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SGLT2 Inhibitors; Suggested Mechanism of Actions in Supporting Post-Myocardial Infarction Patients

2023; Future Medicine; Volume: 19; Issue: 9 Linguagem: Inglês

10.2217/fca-2023-0066

1744-8298

Matthew J. Cotton, Alasdair Hawley,

Metabolism, Diabetes, and Cancer

Future CardiologyAhead of Print EditorialOpen AccessSGLT2 inhibitors; suggested mechanism of actions in supporting post-myocardial infarction patientsMatthew Cotton & Alasdair HawleyMatthew Cotton*Author for correspondence: E-mail Address: m.cotton3@nhs.netTorbay Hospital & South Devon Foundation Trust, Lowes Bridge, Torquay, TQ2 7AA & Alasdair Hawley**Author for correspondence: E-mail Address: alasdair.hawley@nhs.netTorbay Hospital & South Devon Foundation Trust, Lowes Bridge, Torquay, TQ2 7AAPublished Online:13 Sep 2023https://doi.org/10.2217/fca-2023-0066AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: acute coronary syndromescardiomyocytedapagliflozinempagliflozinheart failureHFpEFHFrEFSGLT2 inhibitorsSotagliflozinSGLT2 inhibitors (SGLT2i) are a diverse group of medications that are used in the management of cardiovascular and renal conditions. Some of the most used medications include dapagliflozin, empagliflozin, ertugliflozin and canagliflozin. These SGLT2i have been shown to regulate blood sugar, help with weight control, control albumin levels, reduce blood pressure and support myocardium function [1,2]. Given their multiple clinical uses, various studies are now looking at how SGLT2i can be used in a variety of pathologies and since the medication has shown prognostic benefit in heart failure (HF) patients [3], there are now further trials to see how SGLT2i can preserve and protect myocardium. This includes ischemic heart disease and post-acute coronary syndrome outcomes.Current uses of SGLT2 inhibitorsSGLT2i are currently used for the management of glycaemia through the prevention of glucose reuptake in the proximal renal tubule [4]. This reduces blood glucose levels and as a result can be used in the long-term management of Type II diabetes. However, further trials have also shown the benefit of SGLT2i in HF patients, including reduced hospitalization and cardiovascular death [5]. As a result, dapagliflozin and empagliflozin are now used in the long-term management of patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). This has been the first-time medication has shown prognostic outcomes for patients with HFpEF [6,7]. While these trials show positive outcomes, the exact mechanisms for how SGLT2i improve outcomes for HF patients is not fully understood.Many recent studies looking at the cardiorenal angle aim to analyse the risk-benefit of these medications due to their well-known side effects; yeast infections, elevated cholesterol and lower urinary tract symptoms [8]. Some of the more significant concerns were the risk of euglycaemic diabetic ketoacidosis (DKA) and acute kidney injury (AKI). While the AKI concerns were theoretical and data shows no increased risk for AKI, risks of DKA have resulted in specific guidelines to avoid these complications when using SGLT2i in clinical situations [9,10].Currently SGLT2i are thought to reduce overload symptoms through glycosuria, however further work has also shown how SGLT2i have natriuretic properties [11]. This certainly supports their use in ongoing management of HF, especially considering that SGLT2i seem to have no effect on the renin–angiotensin system (RAAS) whereas loop diuretics can overtime [11].Other articles also highlight the possible effect SGLT2i have on haemodynamic function through a reduction in left ventricular hypertrophy; although the direct mechanism here remains unclear [12]. While SGLT2i cardiovascular mechanisms of action are becoming outlined in heart failure, the very same mechanisms could support patients who are post-acute coronary syndrome (ACS), specifically those who have suffered from a myocardial infarction.Proposed mechanisms of how SGLT2i may help in post-myocardial infarction patientsACS conditions are characterised by an occlusion of the coronary vessels of the heart. The two most severe conditions within this umbrella term include ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI). In these conditions occlusion of the coronary vessels leads to ischemic damage to the myocardium and in turn can result in fatal complications such as ventricular arrhythmias. In most cases, patients will either receive primary percutaneous coronary intervention (PCI) or thrombolysis in areas without access to PCI. This destroys/removes the clot and returns oxygenation to the area of ischemic tissue [13]. In all these cases, patients are offered a package of secondary preventative medications to reduce the risk of further ACS in the future. This includes dual antiplatelet therapy (DAPT), an ACE inhibitor, a statin and a beta-blocker [14]. This has been the same groups of medication for several years. However, with the SGLT2i showing numerous cardiovascular properties it may be time for a new medication to be added to this bundle.Current clinical trials show mixed results with regards to SGLT2i impact on cardiovascular health in post-myocardial infarction (MI) patients. A 2022 double blind trial (n = 93) established those diabetic patients that received low dose empagliflozin after PCI for ACS had no difference in mortality 6 months post-cardiac event when compared with the placebo [15]. However, further ongoing multicentre clinical trials such as EMPACT-MI (NCT04509674) and DAPA MI (NCT04564742) have much larger cohorts with aim to identify if empagliflozin and/or dapagliflozin reduce cardiovascular deaths and the chance of hospitalisation due to heart failure [16,17].The SOLOIST trial (NCT03521934) which focused of Sotagliflozin a SGLT1 and SGLT2 inhibitor, has already shown benefit in acute heart failure [18], which may also be translatable to those ACS patients with associated pump failure.While there are no specific SGLT2 receptors in the heart, there are SGLT1 receptors as well as other receptors that SGLT2i interact with [19]. One of these receptors include the sodium/proton exchanger 1 (NHE1). Inhibition of this receptor through SGLT2i have shown it may be cardioprotective by effecting intracellular flux of sodium ions [20]. Furthermore NHE1 suppression and knockdown studies show a reduction of autosis suggesting that these changes in sodium concentration may reduce the rate of autophagy [21]. However, it is important to recognise further work is needed to establish that this specifically occurs in cardiomyocytes.Further mouse model studies have also suggested that specifically empagliflozin improves cardiomyocyte energy through elevated levels of ATP. By increasing the levels of ATP in these cells, they can maintain function for a longer period when an ischemic event occurs [22]. It also implies they have a greater capacity to recover postinfarct. The proposed mechanism similarly involves the NHE1 channel, which is thought to also be inhibited for a longer period due to abundance of ATP [23].Other groups have also used in vitro studies to highlight how cardiomyocytes exposed to high levels of glucose and lipids typically show an increase in cell stress. This is shown by an increase in oxidative cell stress and of reactive oxygen species [24,25]. Addition of either canagliflozin or dapagliflozin seemed to reduce these parameters implying another possible mechanism for a reduction in cardiac scar formation in post-MI patients with or without concurrent diabetes mellitus [26].Additional groups have examined the antiatherosclerotic effects of SGLT2i in mice and rabbit studies [27]. Data has shown a reduction in cholesterol and triglycerides alongside reduced heart rate and coronary artery plaque size and increased plaque stability in mice treated with canagliflozin [28]. Other SGLT2i were shown to reduce IL1β, IL6, TNFα and ICAM-1 [29]. A reduction in these signalling molecules reduced macrophage build-up in perivascular tissue. This could result in reduced fibrosis and adipocyte death, which provides further cardioprotective mechanisms in post-MI patients [30]. Observational studies have looked at how the use of SGLT2i can improve diastolic function and reduce left ventricular hypertrophy. This can increase the risk of post-MI patients developing HFrEF [31].While several studies have proposed mechanisms for how SGLT2i could improve cardiovascular outcomes in post-MI patients, some clinical trials have yet to show a benefit in the early stages post-MI intervention. A clinical trial examining diabetic patients with ACS that received PCI were part of a trial to assess the cardiovascular outcomes in the context of a SGLT2i. The results found that low dose empagliflozin had no association in a reduction in cardiovascular outcomes with the 6 months of their ACS intervention [32].A further group produced an analysis of 43 randomized control trials and examined diabetic patients treated with SGLT2i. While this was not in post-MI patients, they did find that there was no therapeutic benefit to SGLT2i in the development of ACS, ischemic stroke or peripheral arterial occlusive disease [33].DiscussionWe have shown here that SGLT2i have a role in the management of cardiovascular conditions. However, the numerous mouse models that highlight potential mechanisms for cardioprotection may not be directly translatable. This can be especially relevant with regards to time course, with models not representing the stamina of human cardiomyocytes [21,23,34]. While this may not be the case with the energy related hypotheses, those identifying a potential inflammatory related mechanism may provide a much more translatable answer to the benefits of SGLT2i post-MI [30,31]. Inflammatory processes in both animal models and humans will be acute with regards to tissue ischaemia. This therefore provides greater scope for the introduction of SGLT2i as part of the post-MI secondary prevention medication bundle.Furthermore, studies that dispute the merit of SGLT2i post-ACS have so far been short lived, with a longer timeframe needed to look for associated outcomes, be they negative or positive [32]. This is especially relevant due to the theoretical risk of acute kidney injury and diabetic ketoacidosis, which could cause drastic outcomes in post-MI patients. For further evidence, retrospective studies may be performed in the coming years to see outcomes of HF patients that unfortunately go on to have ACS. With many of these HFrEF and HFpEF patients now being started on SGLT2i as part of their disease modifying agent bundles it will provide a greater cohort to review in the years to come.Other work has also investigated the synergistic properties of SGLT2i with other diabetic medications in cardiovascular disease, which may also provide further mechanisms that could revolutionise the medications we prescribe to patients post-MI [2].Author contributionsEditorial drafted by M Cotton, with A Hawley providing critique and written feedback.Financial & competing interests disclosureThe 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.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/References1. Ishibashi F, Kosaka A, Tavakoli M, Deguchi T, Lorenzo O. Sodium glucose cotransporter-2 inhibitor protects against diabetic neuropathy and nephropathy in modestly controlled Type 2 diabetes: follow-up study. Front. Endocrinol. 13, 864332 (2022).Crossref, Medline, Google Scholar2. Ninčević V, Kolarić TO, Roguljić H et al. Renal benefits of SGLT 2 inhibitors and GLP-1 receptor agonists: evidence supporting a paradigm shift in the medical management of Type 2 diabetes. Int. J. Mol. Sci. 20(23), 5831 (2019).Crossref, Medline, CAS, Google Scholar3. 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SGLT2 inhibitors play a salutary role in heart failure via modulation of the mitochondrial function. Front. Cardiovasc. Med. 6, 186 (2020).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Ahead of Print STAY CONNECTED Metrics History Received 10 May 2023 Accepted 7 August 2023 Published online 13 September 2023 Information© 2023 The AuthorsKeywordsacute coronary syndromescardiomyocytedapagliflozinempagliflozinheart failureHFpEFHFrEFSGLT2 inhibitorsSotagliflozinAuthor contributionsEditorial drafted by M Cotton, with A Hawley providing critique and written feedback.Financial & competing interests disclosureThe 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.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download