Dapagliflozin cuts CV events even in patients with severe kidney disease

The SGLT2 inhibitor (SGLT2i) dapagliflozin consistently reduces cardiovascular (CV) events regardless of baseline kidney function and albuminuria status in patients with type 2 diabetes (T2D) — with the greatest absolute benefit in those with most severe kidney disease, according to a prespecified secondary analysis of the DECLARE-TIMI* 58 trial.

In this secondary analysis, participants in the trial were categorized based on the number of CKD** markers: two markers if they had both reduced eGFR*** (<60 mL/min/1.73m²) and albuminuria (UACR^# ≥30 mg/g); one if they had either marker; and none if their eGFR was ≥60 mL/min/1.73m² and UACR <30 mg/g.

As expected, the more CKD markers the patients had, the higher the rates of the dual primary endpoint of CV events: major adverse CV events (MACE; 7.5 percent, 11.6 percent, and 18.9 percent for zero, one, and two markers, respectively) and the composite of CV death or HHF^## (3.9 percent, 8.3 percent, and 17.4 percent, respectively) at 4 years, among patients assigned to the placebo group.  

Dapagliflozin led to greater relative risk reductions in the dual primary endpoints and its component of CV death and HHF compared with placebo, and the benefits persisted across subgroups regardless of CKD markers (p>0.24 for interaction).

In particular, reductions in the absolute risk of the composite of CV death or HHF were greater in patients with more CKD markers: −8.3 percent for two markers, −1.0 percent for one marker, and −0.5 percent for zero marker (p=0.02 for interaction).

“Consistent with the results in the overall patient population, [these] favourable effects were not counterbalanced by adverse events because there were no differences in major hypoglycaemic events, amputations, or fractures by treatment group in patients with more markers of CKD,” the researchers noted. “Baseline kidney function also did not modify the risk of diabetic ketoacidosis.”

Among patients with two CKD markers, these above-mentioned events were either balance or numerically lower in the dapagliflozin vs the placebo groups.

As CV disease can place a burden on the kidney and lead to kidney complications and vice versa, SGLT2i can interrupt this vicious cycle through its cardiorenal protective effects.

Though the current analysis was secondary from the DECLARE-TIMI 58 CV outcome trial, dedicated kidney outcome trial on SGLT2i such as CREDENCE has lent further support for SGLT2i benefits in patients with CKD. Compared with the population enrolled in CREDENCE which were sicker, DECLARE-TIMI 58 patients had more preserved kidney function at baseline. 

“Treatment with dapagliflozin is not recommended by the US FDA for glycaemic control in patients with an eGFR below 45mL/min/1.73m² and is contraindicated for glycaemic control in patients with an eGFR below 30 mL/min/1.73m² without established CV disease or CV risk factors,” the researchers stated.

“However, these regulations were established because of attenuated urinary glucosuria and thus lower efficacy in HbA1c reductions in those patients and not because of safety concerns,” they pointed out. “In the DECLARE-TIMI 58 trial, we observed lower, albeit still significant, reductions in HbA1c levels in patients with a lower baseline eGFR compared with patients who had more preserved baseline kidney function.”

*DECLARE-TIMI: Dapagliflozin Effect on Cardiovascular Events–Thrombolysis In Myocardial Infarction

**CKD: Chronic kidney disease

***eGFR: estimated glomerular filtration rate

^#UACR: urinary albumin to creatinine ratio

^#HHF: Hospitalization for heart failure