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Effect of SGLT2 Inhibitors on Major Adverse Cardiovascular Outcomes
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Sodium glucose co-transporter 2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear.
METHODS
This was 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 atherosclerotic cardiovascular disease [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 non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. 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% (HR 0.91 [95% CI 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 (Pint=0.02).
CONCLUSIONS
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. This effect is driven primarily by a reduction of CV death, particularly HF and sudden cardiac death, without a significant effect on MI in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.
Additional Info
Disclosure statements are available on the authors' profiles:
Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis
Circulation 2024 Apr 07;[EPub Ahead of Print], SM Patel, YM Kang, K Im, BL Neuen, SD Anker, DL Bhatt, J Butler, DZI Cherney, BL Claggett, RA Fletcher, WG Herrington, SE Inzucchi, MJ Jardine, KW Mahaffey, DK McGuire, JJV McMurray, B Neal, M Packer, V Perkovic, SD Solomon, N Staplin, M Vaduganathan, C Wanner, DC Wheeler, F Zannad, Y Zhao, HJL Heerspink, MS Sabatine, SD WiviottFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
SGLT2 inhibitors have been a wonderful advance over the last seven years, since the publication of the EMPA-REG trial. To date, there have been 14 large randomized trials showing the benefits of this class of agents on various endpoints; nearly every trial showed a significant reduction of approximately 30% in hospitalization for heart failure with this class of drugs.1 Findings for other endpoints such as cardiovascular death, myocardial infarction (MI), or stroke have been mixed and mostly nonsignificant, with many showing a trend towards benefit. There have been several meta-analyses done over the years, and this collaborative meta-analysis of 12 of the trials provides very useful insights.
This meta-analysis focused on MACE (cardiovascular death, myocardial infarction, and stroke as a composite and each endpoint individually). To me, the findings were actually a bit of a surprise. However, as I looked more closely, it did make sense.
There was a significant but modest 9% reduction in MACE; however, this was a make-up of a significant 14% reduction in cardiovascular death and no significant reduction in MI or stroke. There was a consistent reduction in cardiovascular death with SGLT2 inhibitors across each patient population studied (participants with or at high risk of atherosclerotic CVD, heart failure, or CKD), with a significant reduction of about 14% in cardiovascular death in each group. This is an important finding, one that I think we can share with our patients when starting this medication to say that this reduces the risk of dying from heart disease.
The other finding is helpful to see where there was really no effect in any trial on the risk of stroke and no significant reduction in the risk of MI. Looking at the different populations, one would not expect a difference in MI in patients with heart failure, but there was a slight trend in several of the trials for reduction in MI that turned out to be insignificant (HR, 0.92; CI, 0.84–1.00). This is intriguing in that there is an agent that is a combined SGLT1/SGLT2 inhibitor, sotagliflozin (not included in this meta-analysis) that has been seen to have significant reductions in both MI and stroke in its one large trial of patients with CKD.2 This raises the hypothesis that this combined agent may have better effects on these atherosclerotic endpoints. Further trials will hopefully help elucidate this.
Thus, this new collaborative meta-analysis shows a very important effect of SGLT2 inhibitors in reducing cardiovascular death across a broad patient population. Our job as clinicians now is to try to offer this to as many patients who are eligible for this benefit.
References