Empagliflozin: primum inter pares among sodium-glucose cotransporter-2 inhibitors?

Abstract

Sodium/glucose cotransporter 2 (SGLT2) inhibitors are a novel class of anti-diabetic medications which have proved capable of providing breakthrough cardiovascular benefits in a variety of clinical scenarios, including patients with heart failure or obesity, irrespective of diabetic status. Several SGLT2 inhibitors are available, but the most prominent ones are canagliflozin, dapagliflozin, and empagliflozin. Several studies have focused on empagliflozin, and its effects on the risk of heart failure incidence and recurrences. Most recently, empagliflozin has been recently tested in patients with recent myocardial infarction in the EMPAgliflozin on Hospitalization for Heart Failure and Mortality in Patients With aCuTe Myocardial Infarction (EMPACT-MI) randomized trial, with apparently ambiguous findings. The present viewpoint succinctly illustrates the main features of SGLT2 inhibitors as a pharmacologic class, their ever expanding role as a cardiovascular medication, and the comparative effectiveness of different individual SGLT2 inhibitors, explicitly commenting on the recent data on empagliflozin in patients with acute myocardial infarction. The reader will find in this article a poignant perspective on this novel avenue for cardiovascular prevention and treatment, which greatly expands the management armamentarium of cardiovascular practitioners. Indeed, we make the case that SGLT2 inhibitors have a clearly favorable class effect, with differences between individual agents mainly suitable for personalization of care and minimization of side effects.

The worst form of inequality is to try to make unequal things equal

Aristotle

Cardiovascular disease represents a worldwide challenge for patients, physicians and policymakers, and setbacks continue to present despite ongoing developments in prevention, diagnosis and management.¹ Notably, key breakthroughs in cardiovascular therapeutics are represented by the recent introduction and subsequent repurposing of pharmacologic agents originally designed for diabetes mellitus, but clearly shown capable of improving cardiovascular outcomes even in patients without diabetes mellitus, such as glucagon-like peptide-1 receptor agonists (GLP-1ra) and sodium/glucose cotransporter 2 (SGLT2) inhibitors.^2–4 Indeed, from early studies showing improved glycemic control to trials demonstrating cardiovascular benefits in diabetics with or at risk of cardiovascular disease, these agents have been shown quite impactful in a wide range of conditions, even among non-diabetics, such as overweight, obesity, myocardial infarction, and heart failure.^5–8 The evidence base in favor of SGLT2 inhibitors, which include canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin, is expanding momentously, and several agents have been capable of favorably impacting on the prognosis of patients with heart failure, cardiorenal disease, or myocardial infarction, on top of their solidly established benefits in the management of diabetes mellitus and the prevention of its complication (Table 1).^{5, 9–13} Indeed, the recent publication of a series of articles dedicated to exploring the role of the SGLT2 inhibitors empagliflozin in the early phase of acute myocardial infarction is worth perusing attentively.¹⁴

Table 1.

Selection of recent network meta-analyses on sodium-glucose cotransporter-2 (SGLT2) inhibitors.

PMID	Year	Studies included	Patients included	Highlights
36589800	2022	9	71,793	SGLT2 inhibitors and finerenone could reduce the risk of MACE, HHF, MI, CV disease, and renal composite outcomes. Finerenone has no obvious advantage than SGLT2 inhibitors on the effects of cardiovascular and renal protective
36842477	2023	27	50,237	SGLT2 inhibitors −2Is significantly reduced kidney and cardiovascular risk in T2DM and CKD, subsequently GLP-1ra and MRAs
37397500	2023	36	52,264	SGLT2 inhibitors were not associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent
37469980	2023	13	74,804	Empagliflozin ranked the highest compared to the other SGLT-2is in the overall population and the trials including T2DM patients with ASCVD or MRF at baseline, while dapagliflozin ranked the highest in the trials of patients with HF at baseline
38027214	2023	25	12,990	SGLT-2 inhibitors did not significantly increase the risk of harm when comparing different doses, except for dapagliflozin 10mg/d, which showed an increased risk of UTI and may be associated with a higher risk of renal impairment and nasopharyngitis. Additionally, compared with placebo and metformin, the risk of GI was notably elevated for empagliflozin 10mg/d, canagliflozin 300mg/d, and dapagliflozin 10mg/d.
38044937	2023	11	30,952	Sotagliflozin displayed moderate CV benefits and acceptable safety for T2DM patients with HF or CV risk factors
38179304	2024	11	20,438	SGLT2is significantly reduced composite CV death/HFH. Among them, canagliflozin could be considered the preferred treatment for patients with T2DM and a history of HF, but it could also be associated with an increased risk of any AE. HF-specific trials identified sotagliflozin as the most likely agent to reduce CV death/HFH, followed by empagliflozin and dapagliflozin
38273787	2024	79	206,387	SGLT-2 inhibitors and GLP-1ra were beneficial for stroke prevention in patients with T2DM
38639549	2024	84	494,541	In adults with T2DM, SGLT2 inhibitors and GLP1ra (but not DPP4 inhibitors, insulin, or tirzepatide) reduced mortality and MACE compared with usual care. SGLT2 inhibitors reduced CKD progression and HF hospitalization and GLP1 agonists reduced stroke compared with usual care. SAE and severe hypoglycemia were less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU

AF=atrial fibrillation; ASCVD=atherosclerotic cardiovascular disease; CKD=chronic kidney disease; CV=cardiovascular; DKA=diabetic ketoacidosis; DPP4= dipeptidyl peptidase-4; GI=gastrointestinal; GLP1ra=glucagon-like peptide-1 receptor agonist; HF=heart failure; HFH=heart failure hospitalization; MACE=major adverse cardiac events; MI=myocardial infarction; MRA=mineralocorticoid receptor agonist; MRF=multiple cardiovascular risk factors; SAE=serious adverse event; SU=sulfonylureas; T2DM=type 2 diabetes mellitus; UTI=urinary tract infection

Notably, in the main report of the EMPAgliflozin on Hospitalization for Heart Failure and Mortality in Patients With aCuTe Myocardial Infarction (EMPACT-MI) trial, which randomized patients hospitalized for acute myocardial infarction and at high risk for heart failure to empagliflozin (10 mg daily) vs placebo, empagliflozin was not associated with a significant improvement in the primary endpoint of time to the composite of all-cause death or hospitalization for heart failure (hazard ratio=0.90 [95%CI 0.76-1.06], p=0.21).¹⁵ Yet, there was a disconnect between primary endpoint components such that, whereas death was not impacted in a meaningful way (hazard ratio=0.96 [0.78-1.19]), hospitalization for heart failure was clearly reduced by empagliflozin (hazard ratio=0.77 [0.60-0.98]), independently from systolic function or clinical features. These apparent discrepancies could indeed be due to several competing factors, including differential risks in death due to arrhythmias as well as low prevalence of patients with high-risk features.

These findings were confirmed by Udell et al, who clearly showed the capability of empagliflozin to reduce heart failure-related hospitalizations, ranging from time to and rate of first hospitalization, as well as total hospitalization, in patients recently admitted for acute myocardial infarction, with consistent benefits across the range of left ventricular ejection fraction and irrespective of the presence or absence of signs of congestion.¹⁶ The benefits on hospitalizations due to heart failure are even more evident when counting repeat events in the same individuals, as poignantly demonstrated by Hernandez and colleagues.¹⁷ These findings are indeed in keeping with the results of the EMPagliflozin in patients hospitalized with acUte heart faiLure who have been StabilizEd (EMPULSE) trial, which demonstrated the benefits of this drug across the spectrum of systolic dysfunction phenotypes as well as symptoms.^{18, 19}

The elephant in the room is indeed whether SGLT2 inhibitors can impact on all cause death, and whether they are all born equal, for such an effect, as well as for other clinically relevant endpoints. Addressing the first issue represents a challenge as the evidence base is still expanding. Indeed, our personal albeit informed and experienced perspective is that SGLT2 inhibitors can indeed improve overall survival, but patients at high risk must be included in the dedicated studies, without major concomitant competing risks, and for an adequate follow-up time.¹⁰ Regarding the relevance of class effects among SGTL2 inhibitors, some comparative effectiveness analyses suggest that some SGLT2 inhibitors may be more effective than others, but these findings mainly stem from indirect comparison and thus should mostly be viewed as hypothesis generating.^{20, 21}

There is mounting evidence that SGLT2 inhibitors as a class improve the quality of life in HF patients,^{18, 22} yet the mechanistic basis for this remains obscure despite an expanding evidence base in terms of basic, translational and clinical studies.²³ The human heart expresses SGLT1, but not SGLT2, so the proposition that some inhibition of SGLT1 in the heart accounted for their cardio-beneficial effects was once tenable, or via that action in the gut thereby enhancing incretin levels.²⁴ The findings with empagliflozin, which is highly selective for SGLT2 (Figure 1), firmly negate that possibility once and for all. An alternative possibility is that SGLT2 inhibitors may have a positive impact on red blood cell number and iron homeostasis.²⁵ A third possibility arises from the fact that SGLT2 inhibitors increase circulating ketone bodies, in particular β-hydroxybutyrate, which enhance myocardial energetics and mitochondrial biogenesis, reduce reactive oxygen species (ROS) formation, and have anti-arrhythmic effects.^{23, 26, 27} If so, a better understanding of the pharmacokinetics for changes in ketone body levels is needed to distinguish their harmful from beneficial actions.

Figure 1.

Key features of the main sodium-glucose cotransporter-2 inhibitors. DM=diabetes mellitus; HF=heart failure; MI=myocardial infarction; RF=renal failure.

We aimed to poignantly and succinctly summarize the evidence on the comparative effectiveness of SGLT2 inhibitors by perusing recent network meta-analyses on these agents (Table 1). ^{28, 29, 30, 31, 32, 33, 34, 35, 36} These systematic reviews encompass data from a wide range of patients and studies, showcasing the effectiveness of SGLT2 inhibitors and GLP-1ra in reducing mortality, major adverse cardiac events (MACE), and hospitalization due to heart failure, particularly compared to other anti-diabetic treatments such as dipeptidyl peptidase-4 inhibitors, insulin, and sulfonylureas. Notably, SGLT2 inhibitors also demonstrated a quite beneficial capacity to reduce the progression of chronic kidney disease. Specific subgroup analyses may indicate that canagliflozin could be more beneficial for certain subtypes of diabetes mellitus, but these findings require confirmation in dedicated and well-powered trials. Irrespectively, SGLT2 inhibitors are generally well tolerated. While these sources of evidence are insightful, they should not be considered definitive, and instead viewed as complementary to other relevant studies, such as the recent cohort study including as many as 744,914 patients with heart failure, who had never received an SGLT2 inhibitor previously, and were newly started on empagliflozin or dapagliflozin. Indeed, in such observational study adjusting with matching for potential confounders, individuals who initiated empagliflozin were significantly less likely to experience the composite of death or hospitalization compared with those initiated on dapagliflozin in the year following SGLT2 inhibitor initiation, and the same applied to the risk of such outcomes when appraised individually.³⁷

Notwithstanding the adverse effects that may occur when assuming SGLT2 inhibitors, including genitourinary infections, hypoglycemia, or diabetic ketoacidosis, the totality of evidence suggests that these agents are very beneficial across the whole spectrum of heart failure phenotypes, including those conditions, such as diabetes mellitus, chronic renal failure, and, even more poignantly, myocardial infarction, which are de facto prodromes to such condition. The future probably rests on, first and foremost, individualization of prescription, in order to pick the most appropriate molecule for each individual patient. On the other hand, it is clear that combination therapy, in a logic of dual polypill, with SGLT2 inhibitors and GLP-1ra, could provide very remarkable clinical benefits in a wide range of individuals, from those with diabetes mellitus to those with atherosclerotic cardiovascular disease, myocardial infarction or heart failure, with potentially multiplicative rather than simply additive benefits in individuals at higher risk of events or greater symptomatic burden.³⁸

In conclusion, SGLT2 inhibitors have a clearly favorable class effect, with differences between individual agents mainly suitable for personalization of care and minimization of side effects. Future studies will provide additional insights capable of guiding personalized prescription of such agents, together with other lifesaving medications and interventions for patients with heart failure or myocardial infarction.