Empagliflozin in the treatment of heart failure

Abstract

Heart failure (HF) affects more than 60 million individuals globally. Empagliflozin is currently approved for type 2 diabetes and chronic HF. Clinical trials have demonstrated that empagliflozin reduces the composite end point of hospitalizations for HF and mortality and improves the quality of life irrespective of left ventricular ejection fraction. Empagliflozin is a once-daily medication with minimal drug–drug interactions and does not require titration. Empagliflozin causes mild weight loss and does not significantly reduce blood pressure. Empagliflozin acts as an enabler for other HF drugs by reducing the risk of hyperkalemia. Empagliflozin is also beneficial for chronic kidney disease which exists commonly with HF. This review outlines the pharmacokinetics, pharmacodynamics, safety, and efficacy of empagliflozin in HF across various sub-groups and settings.

Plain language summary

Empagliflozin is a one-daily medication and is an effective glucose-lowering drug for the treatment of diabetes. In recent years, researchers and medical professionals have discovered that empagliflozin may also be used to treat some cardiovascular conditions. Numerous people suffer from myocardial infarction (‘heart attack’) each year. According to several clinical trials, empagliflozin may slow the course of myocardial infarction and improve clinical outcomes and quality of life. Additionally, empagliflozin does not result in a substantial decrease in blood pressure and can also lead to mild weight loss. Therefore, empagliflozin shows potential as a useful medication for the treatment of myocardial infarction, especially in individuals with diabetes and impaired kidney function.

Plain language summary

Article highlights.

Pharmacokinetics & metabolism

• Empagliflozin is a once-daily medication and does not require titration, unlike other heart failure (HF) medications. There are currently no reports of suspected drug–drug interactions involving empagliflozin.

Pharmacodynamics

• Empagliflozin induces a natriuretic effect, improves myocardial ischemia-reperfusion injury, and reduces infarct size.

Pharmacodynamics

• Empagliflozin causes mild weight loss, acts as an enabler for other HF drugs by reducing the risk of hyperkalemia, and has been linked to a rise in mean left ventricular ejection fraction. Empagliflozin is also beneficial for chronic kidney disease that frequently coexists with HF.

Clinical efficacy

• Empagliflozin reduces the risk of cardiovascular mortality and hospitalization for HF regardless of the baseline systolic blood pressure, the spectrum of HF risk, type 2 diabetes status, background diuretic use, and baseline ejection fraction status.

1. Background

Heart failure (HF) affects 64 million people worldwide and is associated with an approximately 35% 90-day readmission rate [1]. The prevalence of HF is expected to rise by 25% over the next two decades due to the aging population and an increase in risk factors such as type 2 diabetes (T2D), obesity, coronary artery disease, sleep apnea, chronic kidney disease (CKD), hypertension, valvular heart disease, and atrial fibrillation. Historically, diuretics, mineralocorticoid receptor antagonists (MRAs), angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and beta-blockers have been the mainstay treatment for HF with reduced ejection fraction (HFrEF) [2]. For patients with HF with preserved ejection fraction (HFpEF), which constitutes nearly half of all HF-related hospitalizations, no therapy had definitively improved long-term clinical outcomes [3–5].

Recent studies have demonstrated empagliflozin lowers the risk of a composite of adjudicated cardiovascular (CV) mortality and HF hospitalization when compared with the standard of care across the whole ejection fraction (EF) spectrum [6–8]. Hence, empagliflozin is recommended by the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines for the treatment of HF not just for HFrEF but also for HFpEF [9]. This review outlines the pharmacokinetics, pharmacodynamics, safety, and tolerability of empagliflozin. We also discuss the efficacy of empagliflozin in HF across various subgroups and settings.

2. Pharmacology

2.1. Chemistry

Empagliflozin is a chemical member of the C-glucoside family. The chemical name and molecular formula of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-,(1S) and C23H27ClO7, respectively. Empagliflozin has a molecular weight of 450.91 g/mol.

2.2. Pharmacodynamics

In the Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction (EMPIRE HF) Metabolic trial [10], empagliflozin (10 mg) improved indirect metabolic markers of peripheral and hepatic insulin receptor sensitivity in insulin-resistant patients with HF. The benefit was likely brought on by decreased glucose toxicity and decreased body weight, although it is possible that it was caused by improved skeletal muscle and hepatic perfusion [11]. Empagliflozin induces a metabolic shift in fuel utilization away from the energy-inefficient glycose toward the consumption of fatty acids and ketone bodies, which enhances energetics [12,13]. Additionally, empagliflozin improves myocardial ischemia-reperfusion injury and reduces infarct size [14].

A notable natriuretic effect is observed following empagliflozin in HF by a decrease in sodium reabsorption in the proximal tubule via inhibition of SGLT-2 and NHE3 transporters. However, the continuous delivery of sodium (and chloride) to the distal part of the nephron activates compensatory mechanisms to avoid uncontrolled loss of sodium (and water) [15]. Hence, regardless of the acute natriuretic impact associated with empagliflozin, there is contention regarding the extent of this effect and its durability over an extended period. Diabetic kidney disease (DKD) development is promoted by intraglomerular hypertension and hyperfiltration brought on by tubuloglumeral feedback, which ultimately increases the risk and mortality of CV disease. By pharmacologically blocking SGLT2, empagliflozin reduces renal hyperperfusion and hyperfiltration, which may preserve renal function and reduce the risks associated with the progression of DKD [16].

Additionally, empagliflozin was shown to elevate the fractional elimination of glucose and plasma osmolality [17]. These findings indicate that instead of stimulating adequate natriuresis, empagliflozin in patients with HF-induced osmotic diuresis causes enhanced glycosuria [18]. This finding is consistent with the SGLT2 Inhibition in Combination With Diuretics in Heart Failure (RECEDE-CHF) trial outcomes, in which individuals with T2D and HFrEF who used empagliflozin in conjunction with loop diuretics noticed a substantial rise in 24-h urine volume without any rise in urinary sodium [19]. Meanwhile, in another study [20], empagliflozin (10 mg) significantly increased fractional excretion of sodium relative to placebo among individuals having T2D and chronic stable HF, especially when paired with loop diuretics. This natriuretic response culminated in a decrease in blood volume after 14 days. In another study [21], outcomes were compared between patients who had recently experienced volume overload with those who had not. The results did not suggest a predominant involvement of diuresis in facilitating the therapeutic effects of empagliflozin.

In addition to improving the so-called ‘cardiac energy-deficient state’, empagliflozin is linked to substantial enhancements in myocardial phosphocreatine to-ATP ratio, a surge in mean global longitudinal strain and a rise in mean left ventricular EF (LVEF) [22]. Left ventricular volumes were decreased by empagliflozin, including the prediabetics and those with HFrEF or T2D [23]. The effects of empagliflozin (10 mg) on hemodynamic indicators of stiffened arterial walls led to a reduction in the left ventricle's afterload [24]. Empagliflozin also decreased predicted plasma and extracellular volumes in patients with HFrEF [25]. In one study [26], empagliflozin effectively decongested individuals with T2D and acute decompensated HF by reducing plasma volume without increasing the potential for adverse impacts on kidney function [26]. Empagliflozin reduces hepcidin, which improves iron absorption and iron mobilization. This results in an increase in hematocrit [27] and also in improved cardiac iron content and enhanced mitochondrial function. This improvement in cardiac iron during empagliflozin treatment is the best predictor of improvement of LVEF and peak oxygen consumption (VO₂) [28].

In the EMPIRE HF trial [29], empagliflozin did not significantly affect the N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, daily activity level, or health status. In another study [22], empagliflozin improved cardiac function and demonstrated a significant reduction in NT- proBNP levels by 61% from the baseline level. These discrepancies in the empagliflozin's impact on NT-proBNP levels can be explained by the small size insufficient to draw definitive results. Hence, these discrepancies warrant further research with a larger sample size for a more reliable conclusion.

Whereas in the Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction (EMPA-TROPISM) [30], empagliflozin substantially improved quality of life along with improved cardiac functional capacity, as measured by cardiac magnetic resonance [17]. Additionally, short-term therapeutic effects of any drug on LV remodeling are associated with improved outcomes in the long term [31]. Empagliflozin has been shown to decrease LV volumes and enhance LV remodeling using both MRI [32] and 3D-echo [33]. Figure 1 illustrates the potential mechanisms of empagliflozin.

Figure 1.

Potential mechanism of actions of empagliflozin.

2.3. Pharmacokinetics & Metabolism

The plasma concentration of empagliflozin increases by 18%, 20%, and 66% in those with mild, moderate, and severe kidney dysfunction, respectively. Reduced kidney elimination of empagliflozin was considered to be responsible for these variations. However, individuals with renal impairment are not required to alter empagliflozin dose [34]. The maximum plasma concentration of empagliflozin increased by 36.8%, 26.4%, and 22.1% in mild, moderate, and severe hepatic impairment, respectively [35]. Considering that these elevations in empagliflozin levels remained lower than two-times in individuals with various stages of hepatic dysfunction, empagliflozin doses are not required to be adjusted in those with impaired liver function [35]. There are currently no reports of suspected drug–drug interactions involving empagliflozin [36,37]. Additionally, among all the medicines that could be prescribed to patients with HF, no clinically pertinent interactions involving empagliflozin have been observed. This includes empagliflozin in conjunction with digoxin, verapamil, or ramipril in healthy subjects [38] or diuretics (hydrochlorothiazide and torsemide) [39].

3. Clinical efficacy

The clinical efficacy of empagliflozin in the treatment of HF has been established in several clinical trials. The results of these studies are summarized in Table 1.

Table 1.

Summary of clinical trials with empagliflozin – cardiovascular outcomes.

	EMPA-REG OUTCOME [40]	EMPEROR-Reduced [41]	EMPEROR-Preserved [42]	EMPA-RESPONSE-AHF [43]	EMPULSE [44]
Year	2015	2020	2021	2022	2022
Randomized	Yes	Yes	Yes	Yes	Yes
Double-blinded	Yes	Yes	Yes	Yes	Yes
Placebo-controlled	Yes	Yes	Yes	Yes	Yes
Study drug doses	10, 25 mg/day	10 mg/day	10 mg/day	10 mg/day	10 mg/day
No. of randomized patients	7020	3730	5988	80	530
Follow-up time	3.1 years	16 months	26.2 months	60 days	90 days
Age	≥18	≥18	≥18	≥18	≥18
CV mortality	3.7% (EMPA) vs. 5.9% (placebo); (HR: 0.62; 95% CI: 0.49–0.77)	10.0% (EMPA) vs. 10.8% (placebo); (HR: 0.92; 95% CI: 0.75–1.12)	7.3% (EMPA) vs. 8.2% (placebo); (HR: 0.91; 95% CI: 0.76–1.09)	–	–
All-cause mortality	5.7% (EMPA) vs. 8.3% (placebo); (HR: 0.68; 95% CI: 0.57–0.82)	13.4% (EMPA) vs. 14.2% (placebo); (HR: 0.92; 95% CI: 0.77–1.10)	14.1% (EMPA) vs. 14.3% (placebo); (HR: 1.00; 95% CI: 0.87–1.15)	10% (EMPA) vs. 33% (placebo); p = 0.014	10% (EMPA) vs. 33% (placebo); p = 0.014
HF hospitalizations	2.7% (EMPA) vs. 4.3% (placebo); (HR: 0.65; 95% CI: 0.50–0.85)	13.2% (EMPA) vs. 18.3% (placebo); (HR: 0.69; 95% CI: 0.59–0.81)	8.6% (EMPA) vs. 11.8% (placebo); (HR: 0.71; 95% CI: 0.60–0.83)	10% (EMPA) vs. 33% (placebo); p = 0.014	5.3% (EMPA) vs. 4.5% (placebo); (OR: 1.179; 95% CI: 0.534–2.601)

CI: Confidence interval; CV: Cardiovascular; EMPA: Empagliflozin; HR: Hazard ratio; HF: Heart failure.

3.1. EMPA-REG OUTCOME

The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) evaluated the impact of empagliflozin (10 or 25 mg) against placebo on CV events in individuals with T2D and existing cardiovascular disease (CVD) [40]. Empagliflozin was associated with a significant decrease in the composite results (death from CV causes, nonfatal myocardial infarction or nonfatal stroke) (HR: 0.86; 95% CI: 0.74–0.99; p = 0.04), CV mortality (HR: 0.62; 95% CI: 0.49–0.77; p < 0.001) and hospitalization for HF (HR: 0.65; 95% CI: 0.50–0.85; p = 0.002).

The post hoc studies of the EMPA-REG OUTCOME trial demonstrated that in patients with HF, empagliflozin reduces the risk of CV mortality and HHF regardless of the baseline use of loop diuretics [with (HR: 0.59; 95% CI: 0.38–0.91), without (HR 0.98; 95% CI: 0.51–1.88)] [45], baseline systolic blood pressure (SBP) [1.65 (1.12–2.44); 1.04 (0.71–1.53); 1.11 (0.77–1.60); 1.43 (0.88–2.30)] for SBP <120 mmHg, 130–<140 mmHg, 140–<160 mmHg and >160 mmHg, respectively)] [46], and the spectrum of HF risk [low-to-high (HR: 0.71; 95% CI: 0.52–0.96), high (HR: 0.52; 95% CI: 0.36–0.75), very high (HR: 0.55; 95% CI: 0.30–1.00)] [47].

3.2. EMPEROR-Reduced

The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) randomized 3730 participants (with and without T2D) with New York Heart Association (NYHA) class II–IV HF and an EF of 40% or less to either the empagliflozin 10 mg or a placebo [41]. Empagliflozin significantly reduced the rate of CV mortality and worsening HF (HR: 0.75; 95% CI: 0.65–0.86; p = 0.001), which was primarily driven by the reduction in HHF (HR: 0.70; 95% CI: 0.58–0.85; p = 0.001). Numerous post-hoc studies have shown that in patients with HFrEF empagliflozin improves the risk of CV mortality and HHF regardless of T2D status [with (HR: 0.72; 95% CI: 0.60–0.87), without (HR: 0.78; 95% CI: 0.64–0.97)] [48], baseline use of sacubitril/valsartan [with (HR: 0.64; 95% CI: 0.45–0.89, p = 0.009), without (HR: 0.77; 95% CI: 0.66–0.90, p = 0.0008)] [49], baseline NT-proBNP levels (HR: 0.75; 95% CI: 0.65–0.86) [50] and baseline SBP (p = 0.0015) [51]. One study [52] assessed the effect of empagliflozin across a range of baseline health statuses which was determined using the Kansas City Cardiomyopathy Questionnaires-Clinical Summary Score (KCCQ-CSS). Empagliflozin reduced the rate of CV mortality or HHF regardless of baseline KCCQ-CSS tertiles [HR: 0.83 (0.68–1.02), HR: 0.74 (0.58–0.94) and HR: 0.61 (0.46–0.82) for <62.5, 62.6–85.4 and ≥85.4 score tertiles, respectively)]. Additionally, empagliflozin significantly improved the quality of life [1.88 (0.69–3.08), 1.43 (0.11–2.75) and 1.19 (0.27–2.64); p < 0.05)] at 3, 8 and 12 months, respectively [52]. Table 2 summarizes the results of these post-hoc studies.

Table 2.

Summary of post-hoc studies of EMPEROR-reduced and EMPEROR-preserved trials.

Post-hoc study	Type of HF	Median follow-up	Rationale of subgroup analysis	No. of patients	Primary composite outcome†	Ref.
Anker 2021	HFrEF	16 months	Effect of diabetes status on EMPA	With diabetes: 1856 Without diabetes: 1874	0.72 (0.60–0.87) 0.78 (0.64–0.97)	[48]
Packer 2021	HFrEF	16 months	Effect of sacubitril/valsartan on EMPA	With sacubitril/valsartan: 3003 Without sacubitril/valsartan: 727	0.64 (0.45–0.89) 0.77 (0.66–0.90)	[49]
Januzzi 2021	HFrEF	23 months	Effect of baseline NT-proBNP level on EMPA	Total: 3728	0.75 (0.65–0.86)	[50]
Böhm 2021	HFrEF	16 months	Effect of baseline SBP level on EMPA	SBP >130 = 1047 SBP 110–130 = 1755 SBP <110 = 928	0.82 (0.62–1.09) 0.71 (0.58–0.87) 0.78 (0.61–1.00)	[51]
Butler 2021	HFrEF	12 months	Effect of baseline health status on EMPA	Tertile <62.5 = 1220 Tertile 62.6–85.4 = 1253 Tertile ≥85.4 = 1232	0.83 (0.68–1.02) 0.74 (0.58–0.94) 0.61 (0.46–0.82)	[52]
Filippatos 2022	HFpEF	12 months	Effect of diabetes status on EMPA	With diabetes: 2938 Without diabetes: 3050	0.79 (0.67, 0.94) 0.78 (0.64, 0.95)	[53]
Butler 2021	HFpEF	26.2 months	Effect of diuretics on EMPA	With diuretic: 4636 Without diuretic: 1179	0.81 (0.70–0.93) 0.72 (0.48–1.06)	[54]
Butler 2022	HFpEF	12 months	Effect of baseline health status on EMPA	Tertile <62.5 = 1956 Tertile 62.6–85.4 = 1967 Tertile ≥85.4 = 2019	0.83 (0.69–1.00) 0.70 (0.55–0.88) 0.82 (0.62–1.08)	[55]
Böhm 2023	HFpEF	26.2 months	Effect of baseline SBP level on EMPA	SBP >130 = 3118 SBP 110–130 = 2415 SBP <110 = 455	0.82 (0.68–0.98) 0.78 (0.63–0.96) 0.67 (0.43–1.03)	[56]
Butler 2022	HFrEF/HFpEF	21 months	Effect of EF on EMPA	EF <25% = 999 EF 25–34% = 2230 EF >35–44% = 1272 EF 45–54% = 2260 EF 55–64% = 2092 EF ≥65 = 865	0.77 (0.60–0.98) 0.72 (0.59–0.87) 0.82 (0.63–1.05) 0.74 (0.61–0.91) 0.78 (0.62–0.97) 0.98 (0.68–1.40)	[57]

^†Hospitalization for heart failure or cardiovascular mortality.

Outcome results are expressed as a hazard ratio with a 95% confidence interval.

EF: Ejection fraction; EMPA: Empagliflozin; HF: Heart failure; HFpEF: Heart failure with preserved ejection fraction; HFrEF: Heart failure with reduced ejection fraction; NA: Not available; SBP: Systolic blood pressure.

The effect of empagliflozin was particularly noteworthy in preventing the occurrence of severe hyperkalemia (HR: 0.70; 95% CI: 0.47–1.04) [58]. This effect of empagliflozin was assessed in MRA users and nonusers and the results were shown to be comparable (interaction p = 0.56). Additionally, the use of MRA at baseline did not influence the benefits of empagliflozin to reduce CV mortality or HHF (HR: 0.75; 95% CI: 0.63–0.88) [58]. Hence, these findings indicate that empagliflozin can act as an enabler for the use of MRA. A mild estimated glomerular filtration rate (eGFR) decrease may be expected early on after the initiation of empagliflozin [59].

3.3. EMPEROR-preserved

In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (the EMPEROR-Preserved) study [42], individuals with class II-IV HF and an LVEF greater than 40% were randomized to either a placebo group or an empagliflozin group. Empagliflozin reduced the risk of CV mortality and HHF (HR: 0.79; 95% CI: 0.69–0.90; p = 0.001). Additionally, numerous post-hoc studies have demonstrated that empagliflozin improves the risk of CV mortality and HHF in patients regardless of T2D status (HR: 0.79; 95% CI: 0.67–0.94) [53], background diuretic use (HR: 0.81; 95% CI: 0.70–0.93) [54], baseline KCCQ-CSS (HR: 0.83; [95% CI: 0.69–1.00], 0.70 [95% CI: 0.55–0.88] and 0.82 [95% CI: 0.62–1.08] for scores <62.5, 62.5–83.3 and ≥83.3, respectively) [55], baseline EF status [0.77 (0.60–0.98); 0.72 (0.59–0.87); 0.82 (0.63–1.05); 0.74 (0.61–0.91); 0.78 (0.62–0.97); and 0.98 (0.68–1.40) for EF <25%, 25–34%, 35–44%, 45–54%, 55–64% and ≥65%, respectively)] [57], and baseline SBP [0.82 (0.68–0.98); 0.78 (0.63–0.96); 0.67 (0.43–1.03) for SBP >130 mmHg, 110–130 mmHg and <110 mmHg, respectively)] [56]. Table 2 summarizes the results of these post-hoc studies. Additionally, empagliflozin improved the quality of life as assessed by the improvement in KCCQ scores from baseline [1.10 (0.20–2.00), 1.51 (0.53–2.49), and 1.54 (0.52–2.55); p < 0.05) at 3, 8 and 12 months, respectively.

3.4. EMPA-RESPONSE-AHF & EMPULSE

Early Treatment with a Sodium-glucose Co-transporter 2 Inhibitor in High-risk Patients with Acute Heart Failure (EMPA-RESPONSE-AHF) [43] and Empagliflozin in Patients Hospitalized for Acute Heart Failure (EMPULSE) [44] were trials that addressed the safety and efficacy of empagliflozin in patients with acute HF. In EMPA-RESPONSE-AHF, 80 acute patients with HF (both with and without T2D) were randomized to either empagliflozin 10 mg/day or a placebo for 1 month. Empagliflozin significantly (p = 0.014) decreased the rates of HHF, in-hospital worsening HF and mortality. Whereas, no significant difference was observed between empagliflozin and placebo in terms of NT-proBNP level variations (−46 ± 32% versus −42 ± 31%, p = 0.63), diuretic response (−0.35 ± 0.44 kg/40 mg versus −0.12 ± 1.52 kg/40 mg, p = 0.37) or dyspnea scores (1264 ± 1211 mm × h versus 1650 ± 1240 mm × h, p = 0.18).

In the EMPULSE study, 530 individuals (with or without T2D) were randomized to either empagliflozin 10 mg/day or placebo [44]. After 90 days, empagliflozin improved clinical outcomes (stratified win ratio, 1.36; 95% CI 1.09–1.68; p = 0.0054) of all-cause mortality, HF incidents, and time to first HF incident. A minimum of 5-point variation from the baseline value in the KCCQ-CSS was also seen (stratified win ratio, 1.36; 95% CI 1.09–1.68; p = 0.0054). These clinical effects were consistent regardless of the type of enrollment (acute, newly diagnosed, or chronic HF), LVEF, or the presence of T2D and were linked to a positive tolerance profile. The treatment with empagliflozin resulted in improvements in the number of indexes of congestion status [60].

While several clinical trials have demonstrated the effectiveness of empagliflozin in HFrEF and HFpEF, data on its clinical efficacy in advanced HF is limited. To determine the impact of empagliflozin in critical circumstances, such as severely low eGFR or hyponatremia related to advanced HF, high-quality randomized controlled trials targeting patients with advanced HF are required.

4. Real-world evidence

In a real-world study [61], individuals with diagnosed HF from the Heart Centre or Department of Internal Medicine at the Umea University Hospital had their medical records examined. Of the 150,000 patients, 2433 were diagnosed with HF and 268 with LVEF less than 40% fulfilled the eligibility criterion of EMPEROR-reduced trial. These real-world patients were older (80.3 vs. 67.2 years), had more risk of atrial fibrillation, and had a lower incidence of T2D compared with trial participants. The study concluded that 39–52% of patients with HF with decreased EF or 11–14% of all patients with HF, were optimal candidates for empagliflozin, whereas low NT-proBNP or low eGFR levels were the major factors for ineligibility. Another study [62] evaluated whether patients with T2D who were hospitalized for decompensated HF in a ‘real-world’ environment would be included in accordance with the inclusion and exclusion criteria for the EMPA-REG OUTCOME trial. The majority of patients (68.1%) had HFpEF. Only 17.6% (n = 21) of the 119 individuals would have been included in the EMPA-REG OUTCOME trial. These patients were older, with a low risk of ischemic heart disease and HFrEF compared with the participants of the EMPA-REG OUTCOME trial. Additionally, only a small percentage of these patients fulfilled the EMPA-REG OUTCOME trial's inclusion criteria for hemoglobin A1c (HbA1c), CV risk profile, and eGFR requirements. Hence, a restricted eGFR criterion might limit empagliflozin's utility in the ‘real-world’ HF population and a broader cutoff (e.g. eGFR >30–45 ml/min/1.73 m²) might prove to be more reasonable. Another study [63] of 182,525 patients assessed an outpatient database from 313 locations in the USA. Of these individuals, 26.2% fulfilled the eligibility requirements for the EMPA-REG OUTCOME trial. Another study [64] collected ‘real-world’ data from Swedish national registries and compared the CV outcomes of empagliflozin with dipeptidyl peptidase-4 inhibitors (DPP-4i). 15,785 matched subjects were followed for a period of 6.4 months. Empagliflozin significantly reduced the risk of HHF compared with DPP-4i (HR: 0.67; 95% CI: 0.49–0.91).

5. Safety & tolerability

The frequent adverse effects of empagliflozin include genital yeast infections (4.3%) [65]. These infections are more frequent in elderly women and uncircumcised males and they usually manifest early in the course of empagliflozin. However, empagliflozin is generally not required to be discontinued in such infections as they are readily cured with topical antifungal creams or oral antifungal medications [66]. Additionally, special counseling on maintaining the hygiene of the perineal area should be given to patients.

In 2018, the US FDA issued a warning on 12 cases of Fournier's gangrene [67], a rare but perilous and possibly disfiguring perineal infection linked to empagliflozin. Empagliflozin has also been linked to euglycemic diabetic ketoacidosis in people with T2D [68]. As a result of this, individuals with HF and concurrent T2D should be educated about this especially if they have poor oral intake and are anticipated to have elective surgery [69]. Empagliflozin should be discontinued 3 days prior to the scheduled procedure [69]. Additionally, patients should be instructed to cut back on their consumption of alcohol and counseled about the usual signs of ketoacidosis, which include altered mental state, vomiting, and abdominal discomfort.

Empagliflozin is contraindicated in individuals having type 1 diabetes [44]. Empagliflozin is not recommended in people with a history of a serious adverse reaction to empagliflozin [70] and in pregnant women in their second and third trimesters [70]. Additional adverse effects of empagliflozin include hypotension [71] and peripheral amputations with an average occurrence of 2.5% [72], 1.5% [72], and 1.1% [73], respectively.

Empagliflozin may cause hypotension since it causes osmotic diuresis and reduces interstitial and intravascular volume. However, empagliflozin has only a modest effect on blood pressure (2–4 mmHg drop) [56]. Additionally, loop diuretics, which are routinely prescribed to patients with HF, may interact adversely with empagliflozin, necessitating a dosage modification [74]. Urinary tract infections [75] and mycotic vaginal infections [40] occur frequently in conjunction with the use of empagliflozin, although they can be prevented by maintaining meticulous hygiene [70].

Empagliflozin raises blood phosphate levels, which could potentially have a detrimental effect on bone metabolism [76]. While empagliflozin has not yet been linked with detrimental impacts on bone turnover, it is still important to consider the risks of osteoporosis associated with its application in patients with HF who have more fragile bones [72]. The results of safety outcomes in clinical trials are summarized in Table 3

Table 3.

Summary of safety outcomes in clinical trials.

	EMPA-REG OUTCOME [40]	EMPEROR-reduced [41]	EMPEROR-preserved [42]	EMPA-RESPONSE-AHF [43]	EMPULSE [44]
Serious adverse effects	38.2% (EMPA) vs. 42.3% (placebo)	41.4% (EMPA) vs. 48.1% (placebo)	47.9% (EMPA) vs. 51.6% (placebo)	20% (EMPA) vs. 28.2% (placebo)	15.0% (EMPA) vs. 20.5% (placebo)
Acute renal failure	5.2% (EMPA) vs. 6.64% (placebo)	8.4% (EMPA) vs. 10.6% (placebo)	12.1% (EMPA) vs. 12.8% (placebo)	10% (EMPA) vs. 8% (placebo)	7.7% (EMPA) vs. 12.1% (placebo)
Ketoacidosis	0.1% (EMPA) vs. <0.1% (placebo)	0% (EMPA) vs. 0% (placebo)	0.1% (EMPA) vs. 0.2% (placebo)	0% (EMPA) vs. 3% (placebo)	0% (EMPA) vs. 0% (placebo)
Amputations	–	0.7% (EMPA) vs. 0.5% (placebo)	0.5% (EMPA) vs. 0.8% (placebo)	–	–
Hypoglycemia	27.8% (EMPA) vs. 27.9% (placebo)	1.4% (EMPA) vs. 1.5% (placebo)	2.4% (EMPA) vs. 2.6% (placebo)	0% (EMPA) vs. 3% (placebo)	1.9% (EMPA) vs. 1.5% (placebo)
Bone fractures	3.81% (EMPA) vs. 3.9% (placebo)	–	4.5% (EMPA) vs. 4.2% (placebo)	–	–
Genital infections	6.4% (EMPA) vs. 1.8% (placebo)	4.9% (EMPA) vs. 4.5% (placebo)	3% (EMPA) vs. 3% (placebo)	–	–
Urinary tract infections	18% (EMPA) vs. 18.1% (placebo)	4.9% (EMPA) vs. 4.5% (placebo)	9.9% (EMPA) vs. 8.1% (placebo)	3% (EMPA) vs. 3% (placebo)	4.2% (EMPA) vs. 6.4% (placebo)

EMPA: Empagliflozin.

6. Regulatory affairs

Empagliflozin was originally discovered by Boehringer Ingelheim and co-developed and co-marketed through research collaboration with Eli Lilly and Co. and is sold under the brand name Jardiance^®. Empagliflozin 10 mg film-coated tablets were first approved by the EMA in May 2014, for adults with poorly controlled T2D and as monotherapy when metformin is considered inappropriate due to intolerance. Later in March 2022, Jardiance (empagliflozin) 10 mg film-coated tablets were approved in adults for the treatment of symptomatic chronic heart failure and for the treatment of CKD.

The FDA first approved empagliflozin (10 mg film-coated tablets) on 1 August 2014, under the brand name Jardiance^®, as an addition to diet and exercise to improve glycemic control in adults with T2D. On 2 December 2016, the FDA approved a new indication for Jardiance (empagliflozin) 10 mg film-coated tablets to reduce the risk of CV mortality in adults with T2D and CV disease. On 18 August 2021, the FDA authorized Jardiance (empagliflozin) 10 mg film-coated tablets to lower the risk of CV mortality and HHF in adults with HFrEF with an eGFR as low as 20 ml/min/1.73 m². Furthermore, on 24 February 2022, the FDA expanded the application of Jardiance (empagliflozin) 10 mg film-coated tablets in HF, irrespective of EF, as a measure to lower the risk of CV mortality and HHF. Additionally, as a means to reduce blood sugar levels in children with T2D aged 10 and older, the FDA authorized Jardiance (empagliflozin) film-coated tablets of 10 mg and 25 mg on 21 June 2023.

Jardiance tablets are available as 10 mg pale yellow, round, biconvex and bevel-edged, film-coated tablets debossed with ‘S 10’ on one side and the Boehringer Ingelheim company symbol on the other side and as 25 mg pale yellow, oval, biconvex, film-coated tablets debossed with ‘S 25’ on one side and the Boehringer Ingelheim company symbol on the other side. The recommended dose of Jardiance is 10 mg once daily in the morning, taken with or without food. If tolerated initially, dosing may increase up to 25 mg.

7. Conclusion

Empagliflozin has emerged as a foundational pillar in the management of HF. Numerous trials highlight the efficacy of using empagliflozin in HF across various settings and subgroups. Empagliflozin in patients with HF substantially improves CV outcomes, decreases hospitalization rates and the risk of mortality. Empagliflozin causes mild weight loss and does not significantly reduce blood pressure. Empagliflozin also acts as an enabler for other HF drugs by reducing the risk of hyperkalemia. Additionally, empagliflozin has also been shown to be beneficial for CKD which exists commonly with HF. Empagliflozin is a fixed-dose, once-daily dosage that does not necessitate titration or regular monitoring of kidney function or electrolytes making it safe and plausible to introduce into multidrug regimens for a wide spectrum of patients with HFrEF. Ongoing trials will give further information regarding the effect of empagliflozin on cardiac biomarkers, structure, and hemodynamics.

8. Future perspective

It is uncertain whether the benefits of empagliflozin are drug-specific or the result of a class effect. Therefore, larger-scale clinical trials are required to confirm the efficacy of other SGLT2 inhibitors in the treatment of HF. Additionally, it is undetermined how empagliflozin affects individuals with stage D HF. Since individuals with stage D HF often do not respond well to HF treatment, empagliflozin may present as a compelling substitute. Although empagliflozin has shown significant improvement in HF outcomes, endpoints apart from HF hospitalization should be considered, such as emergency department visits and urgent office visits. Lastly, it is critical to recognize that there is now substantial data supporting the use of empagliflozin in the primary prevention of HF in individuals with diabetes. Given the strong evidence and serious public health implications of concurrent diabetes and HF, clinicians should consider implementing empagliflozin for HF prevention, at least in diabetic patients.

Author contributions

A Shafiq did the original draft writing, visualization, review, and editing. I Hameed, J Biegus, and M Fudim reviewed and edited. MS Khan supervised, validated, reviewed, and did critical edits.

Financial disclosure

The authors have no 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.

Competing interests disclosure

Dr. Khan has served on the advisory board for Bayer. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.