medwireNews: Dapagliflozin significantly reduces the urine albumin-to-creatinine ratio (UACR) versus placebo in people with type 2 diabetes and chronic kidney disease (CKD), but the magnitude of the effect varies per person, study findings indicate.
“These variations, which were consistent after re-exposure, underscore the need for personalized approaches to diabetes and CKD management,” write Hiddo Heerspink (University Medical Center Groningen, the Netherlands) and co-authors in JAMA Network Open.
They explain that although the selective sodium-glucose cotransporter 2 inhibitor dapagliflozin is known to slow estimated glomerular filtration rate (eGFR) decline, reduce the risks for kidney failure and cardiovascular outcomes, and improve risk factors for CKD progression at a population level, individual responses can vary significantly.
The nature of traditional parallel-group clinical trials makes it difficult to determine whether this individual response heterogeneity is caused by pharmacologic response variation or random measurement variation.
To address this, Heerspink and team carried out a crossover randomized trial in which 20 adults (mean age 65 years, 85% men) with type 2 diabetes were assigned to one of four treatment regimens. Each regimen comprised weekly treatment with dapagliflozin 10 mg/day or placebo in a random order for a total of 2 weeks each, with 1-week washout periods between treatments.
The trial design allowed the researchers to assess individual UACR responses to dapagliflozin compared with placebo.
At baseline, the participants had a median diabetes duration of 10.8 years and a UACR of 94.7 mg/g. All had an eGFR above 30 mL/min per 1.73 m2, indicating stage 3b or better CKD, with the mean eGFR being 70.2 mL/min per 1.73 m2, indicating stage 2 CKD.
The researchers report that dapagliflozin significantly reduced UACR after both exposures and that UACR returned to baseline during the washout periods. By contrast there was no significant change in UACR with placebo use.
Specifically, UACR fell by a median of 16.6% during the first dapagliflozin exposure and by 19.1% during the second exposure. With placebo the reductions were 6.7% and 9.1%, respectively, and, overall, dapagliflozin reduced UACR by a significant 15.1% more than placebo.
Heerspink et al note that there were marked variations in the UACR changes among individuals that ranged from a fall of 86.2% to an increase of 54.4% across the two dapagliflozin periods, and from a fall of 86.7% to an increase of 68.3% during the two placebo periods.
However, the investigators found that UACR changes correlated significantly between the two dapagliflozin treatment periods, whereas there was no correlation observed between the two placebo periods.
They say that the correlation across dapagliflozin treatments suggests “genuine therapeutic heterogeneity,” while the lack of correlation between the placebo treatments indicate that the UACR variation with placebo “was random.”
As well as assessing individual UACR responses to dapagliflozin treatment, the researchers explored the feasibility of remote data collection. They found that 99.4% of 816 urine samples and 98.4% of 440 capillary blood samples were successfully delivered to the central laboratory.
The participants did not rate any aspects of the remote data collection as difficult, suggesting that this strategy “could facilitate monitoring treatment responses without requiring hospital visits, offering a more patient-friendly experience,” Heerspink and colleagues remark.
“This approach enables more frequent monitoring of risk markers, enhancing the precision, effectiveness, and safety of CKD management.”
The authors conclude: “Future studies exploring the implementation of treatment adjustments based on remotely collected data are warranted, as they could inform decentralized optimization of individual treatment regimens, ultimately enhancing the quality of care for patients with type 2 diabetes.”
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