Dapagliflozin Significantly Reduces Risk of Cardiovascular Death and Worsening Heart Failure in DAPA-HF Trial, Announced at ESC 2019

The DAPA-HF trial was the first heart failure outcomes study to evaluate an SGLT2 inhibitor in patients with heart failure with reduced ejection fraction, with or without type 2 diabetes. This phase III clinical trial demonstrated that dapagliflozin significantly reduced the risk of the primary composite endpoint of cardiovascular death or worsening heart failure by 26% (p<0.0001), with significant reductions observed in each component of the primary composite endpoint.

(Paris, France, September 1, 2019) Today, AstraZeneca announced the results of the DAPA-HF Phase III study of dapagliflozin, marking a milestone. The study results demonstrated that dapagliflozin, in addition to standard therapy, significantly reduces the risk of cardiovascular death and worsening heart failure.

DAPA-HF is the first heart failure outcomes study to evaluate SGLT2 inhibitor therapy in patients with heart failure with reduced ejection fraction (HFrEF), with or without type 2 diabetes. Dapagliflozin is currently approved for the treatment of patients with type 2 diabetes.

The topline results announced in August 2019 showed that DAPA-HF met its primary endpoint. Detailed results from the DAPA-HF study, presented today at the ESC Congress in Paris, France, demonstrated that dapagliflozin significantly reduced the risk of the primary composite endpoint of cardiovascular (CV) death or worsening heart failure by 26% (p<0.0001), with significant reductions observed in all components of the primary composite endpoint.<>

Mene Pangalos, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, stated: “Dapagliflozin has already established a strong foundation in the treatment of type 2 diabetes. These exciting new findings provide clinically meaningful insights into the potential of dapagliflozin to reduce the disease burden of heart failure in patients with or without type 2 diabetes. At this ESC Congress, we are proud of the impact dapagliflozin has made and its contribution to the future evidence base.”

University of Glasgow Cardiovascular andMedicineProfessor John McMurray, MD, from the Cardiovascular Research Center at the Scientific Research Center, stated: “We are pleased that dapagliflozin demonstrated such efficacy in our trial, meeting all our expectations for a heart failure therapy, including symptom improvement, reduced hospitalization rates, and improved survival. More importantly, dapagliflozin was equally effective in patients with heart failure, regardless of whether they had diabetes.”

The DAPA-HF study also conducted separate analyses of each component of the primary composite endpoint. The risk of first worsening of heart failure was reduced by 30% in the dapagliflozin group (p<0.0001), and the risk of death from cardiovascular causes was reduced by 18% (p=0.0294). The effect of dapagliflozin on the primary composite endpoint was generally consistent across all key subgroups studied.<>

The study results also showed that the overall symptom scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ) submitted by patients were significantly improved in the dapagliflozin group. Meanwhile, the risk of all-cause mortality was significantly reduced by 17% (7.9 vs. 9.5 events per 100 patient-years).

The safety profile of dapagliflozin in the DAPA-HF study was consistent with its previously established safety profile. The incidences of hypovolemia [7.5% vs 6.8%] and renal adverse events [6.5% vs 7.2%], which are often of concern in the treatment of heart failure, were comparable to those with placebo. Severe hypoglycemic events were rare in both treatment groups [0.2% vs 0.2%].

In addition, the DELIVER study in patients with heart failure with preserved ejection fraction (HFpEF) and the DETERMINE study (in HFrEF and HFpEF) involving dapagliflozin are also ongoing.

Regarding the DAPA-HF Study

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) study is an international, multicenter, randomized, double-blind, parallel-group trial. It enrolled patients with heart failure with reduced ejection fraction (LVEF ≤40%), with or without type 2 diabetes mellitus, to evaluate the clinical efficacy of dapagliflozin 10 mg once daily, added to standard care, compared with placebo. The primary composite endpoint consisted of the first occurrence of worsening heart failure (defined as hospitalization for heart failure or an equivalent urgent visit for heart failure) or cardiovascular death.

# About Heart Failure

Heart Failure (HF) is a life-threatening condition characterized by the heart's inability to pump sufficient blood to the entire body during illness.¹There are approximately 64 million prevalent cases worldwide (half of which present with reduced ejection fraction), and it is a chronic progressive disease, with half of the patients dying within five years after diagnosis.^2,3,4The “malignancy” of HF is akin to that of some of the most common cancers in men (prostate cancer and bladder cancer) and women (breast cancer).⁵It is a leading cause of hospitalization among individuals aged 65 years and older, and represents a significant clinical and economic burden.⁶

About Dapagliflozin

Dapagliflozin is the first-in-class, once-daily oral SGLT2 inhibitor indicated to improve glycemic control in adults with type 2 diabetes mellitus, as an adjunct to diet and exercise. It can be used as monotherapy or in combination with metformin hydrochloride or insulin. Dapagliflozin has a comprehensive clinical development program, including more than 35 completed and ongoing Phase IIb/III studies, encompassing a total of over 35,000 patients, and more than 2.5 million patient-years of exposure.

Regarding the DapaCare Clinical Program

AstraZeneca addresses the underlying morbidity, mortality, and organ damage associated with cardiovascular (CV), metabolic, and renal diseases by adopting a comprehensive, patient-centric disease management approach. Given the interrelated nature of these conditions, AstraZeneca launched the DapaCare clinical program to explore cardiovascular and renal outcomes following treatment with dapagliflozin in populations with and without type 2 diabetes. The clinical program will enroll nearly 30,000 patients in randomized clinical trials and will be supported by real-world evidence from multinational studies. DapaCare will generate data for individuals with established cardiovascular disease, cardiovascular risk factors, and various stages of kidney disease, both with and without type 2 diabetes, providing healthcare providers with the evidence needed to improve patient outcomes.

In addition to the DAPA-CKD study targeting patients with chronic kidney disease, dapagliflozin has also initiated the DELIVER (HFpEF) and DETERMINE (HFrEF and HFpEF) studies in patients with heart failure.

References

1. Mayo Clinic. Heart failure; 2017 [cited 2019 Aug 14]. Available from URL: https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142.
2. Vos T et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. The Lancet 2017; 390(10100):1211–59.
3. Mozaffarian D et al. Circulation. 2016 Jan 26;133(4):e38-360 and the CDC: https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm
4. Bhuiyan, Taslima, and Mathew S Maurer. “Heart Failure with Preserved Ejection Fraction: Persistent Diagnosis, Therapeutic Enigma.” Current cardiovascular risk reports vol. 5,5 (2011): 440-449. doi:10.1007/s12170-011-0184-2
5. Mamas, M. A., Sperrin, M., Watson, M. C., Coutts, A., Wilde, K., Burton, C., ... Myint, P. K. (2017). Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. European Journal of Heart Failure, 19(9), 1095-1104. https://doi.org/10.1002/ejhf.822
6. Azad, N., & Lemay, G. (2014). Management of chronic heart failure in the older population. Journal of Geriatric Cardiology: JGC, 11(4), 329-37.