Physicians' Academy for Cardiovascular Education

Type of existing CVD at baseline affects CV benefits of SGLT2 inhibition

SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

Literature - Zelniker TA, Wiviott SD, Raz I et al. - The Lancet 2018: published online ahead of print

Introduction and methods

Although sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended to reduce risk of MACE in patients with atherosclerotic cardiovascular disease (ASCVD) but not multiple risk factors [1,2], it remains unknown whether the CV efficacy of SGLT2i depends on baseline ASCVD risk categories, a history of HF and renal function. Publication of the DECLARE-TIMI 58 results [3] now allows betters investigation of the potential heterogeneity CV efficacy by baseline CVD risk. Moreover, a meta-analysis allows better assessment of some infrequent adverse events that have been observed in some of the SGLT2i CVOTs.

Therefore, this meta-analysis combined data from all large-scale placebo-controlled CVOTs of SGLT2i published up to Sept, 2018 (EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 trials; n=34,322) to gain more reliable estimates of the efficacy and safety of specific outcomes overall and in relevant subgroups. The DECLARE-TIMI 58 also included patients without known ASCVD but with multiple risk factors (59%), and in the pooled cohort this group represented 39.8%. These subgroups consisted of: established ASCVD vs. multiple risk factors, with vs. without a history of HF, and of eGFR levels (low: <60 mL/min/1.73m², middle: 60-90 mL/min/1.73m², and high: ≥90 mL/min/1.73m²).

Efficacy outcomes were MACE, the composite of CV death or hospitalization for HF (HHF), their individual components, and a standardized composite of renal outcomes including worsening eGFR, end-stage renal disease, or renal death. Safety endpoints were non-traumatic lower limb amputations, fractures, and diabetic ketoacidosis.

Main results

Efficacy outcomes: different subgroups

Safety outcomes

Type of existing CVD at baseline affects CV benefits of SGLT2 inhibition


This meta-analysis of the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 trials showed moderate benefits of SGLT2i on atherosclerotic MACE only in those with established ASCVD. In contrast, robust reductions in HHF and progression of renal disease were observed regardless of baseline atherosclerotic risk category or a history of HF.


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