02. Lithiumgerelateerde nierfunctiedaling: kunnen SGLT2-remmers helpen?

Tekstversie

SGLT2 Inhibitors for Lithium-Induced Kidney Decline

The bottom line of this Quick Take: for patients who are on lithium whose kidney function is declining, a new tool is being investigated. One that could allow them to continue lithium instead of having to consider tapering off hoping that some other mood stabilizer would work as well.

First, let’s review the big picture. How risky is lithium in terms of renal function? And then from there, we can look at whether sodium-glucose cotransporter 2 inhibitors (SGLT2is), the new potential tool, might prevent lithium-induced renal damage.

Lithium’s Renal Risk Remains Unclear

How much risk does lithium carry in terms of renal function? Well, there’s diabetes insipidus, which is a hassle for patients — thirst and frequent urination. But diabetes insipidus itself doesn’t mean kidneys are being damaged. Nevertheless, just like high lithium levels and episodes of lithium toxicity, diabetes insipidus raises the risk of chronic renal failure.

Long-term lithium-associated renal failure is due to a different mechanisms: focal interstitial fibrosis, tubular atrophy, dilation of the distal nephron, and microcyst formation. Exactly how lithium leads to these changes is still not clear.

In fact, even the incidence of renal failure due to lithium is not clear. For example, a 2025 Mayo Clinic review found mixed results, some studies suggesting that lithium can compromise renal function but other studies finding minimal impact.

And then, new news to me: when glomerular filtration rate, the eGFR in your lab report, is going down, it’s not even certain that tapering off lithium will prevent further decline. One study affirmed this strategy but several recent ones have not.

Lithium Tapering Dilemma in Bipolar I

Nevertheless, recent expert treatment recommendations like Nierenberg et al. in the JAMA 2023 review do state outright “long-term use of lithium impairs kidney function and reduces glomerular filtration rates.”

So if you treat patients with bipolar I, you’ll end up treating a patient who had serious destructive manic episodes until they started on lithium and then went years without another bad episode, who now has a decreasing glomerular filtration rate. Until now, you and such patients have had to decide when and if to take the risk of tapering lithium hoping to find an equally effective alternative. Perhaps that’s about to change.

SGLT2i Mechanism Protects the Kidney

Enter the SGLT2is: these medications act on an enzyme in the kidney (that sodium-glucose cotransporter) which is responsible for reabsorbing glucose back into the blood from the proximal tubule. Inhibiting this enzyme causes excess sugar to be excreted through the urine.

Thus, SGLT2is (canagliflozin and four other -flozin cousins) were developed for the treatment of diabetes. Through a fascinating but complex mechanism, SGLT2is also protect the kidney from arteriolar hypertension that damages glomeruli and leads to renal failure.

Got that? SGLT2is protect the kidney from arteriolar hypertension, and that’s the mechanism by which ultimately diabetes leads to renal failure. So perhaps SGLT2is might offer protection from lithium-induced damage as well.

SGLT2is Halved Dialysis Risk in Bipolar

Investigating this, a Mayo Clinic team found that patients living with bipolar who had mild to moderate renal failure but were taking an SGLT2i were only half as likely to end up on dialysis as those who were not.

That’s the main finding from this first of these two Quick Takes: patients living with bipolar who had mild to moderate renal failure but were taking an SGLT2i were only half as likely to end up on dialysis.

eGFR Improved After Adding SGLT2i

Given that finding, the team went on, as presented in the second paper reviewed here led by Mete Ercis, to look for patients who’d ever taken lithium and also received an SGLT2i. Mayo Clinic records included 56 such patients. The team looked to see if there was some improvement in these patients’ eGFR or at least a decrease in the rate of decline when they started the SGLT2i.

And the result: in patients who’d ever taken lithium who then started an SGLT2i, eGFR stopped going down. In fact, it went up.

But hold on. When they looked only at patients who were on lithium when the SGLT2i was added, their eGFR decline did slow down, but not significantly. However, there were only 22 patients in this subgroup, so this is just a preliminary look at what SGLT2is can do.

SGLT2i Risks Are Limited and Manageable

Of course, in considering them to lower the risk of renal failure, we have to look at the risks of the SGLT2is themselves. There is diabetic ketoacidosis, but this is rare in people who don’t have diabetes.

Hypoglycemia? No, because interestingly the SGLT2 receptor is downregulated at low glucose levels.

Actually, the most common problem is genital fungal infection, roughly 10% in women but 2% to 3% in men as well. Otherwise, nothing really major that’s common.

The SGLT2is used to be very expensive, but in the US at least the cost has dropped to about $50 a month on average out-of-pocket expense.

Future Directions and Lithium Orotate

So where does this leave us? A simple open trial would be nice, adding SGLT2is for patients on lithium whose renal function is declining.

But meanwhile — in the old days we used to routinely fret about when to taper lithium if a patient’s renal function was declining. Why wait until they have renal failure, I thought? And I advocated for switching early. However, some but not all recent data suggest that lithium can lead to renal failure even if lithium is discontinued.

Well, perhaps the SGLT2is will rescue us and our patients from this dilemma. And while awaiting more data on their risk-benefit ratio, may I add one other thought? What about lithium orotate Most data suggest that at therapeutic levels it has less renal toxicity than lithium carbonate, or at least not more as once thought. So a new world might be opening for us there as well.

References

1. Singh, B., Gonzalez Suarez, M. L., Baweja, R., Abulseoud, O. A., Saunders, E. F., Frye, M. A., & Baweja, R. (2026). Sodium-glucose cotransporter-2 inhibitors lower risk of kidney replacement therapy and mortality in bipolar disorder with chronic kidney disease. Therapeutic Advances in Psychopharmacology, 16, 20451253261423437.
2. Ercis, M., Tarikogullari, I., Pazdernik, V. K., Gonzalez Suarez, M. L., Baweja, R., Miola, A., … & Singh, B. (2026). SGLT2 Inhibitors Associated With Improved Kidney Function in Lithium‐Treated Patients With Mood Disorders: A Real‐World Historical Cohort Study. Bipolar disorders, 28(2), e70094.
3. Ercis, M., Suarez, M. L. G., & Singh, B. (2025, January). Lithium and Kidney Disease. In Mayo Clinic Proceedings (Vol. 100, No. 1, pp. 19-25). Elsevier.
4. Schoretsanitis, G., De Filippis, R., Brady, B. M., Homan, P., Suppes, T., & Kane, J. M. (2022). Prevalence of impaired kidney function in patients with long‐term lithium treatment: a systematic review and meta‐analysis. Bipolar disorders, 24(3), 264-274.
5. Van Alphen, A. M., Bosch, T. M., Kupka, R. W., & Hoekstra, R. (2021). Chronic kidney disease in lithium-treated patients, incidence and rate of decline. International journal of bipolar disorders, 9(1), 1.
6. Nierenberg, A. A., Agustini, B., Köhler-Forsberg, O., Cusin, C., Katz, D., Sylvia, L. G., … & Berk, M. (2023). Diagnosis and treatment of bipolar disorder: a review. Jama, 330(14), 1370-1380.
7. van der Aa, M. J., Zittema, D., Doornebal, J., Hartong, E. G. T. M., Bisseling, E. M., Dammers, J., Klumpers, U. M. H., Kerckhoffs, A. P. M., Kupka, R. W., & Nijenhuis, T. (2026). A Significant Decline of Glomerular Filtration Rate in the Majority of Long-Term Lithium Users: Results of a Dutch Prospective 10-Year Cohort Study. Bipolar disorders, 28(2), e70082. https://doi.org/10.1111/bdi.70082
8. Brown, E., Heerspink, H. J. L., Cuthbertson, D. J., & Wilding, J. P. H. (2021). SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet (London, England), 398(10296), 262–276. https://doi.org/10.1016/S0140-6736(21)00536-5

Abstract

SGLT2 Inhibitors Associated With Improved Kidney Function in Lithium-Treated Patients With Mood Disorders: A Real-World Historical Cohort Study

Mete Ercis, Idil Tarikogullari, Vanessa K. Pazdernik, Maria L. Gonzalez Suarez, Raman Baweja, Alessandro Miola, Osama A. Abulseoud, Jonathan G. Leung, Susan L. McElroy, Alfredo B. Cuellar-Barboza, Michael J. Gitlin, Aysegul Ozerdem, Mark A. Frye, & Balwinder Singh.

Introduction
Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed for type 2 diabetes, have shown promise in improving renal outcomes in patients with and without diabetes. However, their effect on lithium-associated kidney dysfunction remains unknown.

Methods
This historical cohort study included patients from Mayo Clinic (2001–2023) with mood disorders who received lithium for ≥ 6 months and later used SGLT2i for ≥ 1 month. Data on SGLT2i use and lithium treatment were extracted from electronic health records. Serum creatinine values were used to calculate estimated glomerular filtration rate (eGFR) trajectories. Linear mixed-effects models with piecewise linear splines were used to estimate eGFR slopes before and after SGLT2i initiation, adjusted for age and sex.

Results
Fifty-six patients (mean age 57.4 years, 46.4% female), predominantly with bipolar disorder (87.5%), were included. The mean eGFR, measured nearest to SGLT2i initiation, was 77.9 ± 26.0 mL/min/1.73 m2, and the mean duration of SGLT2i use was 19.5 ± 17.8 months. Before SGLT2i initiation, eGFR declined at a rate of −1.43 mL/min/1.73 m2 per year (p < 0.001). After initiation, eGFR increased by 0.69 mL/min/1.73 m2 per year, reflecting a + 2.13 change (p = 0.025). Sensitivity analyses, including only patients on lithium at SGLT2i initiation (n = 22) or who had > 1 year of SGLT2i use (n = 29) showed similar, though non-significant, changes in slopes.

Conclusion
SGLT2i treatment was associated with a significant improvement in eGFR trajectory in patients with mood disorders who received long-term lithium therapy. These findings suggest a potential role for SGLT2is in mitigating lithium-associated kidney dysfunction and highlight the need for randomized controlled trials in this population.

Reference

Ercis, M., Tarikogullari, I., Pazdernik, V., Gonzalez Suarez, M., Baweja, R., Miola, A., Abulseoud, O., Leung, J., McElroy, S., Cuellar-Barboza, A., Gitlin, M., Ozerdem, Frye, M. & Singh, B. (2026). SGLT2 Inhibitors Associated With Improved Kidney Function in Lithium-Treated Patients With Mood Disorders: A Real-World Historical Cohort Study. Bipolar Disorders28, no. 2 (2026): e70094.