# Pooled Hazard Ratio for 3-Point MACE with SGLT2 Inhibitors Versus Placebo in Adults with Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Comprehensive Literature Synthesis

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### Background and Context

Type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) represent a particularly lethal clinical intersection. Globally, an estimated 536.6 million adults were living with diabetes in 2021, a figure projected to reach 783.2 million by 2045 (PMC12277171). Among patients with T2DM, cardiovascular disease is the leading cause of morbidity and mortality, with peripheral arterial disease, heart failure, stable angina, non-fatal myocardial infarction, and cerebrovascular accidents representing dominant complications (PMC12277171). The coexistence of T2DM and established ASCVD creates a compounding risk environment: hyperglycemia promotes endothelial dysfunction, oxidative stress, hypercoagulability, and autonomic neuropathy, each of which independently accelerates atherosclerotic progression and plaque instability. For decades, the pharmacological management of T2DM focused almost exclusively on glycemic control, yet landmark trials such as ACCORD, ADVANCE, and UKPDS demonstrated that intensive glucose lowering alone produced inconsistent and often modest cardiovascular benefits, particularly for macrovascular endpoints such as myocardial infarction and stroke.

The regulatory landscape shifted fundamentally when the United States Food and Drug Administration and the European Medicines Agency required all new antidiabetic drugs to undergo large cardiovascular outcome trials (CVOTs) to rule out excess cardiovascular risk, prompted by the rosiglitazone safety controversy. The primary outcome in cardiovascular outcome trials (CVOTs) mandated by the FDA and EMA was MACE, defined as the composite of cardiovascular mortality, nonfatal MI, and nonfatal stroke (PMC6714383). The SGLT2 inhibitor class — comprising empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin as the principal agents studied in dedicated CVOTs — has pleiotropic cardiorenal protective properties that appear largely independent of their glycemic effects (PMC8680308).

The question of what pooled hazard ratio (HR) for 3-point MACE (3P-MACE: cardiovascular death, non-fatal MI, non-fatal stroke) SGLT2 inhibitors confer versus placebo in adults with T2DM and established ASCVD is clinically critical for several reasons. First, the individual CVOTs — EMPA-REG OUTCOME (empagliflozin), CANVAS Program (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), CREDENCE (canagliflozin, renal/CV), and VERTIS-CV (ertugliflozin) — enrolled populations with varying proportions of established ASCVD versus multiple cardiovascular risk factors only, making direct cross-trial comparisons of MACE hazard ratios potentially misleading. Second, the magnitude of MACE benefit appears to be substantially heterogeneous across the class, with empagliflozin and canagliflozin demonstrating statistically significant MACE reductions in their primary analyses while dapagliflozin and ertugliflozin achieved only non-inferiority. Third, the 2019 European Society of Cardiology guidelines on diabetes and cardiovascular diseases proposed making SGLT2 inhibitors a first-line glucose-lowering drug in patients with type 2 diabetes and cardiovascular disease (PMC8427950). Understanding the precise magnitude of this pooled effect — and its confidence interval — is therefore essential for shared decision-making, guideline development, and health technology assessment.

The historical context of SGLT2 inhibitor development is also relevant. These agents were initially approved as glucose-lowering drugs based on their mechanism of inhibiting renal tubular glucose reabsorption via the SGLT2 transporter in the proximal convoluted tubule, which accounts for approximately 90% of filtered glucose reabsorption (PMC12277171). The EMPA-REG OUTCOME trial enrolled 7,020 patients with T2DM and established cardiovascular disease and was the first to demonstrate the cardiovascular protective effects of empagliflozin (PMC8680308). This unexpected cardiovascular mortality benefit fundamentally reframed the class as cardioprotective agents and triggered a cascade of mechanistic investigations, additional CVOTs, and ultimately regulatory approvals for heart failure indications independent of diabetes status. The present review synthesizes the available evidence from dedicated CVOTs and their meta-analyses to provide the most precise and contextually grounded estimate of the pooled 3P-MACE HR for SGLT2 inhibitors versus placebo in the T2DM plus established ASCVD population.

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### Molecular and Mechanistic Pathways

#### Hemodynamic and Natriuretic Mechanisms

The primary mechanism through which SGLT2 inhibitors exert their cardiovascular effects has been debated extensively, but the hemodynamic hypothesis — centered on natriuresis, osmotic diuresis, and plasma volume contraction — remains the most widely accepted canonical explanation for the rapid onset of cardiovascular benefit observed in trials such as EMPA-REG OUTCOME (PMC8680308). SGLT2 inhibitors prevent reabsorption of glucose and simultaneously reduce sodium reabsorption in the proximal convoluted tubules, increasing urinary sodium excretion; this natriuretic effect increases sodium delivery to the macula densa, reactivating tubuloglomerular feedback and causing afferent arteriolar vasoconstriction via adenosine, which reduces intraglomerular pressure (PMC11857657). The resulting plasma volume contraction reduces cardiac preload, while associated reductions in blood pressure reduce afterload, collectively decreasing myocardial oxygen demand and wall stress.

The diuretic effect of SGLT2 inhibitors has been compared mechanistically to loop diuretics, with both classes associated with a similar natriuretic effect and reduced interstitial fluid; these natriuretic effects may explain the findings in reducing heart failure hospitalization (PMC8733833). Quantitative estimates from EMPA-REG OUTCOME suggested that hemoconcentration — reflected by increases in hematocrit — accounted for approximately 50% of the observed cardiovascular benefit, supporting the hemodynamic hypothesis as a major contributor (PMC9613919). However, this estimate has been contested, as the rapid onset of cardiovascular mortality reduction (within weeks of treatment initiation) is difficult to reconcile with a mechanism that would require sustained hemodynamic remodeling over months. The hypothesis that the cardioprotective mechanism is independent of HbA1c reduction is supported by the observation that SGLT2 inhibitor benefits appear consistent regardless of baseline or time-dependent changes in glycated hemoglobin (PMC8680308).

#### Cardiac Metabolic and Energetic Mechanisms

A competing and increasingly prominent mechanistic hypothesis centers on the shift in myocardial substrate utilization induced by SGLT2 inhibitors. These agents promote lipolysis and increase circulating ketone body concentrations, particularly beta-hydroxybutyrate, which serves as a more oxygen-efficient fuel for the failing myocardium compared to glucose or fatty acids (PMC11857657). The concept of "fasting mimicry" — whereby SGLT2 inhibitor-induced glucosuria activates SIRT1 and AMPK pathways, reducing oxidative stress and improving mitochondrial function — has been proposed as a glucose-independent mechanism of cardioprotection (PMC11868892). Empagliflozin has been shown in preclinical models to suppress autosis by inhibiting the Na+/H+ exchanger 1 (NHE1) in cardiomyocytes, optimizing autophagic flux and reducing myocardial ischemic injury, with downstream improvements in left ventricular function post-acute myocardial infarction (PMC11757226). The cardioprotective effects of SGLT2 inhibitors are also hypothesized to involve improvement in ventricular load through natriuresis and osmotic diuresis, and SGLT2 inhibitors have been associated with inhibition of cardiac fibrosis, which is considered an important heart failure pathway (PMC8733833).

Animal studies demonstrated that empagliflozin can mitigate cardiac fibrosis following acute myocardial infarction through inhibition of the TGF-β1/Smad3 fibrosis pathway, independent of hemodynamic effects. Pre-administration of canagliflozin in a porcine model before coronary artery occlusion resulted in enhanced myocardial performance during ischemic conditions (PMC11868892). These metabolic and energetic mechanisms may explain why SGLT2 inhibitors reduce heart failure hospitalization so robustly across all patient populations — including those without diabetes — while their effects on atherosclerotic endpoints such as myocardial infarction and stroke are more variable and population-dependent.

#### Anti-Inflammatory, Anti-Fibrotic, and Vascular Mechanisms

A third mechanistic axis involves the anti-inflammatory and anti-fibrotic properties of SGLT2 inhibitors. SGLT2 inhibitors reduce markers of systemic inflammation including interleukins and tumor necrosis factor-alpha, and empagliflozin has been proposed to reduce NLRP3 inflammasome activation, possibly secondary to increased circulating beta-hydroxybutyrate (PMC11857657). Canagliflozin and dapagliflozin have demonstrated reductions in inflammatory molecular processes including extracellular matrix turnover and fibrosis in clinical studies (PMC9613919).

From a vascular standpoint, SGLT2 inhibitors decrease uric acid levels through competitive inhibition of urate reabsorption via the GLUT9b transporter in the proximal tubule, and elevated uric acid has been independently associated with hypertension and MACE (PMC10171571). Additionally, SGLT2 inhibitors have been associated with improvements in left ventricular mass index and inhibition of ventricular remodeling in patients with diabetes and ASCVD after six months of treatment (PMC9613919). The inhibition of sympathetic nervous system activity by SGLT2 inhibitors — reflected by reductions in norepinephrine and tyrosine hydroxylase levels — may reduce arrhythmia risk and contribute to the antiarrhythmic properties of this drug class (PMC11262450).

#### Renal Tubuloglomerular Feedback and Intraglomerular Pressure Reduction

The renal mechanism of SGLT2 inhibitors — specifically the restoration of tubuloglomerular feedback through increased distal sodium delivery — is mechanistically linked to cardiovascular protection through multiple pathways. By reducing intraglomerular pressure, SGLT2 inhibitors slow the progression of diabetic nephropathy and reduce albuminuria, which is itself an independent cardiovascular risk factor (PMC10171571). The characteristic early dip in estimated glomerular filtration rate (eGFR) observed upon SGLT2 inhibitor initiation is followed by a slower rate of eGFR decline over time compared to placebo, as demonstrated in CREDENCE, DAPA-CKD, EMPEROR-Reduced, and EMPEROR-Preserved (PMC10171571). This renoprotective mechanism reduces the cardiorenal syndrome burden, whereby progressive kidney disease amplifies cardiovascular risk through fluid retention, neurohormonal activation, and uremic toxin accumulation. SGLT2 inhibitors are associated with a significant reduction in acute kidney injury (AKI) risk, with pooled odds ratios of approximately 0.81 (95% CI 0.74–0.90) versus placebo across multiple meta-analyses (PMC10171571).

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### Dose-Response and Pharmacokinetics

The dedicated CVOTs for SGLT2 inhibitors employed the following dose regimens: empagliflozin at 10 mg and 25 mg once daily (EMPA-REG OUTCOME), canagliflozin at 100 mg and 300 mg once daily (CANVAS Program), dapagliflozin at 10 mg once daily (DECLARE-TIMI 58), canagliflozin at 100 mg once daily (CREDENCE), and ertugliflozin at 5 mg and 15 mg once daily (VERTIS-CV). A critical finding across these trials is that the cardiovascular benefits — particularly the reduction in heart failure hospitalization and cardiovascular mortality — appear to be largely dose-independent within the therapeutic range studied. In the CANVAS Program, the cardiovascular outcomes were analyzed across the combined canagliflozin group (100 mg and 300 mg) versus placebo, with no significant dose-response heterogeneity reported for MACE.

The network meta-analysis by Jiang et al. (PMC8967154) specifically examined dose-level differences among SGLT2 inhibitors across 47 RCTs (n=70,574 participants) and found that empagliflozin 10 mg and 25 mg were both associated with significantly lower all-cause mortality compared to placebo, with no statistically significant difference between the two doses. The network meta-analysis by Jiang et al. (PMC8967154) found that empagliflozin 10 mg and 25 mg were both associated with significantly lower all-cause mortality compared to placebo, with no statistically significant difference between the two doses, while canagliflozin 300 mg was associated with significantly higher volume depletion risk (SUCRA probability 95.5%) compared to canagliflozin 100 mg and all empagliflozin and dapagliflozin doses without additional cardiovascular efficacy.

From a pharmacokinetic standpoint, the cardiovascular benefits of SGLT2 inhibitors appear to manifest rapidly — within weeks of treatment initiation — which is inconsistent with a mechanism requiring prolonged glycemic improvement but consistent with the hemodynamic and metabolic mechanisms described above. The observation that SGLT2 inhibitor cardiorenal benefits appear largely independent of baseline and time-dependent changes in glycated hemoglobin (PMC8680308) has important implications for the dose-response relationship: if the cardiovascular benefit is mediated through hemodynamic and metabolic pathways rather than glycemic control, then the dose-response relationship for cardiovascular outcomes may plateau at lower doses than the dose-response relationship for HbA1c reduction.

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### Clinical Evidence and Implications

#### Individual Cardiovascular Outcome Trials: MACE as the Primary Endpoint

**EMPA-REG OUTCOME (Empagliflozin).** The EMPA-REG OUTCOME trial enrolled 7,020 patients with T2DM and established cardiovascular disease and was the first to demonstrate the cardiovascular protective effects of empagliflozin (PMC8680308). The primary endpoint was 3P-MACE (cardiovascular death, non-fatal MI, non-fatal stroke). Empagliflozin significantly reduced 3P-MACE compared to placebo, and this was the first SGLT2 inhibitor CVOT to demonstrate superiority for MACE. The cardiovascular mortality reduction was particularly striking, driving the overall MACE benefit, with non-fatal MI and non-fatal stroke showing non-significant trends. Heart failure hospitalization was also significantly reduced. The trial enrolled exclusively patients with established cardiovascular disease, making it the most directly applicable CVOT to the secondary prevention population of interest.

**CANVAS Program (Canagliflozin).** The CANVAS Program was an integrated analysis of two trials — CANVAS and CANVAS-R — enrolling a total of 10,142 patients with T2DM and either established cardiovascular disease or two or more cardiovascular risk factors (PMC8680308). The mixed population — with approximately two-thirds of participants having established cardiovascular disease — means that the overall MACE result reflects a diluted effect compared to what would be observed in a pure secondary prevention population (PMC8680308). An increased amputation signal was observed with canagliflozin in the CANVAS Program; this signal was not replicated in CREDENCE or other trials, and the FDA issued a warning specifically for canagliflozin rather than the class as a whole (PMC10171571).

**DECLARE-TIMI 58 (Dapagliflozin).** DECLARE-TIMI 58 enrolled 17,160 patients with T2DM and either established ASCVD (40.6%) or multiple cardiovascular risk factors (59.4%), with a median follow-up of 4.2 years. For 3P-MACE, dapagliflozin was non-inferior but not superior to placebo, while for the co-primary endpoint of cardiovascular death or heart failure hospitalization, dapagliflozin demonstrated a significant reduction (PMC8680308, PMC8733833). The failure to achieve MACE superiority in DECLARE-TIMI 58 has been attributed to the lower baseline cardiovascular risk of the enrolled population — with more than half of participants lacking established ASCVD — which reduced the absolute event rate and statistical power to detect a MACE benefit (PMC6714383).

**CREDENCE (Canagliflozin, Renal/CV).** The CREDENCE trial enrolled 4,401 patients with T2DM and albuminuric chronic kidney disease (eGFR 30–90 mL/min/1.73 m²), with a substantial proportion having established cardiovascular disease at baseline (PMC8680308). The primary endpoint was a renal composite, but 3P-MACE was a pre-specified secondary endpoint. Canagliflozin demonstrated significant reductions in MACE and heart failure hospitalization as secondary endpoints in CREDENCE (PMC8680308).

**VERTIS-CV (Ertugliflozin).** The VERTIS-CV trial enrolled 8,246 patients with T2DM and established ASCVD (PMC8680308). The primary endpoint was 3P-MACE. Ertugliflozin was non-inferior but not superior to placebo for 3P-MACE, while heart failure hospitalization was significantly reduced. The failure of ertugliflozin to demonstrate MACE superiority despite enrolling an exclusively established ASCVD population has been attributed to several factors: the relatively modest sample size compared to DECLARE-TIMI 58, the follow-up duration, and potentially drug-specific differences in cardiovascular efficacy within the SGLT2 inhibitor class. The VERTIS-CV result has been the subject of considerable debate regarding whether it represents a true class effect heterogeneity or a statistical power limitation.

#### Pooled Meta-Analyses of 3P-MACE Across CVOTs

The Giugliano et al. (2021) meta-analysis pooling 11 CVOTs including EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, CREDENCE, DAPA-HF, DAPA-CKD, VERTIS-CV, EMPEROR-Reduced, SCORED, SOLOIST-WHF, and EMPEROR-Preserved (n=77,541 participants) reported a pooled HR for MACE of 0.88 (95% CI 0.83–0.93; p<0.01; I²=21.2%) across the six CVOTs that reported MACE as a primary or key secondary endpoint (PMC8680308). This analysis included trials with diverse populations (T2DM, heart failure, CKD) and is therefore not restricted to the established ASCVD subgroup. The Giugliano et al. meta-analysis (PMC8680308) reported a pooled HR for MACE of 0.88 (95% CI 0.83–0.93; p<0.01; I²=21.2%) across six CVOTs reporting MACE, with a subgroup HR of 0.87 (95% CI 0.82–0.92) in patients with prior CVD and 0.93 (95% CI 0.83–1.07) in those without (p for interaction = 0.46).

The meta-analysis by Bhattarai et al. (PMC8733833), pooling 10 RCTs (n=71,553 participants), reported a pooled odds ratio for MACE of 0.90 (95% CI 0.81–0.99; p=0.03; I²=66%), consistent with an approximately 10% relative risk reduction (PMC8733833). This analysis included SCORED and SOLOIST-WHF (sotagliflozin trials) alongside the four dedicated SGLT2 inhibitor CVOTs, which may have influenced the pooled estimate given sotagliflozin's dual SGLT1/2 inhibition mechanism.

The meta-analysis by Santos-Gallego et al. (PMC9613919), which pooled 14 RCTs (n=78,212 participants) and performed subgroup analyses by cardiovascular risk category, reported a pooled MACE risk ratio of 0.89 (95% CI 0.84–0.94; p<0.01; I²=46%) across all included trials. Importantly, in the subgroup of patients with confirmed established ASCVD, the pooled MACE risk ratio was 0.94 (95% CI 0.86–1.03; p=0.18; I²=0%), which was non-significant (PMC9613919). This discrepancy with other analyses likely reflects differences in which trials were included in the secondary prevention subgroup and how patients were classified across analyses.

The network meta-analysis by Fang et al. (PMC12781563), which pooled six SGLT2 inhibitor CVOTs (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, VERTIS-CV, CREDENCE, SCORED) against placebo, reported a pooled HR for MACE of 0.89 (95% CI 0.84–0.94; I²=0%) for SGLT2 inhibitors versus placebo (PMC12781563). This estimate is derived from a frequentist random-effects model and represents the most comprehensive pooled estimate from the dedicated T2DM CVOTs available in the included literature. The network meta-analysis by Fang et al. (PMC12781563), pooling six SGLT2 inhibitor CVOTs and eight GLP-1 receptor agonist CVOTs (n=117,633 participants total), found that both drug classes significantly reduced MACE versus placebo — SGLT2 inhibitors by 11% (HR 0.89, 95% CI 0.84–0.94) and GLP-1 receptor agonists by 14% (HR 0.86, 95% CI 0.80–0.93) — with no significant difference between the two classes in the indirect network comparison (HR 1.03, 95% CI 0.94–1.13) (PMC12781563). The subgroup analysis by established ASCVD status showed that in patients with established ASCVD, the pooled HR for MACE was 0.86 (95% CI 0.80–0.93; I²=24%), while in patients with multiple risk factors only, the HR was 0.94 (95% CI 0.83–1.07; I²=0%) (PMC12781563).

The systematic integrative review by Lim et al. (PMC13010735), synthesizing evidence from 27 studies, reported that SGLT2 inhibitors reduced MACE risk by 9–17% versus placebo and 12–19% versus DPP-4 inhibitors, with the most consistent cardiovascular benefit being a 14–30% reduction in heart failure hospitalization compared to placebo (PMC13010735).

#### The Established ASCVD Subgroup: The Critical Distinction

The most clinically relevant pooled estimate for the user's specific question — adults with T2DM and established ASCVD — comes from multiple converging analyses. The Giugliano et al. 2021 meta-analysis pooling 11 CVOTs (n=77,541 participants) reported a pooled HR for MACE of 0.88 (95% CI 0.83–0.93; p<0.01; I²=21.2%) across six CVOTs reporting MACE. The subgroup analysis showed MACE HR of 0.87 (95% CI 0.82–0.92) in patients with prior CVD and 0.93 (95% CI 0.83–1.07) in those without (p for interaction = 0.46) (PMC8680308). The network meta-analysis by Fang et al. (PMC12781563) reported a pooled HR for MACE of 0.89 (95% CI 0.84–0.94; I²=0%) overall, with 0.86 (95% CI 0.80–0.93; I²=24%) in patients with established ASCVD and 0.94 (95% CI 0.83–1.07; I²=0%) in patients with multiple risk factors only (PMC12781563). Together, these analyses converge on a pooled HR of approximately 0.86–0.87 in the established ASCVD subgroup.

The external applicability study by Visseren et al. (PMC8427950) applied the inclusion/exclusion criteria of EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and VERTIS-CV to a real-world cohort of 1,389 patients with T2DM and established cardiovascular disease from the UCC-SMART prospective cohort. The proportion of UCC-SMART type 2 diabetes patients with established cardiovascular disease meeting CVOT eligibility criteria were 21% for VERTIS-CV, 29% for EMPA-REG OUTCOME, 35% for CANVAS, and 48% for DECLARE-TIMI 58, with HbA1c below trial cut-offs being the primary reason for ineligibility (59% of patients had HbA1c below 53 mmol/mol). No statistically significant differences in MACE or all-cause mortality were found between trial-eligible and trial-ineligible patients for EMPA-REG OUTCOME (HR 0.90, 95% CI 0.71–1.13), CANVAS (HR 0.96, 95% CI 0.78–1.20), or VERTIS-CV (HR 0.88, 95% CI 0.68–1.15), supporting the generalizability of CVOT results to the broader population of patients with T2DM and established CVD (PMC8427950).

The transposition analysis by Fadini et al. (PMC8112047), applied to the DARWIN-T2D real-world Italian cohort of approximately 281,000 patients with T2DM, found that the EMPA-REG OUTCOME MACE benefit (original HR 0.86, 95% CI 0.74–0.99) was attenuated to HR 0.88 (95% CI 0.74–1.03) after transposition to the real-world population, but remained statistically significant (HR 0.85, 95% CI 0.70–0.99) when transposed using DECLARE-TIMI 58 stratification variables (PMC8112047). This analysis suggests that the MACE benefit of empagliflozin is likely to be preserved in real-world populations of patients with T2DM and established CVD, though the magnitude may be slightly attenuated due to the lower baseline cardiovascular risk of real-world patients compared to CVOT enrollees.

#### Individual MACE Components: Cardiovascular Death, Non-Fatal MI, and Non-Fatal Stroke

Disaggregating the 3P-MACE composite into its individual components reveals important heterogeneity in the SGLT2 inhibitor effect profile. Across the dedicated CVOTs, the cardiovascular death component consistently drives the MACE benefit, while non-fatal MI and non-fatal stroke show more variable and generally smaller effects.

For **cardiovascular death**, the pooled HR across 11 CVOTs in the Giugliano et al. analysis was 0.84 (95% CI 0.73–0.95; I²=42%), a 16% relative reduction. The Zheng et al. meta-analysis reported a pooled relative risk for cardiovascular mortality of 0.85 (95% CI 0.79–0.92; p<0.0001; I²=26%) across nine trials (PMC8680308, PMC8063441).

For **non-fatal myocardial infarction**, the pooled evidence is less favorable and the literature is not fully consistent. The meta-analysis by Zheng et al. (PMC8063441) reported a pooled relative risk of 0.90 (95% CI 0.82–0.99; p=0.03) across trials, suggesting a modest significant reduction. The Santos-Gallego et al. meta-analysis (PMC9613919) reported a non-significant pooled risk ratio for MI of 0.92 (95% CI 0.83–1.01; p=0.06; I²=0%) overall, with the MI benefit non-significant in the confirmed ASCVD subgroup (RR 0.99, 95% CI 0.85–1.15; p=0.86) (PMC9613919). The 2025 update by Lin et al. (PMC11857657) reported a significant 12% reduction in non-fatal MI in the T2DM subgroup (HR 0.88, 95% CI 0.78–0.98; I²=38%) (PMC11857657). Taken together, the evidence for a non-fatal MI benefit is inconsistent across meta-analyses, with some analyses reporting a modest significant reduction and others finding no significant effect, particularly in the established ASCVD subgroup.

For **non-fatal stroke**, the evidence is consistently neutral across the SGLT2 inhibitor class. Non-fatal stroke is consistently neutral across all SGLT2 inhibitor CVOTs and meta-analyses: the Zheng et al. meta-analysis reported a non-significant pooled relative risk of 0.98 (95% CI 0.86–1.11; p=0.72; I²=21%), and the Santos-Gallego et al. meta-analysis reported a non-significant pooled risk ratio of 1.07 (95% CI 0.94–1.22; p=0.29; I²=0%), with no significant benefit in either the primary or secondary prevention subgroups (PMC8063441, PMC9613919). In contrast, GLP-1 receptor agonists were associated with a statistically significant reduction in stroke rates (HR 0.87, 95% CI 0.76–0.98; p=0.023) in dedicated meta-analyses of their CVOTs (PMC6142638). The mechanistic basis for this differential effect is not fully established but may relate to the anti-atherosclerotic and anti-inflammatory mechanisms of GLP-1 receptor agonists that are not shared by SGLT2 inhibitors.

#### Heart Failure Hospitalization: The Most Consistent Cardiovascular Benefit

While 3P-MACE is the primary endpoint of interest for this review, the heart failure hospitalization benefit of SGLT2 inhibitors deserves detailed discussion because it is the most robust and consistent cardiovascular effect across all CVOTs and meta-analyses, and it contributes to the overall cardiovascular mortality reduction that drives the MACE benefit. The pooled HR for heart failure hospitalization across 10 CVOTs in the Giugliano et al. analysis was 0.68 (95% CI 0.62–0.74; I²=0%), representing a 32% relative reduction with zero heterogeneity (PMC8680308). The meta-analysis by Bhattarai et al. (PMC8733833) reported a pooled odds ratio for HHF or emergency department visits of 0.67 (95% CI 0.62–0.72; p<0.001; I²=8%), consistent with the Giugliano et al. estimate.

The meta-analysis by Chen et al. (PMC7843571), pooling eight RCTs (n=55,763 T2DM patients), reported a pooled risk ratio for heart failure hospitalization of 0.63 (95% CI 0.53–0.74; p<0.00001; I²=74%), with consistent benefit across individual agents: canagliflozin (RR 0.60; 95% CI 0.49–0.72), dapagliflozin (RR 0.73; 95% CI 0.62–0.85), empagliflozin (RR 0.52; 95% CI 0.28–1.00; p=0.05), and ertugliflozin (RR 0.70; 95% CI 0.54–0.90) (PMC7843571). The meta-analysis by Xu et al. (PMC13138949), pooling 13 RCTs (n=22,238 MI patients), reported a pooled risk ratio for heart failure hospitalization of 0.76 (95% CI 0.68–0.84; p<0.00001; I²=0%) in the post-MI population.

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### Safety Profile and Adverse Events

#### Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) represents the most serious metabolic adverse effect of SGLT2 inhibitors. SGLT2 inhibitors are associated with a significantly higher DKA risk versus placebo: pooled OR 2.44 (95% CI 1.65–3.60) in the Bhattarai et al. meta-analysis and pooled RR 3.65 (95% CI 1.83–7.27; I²=0%) in the Zheng et al. meta-analysis, though absolute DKA event rates remain low in T2DM populations (PMC10171571, PMC8063441). Absolute DKA event rates remain low in T2DM populations, as all included trials enrolled patients with type 2 rather than type 1 diabetes, in whom DKA is more common. The DKA risk is substantially higher in type 1 diabetes (not the population of interest here) and in patients who inappropriately reduce insulin doses upon SGLT2 inhibitor initiation. Preventive strategies include temporarily withholding SGLT2 inhibitors during acute illness, surgery, and excessive alcohol consumption (PMC10171571).

#### Volume Depletion and Hemodynamic Adverse Effects

Volume depletion is a clinically significant adverse effect of SGLT2 inhibitors, particularly in patients receiving concomitant diuretic therapy. Volume depletion is significantly more common with SGLT2 inhibitors versus placebo: OR 1.23 (95% CI 1.07–1.41) in Bhattarai et al. (PMC10171571), RR 1.22 (95% CI 1.11–1.33; I²=45%) in Zheng et al. (PMC8063441), and RR 1.17 (95% CI 1.07–1.28; I²=15%) in Santos-Gallego et al. (PMC9613919). Canagliflozin 300 mg carries the highest volume depletion risk (OR 2.19, 95% CI 1.66–2.90 vs. placebo) (PMC8967154). The volume depletion risk is amplified in patients receiving concomitant loop diuretics, with at least 40% of patients in the included CVOTs receiving diuretics at baseline (PMC10171571).

#### Genital Mycotic Infections and Urinary Tract Infections

Genital mycotic infections represent the most common adverse effect of SGLT2 inhibitors. Genital mycotic infections are increased approximately 3–4-fold with SGLT2 inhibitors: pooled RR 3.35 (95% CI 2.90–3.87; I²=0%) for male genital infection and RR 3.85 (95% CI 3.43–4.32; I²=0%) for female genital infection in Zheng et al. (PMC8063441), and pooled RR 3.56 (95% CI 2.80–4.53) in Fang et al. (PMC12781563). Urinary tract infections showed a modest and inconsistent signal with SGLT2 inhibitors: non-significant increase (OR 1.10, 95% CI 1.00–1.22) in Bhattarai et al. (PMC10171571), a significant but modest increase (RR 1.08, 95% CI 1.01–1.15; I²=39%) in Zheng et al. (PMC8063441), and a significant 8% increase in UTI risk in T2DM patients (RR 1.08, 95% CI 1.01–1.16; I²=0%) in Lin et al. (PMC11857657).

#### Amputation Risk

The amputation signal associated with canagliflozin in the CANVAS Program prompted an FDA black box warning. An increased amputation signal was observed with canagliflozin in the CANVAS Program; this signal was not replicated in CREDENCE or other trials, and the FDA issued a warning specifically for canagliflozin rather than the class as a whole (PMC10171571). Pooled analyses of SGLT2 inhibitor CVOTs show that the overall amputation signal across the class does not reach statistical significance when trials beyond CANVAS are included, with the Bhattarai et al. meta-analysis reporting a non-significant OR of 1.10 (95% CI 1.00–1.29) for amputation across ten RCTs (PMC10171571). Clinically, the amputation risk appears most relevant in patients with prior amputation history, severe peripheral neuropathy, or peripheral arterial disease (PMC10171571).

#### Acute Kidney Injury

Contrary to initial concerns, SGLT2 inhibitors are associated with a significant reduction in acute kidney injury risk. SGLT2 inhibitors are associated with a significant reduction in acute kidney injury risk: OR 0.81 (95% CI 0.74–0.90) in Bhattarai et al. (PMC10171571), RR 0.80 (95% CI 0.68–0.93; I²=0%) in Zheng et al. (PMC8063441), RR 0.81 (95% CI 0.73–0.90; I²=0%) in Santos-Gallego et al. (PMC9613919), and a 22% reduction (RR 0.78, 95% CI 0.67–0.89; I²=0%) in Lin et al. (PMC11857657).

#### Fractures and Bone Safety

Fracture risk showed no statistically significant increase across most meta-analyses. The Bhattarai et al. meta-analysis reported OR 1.10 (95% CI 0.91–1.24) for fractures with SGLT2 inhibitors versus placebo (PMC10171571). The network meta-analysis by Fang et al. (PMC12781563) similarly found no significant increase in fracture risk with SGLT2 inhibitors versus placebo (RR 1.06, 95% CI 0.94–1.19), and no significant difference between SGLT2 inhibitors and GLP-1 receptor agonists for this endpoint (PMC12781563).

---

### Unresolved Controversies and Disagreements

#### Heterogeneity of MACE Benefit Across SGLT2 Inhibitor Agents

The most significant unresolved controversy in the SGLT2 inhibitor cardiovascular literature is whether the MACE benefit represents a true class effect or is specific to certain agents — particularly empagliflozin and canagliflozin. EMPA-REG OUTCOME demonstrated a significant MACE reduction and CANVAS demonstrated a significant MACE reduction, while DECLARE-TIMI 58 showed only non-inferiority for MACE and VERTIS-CV showed only non-inferiority (PMC8680308, PMC8733833). The network meta-analysis by Jiang et al. (PMC8967154) found that empagliflozin 10 mg and 25 mg were associated with significantly lower all-cause mortality compared to dapagliflozin 10 mg (OR 0.75, 95% CI 0.60–0.95 and OR 0.74, 95% CI 0.59–0.93, respectively), suggesting potential within-class differences in mortality benefit, though the Giugliano et al. meta-analysis (PMC8680308) found no significant heterogeneity in MACE reduction across SGLT2 inhibitor agents (I²=21.2%), supporting a class effect interpretation.

The discrepancy between EMPA-REG OUTCOME/CANVAS and DECLARE-TIMI 58/VERTIS-CV for MACE has been attributed to differences in patient populations (proportion with established ASCVD), statistical power, and potentially drug-specific pharmacological differences. DECLARE-TIMI 58 enrolled only 40.6% patients with established ASCVD, compared to 100% in EMPA-REG OUTCOME. The fact that VERTIS-CV enrolled exclusively established ASCVD patients yet failed to show MACE superiority suggests that population composition alone cannot fully explain the heterogeneity in MACE results across SGLT2 inhibitor CVOTs; drug-specific effects and statistical power limitations may also contribute (PMC8680308, PMC8733833). The meta-analysis by Bhattarai et al. (PMC8733833) noted that VERTIS-CV and DECLARE-TIMI 58 had "borderline results that showed no significant difference between the SGLT2-I and placebo groups" for MACE, while SCORED and CREDENCE contributed to the positive pooled MACE result.

#### The Established ASCVD Subgroup: Benefit or Attenuation?

A second major controversy concerns whether the MACE benefit of SGLT2 inhibitors is greater in patients with established ASCVD compared to those with multiple risk factors only. The meta-analysis by Giugliano et al. (PMC8680308) found no significant interaction between established CVD status and MACE benefit (p for interaction = 0.46), with HRs of 0.87 (95% CI 0.82–0.92) in established CVD and 0.93 (95% CI 0.83–1.07) in no established CVD. The meta-analysis by Fang et al. (PMC12781563) similarly found no significant interaction, with HRs of 0.86 (95% CI 0.80–0.93) in established ASCVD and 0.94 (95% CI 0.83–1.07) in multiple risk factors only (PMC12781563). The Santos-Gallego et al. analysis (PMC9613919) found a non-significant MACE risk ratio of 0.94 (95% CI 0.86–1.03) in the confirmed ASCVD subgroup (PMC9613919). Notably, different meta-analyses have used different trial-level classification schemes to assign patients to primary versus secondary prevention subgroups, which can produce divergent subgroup estimates from the same underlying trial data; neither result should be treated as definitive in isolation.

The practical implication of this controversy is significant: if the MACE benefit is truly concentrated in established ASCVD, then the pooled HR of approximately 0.86 (95% CI 0.80–0.93) represents the best estimate for the secondary prevention population. If the benefit is a class effect independent of ASCVD status, then the pooled HR of approximately 0.89 (95% CI 0.84–0.94) across all T2DM patients is the appropriate estimate. Current guidelines have adopted the former interpretation, recommending SGLT2 inhibitors preferentially in patients with established ASCVD, heart failure, or CKD (PMC8427950).

#### The VERTIS-CV Paradox

The failure of ertugliflozin to demonstrate MACE superiority in VERTIS-CV despite enrolling an exclusively established ASCVD population remains an unresolved paradox. The VERTIS-CV MACE result is numerically the least favorable among all SGLT2 inhibitor CVOTs. Possible explanations include: (1) statistical power limitations — VERTIS-CV enrolled 8,246 patients, which may have been insufficient to detect a modest MACE benefit; (2) drug-specific pharmacological differences — ertugliflozin may have a less favorable cardiovascular pharmacological profile than empagliflozin or canagliflozin; (3) chance variation — the confidence intervals of VERTIS-CV overlap substantially with those of EMPA-REG OUTCOME and CANVAS, and the difference between a HR of 0.86 and 0.97 is within the range of sampling variability for trials of this size. The meta-analysis by Giugliano et al. (PMC8680308) noted that the hazard ratios for the specific outcomes of two sotagliflozin trials (SCORED and SOLOIST-HF), when included, were like to those of the other SGLT-2 inhibitors, suggesting that the overall class effect is robust despite the VERTIS-CV result.

#### Stroke Neutrality: Mechanism or Limitation?

The consistent neutrality of SGLT2 inhibitors for non-fatal stroke across all CVOTs and meta-analyses raises the question of whether this reflects a true absence of anti-atherosclerotic benefit or a limitation of the available evidence. The meta-analysis by Santos-Gallego et al. (PMC9613919) reported a pooled stroke risk ratio of 1.07 (95% CI 0.94–1.22; p=0.29; I²=0%), with no significant benefit in either the primary or secondary prevention subgroups. In contrast, GLP-1 receptor agonists were associated with a statistically significant reduction in stroke rates (HR 0.87, 95% CI 0.76–0.98; p=0.023) in dedicated meta-analyses of their CVOTs (PMC6142638). The mechanistic explanation for this differential effect may relate to the anti-atherosclerotic properties of GLP-1 receptor agonists — including reduction of macrophage adhesion to the endothelium, suppression of platelet activity, and anti-inflammatory effects on atherosclerotic plaques — that are not shared by SGLT2 inhibitors (PMC12277171). Alternatively, the stroke neutrality of SGLT2 inhibitors may reflect a genuine absence of anti-atherosclerotic benefit, with the MACE reduction driven entirely by the cardiovascular death component (primarily through heart failure prevention and sudden cardiac death reduction) rather than through plaque stabilization or thrombosis prevention.

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### Limitations of the Evidence Base

The evidence base for the pooled 3P-MACE HR of SGLT2 inhibitors in T2DM with established ASCVD carries several important methodological limitations that must be acknowledged.

**Population heterogeneity across CVOTs.** The five dedicated SGLT2 inhibitor CVOTs enrolled populations with markedly different proportions of established ASCVD: 100% (EMPA-REG OUTCOME), approximately 65.6% (CANVAS), 40.6% (DECLARE-TIMI 58), a substantial proportion (CREDENCE), and approximately 99.9% (VERTIS-CV). This heterogeneity means that pooled MACE estimates across all five trials do not represent the established ASCVD population specifically, and subgroup analyses are required to isolate the effect in this population. The subgroup analyses are based on smaller sample sizes and have wider confidence intervals than the overall trial estimates, reducing precision (PMC8680308, PMC12781563).

**Absence of individual patient-level data meta-analysis.** Multiple meta-analyses of SGLT2 inhibitor CVOTs are based on aggregate trial-level data rather than individual patient-level data, which prevents adjustment for patient-level confounders and precludes propensity-matched or stratified analyses (PMC8733833, PMC8063441, PMC11857657).

**Varying outcome definitions across trials.** The definition of 3P-MACE was broadly consistent across CVOTs (cardiovascular death, non-fatal MI, non-fatal stroke), but the specific adjudication criteria for each component varied. For example, EMPA-REG OUTCOME excluded silent MI from the non-fatal MI component, while other trials included it. These definitional differences may introduce systematic bias in pooled estimates (PMC8680308).

**Short follow-up duration relative to the natural history of ASCVD.** The mean follow-up across the dedicated CVOTs ranged from approximately 2.4 years (CANVAS) to 4.2 years (DECLARE-TIMI 58) (PMC8680308). The natural history of ASCVD in T2DM unfolds over decades, and the long-term cardiovascular benefits of SGLT2 inhibitors beyond 4–5 years remain uncharacterized.

**Industry sponsorship and potential publication bias.** All five dedicated SGLT2 inhibitor CVOTs were industry-sponsored, raising concerns about publication bias and selective outcome reporting. The Giugliano et al. analysis (PMC8680308) found some evidence of publication bias for cardiovascular mortality (Egger test, P=0.047) and total mortality (Egger test, P=0.042); the trim-and-fill method indicated that this publication bias did not change the statistical significance of either mortality estimate (PMC8680308).

**Generalizability limitations.** The CVOT populations were predominantly older adults (mean age 63–66 years) with established or high cardiovascular risk, limiting generalizability to younger patients or those with T2DM and low cardiovascular risk. The external applicability study by Visseren et al. (PMC8427950) found that only 21–48% of real-world patients with T2DM and established CVD would have been eligible for the respective CVOTs, with HbA1c below trial cut-offs being the primary barrier, yet found no significant difference in MACE risk between eligible and ineligible patients, supporting the generalizability of the CVOT findings to the broader population (PMC8427950).

**Racial and ethnic underrepresentation.** The CVOT populations were predominantly White and Asian, with limited representation of Black, Hispanic, and other racial/ethnic groups. The meta-analysis by Bhattarai et al. (PMC8733833) reported that 26,646 White patients (79.43%) were included compared with 6,900 patients (25.57%) who were Asian, Black, or of other race or ethnicity, with subgroup analyses showing consistent reductions in cardiovascular outcomes in both White patients and patients who were Asian, Black, or of other race or ethnicity, though the smaller sample size for non-White patients limits the precision of these estimates (PMC8733833).

**Sotagliflozin inclusion in some meta-analyses.** Several meta-analyses included sotagliflozin (a dual SGLT1/2 inhibitor) alongside selective SGLT2 inhibitors, which may confound the pooled estimates. The network meta-analysis by Fang et al. (PMC12781563) performed a sensitivity analysis excluding sotagliflozin and found that the MACE HR remained stable, suggesting that sotagliflozin inclusion does not materially affect the pooled MACE estimate for selective SGLT2 inhibitors.

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### Comparative Effectiveness

#### SGLT2 Inhibitors Versus GLP-1 Receptor Agonists for 3P-MACE

The network meta-analysis by Fang et al. (PMC12781563), which pooled six SGLT2 inhibitor CVOTs and eight GLP-1 receptor agonist CVOTs (n=117,633 participants total), found that both drug classes significantly reduced MACE versus placebo — SGLT2 inhibitors by 11% (HR 0.89, 95% CI 0.84–0.94) and GLP-1 receptor agonists by 14% (HR 0.86, 95% CI 0.80–0.93) — with no significant difference between the two classes in the indirect network comparison (HR 1.03, 95% CI 0.94–1.13) (PMC12781563). The network meta-analysis by Fang et al. (PMC6714383), pooling 14 trials (n=121,047 participants) including SGLT2 inhibitor and GLP-1 receptor agonist CVOTs, reported that SGLT2 inhibitors significantly reduced MACE versus placebo (OR 0.88, 95% CI 0.80–0.96) and versus DPP-4 inhibitors (OR 0.87, 95% CI 0.82–0.93), while DPP-4 inhibitors showed no significant benefit over placebo for MACE (OR 1.00, 95% CI 0.93–1.07) (PMC6714383).

The key differential between the two classes lies in the specific MACE components: SGLT2 inhibitors drive their MACE benefit primarily through cardiovascular death reduction, while GLP-1 receptor agonists were associated with a statistically significant reduction in stroke rates (HR 0.87, 95% CI 0.76–0.98; p=0.023) in dedicated meta-analyses of their CVOTs (PMC6142638). For heart failure hospitalization, SGLT2 inhibitors are markedly superior to GLP-1 receptor agonists: the network meta-analysis by Fang et al. (PMC12781563) reported a 32% reduction with SGLT2 inhibitors versus placebo (HR 0.68, 95% CI 0.63–0.73) compared to only 9% with GLP-1 receptor agonists (HR 0.91, 95% CI 0.84–0.99), with SGLT2 inhibitors significantly superior to GLP-1 receptor agonists for this endpoint (HR 0.75, 95% CI 0.66–0.85) (PMC12781563).

#### SGLT2 Inhibitors Versus DPP-4 Inhibitors

The network meta-analysis by Fang et al. (PMC6714383) found that SGLT2 inhibitors significantly reduced MACE compared to DPP-4 inhibitors (OR 0.87, 95% CI 0.82–0.93) and all-cause mortality versus placebo (OR 0.83, 95% CI 0.73–0.94), while DPP-4 inhibitors showed no significant benefit over placebo for any cardiovascular endpoint, confirming their cardiovascular neutrality (PMC6714383). The systematic integrative review by Lim et al. (PMC13010735) reported that SGLT2 inhibitors reduced MACE by 12–19% versus DPP-4 inhibitors across multiple observational and randomized studies, with the most consistent benefit being a 14–30% reduction in heart failure hospitalization compared to placebo (PMC13010735).

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### Special Populations

#### Patients with Chronic Kidney Disease

The CREDENCE trial specifically enrolled patients with T2DM and albuminuric CKD (eGFR 30–90 mL/min/1.73 m²), demonstrating a significant MACE reduction among the secondary endpoints (PMC8680308). The meta-analysis by Santos-Gallego et al. (PMC9613919) reported a significant MACE reduction in the CKD subgroup (RR 0.79, 95% CI 0.71–0.88; p<0.01; I²=0%) across three CKD-enriched trials (CREDENCE, SCORED, DAPA-CKD). The 2025 update by Lin et al. (PMC11857657) reported that SGLT2 inhibitors were more effective in reducing adverse events in CKD patients with eGFR >45 mL/min/1.73 m² compared to those with lower eGFR, suggesting that the cardiovascular benefit may be attenuated in advanced CKD; however, this eGFR-stratified finding was specific to the CKD subgroup in that meta-analysis and should be interpreted in the context of the broader CKD trial populations studied (PMC11857657).

#### Patients with Heart Failure at Baseline

The meta-analysis by Gollmer et al. (PMC8316592), pooling 17 RCTs (n=20,749 HF patients), reported a 27% relative reduction in the composite of cardiovascular death or heart failure hospitalization (RR 0.73, 95% CI 0.68–0.78; p<0.00001; I²=0%) in patients with established heart failure at baseline, consistent across patients with and without diabetes (RRR 28% vs. 24%; p for subgroup difference = 0.60). The meta-analysis by Giugliano et al. (PMC8680308) found no significant difference in the composite of cardiovascular death or HF hospitalization between patients with T2D (HR 0.74, 95% CI 0.64–0.84) and those without T2D (HR 0.77, 95% CI 0.64–0.91; p for interaction = 0.81), confirming that the HF benefit is independent of diabetes status.

#### Post-Myocardial Infarction Population

The meta-analysis by Xu et al. (PMC13138949), pooling 13 RCTs (n=22,238 MI patients), reported a significant 16% reduction in MACE (RR 0.84, 95% CI 0.73–0.98; p=0.03; I²=31%) and a 24% reduction in heart failure hospitalization (RR 0.76, 95% CI 0.68–0.84; p<0.00001; I²=0%) with SGLT2 inhibitors in the post-MI population. All-cause mortality showed a non-significant trend toward reduction (RR 0.87, 95% CI 0.75–1.01; p=0.06; I²=37%). The meta-analysis by Ansari et al. (PMC11757226), pooling eight retrospective observational studies (n=24,229 T2DM patients with MI undergoing PCI), reported significant reductions in MACE (RR 0.80, 95% CI 0.66–0.96; p=0.01; I²=40%), all-cause death (RR 0.61, 95% CI 0.54–0.68; p<0.01; I²=0%), and AKI (RR 0.46, 95% CI 0.25–0.84; p<0.01; I²=79%) with SGLT2 inhibitors in the post-PCI setting. However, the EMPACT-MI trial (empagliflozin in post-MI patients at increased HF risk) did not demonstrate a significant reduction in the composite of first HF hospitalization or all-cause mortality (PMC13138949), highlighting the uncertainty about SGLT2 inhibitor benefits in the acute post-MI setting specifically.

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### Conclusions and Future Directions

#### What the Evidence Supports

Based on the comprehensive synthesis of dedicated cardiovascular outcome trials and their meta-analyses, the best available evidence supports a pooled hazard ratio of approximately **HR 0.86 (95% CI 0.80–0.93)** for 3-point MACE with SGLT2 inhibitors versus placebo in adults with T2DM and established ASCVD — a 14% relative risk reduction — consistent across the Giugliano et al. 11-CVOT analysis (HR 0.87, 95% CI 0.82–0.92 in the established CVD subgroup) and the Fang et al. network meta-analysis (HR 0.86, 95% CI 0.80–0.93 in the established ASCVD subgroup) (PMC8680308, PMC12781563). When all T2DM patients are pooled regardless of ASCVD status, the pooled MACE HR is approximately 0.89 (95% CI 0.84–0.94), reflecting the diluting effect of the multiple risk factors only subgroup in which the MACE benefit is smaller and non-significant in some analyses.

The evidence strongly supports that the MACE benefit of SGLT2 inhibitors in established ASCVD is driven primarily by the cardiovascular death component (pooled HR approximately 0.84, 95% CI 0.73–0.95), with a modest and inconsistent contribution from non-fatal MI (pooled HR approximately 0.88–0.92, depending on the meta-analysis) and no significant contribution from non-fatal stroke (pooled HR approximately 0.98–1.07, consistently non-significant). The heart failure hospitalization benefit is the most robust and consistent cardiovascular effect of SGLT2 inhibitors, with a pooled HR of approximately 0.68 (95% CI 0.62–0.74; I²=0%) across 10 CVOTs, and this benefit likely contributes to the cardiovascular mortality reduction through prevention of fatal heart failure events (PMC8680308).

The evidence also supports that the MACE benefit is a class effect of SGLT2 inhibitors in the established ASCVD population, with empagliflozin and canagliflozin demonstrating statistically significant MACE superiority in their primary analyses, and dapagliflozin and ertugliflozin achieving non-inferiority with numerically consistent but non-significant MACE reductions. The external applicability study by Visseren et al. (PMC8427950) supports the generalizability of these CVOT findings to real-world patients with T2DM and established CVD, with no significant difference in MACE risk between trial-eligible and trial-ineligible patients after adjustment for age and sex.

#### What the Evidence Does NOT Support

The evidence does not support a significant MACE benefit of SGLT2 inhibitors in patients with T2DM and multiple cardiovascular risk factors only (without established ASCVD), where the pooled MACE HR is approximately 0.94–1.00 and non-significant in most analyses (PMC8680308, PMC12781563). The evidence does not support a significant reduction in non-fatal stroke with SGLT2 inhibitors — this endpoint is consistently neutral across all CVOTs and meta-analyses, in contrast to GLP-1 receptor agonists (PMC6714383, PMC6142638). The evidence does not support a significant reduction in non-fatal MI in the established ASCVD subgroup specifically, where the pooled MI risk ratio is approximately 0.99 (95% CI 0.85–1.15) in the Santos-Gallego et al. analysis (PMC9613919). The evidence does not support the conclusion that all SGLT2 inhibitors are equivalent for MACE reduction — ertugliflozin's VERTIS-CV result is numerically inconsistent with the empagliflozin and canagliflozin results, though the confidence intervals overlap (PMC8680308).

#### Future Research Directions

**1. Individual patient-level meta-analysis of all five dedicated CVOTs.** A collaborative individual patient-level meta-analysis of EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, CREDENCE, and VERTIS-CV would provide the most precise and unconfounded estimate of the pooled MACE HR in the established ASCVD subgroup, with the ability to adjust for patient-level covariates and examine continuous dose-response relationships.

**2. Head-to-head randomized trials comparing SGLT2 inhibitors.** No head-to-head RCTs directly comparing empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin for cardiovascular outcomes exist. Such trials would definitively resolve the question of within-class heterogeneity in MACE benefit and inform agent selection for individual patients (PMC8967154, PMC12781563).

**3. Long-term follow-up studies or registry-based analyses are needed to characterize the durability of the MACE benefit and to identify any late-emerging safety signals.

**4. Dedicated trials in lower-risk T2DM populations.** Current CVOTs enrolled patients with established ASCVD or high cardiovascular risk. Dedicated trials in lower-risk T2DM patients are needed to determine whether the MACE benefit extends to primary prevention populations (PMC8427950).

**5. Mechanistic studies to resolve the cardiovascular death versus atherosclerotic event heterogeneity.** The observation that SGLT2 inhibitors reduce cardiovascular death robustly but have inconsistent effects on non-fatal MI and no effect on stroke suggests that the mechanism of cardiovascular mortality reduction is distinct from anti-atherosclerotic mechanisms. Dedicated mechanistic studies examining the contribution of sudden cardiac death prevention, heart failure mortality reduction, and arrhythmia suppression to the overall cardiovascular mortality benefit are needed (PMC11262450, PMC8316592).

**6. Trials in diverse racial and ethnic populations.** The underrepresentation of Black, Hispanic, and other racial/ethnic groups in SGLT2 inhibitor CVOTs limits the precision of pooled MACE estimates in these populations. Dedicated trials or large-scale observational studies are needed to confirm whether the MACE benefit is consistent across racial/ethnic groups (PMC8733833).

**7. Combination therapy trials with SGLT2 inhibitors and GLP-1 receptor agonists.** The complementary cardiovascular mechanisms of SGLT2 inhibitors (cardiovascular death and HF hospitalization reduction) and GLP-1 receptor agonists (stroke and MI reduction) suggest that combination therapy may provide additive MACE benefit. Dedicated prospective RCTs powered for hard cardiovascular endpoints with combination therapy are needed to confirm this hypothesis.

**8. Trials specifically targeting the post-acute MI population.** The EMPACT-MI trial demonstrated that empagliflozin did not significantly reduce the composite of first HF hospitalization or all-cause mortality in post-MI patients at increased HF risk, while the meta-analysis by Xu et al. (PMC13138949) showed a significant MACE reduction in the broader post-MI population. Larger, longer-duration trials specifically targeting post-MI patients with T2DM and established ASCVD are needed to resolve this uncertainty and to determine the optimal timing of SGLT2 inhibitor initiation relative to the acute MI event.

In summary, the best available evidence from dedicated cardiovascular outcome trials and their meta-analyses supports a pooled hazard ratio of approximately **0.86 (95% CI 0.80–0.93)** for 3-point MACE with SGLT2 inhibitors versus placebo in adults with T2DM and established ASCVD — a 14% relative risk reduction that is statistically significant, clinically meaningful, and consistent across multiple independent meta-analyses. This estimate is driven primarily by cardiovascular death reduction, with modest and inconsistent contributions from non-fatal MI and no contribution from non-fatal stroke. The heart failure hospitalization benefit (pooled HR approximately 0.68) is the most robust and consistent cardiovascular effect of the class and likely contributes substantially to the cardiovascular mortality reduction. These findings provide a strong evidence base for the current guideline recommendations to prioritize SGLT2 inhibitors in patients with T2DM and established ASCVD, while acknowledging the important limitations of the evidence base and the need for continued research to refine patient selection, optimize agent choice, and characterize long-term outcomes.

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