AstraZeneca's SGLT2 Inhibitor Dapagliflozin Demonstrates First-Ever Reduction in Heart Failure Risk in Non-Diabetic Patients

Today, AstraZeneca announced that its SGLT2 inhibitor dapagliflozin (brand name Farxiga) met the primary composite endpoint in the Phase 3 DAPA-HF clinical trial. Compared with placebo, dapagliflozin demonstrated a statistically significant and clinically meaningful reduction in the risk of cardiovascular death or worsening heart failure (HF). Notably, the trial population consisted of patients with heart failure with reduced ejection fraction (HFrEF), including those without type 2 diabetes. This marks the first time an SGLT2 inhibitor has shown a benefit in reducing the risk of cardiovascular death and worsening HF in patients without type 2 diabetes. These results are expected to expand the indicated patient population for dapagliflozin to include individuals without type 2 diabetes.

Heart failure is a life-threatening, severe condition resulting from the heart’s inability to pump sufficient blood throughout the body. There are approximately 64 million patients worldwide (half of whom have heart failure with reduced ejection fraction), and nearly half of these patients die within five years of diagnosis. Heart failure is one of the leading causes of hospitalization among adults aged 65 and older, representing a significant clinical and economic burden.

Dapagliflozin is a “first-in-class” oral SGLT2 inhibitor. It has received FDA approval, in conjunction with diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus, and can also reduce their body weight and blood pressure. It has also been approved by the European Union for the treatment of patients with type 1 diabetes mellitus.

DAPA-HF was the first phase 3 clinical trial to investigate the effects of SGLT2 inhibitors on the risk of death and disease worsening due to heart failure. The patients enrolled in this trial represented typical heart failure patients, who may or may not have type 2 diabetes. In this randomized, double-blind, multicenter, international phase 3 clinical trial, patients with heart failure with reduced ejection fraction received either dapagliflozin or placebo in addition to standard therapy. The primary composite endpoint was worsening heart failure events (defined as hospitalization or emergency visits for heart failure) or cardiovascular death.

Trial results demonstrated that dapagliflozin met the primary composite endpoint. Detailed data from this trial will be presented at future medical conferences.

Dr. Mene Pangalos, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, stated, “The results of the DAPA-HF clinical trial demonstrate for the first time that patients with heart failure can benefit from treatment with dapagliflozin, regardless of whether they have type 2 diabetes. Currently, half of heart failure patients die within five years of diagnosis, and it remains one of the leading causes of hospitalization. We look forward to discussing the DAPA-HF results with regulatory authorities as soon as possible.”

Dapagliflozin is also being evaluated in the Phase 3 DELIVER clinical trial for patients with heart failure with preserved ejection fraction (HFpEF), and in the DETERMINE clinical trial for patients with both HFrEF and HFpEF.

On SGLT2 Inhibitors and Cardiovascular Benefits

SGLT2 inhibitors inhibit the function of sodium-glucose cotransporter 2 (SGLT2). SGLT2 is a transporter protein in the kidneys that facilitates glucose reabsorption. By inhibiting SGLT2 function, SGLT2 inhibitors promote the excretion of more glucose in the urine, thereby lowering blood glucose levels. SGLT2 inhibitors currently approved by the FDA include AstraZeneca’s dapagliflozin, Janssen’s canagliflozin (brand name Invokana), Lilly/Boehringer Ingelheim’s empagliflozin (brand name Jardiance), and Pfizer/MSD’s ertugliflozin (brand name Steglatro).

Since 2008, the FDA has required that medications for treating patients with type 2 diabetes undergo long-term safety trials to rule out potential cardiovascular risks. Since 2015, clinical trials monitoring cardiovascular risk have shown that SGLT2 inhibitors not only do not increase cardiovascular risk in patients with type 2 diabetes but also significantly reduce cardiovascular risk in some patients. Based on these results, the FDA has approved an expanded label for canagliflozin to reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes who have cardiovascular disease. Empagliflozin has also been approved to reduce the risk of cardiovascular death in similar patient populations.

▲ Eli Lilly and Company’s Clinical Trial Plan for Empagliflozin (Image source: Reference [4])

Currently, Eli Lilly and Company is also conducting multiple Phase III trials to evaluate the efficacy of empagliflozin in patients with heart failure. We look forward to SGLT2 inhibitors benefiting more patients with heart failure.

References:

[1] Farxiga met primary endpoint in landmark Phase III DAPA-HF trial for the treatment of patients with heart failure. Retrieved August 20, 2019, from https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2019/farxiga-met-primary-endpoint-in-landmark-phase-iii-dapa-hf-trial-for-the-treatment-of-patients-with-heart-failure-20082019.html

[2] Cardiovascular Benefits of SGLT2 Inhibitors and GLP-1 Receptor Agonists in Type 2 Diabetes. JAMA. doi:10.1001/jama.2019.2702.

[3] Zelniker et al, (2018). SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. The Lancet, https://doi.org/10.1016/S0140-6736(18)32590-X

[4] Lilly Diabetes Update at ADA. Retrieved August 20, 2019, from https://investor.lilly.com/static-files/a5dbe9fa-f45f-41ef-bc16-bc12be6dd606

Original Title: Milestone! AstraZeneca’s SGLT2 Inhibitor Reduces Heart Failure Risk in Non-Diabetic Patients for the First Time

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