Skip to main content

Impact of chronic GLP-1 RA and SGLT-2I therapy on in-hospital outcome of diabetic patients with acute myocardial infarction

Abstract

Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i) demonstrated cardiovascular and renal protection. Whether their benefits occur also during hospitalization for acute myocardial infarction (AMI) in patients with diabetes mellitus (DM) is not known. We evaluated in-hospital outcomes of patients hospitalized with AMI according to their chronic use of GLP-1 RA and/or SGLT-2i.

Methods

Using the health administrative databases of Lombardy, patients hospitalized with AMI from 2010 to 2019 were included. They were stratified according to DM status, then grouped into three cohorts using a propensity score matching: non-DM patients; DM patients treated with GLP-1 RA and/or SGLT-2i; DM patients not treated with GLP-1 RA/SGLT-2i. The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy.

Results

We identified 146,798 patients hospitalized with AMI (mean age 71 ± 13 years, 34% females, 47% STEMI; 26% with DM). After matching, 3,090 AMI patients (1030 in each group) were included in the analysis. Overall, the primary endpoint rate was 16% (n = 502) and progressively increased from non-DM patients to DM patients treated with and without GLP-1 RA/SGLT-2i (13%, 16%, and 20%, respectively; P < 0.0001). Compared with non-DM patients, DM patients with GLP-1 RA/SGLT-2i had a 30% higher risk of the primary endpoint, while those not treated with GLP-1 RA/SGLT-2i had a 60% higher risk (P < 0.0001).

Conclusion

Chronic therapy with GLP-1 RA and/or SGLT-2i has a favorable impact on the clinical outcome of DM patients hospitalized with AMI.

Introduction

Diabetes mellitus (DM) is a relevant risk factor and frequent comorbidity in patients hospitalized with acute myocardial infarction (AMI), with a prevalence of 20–30% [1,2,3]. Although current treatments have considerably improved survival in both DM and non-DM patients with AMI, the presence of DM still carries a higher risk of in-hospital mortality and major cardiovascular complications, doubling the case fatality rate [4,5,6,7]. This is likely due to multifactorial causes, including a higher number of comorbidities and burden of coronary artery disease, as well as an increase in inflammation and prothrombotic state [7]. Moreover, it has been recently demonstrated that the higher in-hospital mortality in DM patients with AMI is mainly driven by their higher rate of cardiac and renal dysfunction [8]. This suggests that an improvement in hospital outcomes in the DM population may be achieved through the early implementation of cardio-protective and renal-protective therapies, in addition to standard of care.

Long-term treatment with two classes of drugs for DM—glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i)—demonstrated cardiovascular and renal protection in addition to their glucose-lowering effect [9,10,11,12,13]. Whether the benefit of these drugs on cardio-renal protection can also be observed in the acute phase of AMI, with a favorable impact on hospital outcomes, has not been investigated yet. Few preliminary data seem to support this hypothesis. Indeed, GLP-1 RA therapy was shown to reduce myocardial infarct size in animal models [14] and reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI) [15]. More recently, SGLT-2i were found to preserve cardiac contractile function during myocardial ischemia–reperfusion injury in an animal model [16]. They were also shown to prevent kidney function decline in DM patients after AMI [17]. While waiting for the results of ongoing randomized clinical trials focusing on the protective role of these drugs in AMI patients [18], the evaluation of in-hospital outcomes in DM patients, chronically treated with these anti-hyperglycemic agents at the time of hospitalization with AMI, represents a good opportunity to explore their potential role in this acute clinical setting.

In this study, we analyzed administrative data from Lombardy, the most populous Italian region, with the aim to evaluate in-hospital outcomes in patients hospitalized with AMI according to their DM status and their anti-hyperglycemic therapy at the time of hospitalization. In particular, we focused our analysis on the in-hospital prognosis of patients on chronic GLP-1 RA and/or SGLT-2i therapy.

Methods

Data source

Our study used connected administrative health databases of the Lombardy region, Italy, which include population registries with demographic data of all residents and detailed information on drug prescriptions, hospital records, and medical exemptions. Data are available for about 10 million inhabitants since 2000. Healthcare in Italy is publicly funded for all residents, irrespective of social class or employment, and everyone is assigned a personal identification number kept in the National Civil Registration System. All residents are assisted by general practitioners under the national health system. The pharmaceutical prescription database contains the medication name and Anatomic Therapeutic Chemical classification (ATC) code, quantity, and date of the dispensation of drugs reimbursed by the national health system. The hospital databases contain information on the date of admission, discharge, death, primary diagnosis, and up to five co-existing clinical conditions and procedures received.

The diagnoses are uniformly coded according to the 9th International Code of Diseases (ICD-9-CM) and standardized in all Italian hospitals. They are compiled by the hospital specialists directly in charge of the patients upon their discharge, and are validated by hospitals against detailed clinical-instrumental data, as they determine reimbursement from the national health system. A unique identification code allows the linkage of all databases. To ensure privacy, each identification code was automatically converted into an anonymous code before we received the dataset. In Italy, studies using retrospective aggregated-anonymous data from administrative databases do not require Ethics Committee approval nor notification. The data underlying this article were provided by the Lombardy region by permission and cannot be shared without permission of the Lombardy region.

Study cohorts

All patients with a hospitalization due to AMI as a primary diagnosis (both STEMI and non-ST-elevation myocardial infarction [ICD-9-CM codes 410.x]) from January 1, 2010, through December 31, 2019, were initially screened. We included in this study patients since 2010 because GLP-1 RA and SGLT-2i were available in the Italian market from 2010 and 2015, respectively. Patients were stratified according to their DM status at the time of hospitalization. Diabetes mellitus was defined as chronic exposure to anti-hyperglycemic agents (at least two prescriptions of ATC code A10* within the year preceding index hospitalization). Patients with DM were further stratified according to GLP-1 RA/SGLT-2i treatment for at least 3 months before index hospitalization. When patients were transferred between hospitals, we evaluated the complete episode of care.

Study endpoints

The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy (RRT). To avoid interference, each patient could only account for one event classification. Each component of the primary endpoint evaluated separately was considered as the secondary endpoint. The two non-fatal components of the primary endpoint were retrieved from the clinical conditions (acute heart failure) and procedures (RRT) coded in hospital records.

Statistical analysis

A propensity score matching was used to reduce confounding due to imbalance in study covariates. The score was used to match the following three cohorts: non-DM patients; DM patients treated with GLP-1 RA and/or SGLT-2i as part of their therapy; and DM patients not treated with GLP-1 RA and/or SGLT-2i. The three groups were matched in a 1:1:1 ratio using all variables included in Table 1 (age, gender, year of index hospitalization, major comorbidities, AMI type, cardiovascular medications before hospital admission, and percutaneous coronary intervention during hospitalization). Anti-hyperglycemic therapy before hospitalization, not present by definition in patients without DM, was excluded from the propensity score matching.

Table 1 Clinical characteristics of patients hospitalized with acute myocardial infarction from 2010 to 2019 prior to propensity score matching

Continuous variables are presented as mean ± standard deviation while non-normally distributed variables as median and interquartile ranges. The differences between the three study groups were assessed using ANOVA and Mann–Whitney tests, as appropriate. Categorical variables were described using frequencies and percentages, and compared using χ2 -test. Differences among the three groups for continuous and categorical variables were assessed by ANOVA and χ2-test, respectively.

Univariate and multivariate logistic regression analyses were performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for each study endpoint. The P-values of interaction between gender and the three study groups were calculated.

A sensitivity analysis having DM patients with AMI and treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) as a comparator cohort was also carried out. This comparison allowed to assess the effects of GLP-1 RA and/or SGLT-2i versus a drug class, i.e. DPP4-i, known to exhibit neutral effects on major cardiovascular and renal outcomes in DM patients [20, 21]. Moreover, GLP-1 RA, SGLT-2i, and DPP-4i are only prescribed by diabetes specialists in Italy.

A two-sided P-value less than 0.05 was required for statistical significance. All the analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

During the considered study period (2010–2019), 146,798 patients hospitalized with a primary diagnosis of AMI (mean age 71 ± 13 years, 34% females, 47% STEMI; 26% patients with DM) were identified. Of them, 1,030 patients with DM were treated with GLP-1 RA/SGLT-2i (median time of drug administration prior to AMI 19 [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27] months). Clinical characteristics and pharmacological therapy at hospital admission of the three groups before propensity score matching are reported in Table 1. After propensity score matching, the study population included 3,090 AMI patients (1030 patients in each group) (Fig. 1). Baseline characteristics of study patients after propensity score matching are shown in Table 2. After matching, all variables were well-balanced among groups but anti-hyperglycemic agents.

Fig. 1
figure 1

Screening and Selection. Flow chart illustrating study patient screening and selection. AMI acute myocardial infarction, DM diabetes mellitus, GLP-1 RA glucagon-like peptide-1 receptor agonists, SGLT-2i sodium glucose cotransporter-2 inhibitors

Table 2 Clinical characteristics of the final study population hospitalized from 2010 to 2019 after propensity score matchinga

The primary endpoint rate in the overall (non-matched) population was 20% (n = 29,032), and it was 17%, 16%, and 29%, in non-DM patients, in DM patients treated with GLP-1 RA/SGLT-2i, and in DM patients not treated with GLP-1 RA/SGLT-2i, respectively (Table 1). The primary endpoint rate in the overall matched population was 16% (n = 502). It was higher in patients with DM than in those without (18% vs. 13%; P < 0.0001; OR 1.45 [1.17–1.80]) and it progressively increased going from non-DM patients to DM patients not treated with GLP-1 RA/SGLT-2i (Fig. 2). Notably, the positive clinical effect associated with these two classes of drugs was mainly driven by the reduction in the incidence of acute heart failure.

Fig. 2
figure 2

Primary endpoint in the three study groups, after propensity score matching. Composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy in patients without diabetes mellitus and in those with diabetes mellitus treated or not with GLP-1 RA/SGLT-2i. AKI acute kidney injury, DM diabetes mellitus, GLP-1 RA glucagon-like peptide-1 receptor agonists, RRT renal replacement therapy, SGLT-2i sodium glucose cotransporter-2 inhibitors

Compared with non-DM patients, DM patients treated with GLP-1 RA/SGLT-2i had an almost 30% increased risk of the primary endpoint, while DM patients not treated with GLP-1 RA/SGLT-2i had an almost 60% increased risk (Fig. 3). When only patients with DM were considered, after adjustment for chronic anti-hyperglycemic therapy, those not treated with GLP-1 RA/SGLT-2i had a 30% higher risk of the primary endpoint than those treated with GLP-1 RA/SGLT-2i (Fig. 3). Incidence and risks of the secondary endpoints in the three study groups are reported in Table 3. A lower risk of each secondary endpoint was observed in DM patients treated with GLP-1 RA/SGLT-2i, when compared with DM patients not treated with these drugs.

Fig. 3
figure 3

Primary endpoint risk in the study groups, after propensity score matching. Odds ratio and 95% confidence interval of the primary endpoint (composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy) between the study groups, after propensity score matching. *OR was adjusted for chronic anti-hyperglycemic therapy. CI confidence interval, DM diabetes mellitus, GLP-1 RA glucagon-like peptide-1 receptor agonists, OR odds ratio, SGLT-2i sodium glucose cotransporter-2 inhibitors

Table 3 Rate and risk of the secondary endpoints in the three study groups after propensity score matching

Among DM patients treated with GLP-1 RA/SGLT-2i, 48% of patients (n = 494) were on GLP-1 RA therapy at the time of admission, 50% (n = 516) were on SGLT-2i therapy and, finally, 2% (n = 20) were taking both drugs. Additional file 1: Table S1 reports the clinical characteristics of patients with DM treated with GLP-1 RA or SGLT-2i. A similar incidence of the primary endpoint was found between patients on GLP-1 RA and those on SGLT-2i (17% vs. 15%; P = 0.46, adjusted OR 1.34 [0.94–1.91]).

At the sensitivity analysis comparing DM patients treated with GLP-1 RA/SGLT-2i and those treated with DPP-4i, the former showed a significant adjusted lower risk of the primary endpoint (OR 0.45; 95% CI 0.37–0.55).

Discussion

The results of the present study showed that patients with DM on chronic GLP-1 RA and/or SGLT-2i therapy have a better clinical outcome during hospitalization for AMI compared to those not treated with these anti-hyperglycemic drugs. In particular, the risk of in-hospital mortality, acute heart failure, and acute kidney injury requiring RRT in patients taking GLP-1 RA/SGLT-2i therapy was intermediate between that of patients without DM and that of DM patients not taking these drugs (Fig. 4).

Fig. 4
figure 4

Summary of study design and main findings. Impact of chronic GLP-1 RA and/or SGLT-2i on in-hospital outcome of patients with diabetes mellitus hospitalized with acute myocardial infarction. AMI acute myocardial infarction, CI confidence interval, DM diabetes mellitus, GLP-1 RA glucagon-like peptide-1 receptor agonists, OR odds ratio, SGLT-2i sodium-glucose cotransporter-2 inhibitors

Over the past decades, a significant improvement of outcomes in patients with AMI has been achieved, including in those with DM [22]. Despite this, worse in-hospital outcomes and a two-fold higher mortality have been consistently reported in DM patients [4, 23]. Their adverse prognosis has been traditionally associated with the presence of a higher burden of cardiovascular risk factors [24], a more diffuse and severe coronary atherosclerosis, less symptomatic AMI resulting in delayed hospital presentation, increased platelet activation and pro-coagulant state, and chronic inflammation [25]. More recently, it has been demonstrated that in AMI patients with DM the higher in-hospital mortality and major complication rates—including cardiogenic shock and acute kidney injury—are mainly driven by their more frequent cardiac and renal dysfunction at hospital presentation [8]. Thus, it can be speculated that preventive therapeutic interventions able to counteract acute cardio-renal injury during AMI may reduce the still existing mortality gap between DM and non-DM patients. In this regard, two classes of glucose-lowering agents—GLP-1 RA and SGLT-2i—are potential options to further reduce mortality in DM patients hospitalized with AMI. Indeed, data from large cardiovascular and renal outcome trials have highlighted that these drugs confer protection against major cardiac and renal events through mechanisms beyond their glucose-lowering effect. Most of these trials enrolled patients with established atherosclerotic cardiovascular disease, including those with a prior AMI, but only two trials were specifically focused on patients with a recent AMI. The ELIXA (Evaluation of LIXisenatide in Acute coronary syndromes) trial randomly assigned patients to receive lixisenatide (a GLP-1 RA) or placebo within 180 days from hospitalization for AMI (mean 72 days) [26]. In this trial, no difference in the primary composite endpoint (cardiovascular death, myocardial infarction, stroke, or unstable angina) rate and risk was found between the two arms at 3-year follow-up. The EMBODY study investigated the effects of empagliflozin, a SGLT-2i, initiated two weeks after AMI, in 105 patients with DM [27]. This trial reported that empagliflozin improved the cardiac sympathetic activity and prevented renal function decline at 6-month follow-up. Recent data from the SWEDEHEART registry confirmed that treatment with GLP-1 RA initiated soon after a first AMI in patients with DM is associated with a lower risk of major cardiovascular events at a median follow-up of 3 years [28]. To date, no study has evaluated the clinical effects of these two classes of drugs during the in-hospital phase of AMI.

To the best of our knowledge, our study is the first evaluating the potential impact of chronic GLP-1 RA and/or SGLT-2i therapy on in-hospital outcomes of DM patients hospitalized with AMI and treated with current standards of care. Indeed, although data collection of our study lasted 10 years, the matching procedure focused on patients in more recent years, mainly due to the progressively greater prescription of these drugs. Our analysis confirmed the close association between DM and worse in-hospital outcomes. However, when patients with DM were grouped according to their chronic anti-hyperglycemic therapy, those already treated with GLP-1 RA and/or SGLT-2i experienced a 30% lower risk of the primary endpoint than DM patients not on this therapy. The mechanisms underlying the clinical benefit of these drugs in the acute phase of AMI cannot be deduced from our data. However, we chose to combine acute heart failure and acute kidney injury requiring RRT with in-hospital mortality because of their strong prognostic impact on AMI, because they are less likely to be subject to coding error, and because of the well-known cardio- and renal-protective effects of these drugs. The finding that DM patients treated with GLP-1 RA and/or SGLT-2i showed a lower risk than those not treated with these drugs for each component of the primary endpoint supports a cardiac and renal protective effect of these drugs also during AMI hospitalization.

In line with our results, GLP-1 RA was demonstrated to improve myocardial function during AMI soon after successful percutaneous reperfusion and to reduce myocardial infarct size in both the clinical and preclinical settings [14, 15, 29]. In particular, Noyan-Ashraf et al. [30] showed, in an experimental model, that liraglutide administration for 7 days before AMI induction reduces infarct size and improves survival by engaging pro-survival pathways in cardiomyocyte. Moreover, chronic treatment with GLP-1 RA has been shown to reduce blood pressure and plasma levels of atherogenic lipoproteins, potentially resulting in a better hemodynamic profile and in a lower coronary atherosclerotic burden when AMI occurs [31,32,33]. Similarly, SGLT-2i administration was found to preserve cardiac contractile function and efficiency during myocardial ischemia–reperfusion injury, and also to improve metabolism and up-regulation of antioxidative proteins after coronary artery ligation in animal models [34]. Jiang et al. [35], using AMI mouse models with and without DM, demonstrated that treatment with a SGLT-2i significantly reduces infarct size and myocardial fibrosis, leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, SGLT-2i directly inhibits the activity of the Na + /H + exchanger 1 (NHE1) in the cardiomyocytes, significantly reducing autosis induced by glucose deprivation [35]. In contrast, overexpression of NHE1 aggravated the death response of cardiomyocytes to starvation, which was effectively reduced by SGLT-2i treatment. The analysis of NHE1, both in-vitro and in-vivo, confirmed that the cardioprotective effects of SGLT-2i occur, at least in part, via the downregulation of autophagy [35]. Finally, administration of SGLT-2i to patients with DM and a recent AMI was shown to reduce the progression of renal dysfunction [17]. It is also possible that dual SGLT-1 and SGLT-2 inhibition may give a clinical advantage, compared with GLP-1 RA and/or other SGLT-2i, in AMI patients. Indeed, it has been recently demonstrated that the relative increase in SGLT-1 inhibition with sotagliflozin is associated with a greater cardiovascular protection in patients with DM than the currently available SGLT-2i, that provide less degree of SGLT-1 inhibition [36].

Our findings, derived from administrative data, cannot be transferred directly into the clinical practice, but they do provide a strong rationale for further investigation on the potential clinical benefit of these agents also in the in-hospital treatment of AMI. Of note, information on ClinicalTrials.gov (updated to December 2022) shows that several randomized clinical trials focusing on the use of GLP-1 RA or SGLT-2i during AMI are currently ongoing. If the effects observed in the cardiovascular outcome studies are also reproduced in these trials, a sizeable proportion of patients hospitalized with AMI, and not only those with DM, will benefit from early treatment with these drugs [37]. Pending the results of these ongoing studies, our data suggest that in patients already on treatment with GLP-1 RA or SGLT-2i, these drugs should not be discontinued during AMI.

Study limitations

Administrative databases are a reliable tool to describe outcomes of patient cohorts representing the real clinical care, since they collect data over time in a standardized way and at low cost. However, limitations that are typical of all the studies based on administrative datasets need to be acknowledged. Administrative data can suffer from systematic biases as their quality depends on the accuracy of coding. However, it should be highlighted that the endpoints considered in our study, as well as the variables chosen for risk adjustment, are less likely to be subject to coding error. Second, in our study, DM was defined according to chronic exposure to anti-hyperglycemic agents. Thus, patients with unknown DM and those treated with lifestyle and diet modification only were misclassified. Similarly, we were unable to distinguish between type 1 and type 2 DM. Third, the small number of events does not allow us to detect a potentially significant difference in the beneficial effect between GLP-1 RA and SGLT-2i or among single agents of the same class of drugs. Clinical trials of patients randomized to GLP-1 RA vs. SGLT-2i vs. both together are not currently available. However, one observational study found SGLT-2i to be more effective than GLP-1 RA in improving cardiovascular outcomes of DM patients [38] while another showed the superiority of GLP-1 RA [39], and a third one reported no differences in major cardiovascular events between these two drug classes [40]. In all these studies, the comparison was made in terms of prevention of cardiovascular events and not of protection during AMI, as in the present study. Fourth, GLP-1 RA and SGLT-2i can be prescribed in Italy only by diabetes specialists and this can represent a selection bias potentially identifying a population in which control of risk factors is more rigorous. However, at our sensitivity analysis comparing these drugs with DPP-4i, that similarly require a specialist prescription, the benefit observed with the former drugs was confirmed. Finally, some specific pieces of information on clinical variables or laboratory tests, including glycated hemoglobin, body mass index, estimated glomerular filtration rate, and left ventricular ejection fraction, which deserve attention when referring to outcomes in AMI, were not available. Similarly, information on withdrawal of oral diabetic medication during hospitalization for AMI could not be retrieved.

Conclusions

Our study indicates that chronic therapy with GLP-1 RA and/or SGLT-2i has a favorable impact on the clinical outcome of DM patients hospitalized with AMI and seems to reduce the prognostic gap still existing between DM and non-DM patients. These promising data further support the rationale for the ongoing randomized clinical trials investigating these drugs in patients with AMI.

Availability of data and materials

The data underlying this article were provided by the Lombardy region by permission and cannot be shared without permission of the Lombardy region.

Abbreviations

AMI:

Acute myocardial infarction

ATC:

Therapeutic chemical classification

CI:

Confidence intervals

DM:

Diabetes mellitus

DPP-4i:

Dipeptidyl peptidase 4 inhibitors

GLP-1 RA:

Glucagon-like peptide-1 receptor agonists

OR:

Odds ratio

SGLT-2i:

Sodium glucose cotransporter-2 inhibitors

STEMI:

ST-segment elevation myocardial infarction

References

  1. Standl E, Khunti K, Hansen TB, Schnell O. The global epidemics of diabetes in the 21st century: current situation and perspectives. Eur J Prev Cardiol. 2019;26(2):7–14.

    Article  Google Scholar 

  2. Ovbiagele B, Markovic D, Fonarow GC. Recent US patterns and predictors of prevalent diabetes among acute myocardial infarction patients. Cardiol Res Pract. 2011;2011:1–8.

    Article  Google Scholar 

  3. Marenzi G, Cosentino N, Milazzo V, et al. Prognostic value of the acute-to-chronic glycemic ratio at admission in acute myocardial infarction: a prospective study. Diabetes Care. 2018;41:847–53.

    Article  CAS  Google Scholar 

  4. Ahmed B, Davis HT, Laskey WK. In-hospital mortality among patients with type 2 diabetes mellitus and acute myocardial infarction: results from the national inpatient sample, 2000–2010. J Am Heart Assoc. 2014. https://doi.org/10.1161/JAHA.114.001090.

    Article  Google Scholar 

  5. Berry C, Tardif J-C, Bourassa MG. Coronary heart disease in patients with diabetes. J Am Coll Cardiol. 2007;49:643–56.

    Article  CAS  Google Scholar 

  6. Burgess S, Juergens CP, Yang W, et al. Cardiac mortality, diabetes mellitus, and multivessel disease in ST elevation myocardial infarction. Int J Cardiol. 2021;323:13–8.

    Article  Google Scholar 

  7. Milazzo V, Cosentino N, Genovese S, et al. Diabetes mellitus and acute myocardial infarction: impact on short and long-term mortality. Adv Exp Med Biol. 2021;1307:153–69.

    Article  CAS  Google Scholar 

  8. Marenzi G, Cosentino N, Genovese S, et al. Reduced cardio-renal function accounts for most of the in-hospital morbidity and mortality risk among patients with type 2 diabetes undergoing primary percutaneous coronary intervention for st-segment elevation myocardial infarction. Diabetes Care. 2019;42:1305–11.

    Article  Google Scholar 

  9. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7:776–85.

    Article  CAS  Google Scholar 

  10. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019;139:2022–31.

    Article  CAS  Google Scholar 

  11. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394:121–30.

    Article  CAS  Google Scholar 

  12. Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018;138:1537–50.

    Article  CAS  Google Scholar 

  13. Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137:119–29.

    Article  CAS  Google Scholar 

  14. Noyan-Ashraf MH, Momen MA, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:975–83.

    Article  CAS  Google Scholar 

  15. Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33:1491–9.

    Article  Google Scholar 

  16. Andreadou I, Efentakis P, Balafas E, et al. Empagliflozin limits myocardial infarction in vivo and cell death in vitro: role of STAT3, mitochondria, and redox aspects. Front Physiol. 2017;8:1077.

    Article  Google Scholar 

  17. Mozawa K, Kubota Y, Hoshika Y, et al. Empagliflozin confers reno-protection in acute myocardial infarction and type 2 diabetes mellitus. ESC Hear Fail. 2021;8:4161–73.

    Article  Google Scholar 

  18. Tripolt NJ, Kolesnik E, Pferschy PN, et al. EMMY study group. Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction—the EMMY trial. Am Heart J. 2020;221:39–47.

    Article  CAS  Google Scholar 

  19. Clinicaltrials.gov. NCT04564742—Dapagliflozin effects on cardiovascular events in patients with an acute heart attack (DAPA-MI). https://clinicaltrials.gov/ct2/show/NCT04564742. Published 2021.

  20. Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of Saxagliptin on renal outcomes in the SAVOR-TIMI 53 Trial. Diabetes Care. 2017;40:69–76.

    Article  CAS  Google Scholar 

  21. Rosenstock J, Perkovic V, Johansen OE, et al. CARMELINA investigators effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAM. 2019;321:69–79.

    Article  CAS  Google Scholar 

  22. Gore MO, Patel MJ, Kosiborod M, et al. National registry of myocardial infarction investigators diabetes mellitus and trends in hospital survival after myocardial infarction, 1994 to 2006. Circ Cardiovasc Qual Outcomes. 2012;5:791–7.

    Article  Google Scholar 

  23. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298:765.

    Article  CAS  Google Scholar 

  24. Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW. Coronary angioplasty in diabetic patients. Circulation. 1996;94:1818–25.

    Article  CAS  Google Scholar 

  25. Odegaard AO, Jacobs DR, Sanchez OA, Goff DC, Reiner AP, Gross MD. Oxidative stress, inflammation, endothelial dysfunction and incidence of type 2 diabetes. Cardiovasc Diabetol. 2016;15:51.

    Article  Google Scholar 

  26. Pfeffer MA, Claggett B, Diaz R, et al. ELIXA investigators lixisenatide in patients with Type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.

    Article  CAS  Google Scholar 

  27. Shimizu W, Kubota Y, Hoshika Y, et al. EMBODY trial investigators. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol. 2020. https://doi.org/10.1186/s12933-020-01127-z.

    Article  Google Scholar 

  28. Trevisan M, Fu EL, Szummer K, et al. Glucagon-like peptide-1 receptor agonists and the risk of cardiovascular events in diabetes patients surviving an acute myocardial infarction. Eur Heart J Cardiovascular Pharmacother. 2021;7:104–11.

    Article  Google Scholar 

  29. Timmers L, Henriques JP, de Kleijn DP, et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol. 2009;53:501–10.

    Article  CAS  Google Scholar 

  30. Noyan-Ashraf MH, Momen MA, Ban K, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:975–83.

    Article  CAS  Google Scholar 

  31. Lundgren JR, Færch K, Witte DR, et al. Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures. Cardiovasc Diabetol. 2019;18:130.

    Article  Google Scholar 

  32. Engelbrechtsen L, Lundgren J, Wewer Albrechtsen NJ, et al. Treatment with liraglutide may improve markers of CVD reflected by reduced levels of apoB. Obes Sci Pract. 2017;3:425–33.

    Article  CAS  Google Scholar 

  33. Torekov SS, Kipnes MS, Harley RE, Holst JJ, Ehlers MR. Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:639–43.

    Article  CAS  Google Scholar 

  34. Mizuno M, Kuno A, Yano T, et al. Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts. Physiol Rep. 2018;6:e13741.

    Article  Google Scholar 

  35. Jiang K, Xu Y, Wang D, et al. Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis. Protein Cell. 2022;13:336–59.

    Article  CAS  Google Scholar 

  36. Pitt B, Steg G, Leiter LA, Bhatt DL. The role of combined SGLT1/SGLT2 inhibition in reducing the incidence of stroke and myocardial infarction in patients with type 2 diabetes. Cardiovasc Drugs Therapy. 2022. https://doi.org/10.1007/s10557-021-07291-y.

    Article  Google Scholar 

  37. Cosentino N, Bonomi A, Campodonico J, et al. Can the in-hospital mortality gap between STEMI patients with and without diabetes mellitus be reduced? The cardio-renal hypothesis. Nutr Metab Cardiovasc Dis. 2021;31:1516–20.

    Article  Google Scholar 

  38. Longato E, Di Camillo B, Sparacino G, Gubian L, Avogaro A, Fadini GP. Cardiovascular outcomes of type 2 diabetic patients treated with SGLT-2 inhibitors versus GLP-1 receptor agonists in real-life. BMJ Open Diabetes Res Care. 2020;8: e001451.

    Article  Google Scholar 

  39. Baviera M, Foresta A, Colacioppo P, et al. Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study. Cardiovasc Diabetol. 2022;21:162.

    Article  CAS  Google Scholar 

  40. Patorno E, Pawar A, Bessette LG, et al. Comparative effectiveness and safety of sodium-glucose cotransporter 2 inhibitors versus glucagon-like peptide 1 receptor agonists in older adults. Diabetes Care. 2021;44:826–35.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge Erica Rurali, Ph.D. for her precious help and all researchers involved in the EASY-NET network program.

Funding

This work was partly financed by the Italian Ministry of Health and the Lombardia Region (Grant NET-2016-02364191-EASY-NET).

Author information

Authors and Affiliations

Authors

Contributions

Dr. M and Dr. T and Dr. C had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: GM, SG, FT, NC. Acquisition of data: FT, ML, LG, PP, AB. Analysis and interpretation of data: GM, NC, SG, FT, PA. Drafting the manuscript: GM, NC, SG, PA. Critical revision of the manuscript for important intellectual content: MB, PC, MCR, OL. Statistical analysis: AB, ML. Obtained funding: GM. Administrative, technical, or material support: GM. Study supervision: GM, SG, PA. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Giancarlo Marenzi.

Ethics declarations

Ethics approval and consent to participate

In Italy, studies using retrospective aggregated-anonymous data from administrative databases do not require Ethics Committee approval nor notification. The data underlying this article were provided by the Lombardy region by permission and cannot be shared without permission of the Lombardy region.

Consent for publication

Not applicable.

Competing interests

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file1

: Table S1. Clinical characteristics of DM patients treated with GLP-1 RA or SGLT-2i and hospitalized with acute myocardial infarction from 2010 to 2019.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trombara, F., Cosentino, N., Bonomi, A. et al. Impact of chronic GLP-1 RA and SGLT-2I therapy on in-hospital outcome of diabetic patients with acute myocardial infarction. Cardiovasc Diabetol 22, 26 (2023). https://doi.org/10.1186/s12933-023-01758-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12933-023-01758-y

Keywords