Consistent effect of SGLT2i on CV outcomes across eGFR and UACR groups in T2DM
Relative risk reductions by dapagliflozin on CV outcomes were irrespective of baseline eGFR and albuminuria status in T2DM patients who had or were at risk of ASCV, shown in a secondary analysis of DECLARE-TIMI 58.
Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical TrialLiterature - Zelniker TA, Raz I, Mosenzon O et al. - JAMA Cardiol 2021, DOI: 10.1001/jamacardio.2021.0660
Introduction and methods
Glucosuria by an SGLT2 inhibitor is attenuated in patients with kidney failure and therefore the glucose-lowering efficacy in these patient is reduced [1], but benefit for HF hospitalization (HHF) by SGLT2i was greatest among patients with lower baseline eGFR in a recent meta-analysis [2]. These findings support the paradigm shift from a glucocentric approach to a broader CV risk reduction approach for the management of T2DM patients.
This study is a prespecified secondary analysis of the DECLARE-TIMI 58 trial to examine CV efficacy and safety of dapagliflozin across subgroups of kidney function and albuminuria status [3-5]. Dapagliflozin reduced the risk of CV death and HHF compared to placebo in 17,160 T2DM patients with multiple risk factors for or established ASCVD [5]. It is important to investigate the safety profile of dapagliflozin in CKD patients, as this cohort is susceptible to adverse events.
Patients with a creatinine clearance below 60 mL/min at screening were excluded from the trial. Primary efficacy outcomes of this analysis were composite of CV death of HHF and of MACE. Safety outcomes of interest included major hypoglycemia, amputation, diabetic ketoacidosis, and fracture. Patients were categorized according to baseline eGFR (<60 vs ≥60 mL/min/1.73 m2 and baseline urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g) and categorically ranked by number of CKD markers (0,1 or 2).
Main results
- 1265 Patients (7.4%) had eGFR <60 mL/min/1.73 m2 and 5199 Patients (30.9%) had albuminuria. 10,958 patients (65.1%) had no markers of >stage 2 CKD, and 5336 patients (37.1%) had 1 CKD marker and 548 (3.3%) had 2 markers.
- In the placebo group, patients with more markers of CKD had higher risk for the composite of CV death or HHF (aHR 1.84, 95%CI: 1.52-2.23 for 1 marker, aHR 2.97, 95%CI: 2.17-4.07 for 2 markers, both P<0.001) and for MACE ((aHR 1.38, 95%CI: 1.19-1.61 for 1 marker, aHR 2.00, 95%CI: 1.51-2.65 for 2 markers, both P<0.001).
- Consistent relative risk reduction for composite of CV death or HHF by dapagliflozin compared to placebo was observed across kidney function subgroups (Pinteraction=0.24), but greatest numerical risk reduction was seen in patient with both reduced eGFR and albuminuria (HR 0.87, 95%CI: 0.72-1.06 for no CKD; HR 0.87, 95%CI: 0.72-1.05 for 1 CKD marker; HR 0.58, 95%CI:0.36-0.94 for 2 markers).
- Similar relative risk reductions for MACE were observed by dapagliflozin when compared to placebo across subgroups, and absolute risk difference was numerically greatest in patients with more CKD markers.
- Patients with a greater UACR tended to have a greater reduction in all-cause mortality by dapagliflozin compared to placebo (Pinteraction=0.007).
- The safety profile of dapagliflozin was similar across all subgroups. Number of amputations, cases of diabetic ketoacidosis, fractures and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo in patients with eGFR <60 mL/min/1.732 and an UACR of 30 mg/g or higher.
Conclusion
This secondary analysis of the DECLARE-TIMI 58 trial showed that relative risk reduction of CV outcomes (composite of CV death or HHF) by dapagliflozin was irrespective of baseline eGFR and albuminuria status in T2DM patients with ASCVD or at high risk for ASCVD. Patients with more markers of CKD had a greater absolute risk reduction of CV outcomes by dapagliflozin. These favorable effects were not counterbalanced by adverse events in those with lower eGFR or albuminuria.
References
1. Perkovic V, Jardine MJ, Neal B et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380(24):2295-2306. Doi:10.1056/NEJMoa811744
2. Zelniker TA, Wiviott SD, Raz I et al. 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. Lancet 2019;393 (10166):31-39. Doi:10.1016/S0140-6736(18)32590-X
3. Wiviott SD, Raz I, Bonaca MP, et al. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J. 2019; 2018:84-89.doi:10.1016/j.ahj.2018.01.012
4. Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: participants’ baseline characteristics. Diabetes Obes Metab. 2018;20(5):1102-1110. Doi:10.1111/dom.13217
5. Wiviott SD, Raz I, Bonaca MP, et al. DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347-357. Doi:10.1056/NEJMoa1812389