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

• Overall, SGLT2i reduced the risk of MACE by 11% (HR: 0.89, 95%CI: 0.83-0.96, P=0.0014). When stratifying for history of ASCVD, this effect was only observed in patients with ASCVD (HR: 0.86, 95%CI: 0.80-0.93, P=0.0002), but not in patients with multiple risk factors (HR: 1.00, 95%CI: 0.87-1.16, P=0.98) (P-interaction=0.0501).
• In patients with ASCVD, SGLT2i reduced the risk of MI (HR: 0.85, 95%CI: 0.76-0.95) and CV death (HR: 0.80, 95%CI: 0.71-0.91), whereas no effect was seen in patients without ASCVD (HR: 0.80, 95%CI: 0.71-0.91). In both groups, SGLT2 inhibition did not significantly affect stroke.
• Overall, SGLT2i significantly reduced the risk for the composite of CV death or HHF by 23% (HR: 0.77, 95%CI: 0.71-0.84, P<0.0001). In patients with ASCVD, the HR for the composite of CV death or HHF was 0.76 (95%CI: 0.69-0.84, P<0.0001) and in patients with multiple risk factors it was 0.84 (95%CI: 0.69-1.01, P=0.0634) (P-interaction=0.41).
• The reduction in the composite of CV death or HHF was not statistically significantly different in patients with (HR: 0.71, 95%CI: 0.61-0.84, P<0.0001) or without (HR: 0.79, 95%CI: 0.71-0.88, P<0.0001) a history of HF at baseline (P-interaction=0.51), nor were the individual component outcomes.
• Overall, SGLT2i were renoprotective and reduced the composite of worsening of renal function, end-stage renal disease, or renal death by 45% (HR: 0.55, 95%CI: 0.48-0.64, P<0.0001), which was similar in patients with ASCVD (HR: 0.56, 95%CI: 0.47-0.67, P<0.0001) and in those with multiple risk factors (HR: 0.54, 95%CI: 0.42-0.71,P<0.0001) (P-interaction=0.71).
• The reduction in the composite renal endpoint was present across all baseline eGFR levels, but it was greatest in those with preserved renal function at baseline, with a 33% reduction in the low eGFR group (HR: 0.67, 95%CI: 0.51-0.89, P=0.0054), 44% in the middle group (HR: 0.56, 95%CI: 0.46-0.70, P<0.0001), and 56% in the highest group (HR: 0.44, 95%CI: 0.32-0.59, P<0.0001) (P-trend=0.0258).
• The reduction in HHF was 40% in the lowest eGFR group (HR: 0.60, 95%CI: 0.47-0.77, P<0.0001), 31% in the middle group (HR: 0.69, 95%CI: 0.57-0.83, P<0.0001), and a non-significant 12% in the highest group (HR: 0.88, 95%CI: 0.68-1.13, P=0.31) (P-trend=0.0073).
• The effect of baseline eGFR on MACE was less clear, and showed a non-significant trend (P=0.23), towards a higher treatment benefit in the lowest eGFR category.

Safety outcomes

• Significant heterogeneity was observed among the trials for amputations (I²=79.1%) and fractures (I²=78.2%), with an increased risk seen only in one trial.
• Diabetic ketoacidosis showed a consistently increased risk in patients treated with SGLT2i compared to placebo (HR: 2.20, 95%CI: 1.25-3.87, P=0.0060), but event rates were lower than 1 per 1000 patient-years.

Conclusion

References

Download the slideFind this article online at the Lancet