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SGLT2 Inhibitors and Major Adverse CV Outcomes
Quick Takes
- SGLT2i reduce the risk of MACE across a broad range of patient populations and key subgroups.
- The primary benefit of SGLT2i for MACE is driven by a reduction in CV death mediated primarily by a reduction in the risk of HF death and sudden cardiac death.
- SGLT2i have beneficial effects on MACE, which are consistent irrespective of established ASCVD or diabetes status at baseline, and across a wide range of kidney function and may help inform selection of SGLT2i therapy across a broad range of patients encountered in clinical practice.
Study Questions:
What is the effect of sodium glucose co-transporter 2 inhibitors (SGLT2i) on the risk of major adverse cardiovascular events (MACE) and its individual components, overall and within clinically relevant subgroups of patients, irrespective of atherosclerotic cardiovascular disease (ASCVD), diabetes, and kidney function?
Methods:
The investigators conducted a collaborative trial-level meta-analysis from the SGLT2i meta-analysis cardio-renal trialists consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across three patient populations (diabetes at high risk for ASCVD, heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established ASCVD, prior MI, diabetes, prior HF, albuminuria, CKD stages, and risk groups).
Results:
A total of 78,607 patients across 11 trials were included: 42,568 (54.2%), 20,725 (26.4%), and 15,314 (19.5%) were included from trials of patients with diabetes at high risk for ASCVD, HF, or CKD, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ratio [HR], 0.91 [95% confidence interval, 0.87-0.96]; p < 0.0001) with a consistent effect across all three patient populations (I2 = 0%) and across all key subgroups. This effect was primarily driven by a reduction in CV death (HR, 0.86 [0.81-0.92]; p < 0.0001), with no significant effect for MI in the overall population (HR, 0.95 [0.87-1.04]; p = 0.29), and no effect on stroke (HR, 0.99 [0.91-1.07]; p = 0.77). The benefit for CV death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [0.46-1.02] and HR, 0.86 [0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (p for interaction = 0.02).
Conclusions:
The authors report that SGLT2i reduce the risk of MACE across a broad range of patients irrespective of ASCVD, diabetes, kidney function, or other major clinical characteristics at baseline.
Perspective:
This collaborative meta-analysis of approximately 78,000 patients across 11 randomized trials reports that SGLT2i reduce the risk of MACE (composite of CV death, MI, or stroke) across a broad range of patient populations and key subgroups. Furthermore, the primary benefit of SGLT2i for MACE is driven by a reduction in CV death, without a clear effect on MI or stroke, and mediated primarily by a reduction in the risk of HF death and sudden cardiac death. Overall, these data suggest that SGLT2i have beneficial effects on MACE, which are consistent irrespective of established ASCVD or diabetes status at baseline, and across a wide range of kidney function including the subset of patients with advanced stage CKD and may help inform selection of SGLT2i therapy across a broad range of patients encountered in clinical practice.
Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention
Keywords: Cardiometabolic Risk Factors, Sodium-Glucose Transporter 2 Inhibitors
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