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<0.001) and by -22.4% (95%CI -29.7, -12.5, p<0.001) at re-exposure (between exposure difference: 22.1% [95%CI 12.5, 30.8; p<0.001]) . The difference in UACR response between the individual best performing drug and the other three drugs was -40.5% (95%CI -45.9, -34.6, p<0.0vs. between exposure difference) . The correlation in UACR response of the best performing drug at exposure and re-exposure was r=0.389, p=0.017.
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.
Disclosure
V.Rotbain curovic: None. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.Y.A.Kroonen: None. N.Jongs: None. T.Sen: None. E.Zobel: Employee; Novo Nordisk. T.W.Hansen: Stock/Shareholder; Novo Nordisk A/S. G.D.Laverman: Advisory Panel; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Vifor Pharma Management Ltd., Research Support; AstraZeneca, Lilly Diabetes, Sanofi, Vifor Pharma Management Ltd. A.Kooy: Advisory Panel; Bayer AG, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk, Speaker's Bureau; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk. F.Persson: Advisory Panel; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.
