ESKD in Veterans with Type 2 Diabetes: Comparative Effectiveness of Valproic Acid and Lamotrigine

Background: Although SGLT2i and GLP-1RA are changing the landscape of diabetic kidney disease management, they do not completely prevent ESKD and can be cost-prohibitive. Inexpensive medications with novel mechanisms to slow CKD progression are needed. One such agent is valproic acid (VPA), a well-known anti-epileptic medication that is also a histone deacetylase (HDAC) inhibitor. Decreased glomerular damage has been noted with HDAC inhibition due to downregulation of profibrotic and inflammatory genes in animal models. In a previous analysis of Veterans Aging Cohort Study, exposure to VPA was associated with slower decline in eGFR vs comparator agents. Herein, we compared VPA to lamotrigine, an agent used for similar indications however with different mechanism of action, on hard kidney end-points and death. Methods: Using data from Veterans Affairs (VA) Corporate Data Warehouse, we used an active comparator, new user study design to emulate a two-arm randomized control trial comparing VPA and lamotrigine initiation in veterans with T2D between 01/01/18 to 12/31/21. Follow up was until 12/31/23. In inverse probability weighted (IPW) Cox models, drug classes were related to time to kidney failure (CKD 5 or ESKD), CKD 5 (sustained eGFR < 15), ESKD, death and a composite of kidney failure/death. Results: Of the 19,798 veterans included, mean age was 61±13 years with 12% female, 21% African Americans. 65% were initiated on VPA and were more likely to have CKD, CAD, HF, schizophrenia and longer duration of T2D. Veterans who were younger, female, white and have bipolar disorder were more likely to be initiated on lamotrigine. In IPW Cox models, there were no significant differences for kidney outcomes. Lamotrigine had a significantly decreased hazard of death. Conclusion: There is no evidence that VPA lowers kidney failure risk but may be associated with higher mortality. Funding: NIDDK Support, Private Foundation Support