Association between individual cholesterol and proteinuria response and exposure to atorvastatin or rosuvastatin

AIM: The PLANET trials showed that atorvastatin 80 mg but not rosuvastatin at either 10 or 40 mg reduced urinary protein to creatinine ratio (UPCR) at similar effects on LDL-cholesterol. However, individual changes in both UPCR and LDL-cholesterol during treatment with these statins varied widely between patients. This inter-individual variability could not be explained by patients' physical or biochemical characteristics. We assessed whether the plasma concentrations of both statins were associated with LDL-cholesterol and UPCR response. MATERIALS AND METHODS: The PLANET trials randomized patients with a UPCR of 500-5000 mg/g and fasting LDL-cholesterol >2.33 mmol/l to a 52-week treatment with atorvastatin 80 mg, rosuvastatin 10 mg or 40 mg. For the current analysis, patients with available samples at week 52 and treatment compliance >80% by pill count were included (N = 295). The main outcome measurements were percentage change in UPCR and absolute change in LDL-cholesterol (delta LDL) from baseline to week 52. RESULTS: Median (interquartile range) plasma concentration at week 52 for atorvastatin 80 mg was 3.9 ng/ml (IQR: 2.1 to 8.7), for rosuvastatin 10 mg 1.0 ng/ml (IQR: 0.7 to 2.0) and for rosuvastatin 40 mg 3.5 ng/ml (IQR: 2.0 to 6.8). Higher plasma concentration of statin was associated with larger LDL-cholesterol reductions at week 52 [rosuvastatin r = -0.40 (P < 0.001); atorvastatin r = -0.28 (P = 0.006)]. The plasma concentration of both statins did not correlate with UPCR change [rosuvastatin r = 0.07 (P = 0.30); atorvastatin r = 0.16 (P = 0.13)]. CONCLUSIONS: Individual variation in plasma concentrations of rosuvastatin and atorvastatin was associated with LDL-cholesterol changes in patients. The individual variation in UPCR change was not associated with the plasma concentration of both statins. This article is protected by copyright. All rights reserved

Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers

Aims: To quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re-exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter-individual variation in response to dapagliflozin with regard to multiple renal risk markers. Methods: Data were used from a crossover randomized clinical trial that assessed the albuminuria-lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed-effects models were used to quantify the exposure–response relationships. Results: The median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively (P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 (P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log-transformed urinary albumin:creatinine ratio (β = −5.9, P < 0.01), body weight (β = −0.3, P < 0.01) and estimated glomerular filtration rate (β = −0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001). Conclusion: An individual's exposure to dapagliflozin is consistent upon re-exposure and correlates with pharmacodynamic response in renal risk markers