OBJECTIVE

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

RESEARCH DESIGN AND METHODS

We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR between 30 and 500 mg/g and estimated glomerular filtration rate >45 mL/min/1.73 m2 to 4-week treatment periods with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg, and baricitinib 2 mg in random order, separated by 4-week washout periods. Each participant was then re-exposed for 4 weeks to the drug that induced that 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 for 33 participants (52%), empagliflozin and linagliptin in 11 (17%), and baricitinib in 8 participants (13%). The individuals’ best-performing drug changed UACR from baseline during the first and confirmatory exposures by a mean of −39.6% (95% CI −44.8, −33.8; P < 0.001) and −22.4% (95% CI −29.7, −12.5; P < 0.001), respectively. The Pearson correlation for first versus confirmatory exposure was 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 versus baseline; difference versus individuals’ best-performing drug at confirmation, 30.9% [95% CI 18.0, 45.3]; P < 0.001).

CONCLUSIONS

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

Clinical trial reg. no. NTR5602 and NTR5603, trialregister.nl

This article contains supplementary material online at https://doi.org/10.2337/figshare.21753461.

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