Dapagliflozin cuts risk of CV death/HHF even in patients with more severe CKD
Dapagliflozin consistently reduced the composite outcome of cardiovascular (CV) death and HHF* in patients with type 2 diabetes (T2D) regardless of kidney function, with the greatest benefit seen in those with both reduced eGFR and albuminuria, new insights from the DECLARE-TIMI 58** trial revealed.
“These data add to the growing body of evidence that treatment with SGLT-2i*** in patients with chronic kidney disease [CKD] is safe and should be considered for the prevention of CV events in these patients with T2D at very high risk,” said Dr Thomas Zelniker from the Brigham and Women's Hospital in Boston, Massachusetts, US, who presented the study at the 2019 ESC Congress.
Dapagliflozin has previously been shown to significantly reduce the risk of CV death/HHF in the primary analysis involving 17,160 patients with T2D. [N Engl J Med 2019;380:347-357] As dapagliflozin works by blocking the reabsorption of glucose and sodium ion in the renal tubule and that kidney dysfunction has been shown to predict CV outcomes, the investigators went on to find out if the CV benefit of dapagliflozin was affected by baseline renal function and albuminuria status.
In the current analysis, patients were categorized as having two markers of CKD if they had abnormal levels of both eGFR (<60 mL/min/1.73 m2) and UACR (≥30 mg/g), having one marker of CKD if either eGFR or UACR level was abnormal, and none if both eGFR (≥60 mL/min/1.73 m2 ) and UACR (<30 mg/g) were normal. [ESC 2019, abstract 192]
The more CKD markers the patients had at baseline — reflecting more extensive kidney damage — the higher the event rates of CV death/HHF at 4 years (3.9 percent, 8.3 percent, and 17.4 percent for those with none, one, or two CKD markers respectively; adjusted hazard ratios [HRs], 1.84 and 2.97 for one and two CKD markers, respectively, vs none). Similar finding was observed for the 4-year event rate of MACE*** (7.5 percent, 11.7 percent, and 18.9 percent, respectively; HRs, 1.38 and 2.00, respectively, vs no CKD).
“[These data indicate that] patients with T2D and CKD are at a very high risk for CV events,” pointed out Zelniker.
The treatment effects of dapagliflozin in terms of relative risk reductions of CV death/HHF vs placebo were consistent across subgroups, regardless of whether they had two, one, or no CKD markers (HRs, 0.58, 0.87, and 0.87, respectively; p-interaction=0.24) — with numerically larger reductions in those with two CKD markers (by 42 percent). So were the relative reductions for the risk of MACE (HRs, 0.79, 0.96, 0.95, respectively; p-interaction=0.65).
While dapagliflozin benefited all subgroups of patients, the CV death/HHF benefit was significantly greater in the subgroup with both reduced eGFR and albuminuria (two CKD markers) compared with those with just one CKD marker or those without, in terms of absolute risk reduction (-8.3, -1.0, -0.5; p-interaction=0.023).
“The subgroup with two CKD markers had significantly larger reduction in absolute risk, reflecting the higher baseline risk of these patients,” Zelniker said.
Similarly, the absolute risk reduction for MACE was greatest in the subgroup with two CKD markers compared with those with one or no CKD marker (-5.3, -0.3, -0.3, respectively; p-interaction=0.31), although the treatment effect was not significantly modified by the presence of CKD markers.
“Consistent with the results in the overall patient population, there was no difference in major hypoglycaemic events, diabetic ketoacidosis, amputations, or fractures in patients with greater kidney damage,” noted Zelniker.