Farxiga (dapagliflozin) - 4 indications

Scroll down for information on each indication:

• type II diabetes; approved January of 2014
• to reduce the risk of hospitalization for HF in adult patients with T2D and established CV disease; approved October 2019
• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without type 2 diabetes; approved May of 2020
• adults with chronic kidney disease who are at risk of disease progression; approved April of 2021

General Information

Farxiga (dapagliflozin) is an orally active sodium glucose cotransporter type 2 (SGLT-2) inhibitor. Inhibiting SGLT2 activity modulates reabsorption of glucose in the kidney, resulting in excretion of glucose in the urine.

Farxiga is specifically indicated for the following conditions:

• as an adjunct to diet and exercise to improve glycemic control in adults with type II diabetes mellitus.
• to reduce the risk of hospitalization for heart failure in adult patients with type 2 diabetes and established cardiovascular (CV) disease or multiple CV risk factors.
• to reduce the risk of CV death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without type 2 diabetes.
• to reduce the risk of sustained eGFR decline, end stage kidney disease cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease at risk of progression

Farxiga is supplied as a tablet for oral administration. Dosage recommendations are based on estimated glomerular filtration rate (eGFR).

• eGFR 45 or greater: to improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control. For all other indications, the recommended starting dose is 10 mg orally once daily.
• eGFR 25 to less than 45: 10 mg orally once daily
• eGFR less than 25: Initiation is not recommended, however patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF.
• On dialysis: Contraindicated

Farxiga is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2 . Farxiga is likely to be ineffective in this setting based upon its mechanism of action.

Mechanism of Action

Farxiga (dapagliflozin) is an inhibitor of Sodium-glucose cotransporter 2 (SGLT2). Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

Side Effects

Adverse events associated with the use of Farxiga may include, but are not limited to, the following:

• female genital mycotic infections
• nasopharyngitis
• urinary tract infections

Indication 1 - type II diabetes

approved January of 2014

The FDA approval of Farxiga was based on monotherapy and combination studies, when combined with metformin, pioglitazone, glimepiride, sitagliptin (with or without metformin), or insulin (with or without other oral antidiabetic therapy).
Monotherapy Studies: Two placebo controlled studies were conducted in 840 treatment-naive subjects with inadequately controlled type II diabetes. One of these was a 24-week study in 558 subjects. Following a 2-week diet and exercise placebo lead-in period, 485 subjects with HbA1c >7% and <10% were randomized to Farxiga 5 mg or 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo. At Week 24, treatment with Farxiga 10 mg QAM provided significant improvements in HbA1c and FPG compared with placebo. Change from baseline in HbA1c for Farxiga: -.9 vs. placebo: -.2; change from baseline in FPG for Farxiga: -28.8 vs. placebo: -4.1.Combination Therapy Studies: Farxiga in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline BMI.

Indication 2- to reduce the risk of hospitalization for HF in adult patients with T2D and established CV disease

approved October 2019

The FDA approval of Farxiga to reduce the risk of hospitalization for heart failure in adult patients with type 2 diabetes and established cardiovascular (CV) disease or multiple CV risk factors was based on the DECLARE–TIMI 58 trial. This was as a randomized, double-blind, multinational, placebo-controlled, phase 3 trial of dapagliflozin in patients with type 2 diabetes and established atherosclerotic cardiovascular disease or multiple risk factors for atherosclerotic cardiovascular disease. The trial evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE. In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group, but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%), which reflected a lower rate of hospitalization for heart failure there was no between-group difference in cardiovascular death.

Indication 3 - to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without type 2 diabetes

approved May of 2020

The FDA approval of Farxiga to reduce the risk of CV death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without type 2 diabetes was based on the Phase III DAPA-HF trial, which showed Farxiga achieving a statistically significant and clinically meaningful reduction of CV death or hospitalization for heart failure, compared to placebo. Farxiga, in addition to standard of care, reduced the risk of the composite outcome of CV death or the worsening of HF versus placebo by 26% (absolute risk reduction [ARR] = 5% [event rate/100 patient years: 11.6 vs 15.6, respectively]) in patients with HFrEF. During the trial duration, one CV death or hospitalization for HF or an urgent visit associated with HF could be avoided for every 21 patients treated with Farxiga.

Indication 4 - adults with chronic kidney disease who are at risk of disease progression

approved April of 2021

The FDA approval of Farxiga for adults with chronic kidney disease who are at risk of disease progression was based on the multicenter, double-blind DAPA-CKD Phase III study. In this study, 4,304 patients with CKD Stages 2-4 and elevated urinary albumin excretion, with and without T2D were randomly assigned to receive either Farxiga 10mg or placebo. The primary composite endpoint was worsening of renal function or risk of death (defined as a composite of an eGFR decline ≥50%, onset of ESKD or death from CV or renal cause). The secondary endpoints included the time to first occurrence of the renal composite (sustained ≥50% eGFR decline, ESKD or renal death), the composite of CV death or hHF, and death from any cause. The trial demonstrated that Farxiga, on top of standard-of-care treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, reduced the relative risk of worsening of renal function, onset of ESKD, or risk of CV or renal death by 39%, the primary composite endpoint, compared to placebo in patients with CKD Stages 2-4 and elevated urinary albumin excretion. The absolute risk reduction (ARR) was 5.3% over the median time in study of 2.4 years. Farxiga also significantly reduced the relative risk of death from any cause by 31% (ARR=2.1%) compared to placebo.