Farxiga Liver Function Impact: What Dapagliflozin Does to ALT, AST, and Hepatic Fat

Does dapagliflozin raise liver enzymes?

The Farxiga label does not list liver injury among its warnings [3]. Its Warnings and Precautions section covers four problems: ketoacidosis, volume depletion with acute kidney injury, genitourinary infections including necrotizing fasciitis of the perineum (Fournier's gangrene), and hypoglycemia when the drug is combined with insulin or an insulin secretagogue [3]. The label carries no boxed warning [3].

ALT and AST are standard blood markers of liver-cell stress. In a 12-week trial of people with type 2 diabetes and fatty liver, ALT, AST and GGT decreased from baseline with dapagliflozin alone [1].

What the trials measured for ALT, AST and GGT

The clearest dapagliflozin-specific data come from a 12-week double-blind trial of 84 people with type 2 diabetes and fatty liver [1]. Participants were assigned to dapagliflozin 10 mg (21 people), omega-3 carboxylic acids 4 g (20 people), both (22 people) or placebo (21 people). Dapagliflozin alone reduced ALT, AST, GGT, two cytokeratin 18 fragments and FGF21 [1]. Across the trial, changes in GGT correlated with changes in liver fat (correlation 0.53, P=0.02) [1].

A meta-analysis pooled 12 randomized trials of SGLT2 inhibitors in people with fatty liver, six of which tested dapagliflozin, with data on 850 middle-aged overweight or obese participants (about 90% with type 2 diabetes) and a median treatment period of 24 weeks [2]. Compared with placebo or reference therapy, ALT fell by a weighted mean of 10.0 IU/L (95% CI -12.2 to -7.79) and GGT by 14.49 IU/L (95% CI -19.35 to -9.63) [2]. Those are class-level numbers, not a dapagliflozin-only result.

Empagliflozin, a different SGLT2 inhibitor, has its own liver data and they do not transfer to dapagliflozin. In the 20-week E-LIFT trial of 50 patients, empagliflozin produced a significant difference in ALT from control (P=0.005) but not in AST (P=0.212) or GGT (P=0.057) [4].

Does dapagliflozin reduce liver fat?

In the 12-week trial above, all active treatments lowered liver fat measured by MRI proton density fat fraction from a baseline average of 18%: omega-3 carboxylic acids by 15% relative, dapagliflozin by 13%, and the combination by 21% [1]. Only the combination reduced liver fat compared with placebo (P=0.046), and only the combination reduced total liver fat volume (relative change -24%, P=0.037) [1]. Dapagliflozin also lowered body weight and abdominal fat volume in that trial [1].

Across the 12 pooled SGLT2 inhibitor trials, the absolute percentage of liver fat on magnetic resonance measures was 2.05 percentage points lower than with placebo or reference therapy (95% CI -2.61 to -1.48) [2]. That is a real but modest average, and it describes the drug class rather than dapagliflozin alone.

What about fibrosis and liver biopsy?

The meta-analysis found no randomized trials with paired liver biopsy data through October 2020, so it could not establish whether dapagliflozin changes liver fibrosis [2]. Biopsy studies exist for other drugs in the class: canagliflozin in 10 patients with biopsy-confirmed steatohepatitis over 12 weeks, and empagliflozin in a 9-patient pilot over 24 weeks [5][6]. Neither tells you what dapagliflozin does to human liver histology.

What the Farxiga label says to watch for

Ketoacidosis is the label's first warning. Blood glucose at presentation may be below the level usually expected for ketoacidosis, for example under 250 mg/dL, and alcohol abuse is listed among the conditions that can precipitate it [3]. The label instructs patients to stop Farxiga and seek medical attention immediately if signs and symptoms of ketoacidosis occur, and directs withholding the drug for at least 3 days, if possible, before surgery or procedures with prolonged fasting [3].

Volume depletion and acute kidney injury are the second warning, with higher risk in people whose eGFR is under 60 mL/min/1.73 m2, older adults, and those taking loop diuretics [3]. The label calls for assessing kidney function and volume status before starting treatment [3]. For glycemic control the label gives a starting dose of 5 mg once daily, which can be raised to 10 mg; for heart failure and chronic kidney disease the dose is 10 mg once daily, and the label says the drug is not recommended for glycemic control when eGFR is below 45 mL/min/1.73 m2 [3].

Dapagliflozin in heart failure and kidney disease

The heart-failure and kidney trials reported heart-failure, cardiovascular and kidney outcomes, not liver endpoints, so they do not answer what dapagliflozin does to liver enzymes or liver fat [7][8]. The label states that no new adverse reactions were identified in the DAPA-HF, DELIVER or DAPA-CKD trials [3].