state such as recent coronary artery bypass grafting (CABG). Additional exclusion criteria were severe dehydration, significant gastrointestinal losses, or hypotensive volume depletion [34], as well as concurrent SGLT2 inhibitor therapy without adequate monitoring. Patients meeting these criteria were excluded from initiation during hospitalization and were advised to be reassessed at a later stage.

The optimal window for initiation was 24–72 h PCI, provided hemodynamic stability had been achieved, diuretic and ACE inhibitor/ARB/mineralocorticoid receptor antagonist (MRA) therapy had been reconciled, and there was no evidence of active renal decline [22, 31, 32]. Coordination with the cardiology, nephrology, and diabetes teams was recommended to ensure safe and effective implementation.

The following “START” checklist (Table 2) may assist clinicians in deciding whether to initiate an SGLT2 inhibitor during the index STEMI admission. It was derived from inclusion/exclusion criteria of contemporary randomized trials (DAPA-MI, EMPACT-MI, EMMY, EMPRESS-MI) and augmented by expert clinical judgment. Because large outcome studies such as EMPA-STEMI and the follow-up phase of EMPRESS-MI are still in progress, the thresholds below remain interim guidance rather than a formal guideline recommendation. These criteria are intended to guide, not dictate, practice and should be re-evaluated once the results of ongoing trials are published and incorporated into professional society statements.

Monitoring included assessment of vital signs, with blood pressure and heart rate measured every 8–12 h during the first 48 h, and vigilance for postural changes or symptomatic hypotension [33, 35]. Laboratory evaluation comprised creatinine and eGFR measurement at 48–72 h and again at 1–2 weeks, with serum ketones checked if symptoms suggestive of acidosis emerged [34]. Drug interaction precautions involved monitoring for volume depletion when using loop diuretics, with dose reduction if orthostatic symptoms developed [31, 36]. Avoidance of concurrent NSAID use and patient education on sick-day rules prior to discharge [37].