Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL

Dec 8, 2018Diabetes care

SGLT2 Inhibitors, Including Dapagliflozin, Consistently Lower Heart Risk and Improve Kidney Function

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Abstract

SGLT2 inhibitors are associated with a 51% lower risk of all-cause mortality compared to nonusers.

SGLT2 inhibitor users had a numerically lower risk of major adverse cardiovascular events (MACE) compared to nonusers.
Dapagliflozin users exhibited a lower risk of MACE, although findings were not statistically significant.
SGLT2 inhibitor users showed a significantly lower risk of all-cause mortality (ACM) compared to nonusers.
Dapagliflozin users also had a lower risk of ACM, but the result lacked statistical significance.
The estimated glomerular filtration rate (eGFR) slope improved significantly for SGLT2 inhibitor users compared to nonusers.
Dapagliflozin users experienced a greater improvement in eGFR slope than nonusers.

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OBJECTIVE: The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole.

RESEARCH DESIGN AND METHODS: SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers (= 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2i at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis. n

RESULTS: In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49-1.28]), as did dapagliflozin users (0.55 [0.26-1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27-0.95]; dapagliflozin: 0.66 [0.25-1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87-2.69] mL/min/1.73 mper year) and for dapagliflozin users (+2.28 [1.01-3.54] mL/min/1.73 mper year). 2 2

CONCLUSIONS: This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline.

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Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL

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