What is the clinical evidence from this study?

Study design: Meta-Analysis. Population: type 2 diabetes (n=79504). Intervention: SGLT2 inhibitors vs. placebo or oral hypoglycemic drugs. Primary outcome: Acute coronary syndrome (ACS) (RR 0.97, 95% CI 0.89-1.05).

What does this research mean for the field?

SGLT2 inhibitors do not significantly reduce the risk of acute coronary syndrome, peripheral arterial occlusive disease, or ischemic stroke compared to placebo or oral hypoglycemic drugs in patients with type 2 diabetes. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

March 13, 2023Open Access

Neutral effects of SGLT2 inhibitors in acute coronary syndromes, peripheral arterial occlusive disease, or ischemic stroke: a meta-analysis of randomized controlled trials

Key Result

SGLT2 inhibitors did not significantly reduce the risk of acute coronary syndrome (RR 0.97), peripheral arterial occlusive disease (RR 0.98), or ischemic stroke (RR 0.95) compared to placebo or oral hypoglycemic drugs in patients with type 2 diabetes.

Study Design

Type

Meta-Analysis (n=79,504)

Structured PICO

Does SGLT2 inhibitor therapy reduce the incidence of acute coronary syndrome, peripheral arterial occlusive disease, or ischemic stroke in patients with type 2 diabetes?

Population

79,504 patients with type 2 diabetes from 43 randomized controlled trials, followed for a median of 1.9 years.

Intervention

SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin) in combination with background treatment

Comparator

Placebo or active therapy using oral hypoglycemic drugs

Outcome

Incidence of acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS)hard clinical

SGLT2 inhibitors do not significantly reduce the incidence of acute coronary syndrome, peripheral arterial occlusive disease, or ischemic stroke in patients with type 2 diabetes, despite reducing cardiovascular and all-cause mortality.

Main Result

Relative Risk: 0.97 (95% CI 0.89–1.05)

Absolute Event Rate: 3.1% vs 3.45%

Limitations

Baseline variations in clinical settings, age, follow-up and disease duration may bias the results.
Assumption that studies used the same definitions of adverse events and inclusion/exclusion criteria.
Potential discrepancies in the number of cases reported for the same disease on ClinicalTrials.gov across funding organizations.
Possible under-estimation of the actual incidence due to strict disease definitions applied to prevent multiple-counting.

Abstract

BACKGROUND: Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently. METHODS: We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane's risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria. RESULTS: We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89-1.05), PAOD (RR = 0.98, 95% CI 0.78-1.24), or IS (RR = 0.95, 95% CI 0.79-1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77-0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82-0.94). CONCLUSION: Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.

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