Dapagliflozin benefits for CV mortality, hospitalization consistent regardless of PAD status
The benefits of dapagliflozin in reducing the risk of cardiovascular (CV) death, hospitalization for heart failure (HHF), and renal outcomes* were consistent in patients with type 2 diabetes (T2D) regardless of whether or not they had peripheral artery disease (PAD), according to a subgroup analysis of the DECLARE-TIMI 58** trial. Moreover, dapagliflozin-treated patients did not have an elevated risk of limb ischaemic events.
Study participants were 17,160 patients with T2D who were randomized to receive either dapagliflozin (10 mg/day) or placebo. Of these, 6 percent (n=1,025, median age 62 years, 32 percent female) had PAD. The patients were followed up for a median 4.2 years.
Among placebo recipients, the risk of major adverse cardiovascular events (MACE)*** was higher among those with than without PAD (15.9 percent vs 9.0 percent, adjusted hazard ratio [adjHR#], 1.23), as was the risk of CV death or HHF (12.1 percent vs 5.4 percent, adjHR, 1.60) or renal outcomes (10.9 percent vs 5.3 percent, adjHR, 1.51). [ACC.19, abstract 413-14]
Similar outcomes were demonstrated among patients with vs without PAD who received dapagliflozin (16.9 percent vs 8.3 percent [MACE], 10.7 percent vs 4.5 percent [CV death or HHF], and 8.8 percent 4.0 percent [renal outcomes]).
Due to their elevated risk, patients with PAD had greater absolute risk reductions (ARR) with dapagliflozin than those without PAD with regard to CV death or HHF (ARR, 1.4 percent vs 0.9 percent) or renal outcomes (ARR, 2.1 percent vs 1.3 percent).
Reduced risk of limb complications
A total of 560 limb ischaemic events, 454 peripheral revascularizations, and 236 amputations occurred over the study period.
Among placebo recipients, incidence of limb-related adverse events (AEs) was higher among patients with PAD than without (20.3 percent vs 2.1 percent, adjHR, 8.37), regardless of type of event (3.4 percent vs 0.1 percent, adjHR, 19.69 for acute limb ischaemia [ALI], 5.0 percent vs 0.3 percent, adjHR, 12.99 for chronic critical limb ischaemia [CLI], 5.6 percent vs 1.1 percent, adjHR, 4.47 for amputation, and 8.2 percent vs 3.3 percent, adjHR, 2.13 for limb infection; p<0.01 for all).
“Infection is the dominant driver of amputations whether or not [there is] PAD in patients with diabetes,” pointed out study author Dr Marc Bonaca from the Brigham and Women’s Hospital, Boston, Massachusetts, US.
Specifically among patients with PAD, the risk of limb ischaemic AEs was comparable between dapagliflozin and placebo recipients (19.4 percent vs 20.3 percent, HR, 0.93), specifically ALI (2.9 percent vs 3.4 percent, HR, 0.84), CLI (5.8 percent vs 5.0 percent, HR, 1.12), revascularization (4.0 percent vs 5.0 percent, HR, 0.79 [urgent] and 12.1 percent vs 14.1 percent, HR, 0.84 [elective]), or amputation (8.4 percent vs 5.6 percent, HR, 1.51; p>0.05 for all).
This was similar to the overall study population where dapagliflozin recipients did not have a higher risk of ischaemic limb AEs compared with placebo recipients (3.37 percent vs 3.16 percent, HR, 1.07), be it ALI (0.33 percent in each group), CLI (0.82 percent vs 0.58 percent, HR, 1.40), urgent or elective revascularization (0.52 percent vs 0.61 percent, HR, 0.86 and 1.57 percent vs 1.48 percent, HR, 1.06, respectively), or amputation (1.43 percent vs 1.32 percent, HR, 1.09; p>0.05 for all).
Previously published data among the overall DECLARE TIMI-58 population demonstrated a 17 percent lower risk of CV death or HHF among dapagliflozin compared with placebo recipients (4.9 percent vs 5.8 percent, HR, 0.83; p=0.005 for superiority), with a proportionally but not significantly lower risk of MACE with dapagliflozin (8.8 percent vs 9.4 percent, HR, 0.93; p=0.17 for superiority). [N Engl J Med 2019;380:347-357]
“[In the present analysis], patients with PAD were at heightened risk of cardiac, renal, and limb complications [compared with] those without and the efficacy [of dapagliflozin] for CV death or HHF and renal outcomes was consistent whether or not you had PAD although the absolute benefits were greater in the PAD subgroup by nature of their higher baseline risk,” said Bonaca.
Although SGLT2## inhibitors reduce the risk of heart failure and renal complications in patients with T2D, “there have been safety concerns particularly after the unexpected observation of an associated risk of amputation with canagliflozin that was not seen with the other two available agents”, he said.
“There was no significant excess risk of amputations or limb ischaemic events with dapagliflozin in the overall population and there was no consistent pattern of risk or benefit related to limb events in patients with PAD or other high-risk subgroups [including age ≥65 years, T2D duration >20 years, and chronic kidney disease],” he added.