Optimization of Albuminuria-Lowering Treatment in Diabetes by Crossover Rotation to Four Different Drug Classes: A Randomized Crossover Trial

Viktor Rotbain Curovic, Niels Jongs, Marjolein Y A M Kroonen, Emilie H Zobel, Tine W Hansen, Taha Sen, Gozewijn D Laverman, Adriaan Kooy, Frederik Persson, Peter Rossing, Hiddo J L Heerspink

10 Citationer (Scopus)


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.

TidsskriftDiabetes Care
Udgave nummer3
Sider (fra-til)593-601
Antal sider9
StatusUdgivet - 1 mar. 2023


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