What are the results of Dapagliflozin (Forxiga) trials?

From the Guidelines

Dapagliflozin has been shown to significantly reduce the risk of worsening heart failure and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), regardless of diabetes status, as demonstrated in the DAPA-HF and DELIVER trials. The DAPA-HF trial, which is the most recent and highest quality study, found that dapagliflozin treatment had a lower risk of the primary outcome of a composite of worsening heart failure or cardiovascular death (HR 0.74 [95% CI 0.65–0.85]) compared with placebo 1. The DELIVER trial extended these benefits to patients with HFpEF, demonstrating an 18% reduction in the primary outcome of a composite of worsening heart failure, defined as hospitalization or urgent visit for heart failure, or cardiovascular death (HR 0.82 [95% CI 0.73–0.92]; P < 0.001) 1.

Key findings from the DAPA-HF and DELIVER trials include:

• Reduced risk of worsening heart failure and cardiovascular death in patients with HFrEF and HFpEF
• Consistent benefits regardless of diabetes status
• Well-tolerated treatment with common side effects including genital mycotic infections and volume depletion
• Need for monitoring for diabetic ketoacidosis, particularly in patients with type 1 diabetes

The mechanism of action of dapagliflozin involves inhibiting sodium-glucose cotransporter-2 in the kidneys, promoting glucose excretion while also providing cardiorenal protection through multiple mechanisms including reduced inflammation, oxidative stress, and improved hemodynamics 1.

Overall, the evidence supports the use of dapagliflozin in patients with heart failure with reduced and preserved ejection fraction, regardless of diabetes status, to reduce the risk of worsening heart failure and cardiovascular death. The most recent and highest quality study, the DAPA-HF trial, provides strong evidence for the benefits of dapagliflozin in this patient population 1.

From the FDA Drug Label

In a pediatric trial (NCT03199053), patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1c ≥6.5% and ≤10. 5%) were randomized to dapagliflozin (81 patients) or placebo (76 patients) as add-on to metformin, insulin or a combination of metformin and insulin. At Week 26, treatment with dapagliflozin provided statistically significant improvements in HbA1c compared with placebo (Table 14). In combination with sitagliptin (with or without metformin), dapagliflozin 10 mg provided statistically significant improvements in HbA1c, FPG, and a statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24. Dapagliflozin 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs.

The results of Dapagliflozin (Forxiga) trials show that it provides statistically significant improvements in:

• HbA1c levels in patients with type 2 diabetes mellitus
• Fasting plasma glucose (FPG) levels
• Body weight reduction These improvements were seen in various patient populations, including:
• Adults with type 2 diabetes mellitus
• Pediatric patients aged 10 to 17 years with type 2 diabetes mellitus
• Patients with moderate renal impairment
• Patients on different background therapies, such as metformin, insulin, and DPP4 inhibitors 2, 2.

From the Research

Dapagliflozin Trials Overview

• Dapagliflozin, also known as Forxiga, is a sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the treatment of type 2 diabetes mellitus (T2DM) and heart failure (HF) with reduced ejection fraction 3, 4, 5, 6, 7.
• The results of various clinical trials, including DECLARE TIMI 58, DAPA-HF, and DAPA-CKD, have demonstrated the efficacy and safety of dapagliflozin in reducing major adverse cardiovascular events (MACE), hospitalization for heart failure, and cardiovascular death in patients with T2DM and HF 3, 4, 5, 7.

Efficacy of Dapagliflozin

• The DECLARE TIMI 58 study showed that dapagliflozin was non-inferior to placebo in reducing MACE in patients with T2DM and high cardiovascular risk, with a 27% risk reduction in heart failure hospitalization 3.
• The DAPA-HF trial demonstrated that dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 26% in patients with HF and reduced ejection fraction, regardless of the presence or absence of diabetes 4, 5, 7.
• The DAPA-CKD trial found that dapagliflozin significantly lowered the risk of a sustained decline in estimated glomerular filtration rate (eGFR) of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes in patients with chronic kidney disease (CKD), with or without T2DM 3, 5.

Safety Profile of Dapagliflozin

• Dapagliflozin has been shown to have a favorable safety profile, with no increased risk of amputation, volume depletion, adverse renal events, hypoglycemia, or ketoacidosis in clinical trials 3, 4, 5, 6, 7.
• The frequency of adverse events related to genital infections and urinary tract infections was higher with dapagliflozin compared to placebo, but this was considered to be related to the mechanism of action of the drug 6.