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

Abstract

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.

Graphical abstract

Figure 1

Change from baseline in UACR during each intervention of the rotation scheme. The colored circles represent the mean (95% CI) change from baseline at end of treatment or end of washout. The gray circles represent UACR changes in individual participants.

Figure 2

Correlation in UACR changes. A: The correlation in UACR changes during each treatment and washout period. A larger reduction in UACR during treatment was associated with a more pronounced increase during washout. B: The correlation in UACR changes during the first and confirmation treatment period. UACR changes correlated between first and confirmation treatments.

Figure 3

UACR changes of each individual during each treatment of the rotation scheme. The closed colored squares (type 1 diabetes) or circles (type 2 diabetes) represent the UACR change of best drug during the first exposure. The open colored squares or circles represent the UACR change during the confirmation treatment period. The gray circles represent the UACR changes of the other three drugs. The squares to the right of the vertical line represent the mean UACR (95% CI) change of the individual’s best-performing drug during the first and confirmation treatment periods. The orange circle to the right of the vertical line shows the mean UACR change of the other three drugs of the rotation scheme. The primary outcome was the difference in UACR between the confirmatory exposure of the participants’ best-performing drug compared with the mean UACR response of the other three drugs (represented by the light blue square and orange circle). ACR, albumin to creatinine ratio.

Figure 4

Correlation between UACR changes resulting from four drugs used by participants with type 1 or type 2 diabetes. The figure shows (down the diagonal) the frequency plot for the UACR change for each treatment and (in the other six panels) the correlations between the UACR change on each drug pairing. The UACR changes for participants showing one of the four best responses to any of the four treatments are indicated by colored symbols.