Farxiga Mental Health and Mood Impact: What the Evidence Actually Shows

Does dapagliflozin cause depression or anxiety?

Depression and anxiety are not listed in Farxiga's adverse-reaction table. That table comes from 12 placebo-controlled trials in adults with type 2 diabetes lasting 12 to 24 weeks, with 1,393 people on placebo, 1,145 on 5 mg and 1,193 on 10 mg, and it includes reactions reported in at least 2% of patients on either dose. Listed as placebo / 5 mg / 10 mg: female genital mycotic infections 1.5% / 8.4% / 6.9%; male genital mycotic infections 0.3% / 2.8% / 2.7%; urinary tract infection 3.7% / 5.7% / 4.3%; nasopharyngitis 6.2% / 6.6% / 6.3%; increased urination 1.7% / 2.9% / 3.8%; back pain 3.2% / 3.1% / 4.2%; nausea 2.4% / 2.8% / 2.5%; dyslipidemia 1.5% / 2.1% / 2.5%; and discomfort with urination 0.7% / 1.6% / 2.1% [1]. No psychiatric reaction appears in that table [1].

The same label states that no new adverse reactions were identified in the DAPA-HF and DELIVER heart failure trials or in DAPA-CKD [1]. The only contraindication is a history of a serious hypersensitivity reaction to dapagliflozin or any excipient, such as anaphylaxis or angioedema [1].

Absence from a table does not prove a reaction cannot occur. The table pools glycemic-control trials in adults with type 2 diabetes, while the heart failure and kidney trials reported cardiovascular and kidney outcomes [1][2][3][4].

What the large trials measured instead

DAPA-HF randomized 4,744 adults with heart failure and an ejection fraction of 40% or less. Over a median of 18.2 months, worsening heart failure or cardiovascular death occurred in 16.3% of the dapagliflozin group versus 21.2% on placebo (hazard ratio 0.74, 95% CI 0.65 to 0.85), and cardiovascular death in 9.6% versus 11.5% [2].

DELIVER randomized 6,263 adults with heart failure and an ejection fraction above 40%. Over a median of 2.3 years, the primary composite occurred in 16.4% versus 19.5% (hazard ratio 0.82, 95% CI 0.73 to 0.92). Cardiovascular death alone was 7.4% versus 8.3%, which was not a significant difference (hazard ratio 0.88, 95% CI 0.74 to 1.05) [3].

DAPA-CKD randomized 4,304 adults with chronic kidney disease, with or without type 2 diabetes, and was stopped early for efficacy. The primary composite occurred in 9.2% versus 14.5% (hazard ratio 0.61, 95% CI 0.51 to 0.72), a number needed to treat of 19 [4].

Is symptom burden a stand-in for mood?

In DELIVER, total events and symptom burden were lower in the dapagliflozin group than in the placebo group [3]. The reported results do not identify a mood outcome.

Side effects that affect daily comfort

The label's most common reactions, at 5% or more, are female genital mycotic infections, nasopharyngitis and urinary tract infections [1]. Genital yeast infections were reported by 8.4% of women on 5 mg and 6.9% on 10 mg, versus 1.5% on placebo, and by 2.8% and 2.7% of men, versus 0.3% [1]. Increased urination was reported in 2.9% and 3.8% versus 1.7% on placebo, and discomfort with urination in 1.6% and 2.1% versus 0.7% [1]. Volume depletion events were 0.6% on 5 mg and 0.8% on 10 mg versus 0.4% on placebo in the 12-trial pool, and 2.5% on dapagliflozin versus 2.4% on placebo in DECLARE-TIMI 58 [1].

The label says Farxiga increases urinary glucose excretion and increases the risk of genitourinary infections, and that its osmotic diuresis may lead to a reduction in intravascular volume [1].

Ketoacidosis symptoms the label describes

The Farxiga label lists nausea, vomiting, abdominal pain, generalized malaise and shortness of breath as signs of ketoacidosis, and says blood glucose at presentation may be below 250 mg/dL. It instructs patients with these signs to discontinue Farxiga and seek medical attention immediately [1]. The label says ketoacidosis risk is markedly increased in type 1 diabetes, where the drug is not recommended for glycemic control, and that Farxiga should be withheld for at least 3 days, if possible, before surgery or procedures with prolonged fasting [1].

Antidepressants and lithium

The label's interaction table names insulin and insulin secretagogues, lithium, urine glucose tests and 1,5-anhydroglucitol assays, and lists no antidepressant [1]. In vitro, dapagliflozin and its 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6 or 3A4 nor induced CYP 1A2, 2B6 or 3A4 [1].

For lithium, the label says concomitant use of an SGLT2 inhibitor may decrease serum lithium concentrations and that serum lithium should be monitored more frequently during Farxiga initiation and dosage changes [1].