Optimization of Albuminuria Lowering Treatment by Crossover Rotation to Four Different Drug Classes

Introduction: Renin-angiotensin system (RAS) inhibitors decrease urinary albumin:creatinine ratio (UACR) and are guideline recommended drugs for kidney protection but are ineffective in lowering UACR in up to 40% of cases. We hypothesized that rotation to another drug class overcomes resistance to RAS inhibition and tested this hypothesis in a randomized cross-over trial.

Methods: We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR ≥30 and ≤500 mg/g to 4-week treatment periods with telmisartan 80 mg, empagliflozin mg, linagliptin 5 mg, and baricitinib 2 mg in random order, separated by 4-week wash-out periods. Participants were then re-exposed for 4-weeks to the individual drug that induced the largest UACR reduction. Primary outcome was the difference in UACR response between the first and second exposure to the best performing drug, versus the difference in UACR response between the best performing drug and the other three drugs.

Results: There was substantial between person variation in the best performing drug: telmisartan was best performing in 33 (52%) participants, followed by empagliflozin and linagliptin in (17%) participants each, and baricitinib in 8 (13%) participants. The individual best performing drug changed UACR during the first exposure by -39.6% (95%CI -44.8, -33.8, p
Conclusion: We demonstrated a large and reproducible variation in UACR lowering responses to different drug classes reinforcing the need for personalized therapy approaches to overcome therapy resistance to guideline recommended treatment.