Dapagliflozin lowers CV risk in patients with T2DM irrespective of CKD severity
The landmark DECLARE-TIMI 58 trial demonstrated superiority of dapagliflozin vs placebo in reducing the composite outcome of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM). At the European Society of Cardiology (ESC) Congress 2019 and World Congress of Cardiology (WCC) 2019 held in Paris, France, Dr Thomas Zelniker of the Brigham and Women's Hospital, Boston, Massachusetts, US, shared new insights from the trial which revealed that dapagliflozin’s benefit is consistent regardless of kidney function, with the greatest benefit seen in patients with both reduced estimated glomerular filtration rate (eGFR) and albuminuria.
Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that blocks glucose and sodium reabsorption in the kidneys and thereby lowers HbA1c in patients with T2DM. [Am Coll Cardiol 2018;72:1845-1855] The DECLARE-TIMI 58 trial evaluated dapagliflozin’s CV efficacy and safety vs placebo (both given on top of standard of care medical therapy) in 17,160 patients with T2DM and established CV disease or multiple risk factors. In the primary analysis, dapagliflozin significantly lowered the risk of CV death or HHF vs placebo (hazard ratio [HR], 0.83; 95 percent confidence interval [CI], 0.73 to 0.95; p=0.005), and was noninferior with regard to major adverse cardiovascular events (MACE). [N Engl J Med 2019;380:347-357]
“Kidney dysfunction, including both reduced eGFR and the presence of albuminuria, each independently predicts CV outcomes in T2DM,” said Zelniker. [J Am Soc Nephrol 2009;20:1813-1821]
“The relative CV efficacy and safety profile of dapagliflozin in patients with chronic kidney disease [CKD] is not well established,” he added.
DECLARE-TIMI 58: Prespecified subgroup analysis
A subgroup analysis of the DECLARE-TIMI 58 trial was performed to analyze the CV efficacy and safety of dapagliflozin according to patients’ baseline renal function and albuminuria status.
At enrollment, patients with creatinine clearance <60 mL/min were excluded. [N Engl J Med 2019;380:347-357] In the subgroup analysis, patients were categorized according to their baseline eGFR (<60 vs ³60 mL/min/1.73m2) and urine albumin-to-creatinine ratio (UACR) (³30 vs <30 mg/g), and were ranked by whether they had abnormal levels (eGFR <60 mL/min/1.73m2, UACR ³30 mg/g) of neither, one or both. [Zelniker TA, et al, ESC 2019, abstract 192]
“The mean baseline eGFR and median UACR in the total population were 85 mL/min/1.73m2 and 13 mg/g, respectively. Overall, 65 percent of patients [n=10,958] had no markers of CKD, while 32 percent [n=5,336] had one marker and 3 percent [n=548] had both markers present at baseline. Patients with more markers of CKD were more likely to be older, male, and have a higher body mass index [BMI], atherosclerotic CV disease, heart failure, amputations, and higher use of CV drugs,” reported Zelniker.
More abnormal CKD markers associated with higher CV event rates
Presence of more CKD markers at baseline, which is indicative of more extensive kidney damage, correlated with higher event rates at 4 years for CV death or HHF (3.9 percent, 8.3 percent and 17.4 percent for those with no, one or two CKD markers, respectively) and MACE (7.5 percent, 11.7 percent and 18.9 percent). (Figure 1) [Zelniker TA, et al, ESC 2019, abstract 192]
At 6 months, dapagliflozin treatment resulted in changes in CV risk factors that differed according to baseline kidney function. “The extent of HbA1c reduction with dapagliflozin was significantly smaller in patients with lower baseline eGFR as compared with those with more preserved kidney function. The average differences were 0.39 percent, 0.47 percent and 0.7 percent in patients with baseline eGFR <60 mL/min/1.73m2, 60–90 mL/min/1.73m2, and ≥90 mL/min/1.73m2, respectively [pinteraction<0.001]. Conversely, the differences in systolic blood pressure reduction were similar and numerically even higher in patients with lower eGFR. The differences in BMI decrease were qualitatively similar across eGFR strata, with a trend for interaction indicating a smaller difference in patients with lower eGFR,” noted Zelniker.
Relative risk reductions in CV events consistent across subgroups
The treatment effect of dapagliflozin on reducing the relative risk of CV death or HHF vs placebo was similar among patients with varying degrees of renal disease (HRs, 0.87, 0.87 and 0.58 for no, one or two CKD markers, respectively; pinteraction=0.24), with numerically greater reductions (42 percent) in patients with both reduced eGFR and albuminuria. Similarly, the relative risk reductions for MACE were consistent across the subgroups (HRs, 0.95, 0.96 and 0.79, respectively; pinteraction=0.65). (Figure 2) [Zelniker TA, et al, ESC 2019, abstract 192]
Although dapagliflozin benefited all subgroups of patients, the absolute risk reduction for CV death or HHF was significantly larger in patients with two CKD markers compared with those with one or no markers (8.3 percent, 1.0 percent and 0.5 percent, respectively; pinteraction=0.023).
“Additionally, the absolute risk reduction for MACE was numerically the greatest in patients with more severe CKD, reflecting the higher baseline risk of these patients,” pointed out Zelniker.
Notably, the analysis also revealed a greater benefit in all-cause mortality for dapagliflozin-treated patients with more extensive kidney damage (pinteraction=0.036). This effect modification appeared to be mainly driven by UACR rather than by eGFR, where patients with greater UACR tended to benefit from greater reduction in all-cause mortality (pinteraction=0.007). A similar pattern was observed for CV death, although not statistically significant. (Figure 3) [Zelniker TA, et al, ESC 2019, abstract 192]
Safety profile similar across subgroups
“Consistent with the findings in the overall population, the safety profile of dapagliflozin was similar across all evaluated subgroups,” commented Zelniker. Compared with placebo, no differences were observed in amputations, diabetic ketoacidosis, fractures or major hypoglycaemic events in patients with greater kidney damage. (Figure 4) [Zelniker TA, et al, ESC 2019, abstract 192]
Patients with T2DM and CKD are at very high risk of CV events. The glucose-lowering effect of dapagliflozin is attenuated in patients with reduced eGFR, whereas the magnitude of blood pressure and BMI reductions are similar irrespective of baseline kidney function. The relative risk reductions with dapagliflozin for CV death or HHF and MACE were generally consistent across CKD marker subgroups. However, patients at the highest risk derived the greatest absolute risk reduction, reflecting their higher baseline risk. No safety concerns were apparent with dapagliflozin in patients with greater kidney damage.
“These data add to the growing body of evidence that treatment with SGLT2 inhibitors in patients with T2DM and CKD is safe and should be considered for the prevention of CV events in these patients, who are at very high risk,” concluded Zelniker.