Serum Lithium After Initiation of Sodium-Glucose Cotransporter 2 Inhibitor Treatment

Sodium-glucose cotransporter 2 (SGLT2) inhibitors may increase renal clearance of lithium, but prior results are mixed. We investigated this aspect using data from Danish nationwide registers.

We identified all patients with bipolar disorder or unipolar depression between January 1, 2000, and June 1, 2024, who initiated SGLT2 inhibitor treatment (index date). Concurrent lithium treatment was defined by a serum lithium measurement within 90 days before the index date. Changes in serum lithium levels from the pre-index measurement to the first, second, and third post-index measurements were assessed. Furthermore, an analogue positive control analysis based on data from patients who initiated treatment with a thiazide diuretic was performed, as this class of drugs is known to increase lithium levels.

We identified 131 patients with pre-index and post-index serum lithium measurements (ie, before and after initiation of SGLT2 inhibitor treatment). Mean serum lithium decreased from 0.59 mmol/L pre-index to 0.52 mmol/L at the first post-index measurement [difference: -0.07 (95% CI: -0.11, -0.03) mmol/L, P<0.001]. At the time of the first post-index measurement, 94 patients (71.8%) had a serum lithium level below the therapeutic index (0.6 to 0.8 mmol/L), compared with 57 patients (43.5%) at the pre-index measurement, corresponding to an absolute increase of 28.2 percentage points (95% CI: 17.3 to 39.2, P<0.001). Subsequent measurements did not differ from the pre-index measurement, likely due to compensatory increases in lithium doses. For patients initiating a thiazide diuretic, the mean pre-index serum lithium level was 0.61 mmol/L and the first post-index mean serum lithium was 0.70 mmol/L, that is, the expected increase [0.09 (95% CI: 0.05 to 0.13) mmol/L, P<0.001].

Initiation of SGLT2 inhibitor treatment may reduce serum lithium levels to subtherapeutic levels.