Can canagliflozin affect the progression of kidney disease in patients with type 2 diabetes?
Canagliflozin is a member of the sodium glucose cotransporter 2 (SGLT2) inhibitors. This class of antihyperglycemic medications has been shown to be an effective means of reducing blood glucose as well as providing an observed cardiovascular risk reduction. They exert their antihyperglycemic effect via blocking glucose reabsorption in the proximal tubules. In doing so, they also block the reabsorption of sodium in the proximal tubules, which activates tubuloglomerular feedback. This mechanism may reduce hyperfiltration and thus provide a potentially renoprotective effect.
The aim of this trial is to evaluate the renoprotective effect of canagliflozin in patients with type 2 diabetes and chronic kidney disease. Consequently, a randomized controlled trial design was used in order to determine causality of any observed benefit. The trial was based out of a single center, the Nihon University Itabashi Hospital in Japan. Participants were considered for inclusion if they had: a diagnosis of type 2 diabetes with nephropathy, albuminuria, eGFR between 45 and 89 mL/min/1.73m2, and were being treated with a consistent dose of RAS inhibitors for a minimum of 12 weeks prior to the start of the study. Participants were excluded if they: had an HbA1c ≥ 10%, were >80 or <20 years of age, or if they had any cardiovascular event occurring within the previous 6 months. Once deemed eligible, participants were randomized into either the intervention group (which received canagliflozin 100 mg per day) or the control group (which received usual care) and received their respective treatment for a total of 52 weeks. The primary endpoint used to assess renal function is change in urinary albumin to creatinine ratio (UACR) from baseline. Secondarily, change in vital signs, safety, and other kidney specific lab values (liver-type fatty acid binding protein [L-FABP], N-acetyl-B-D-glucosaminidase [NAG], and B2 microglobulin [B2MG]) were also monitored. Study data was analyzed via x2 or Fisher’s exact test (for categorical data) and student t-test or Mann-Whitney U test (for continuous data).
In total, there were 42 participants enrolled in this study; however, 2 were withdrawn due to hospitalizations that affected regimen adherence. As a result, each group had 20 patients who were included in the final analysis. For the primary outcome, there was a statistically significant difference in change of UACR, from baseline, in favor of the intervention group (-83 and +27 mg/gCr for the intervention and control groups respectively, p=0.004).
Likewise, all other kidney specific lab values indicated a significant difference in favor of the intervention group. With regards to calculated eGFR, an initial decline was noted in the intervention group; however, the eGFR rebounded at week 26 and at study’s end, indicated a slight increase compared to baseline. eGFR declined steadily in the control group and when compared against the intervention group, a significant difference was noted (-3.4 and +0.7 mL/min/1.73m2 for control and intervention groups respectively, p=0.024). Of note, there was also a statistically significant reduction in BMI and blood pressure in the intervention group. No adverse events were reported in either the intervention or the control group.
The study data indicates that all of the kidney function markers observed during the study were improved in the intervention group and either declined or the same in the control group. Additionally, the differences between groups were deemed to be statistically significant. This suggests that canagliflozin may provide the renoprotective effect that was hypothesized by the authors of the study. Despite the results, this study does have a few shortcomings, which may limit its applicability. For instance, the study was conducted from a single center in Japan and the enrollment was fairly low. Consequently, this study provides a good basis upon which further research can be conducted (i.e. larger, multicenter trials) but may not provide sufficient evidence, on its own, to definitively prove the researcher’s hypothesis.
- Canagliflozin is an effective antihyperglycemic agent that has proven weight reducing and cardiovascular benefits.
- Canagliflozin may be safely considered in patients with type 2 diabetes and mild renal impairment (eGFR between 45 and 89 mL/min/1.73m2).
- Further research is required to validate the findings of this study.
Takashima H, et al. “Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial”. Diabetes and Vascular Disease Research, vol. 15, no. 5, 2018, pp. 469-472., doi:10.1177/1479164118782872
Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy