The Effect of SGLT-2i and GLP-1RA on Major Cardiovascular Conditions: A Meta-Analysis

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Background
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with diabetes mellitus.Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) and Glucagon-like Peptide-1 Receptor Agonists (GLP-1RA) are two anti-hyperglycemic agents that have emerged as new therapies for patients with Type Two Diabetes Mellitus (T2DM) and are currently being prescribed by a vast number of clinicians.SGLT-2i prevent the reuptake of sodium, glucose, and water at the proximal convoluted tubule of the nephron 1 .GLP-1RA help stimulate the endogenous production of insulin 2 .While elevated blood glucose and T2DM were the original indications of use for these medications, utility in heart failure (HF) and other cardiac conditions have been recently explored.Some of the mechanisms that have been postulated that have helped include afterload reduction as well as improved glycemic control.Afterload reduction, achieved through proper blood pressure management, is thought to improve cardiac strain.Glycemic control is thought to reduce the risk for metabolic events and coronary artery disease [1,2].
Due to initial landmark trials demonstrating the benefit of SGLT-2i, the Food and Drug Administration (FDA) approved the use of this medication class for use in heart failure and other heart-related medical conditions in 2020 [3].Many other anti-hyperglycemic medications, including GLP-1RA, have been studied for their role in improving cardiovascular outcomes.Some GLP-1RA, including Dulaglutide, have also been approved for reduction of cardiovascular events [4].Randomized controlled trials (RCTs) have demonstrated the benefit in many aspects of the cardiovascular profile including Major Adverse Cardiac Events (MACE), heart failure (HF) hospitalization rates, atrial fibrillation (AF) rates, and the development of HF symptoms.Data regarding the benefit of different medications in either of the two medication classes in the aforementioned disease categories needs to be explored further.Thus, the purpose of this meta-analysis is to determine which cardiac diseases have been shown by the current literature to be most positively impacted by SGLT-2i and GLP-1RA and to discuss the relative performance of both drugs in various cardiovascular disease categories.The results of this study would allow clinicians to effectively manage patients with these co-morbidities or at risk for these comorbidities.If these medications demonstrated statistically significant benefit in any of the studied cardiovascular conditions, this could help reduce the rate of development of condition or incidence of severe outcomes.

Methods
A literature search, conducted by all authors listed in the authorship, using the databases PubMed and Google Scholar were performed, ranging from the years 2010-2022.The search for studies lasted three months, occurring mostly in the first quarter of 2022.The following keywords and their MeSH terms were used for the search: '(sodium-glucose co-transporter inhibitor OR SGLT2 inhibitor OR SGLT-2 inhibitor OR SGLT 2 inhibitor), (Glucagon-like Peptide-1 Receptor agonist OR GLP-1RA OR GLP1 agonist), (heart failure or cardiac failure OR CHF)'.The effect of both drug classes (SGLT-2i and GLP-1RA) on the rates of the following categories was researched: Major Adverse Cardiac Events (MACE), HF symptoms and hospitalizations, AF, stroke, and myocardial infarction.MACE was defined as the traditional three-point definition: death from cardiovascular cause, nonfatal stroke, or nonfatal myocardial infarction.The criteria used for selection of the categories included availability of data from chart review and results of prior available studies.While most other studies focus on MACE and HF, other aspects of cardiovascular disease, such as atrial fibrillation, stroke, and MI, are not well-covered.This was decided after database review on PubMed and Google Scholar platforms.As a result, the decision to study the effects of SGLT-2i and GLP-1RA on these other cardiovascular diseases was made.
Regarding the criteria of studies chosen, those that met the criteria above were included in the study.It is approximated that more than 50% of the search results did not meet the inclusion criteria.

Inclusion Criteria and Outcomes of Interest
Inclusion criteria for the studies included: 1.Large randomized controlled trials (RCTs) or meta-analyses of previously performed RCTs.Large Randomized controlled trials were defined as studies whose patient populations were greater than 1,000 participants.2. Patients who took either SGLT-2i or GLP-1RA.The outcomes of interest included the hazard ratios (HR) and percent changes compared to placebo within each disease type for both SGLT-2i and GLP-1RA.3. Studies that assessed the effect of SGLT-2 or GLP-1 agonists on any of the following cardiovascular profiles: primary cardiovascular outcomes, HF symptoms and hospitalizations, AF, stroke, and myocardial infarction.

Statistical Analysis
For all meta-analyses, the Bayesian Hierarchical model for Meta Analysis was applied as presented in section 5.6 of Gelman to estimate the overall hazard ratio along with central 95% credible interval.This model is the Bayesian version of the random-effects meta-analysis introduced by DerSimonian and Laird (1986) [5,6].More specifically, for each study , we performed the log of the hazard ratio, , and computed the standard deviation of the log hazard ratio estimate, , based on the length of the log transformed confidence intervals.We fit the Bayesian mode with standard deviation and priors and proportional to 1.For meta-analysis that consider four or fewer studies, priors proportional to 1 and a standard normal restricted to the positive real line were used.The overall hazard ratio estimate is the posterior expected value of with central 95% credible interval given by the 0.025 and 0.975 posterior quantiles of .To standardize notation, in this paper we call P-Value the Bayesian measure of evidence against the Null hypothesis (Pereira and Stern, 1999), defined as the smallest number ev such that the 1-ev central credible interval for estimate overall HR (i.e., exp(mu)) does not contain the null value (HR=1) indicating overall no difference between the treatment groups [7].The Bayesian measure of evidence is a P-value in the sense that it is the result of "inverting the credible interval" similar to the inversion of the confidence interval to compute a p-value.Additionally, as a measurement of heterogenicity in the outcomes across studies, we compute the Bayesian version of that is interpreted as the total variation in the estimates of treatment effect that is due to heterogeneity between studies 8 .Values of close to zero indicate that the clinical trials are homogeneous for the category while values close to 1 indicate heterogenicity [8].
P-values, for determination of statistical significance, were evaluated against an alpha value of 0.05.A p-value less than the alpha value of 0.05 was determined to be statistically significant and the null hypothesis of no difference between treatment and placebo was rejected.For the Ejection Fraction analysis, analysis of variance was performed to detect the main effects, and difference between SGLT-2 inhibitors and GLP-1RA.Computations were carried out using R statistical programming language and R package rstan.

Results (Data) Major Adverse Cardiovascular Event (MACE)
The overall aggregate of the studies demonstrated statistical significance for both SGLT-2i and GLP-1RA in prevention of MACE.Both groups employed studies with large sample sizes.Even within individual studies, a majority of the studies that were included for each drug type demonstrated statistical significance with respect to MACE.

Atrial Fibrillation
The overall aggregate of studies showed no statistically significant benefit for SGLT-2i in preventing AF.Individually, 2/3 of the studies did show benefit.Data for GLP-1RA were limited.

Stroke
The overall aggregate of studies for GLP-1RA demonstrated statistically significant benefit in preventing stroke, but not SGLT-2 inhibitors.Individually, three of the studies for GLP-1RA showed benefit with respect to stroke reduction while none of the studies for SGLT-2i demonstrated statistical significance.

Myocardial Infarction
No statistically significant benefit for either SGLT-2i or GLP-1RA.Individually, none of the studies demonstrated statistical significance for SGLT-2i while only one of the studies for GLP-1RA demonstrated statistical significance.

Author Study Population SGLT-2i Type Hazard Ratio [95% Confidence Interval]
EMPA-REG (Zinman et al. ) [11] 7   [18] Randomized, double-blind, placebo-controlled trial.9,901 Men and women aged at least 50 years with T2DM who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned PIONEER-6 (Husain et al.) [19] 3183 patients were randomly assigned to receive oral semaglutide or placebo.The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease.
Semaglutide 1.18 [0.73-1.90]Exscel Trial (Holman et al.) [20] 14,752 patients with T2DM were randomly assigned, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly.Patients were followed for a median of 3.

Discussion
This meta-analysis of the current landmark trial data regarding the utility of SGLT-2i and GLP-1RA explored the efficacy of both anti-hyperglycemic medications in reduction of cardiovascular conditions and symptoms while also exploring differences between the two medication classes.Our findings are consistent with other published studies and confirm the various cardioprotective effects of these medications.Moreover, in this analysis we studied varying efficacies of different medications in either of the drug class in preventing MACE (major adverse cardiovascular events), heart failure hospitalizations, atrial fibrillation, stroke, and myocardial infarction.Additionally, this analysis studied the ability of both medications in either drug class in improving heart failure symptoms.
This study had two major findings: both medication classes help prevent major cardiovascular events (MACE) and that patient underlying conditions should not necessarily guide which class of medication to choose.
Regarding MACE, analysis of the above trials of SGLT-2i and GLP-1RA clearly demonstrated that both antihyperglycemics had a statistically significant reduction in the incidence of major adverse cardiovascular events.A similar magnitude of reduction in MACE has been noticed in previously published studies comparing the two drug class 32 .This shows that these medications can be of major benefit to patients at risk of major cardiovascular events.Cardiac events are among the leading causes of death.As a result, these results mean that these classes of medications can be among the leading agents in prevention of death overall.
Regarding individual effects, SGLT-2i and GLP-1RA do not appear to have much in the way of preventing individual conditions, with the exception of SGLT-2i with respect to Heart Failure and GLP-1RA with respect to stroke.Furthermore, this means that with regards to atrial fibrillation, stroke, and myocardial infarction, there is no demonstrated improvement in either class of medication.This suggests that individual conditions should not be the primary focus of these medications.Preventing overall cardiovascular outcomes should be the primary focus of prescribing either SLGT-2 inhibitors or GLP-1RA.If a patient has either heart failure or pre-disposition to stroke, it may be then wise to prescribe SGLT-2i or GLP-1RA agonists, respectively.It also means that more studies on alternative agents in preventing atrial fibrillation, stroke, or myocardial infarction must be purused.
On the topic of heart failure hospitalizations, there was a striking difference noticed in terms of heart failure hospitalization rates with use of SGLT-2i compared with GLP-1RA agonists.This is consistent with results from a large population-based analysis by Patorno et al. in which the initiation of SGLT-2i versus GLP-1RA therapy was associated with an approximately 30% reduction in the risk for the primary HHF outcome in all included patients, regardless of the presence or absence of cardiovascular disease at baseline 33 .This finding is also consistent with the effects of SGLT2 inhibitors on heart failure hospitalizations in cardiovascular outcome trials and in other real-world comparisons to other antidiabetic drugs 34 .
Multiple mechanisms have been proposed for cardioprotective effects of SGLT-2i, while mechanism for the cardioprotective effects of GLP-1RA is still relatively unknown.Lopaschuk and Verma proposed that SGLT-2i increase diuresis, decrease blood pressure, and decrease sympathetic response 35 .This may translate into reduced cardiac afterload and improved ventricular-atrial coupling, possibly explaining why SGLT-2i perform better in reducing heart failure hospitalizations and improving heart failure symptoms 34 .Cox et al. demonstrated that GLP-1RA reduce the blood sugar levels and indirectly reduce inflammation or atherosclerotic plaque formation 36 .Given that atherosclerotic plaque formation and rupture are among the foundational causes of strokes, this can be hypothesized to explain a reduction in stroke events seen in patients on GLP-1RA agnostic therapy.This meta-analysis includes a diverse number of studies and presents a holistic picture of how SGLT-2i and GLP-1RA perform in the general cardiovascular risk population.This study may be particularly useful for clinicians needing to decide appropriate treatment regimens for patients with diabetes and concurrent cardiovascular symptoms.However, this study still has certain limitations.First, the availability of data on GLP-1RA were limited compared to the data available on SGLT-2 inhibitors, making some comparison computations heterogeneous.Second, the current study suffers from the inherent limitation of meta-analysis that can arise as the positive results might be published more easily than the negative results.Thirdly, there could be other confounding variables present with regards to test subjects.Dietary habits, lifestyle differences, and inherent genetic differences all are factors that are difficult to control for in an randomized controlled trial.Consequently, it is difficult to say that the treatment alone accounts for differences present between treatment and placebo groups.Additionally, the number of trials included in SGLT2 inhibitors treatment and GLP-1RA treatment might not be comparable.Therefore, more complete data must be available in order to create a more thorough meta-analysis.

Conclusions
The data of this meta-analysis suggests that both SGLT-2iand GLP-1RA are important considerations in the medication repertoire for physicians treating patients with diabetes, heart failure, those at risk for a major cardiovascular event, or a combination of these conditions.These meta-analyses demonstrate that both SGLT-2iand GLP-1RA provide statistically significant benefits in a diverse array of cardiovascular conditions.Both classes of anti-hyperglycemics provide protection against major cardiovascular events.With regard to specific conditions, SGLT-2i demonstrate greater benefit in patients with heart failure, while GLP-1RA demonstrate greater benefit in patients at risk for a stroke.

Ethics approval and consent to participate:
Not applicable 4. LLN obtained, analyzed, and interpreted the data.LLN participated in the statistical analysis.LLN was a major contributor to writing the manuscript.
5. TK obtained, analyzed, and interpreted the data.TK participated in the statistical analysis.TK was a major contributor to writing the manuscript.
6.All authors read and approved the final manuscript.

4 ,Table 3 :Figure 3 :
Figure 3: Forest Plot of Results of Studies Investigating the effect of SGLT-2i on HF Hospitalizations

4 ,Table 4 :Figure 4 :
Figure 4: Forest Plot of Studies Investigating the effect of GLP-1RA on HF Hospitalizations

Figure 5 :
Figure 5: Forest Plot of Studies Investigating the effect of SGLT-2i on Atrial Fibrillation

4 ,
731 patients were assigned to receive albiglutide and 4,732 patients to receive placebo.Patient ages were 40 years and older.Underlying conditions included T2DM and cardiovascular disease (at a 1:1 ratio).Albiglutide 0.86 [0.66-1.14]

Total: 9 ,
463 patients.Double-blind, randomized, placebo-controlled trial: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo; patient ages 40 years and older with T2DM and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30-50 mg, based on glycemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care.Albiglutide 0.75 [0.61-0.90]Elixa Trial (Pfeffer et al.) [22] 6,068 patients with T2DM who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo Lixisenatide 1.03[0.87-1.22]Overall Results 0.92 [0.79-1.05]

Table 6 :
Data Results of Studies Investigating the effect of SGLT-2i on Stroke CANVAS (Neal et al.) EMPA-REG (Zinman et al.) VERTIS CV (Cannon et al.) Hazard Ra�o [95% Confidence Interval] Study Figure 6: Forest Plot of Studies Investigating the effect of SGLT-2i on Stroke

Table 8 :
Data Results of Studies Investigating the effect of SGLT-2i on Myocardial Infarction CANVAS (Neal et al.) EMPA-REG (Zinman et al. ) Hazard Ra�o [95% Confidence Interval] Study Figure 8: Forest Plot of Studies Investigating the effect of SGLT-2i on Myocardial Infarction

Table 9 :
Data Results of Studies Investigating the effect of GLP-1RA on Myocardial Infarction

Figure 9 :
Forest Plot of Studies Investigating the effect of GLP-1RA on Myocardial Infarction

Table 10 :
Data Results of Studies Investigating the effect of SGLT-2i on HF Symptoms