In a trial-level meta-analysis published in the journal Circulation, researchers assessed the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) on major adverse cardiovascular events (MACE) across three patient populations: diabetes at high risk for atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD). They found that SGLT2i reduced the rate of MACE by 9% with a consistent effect across all patient populations and key subgroups, primarily driven by a reduction in cardiovascular (CV) death, particularly HF and sudden cardiac death.
Study: Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis. Image Credit: Lightspring / Shutterstock
Background
SGLT2i have been extensively studied in large, randomized, placebo-controlled trials involving diverse populations of patients, including those with type 2 diabetes mellitus (T2DM) and ASCVD, HF, and CKD. While SGLT2i was primarily developed for diabetes, the trials have consistently shown these drugs to reduce HF and kidney-related issues, regardless of diabetes status. However, their impact on MACE remains unclear, with variations observed among trial results. Prior meta-analyses failed to assess the effects on MACE components definitively. Uncertainty persists, particularly in subgroups without ASCVD or diabetes and those with advanced chronic kidney disease stages. Therefore, using data from all significant placebo-controlled trials, researchers in the present study performed a collaborative meta-analysis to explore SGLT2i's effects on MACE risk and its components and death subtypes across relevant patient subgroups.
About the study
The researchers conducted a collaborative trial-level meta-analysis within the SGLT2i Meta-Analysis Cardio-Renal Trialists Consortium (SMART-C). A systematic literature search was conducted, and the included studies were phase 3 placebo-controlled, double-blind, randomized trials with ≥ 1,000 participants in every arm and median follow-up of six months and above. Combination SGLT1/2 inhibitors studies were excluded.
The study included 11 randomized trials comparing SGLT2i to placebo, with 78,607 participants in total. Among them, 54.2%, 26.4%, and 19.5% of individuals participated in trials focused on diabetes at high ASCVD risk, established HF, or CKD, respectively. The mean age of participants was between 62 and 72 years. While 34.4% of them were females, 74.5% of them were white. At baseline, about 79.7% of the patients had diabetes, 36% had HF, and 37.2% had eGFR (short for estimated glomerular filtration rate) less than 60 mL/min/1.73 m². Established ASCVD was present in 58.9%, and 28.5% had prior MI.
The median follow-up duration ranged between 2.4 – 4.2 years, 1.3 – 2.2 years, and 2.0 – 2.6 years for trials focused on diabetes at high ASCVD risk, HF, and CKD, respectively. The primary outcome was the composite of 3-point MACE, including cardiovascular death, myocardial infarction (MI), and all types of stroke. The analysis also assessed the individual components of MI and stroke, including fatal and non-fatal events. Additionally, all-cause mortality (ACM) and death subtypes such as fatal MI, fatal stroke, HF death, sudden cardiac death, as well as other CV and non-CV deaths were examined. The analysis treated each outcome as a time-to-event event, and the effect estimates from each trial were derived from intention-to-treat analysis.
Trial effect estimates were meta-analyzed within primary patient groups using fixed-effects models and then combined as random effects for overall estimates. Sensitivity analysis was conducted using fixed effects. Heterogeneity was assessed using the Cochrane Q statistic and Higgins and Thompson's I2.
Results and discussion
About 10.1% of participants experienced MACE, with 5.3% experiencing CV death, 3.6% experiencing MI, and 2.8% experiencing a stroke. SGLT2i was found to reduce the rate of MACE by 9% overall, with consistent effects across trial populations. The most evident effect was observed on CV death, with reductions in HF death and sudden cardiac death driving the reduction in CV death. There was no significant effect on MI or stroke overall. SGLT2i were also found to reduce ACM, with the most significant effects observed in CKD trials.
Patients with established ASCVD were found to have higher MACE incidence rates across all trial types. SGLT2i consistently reduced the risk of MACE and CV death regardless of established ASCVD status at baseline. Similarly, the effects remained consistent across subgroups stratified by diabetes status, prior HF, kidney function, and baseline eGFR. Stratification by albuminuria suggested a potential benefit primarily among those with ≥30 mg/g albuminuria. Across all the Kidney Disease Improving Global Outcomes (KDIGO) risk groups, the benefits for MACE and CV death were found to be consistent.
The study is limited by fewer trials in each drug in each disease state and variations in eligibility criteria, follow-up duration, and subgroup definitions across studies. These restrictions restrict robust comparisons within the SGLT2i class and lower the generalizability of findings to broader patient populations.
Conclusion
In conclusion, SGLT2i consistently lowers the risk of MACE across diverse patient populations, regardless of baseline ASCVD, diabetes, or kidney function. This benefit predominantly comes from reduced cardiovascular death, notably HF and sudden cardiac death, with no significant impact on MI or stroke overall. These findings suggest the potential utility of SGLT2i across the spectrum of cardiovascular-kidney-metabolic disease, aiding in therapeutic decision-making.
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