SGLT2i treatment effect not dependent on age or health status at baseline

Effect of Treatment According to Age in the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF)

News - Nov. 26, 2019

Presented during the AHA Scientific Sessions 2019 by John J V McMurray, (University of Glasgow, Glasgow, United Kingdom).

Effect of Treatment on the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF)

//Presented during the AHA Scientific Sessions 2019 by Mikhail N Kosiborod (St. Luke's Health System, Kansas City, MO, USA)

Introduction and methods

Although the number of elderly patients with heart failure (HF) is increasing, the age of people with HF varies geographically. People with HF in Latin America, Africa and Asia are typically younger than patients in North America and Western Europe. That makes it important to understand efficacy and safety of new treatments in all age groups.

Tolerability is a particular concern in the elderly, not only because of advanced age and comorbidity, but also because of polypharmacy. In addition, the benefit of treatment may be questioned in the elderly.

This post hoc analysis of DAPA-HF results studied the efficacy and safety of dapagliflozin according to age. DAPA-HF was a placebo-controlled trial in which dapagliflozin was added to other guideline-recommended therapies in patients with HF and reduced ejection fraction (HFrEF). 4744 Patients with LVEF ≤40%, NYHA class II-IV and NT-proBNP ≥600 pg/ml were randomized to dapagliflozin 10 mg once daily or placebo. The primary endpoint was a composite of CV death, HF hospitalization (HFH) and urgent HF visit. In this study, age was considered as both a categorical (<55, 55-64, 65-74, ≥75 years) and continuous variable.

Another analysis of DAPA-HF data presented at AHA Scientific Sessions regarded effect of dapagliflozin on quality of life (QoL). In addition to reducing death and hospitalization, another goal of care in HF is to improve health status. This was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, after 4 and 8 months. KCCQ addresses four clinical domains: symptoms (frequency and severity), physical limitation, QoL and social limitation. It represents the patient’s perspective. Scores can be 0-100, with higher scores reflecting better health.

Main results

Treatment effect according to age

  • The primary outcome was significantly improved with dapagliflozin in those 55-64 (HR: 0.71, 95%CI: 0.55-0.93), HR: 0.76, 95%CI: 0.61-0.95) and in those ≥75 years (HR: 0.68, 95%CI: 0.53-0.88), but not in those <55 years (HR: 0.87, 95%CI: 0.60-1.28).
  • When age was considered as a continuous variable, the primary endpoint showed a stably reduced HR, which declined at higher age. HRs for CV death and all-cause death with dapagliflozin vs. placebo were very stable across age, and HFH/urgent visit showed a more gradual decline of HR across age.
  • None of the endpoints showed an interaction with age (P values were 1 or 0.99).
  • Clinically meaningful change (≥5 points) in KCCQ-TSS score from baseline to 8 months was significant in age groups from 55 years and older, both for more improvement and less deterioration.
  • No interaction of age was seen with the effect of treatment on volume depletion-related adverse events (AE), nor on serious AEs or treatment discontinuation.
  • Renal safety events were more common among the elderly and renal AE, serious renal AE and doubling of serum creatinine showed significant interactions with age.

Treatment effect on health status

  • When patients were divided in tertiles based on KCCQ total symptom scores (TSS) at baseline, all tertiles showed significant benefit of dapaglifozin treatment (P-interaction: 0.52).
  • No significant interactions of KCCQ-TSS tertile at baseline were seen with the treatment effect on secondary endpoints or components of the primary endpoint.
  • Significantly higher mean KCCQ-TSS scores compared with baseline were seen in the dapagliflozin vs. placebo groups at 4 months (+1.91, P<0.0001) and at 8 months (+2.76, P<0.0001). KCCQ-clinical summary score (1.80 and 2.55) and KCCQ overall summary score (1.74 and 2.31) were also significantly improved with dapagliflozin at these time points.
  • Number needed to treat (NNT) for improvement on the TSS score was 14 for ≥5 points, 15 for ≥10 points and 18 for ≥15 points. For the clinical score, NNT’s were 12, 12 and 17, respectively, and for the overall summary score they were 15, 13 and 17.


This analysis shows that the benefit of dapagliflozin in reducing the risk of worsening HF events and CV death and in improving symptoms in patients with HFrEF, as reported before, is consistent across the range of ages studied. The absolute benefits in older patients are larger because they are at higher risk than younger patients. Dapagliflozin is well tolerated and discontinuation rates are low in all age groups.

The QoL analysis showed that dapagliflozin improved key clinical outcomes across the entire range of KCCQ at baseline. Moreover, dapagliflozin favorably affected all major components of KCCQ. Clinically meaningful improvements in all key domains were noted in those treated with dapagliflozin, and fewer patients had significant deterioration.


Discussant Carolyn Lam (National Heart Centre Singapore, Duke-National University of Singapore) reminded the audience of a previous subgroup analysis that suggested that patients with NYHA class III or IV seems to have no treatment benefit of SGLT2 inhibition, and that benefit was limited to those with class II. That question seems to be solved now; treatment effect does not seem to be affected by symptoms and QoL as assessed by KCCQ.

The question around treatment effect and age is now also solved. The data do also make clear that older patients are less likely to be treated according to guidelines. Thus, there is inertia in these patients. The current data show that these patients respond well to treatment.

A statement of the American FDA says that evidence of effectiveness for a HF drug could be based on improvements in symptoms and/or function and Lam therefore appreciates patient-reported outcomes. They should receive more attention. It remains to be established what tool is best to use, or which KCCQ domains are most relevant.

Overall, based on these data Lam concluded that dapagliflozin meets the three critical goals in HF management: reduced mortality, reduced hospitalizations and improved HF-related health status. She went as far as to say that this provides further important data supporting SGLT2 inhibition with dapagliflozin as the next foundational pillar of HFrEF treatment.

  • Our reporting is based on the information provided during AHA Scientific Sessions 2019 –

The primary DAPA-HF results were published in N Eng J Med on November 21, 2019

The age results were published simultaneously in CirculationThe QoL results were published simultaneously in Circulation

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