SGLT2i gives consistent CV benefit in HFrEF patients with or without T2DM
The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF): Results in Nondiabetic Patients)
Presented during the AHA Scientific Sessions 2019 by John J V McMurray (BHF Cardiovascular Res Ctr, Glasgow, United Kingdom).
Introduction and methods
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to prevent the development of heart failure (HF) in patients with type 2 diabetes (T2DM). That raised the question whether they can be used to treat patients with established HF. The benefits of SGLT2 inhibitors may be glucose-independent, which raised the question whether SGLT2 inhibitors can be used to treat patients without T2DM?
DAPA-HF tested the SGLT2 inhibitor dapagliflozin, 10 mg once daily, added to standard therapy, in patients with HF and reduced ejection fraction (HFrEF) both with and without T2DM. 4744 Patients with NYHA class II-IV with LVEF ≤40% and NT-proBNP ≥600 pg/mL were enrolled in 20 countries. They were randomized to dapagliflozin or placebo and followed until at least 844 events of the primary composite endpoint of CV death, HF hospitalization and urgent HF visit occurred. Patients visited the clinic at day -14 (enrolment), day 0 (randomization), day 13, day 60, day 120 and then every 120 days.
This analysis compared the effect of dapagliflozin in those with compared to those without diabetes. At baseline, patients were stratified for having diabetes (n=2139) or not (n=2605). Groups showed roughly similar baseline characteristics, except that those with diabetes more often showed ischemic aetiology (62% vs. 51%) and more often eGFR <60 ml/min/1.73m². Moreover, the distribution of patients in class II/III/IV was 64%, 35% and 1% in those with diabetes and 71%, 29% and 1% in those without diabetes. The primary endpoint was a composite of CV death, HF hospitalization (HFH) or urgent HF visit.
- The primary composite endpoint was reduced with dapagliflozin vs. placebo, in both the diabetes (HR: 0.75, 95%CI: 0.63-0.90) and the no diabetes group (HR: 0.73, 95%CI: 0.60-0.88). There was not interaction between diabetes status and treatment effect (P=0.80).
- CV death was numerically reduced in both groups. Worsening HF events was reduced in both groups (HR: 0.77, 95%CI: 0.61-0.95 and HR: 0.62, 95%CI: 0.48-0.80), without an interaction for diabetes status (P=0.23).
Secondary outcomes showed, in order of hierarchical testing
- Risk of CV death or HFH was reduced in those with diabetes (HR: 0.75, 95%CI: 0.63-0.90) and without diabetes (HR: 0.73, 95%CI: 0.60-0.89, P-interaction: 0.83).
- Total HFH (first and repeat hospitalizations) and CV death events were reduced (HR: 0.77, 95%CI: 0.63-0.94 and HR: 0.73, 95%CI: 0.73-0.91, P-interaction: 0.74).
- Clinically meaningful change (≥5 points) in KCCQ-TSS was better with dapagliflozin vs. placebo, meaning less deterioration (HR: 0.78 for diabetes and HR: 0.88 for no diabetes) and more improvement (HR: 1.20 and HR: 1.12, respectively). P-interaction=0.75).
- A worsening renal function endpoint showed no significant reduction in those with diabetes (HR: 0.73, 95%CI: 0.39-1.34), nor in those without (HR: 0.67, 95%CI: 0.30-1.49). (P-interaction=0.86).
- All-cause death was only significantly reduced with dapagliflozin in those with diabetes (HR: 0.78, 95%CI: 0.63-0.97) but not in those without (HR: 0.88, 95%CI: 0.70-1.12).
Treatment effect by diabetes status and HbA1c
- When looking at the effect of dapagliflozin across tertiles of HbA1c, a similar effect on the primary outcome was seen in all tertiles. The benefit of dapagliflozin on CV death increased with higher HbA1c.
These data show that, when added to standard therapy, dapagliflozin reduced the risk of worsening HF events and CV death, and improved symptoms, in patients with HFrEF, both with and without T2DM. Relative and absolute risk reductions in death and hospitalizations were found to be substantial, clinically important and consistent in patients with and without T2DM.
Dapagliflozin was well tolerated and the rate of treatment discontinuation was low in patients with and without T2DM.
Larry A Allen, the discussant concluded that meaningful outcomes were improved with dapagliflozin treatment: CV death and HF hospitalization and urgent HF visits changed from 15.6% to 11.6%, resulting in an absolute risk reduction (ARR) of 5%. The effects were essentially independent of HbA1c: about 55% of patients did not have DM. The study had a short time horizon of 18 months, and over this period continuously diverging curves were seen. The effects were observed on excellent background HFrEF therapy. No signal of side effects or adverse events was noted.
He compared this effect of dapagliflozin with that of sacubitril/valsartan in the PARADIGM-HF trial, both new drugs to manage HFrEF. PARADIGM-HF showed a greater ARR of 2.7%, but this was over 27 months of follow-up, as compared to ARR=2.3% in DAPA-HF during 18 months. But, in any case, he most wanted to stress that we do not use either agents enough. We need to think of how to implement these new treatment options, also in light of polypharmacy and the associated costs. Likely, patients with DM and HF and CAD will benefit from an SGLT2i or a GLP-1RA.
Applications of SGLT2i are now involving: it had already been established that they are helpful in those with T2DM. Now we also know that they are good for patients with HFrEF without T2DM. Moreover, the data of CREDENCE have shown that they seem helpful in those with kidney disease. Efficacy in HFpEF remains to be established.
- Our reporting is based on the information provided during AHA Scientific Sessions 2019 -