Optimization of albuminuria lowering treatment in diabetes by cross-over rotation to four different drug classes – a randomized cross-over trial

Introduction: Renin-angiotensin-system (RAS) inhibitors decrease urinary albumin:creatinine ratio (UACR) but are ineffective in up to 40% of patients. We hypothesized that rotation through different drug class overcomes RAS inhibitor resistance and tested this in a randomized cross-over trial.

Research_Design_and_Methods: We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR ≥30 and ≤500mg/g to 4-week treatment periods with telmisartan 80mg, empagliflozin 10mg, linagliptin 5mg, and baricitinib 2mg in random order, separated by 4-week wash-out periods. Participants were then re-exposed for 4-weeks to the drug that induced this individual’s largest UACR reduction. Primary outcome was the difference in UACR response to the best performing drug during the confirmation period versus UACR response to the other three drugs.

Results: There was substantial variation in the best performing drug: telmisartan was best performing in 33 (52%) participants, empagliflozin and linagliptin in 11 (17%), and baricitinib in 8 (13%) participants. The individuals’ best performing drug changed UACR from baseline during the first and confirmatory exposure by -39.6% (95%CI -44.8, -33.8, p<0.001) and

-22.4% (95%CI -29.7, -12.5, p<0.001) respectively; Pearson correlation first vs. confirmatory exposure 0.39 (p=0.017). The mean change in UACR with the other three drugs was +1.6% (95%CI -4.3%, 8.0%, p=0.593 vs baseline; difference versus individuals’ best performing drug at confirmation 30.9% [95%CI 18.0, 45.3,_p<0.001]).

Conclusion: We demonstrated a large and reproducible variation in participants’ response to different UACR lowering drug classes. These data support systematic rotation through different drug classes to overcome therapy resistance to RAS inhibition.