There has been significant interest in SGLT2 inhibitors (SGLT2i) as novel oral anti-hyperglycemic agents that have been recently approved for the treatment of type 2 diabetes mellitus (T2DM). Studies such as CANVAS allude to their glucose-lowering effect, as well as metabolic effects, including reductions in blood pressure, body weight, and albuminuria. These effects have contributed, at least in part, to reductions in cardiovascular and renal outcomes observed in these trials. In light of these, the American Diabetes Association’s 2019 Standards of Medical Care in Diabetes currently recommends SGLT2 inhibitors as second line therapy (after metformin) in patients with T2DM and specific comorbidities, including chronic kidney disease (CKD), heart failure, or atherosclerotic cardiovascular disease.

A characteristic feature of SGLT2 inhibitors is that their glucose-lowering effect is dependent on glomerular filtration. Therefore, as eGFR declines, less serum glucose is filtered by the glomerulus.  In this scenario, SGLT2 inhibitors would be expected to have diminished capacity to increase urine glucose excretion and lower plasma glucose in the setting of kidney dysfunction. To this end, post hoc analyses of the EMPA-REG OUTCOME trial and the CANVAS program showed that with decreasing renal function, their effects on hemoglobin A_1C were less. Nevertheless, the effects of these drugs on cardiovascular and renal outcomes were similar regardless of baseline kidney function down to eGFR 30 mL/min/1.73 m².

Bexagliflozin is an SGLT2 inhibitor with high potency and high selectivity for the SGLT2 transporter. Allegretti et al recently published in AJKD a phase 3, double-blinded, placebo-controlled randomized trial to determine whether the glucose-lowering effect of bexagliflozin could be extended safely to patients with T2DM with greater decreases in kidney function, in particular those with eGFR < 45 mL/min/1.73 m².  This trial enrolled patients across 54 sites across 4 countries to bexaglifozin 20 mg/day vs placebo for 24 weeks.

The authors found statistically significant reduction in hemoglobin A_1c in patients taking bexaglifozin as early as 6 weeks, and this trend continued throughout the 24-week treatment period (as well as secondary end points such as body weight reduction, decrease in SBP, decrease in fasting plasma glucose levels, and reduction of albuminuria). This hemoglobin A_1c-lowering effect was more marked in those with CKD stage 3b.

Estimated mean change from baseline in hemoglobin A1c (HbA1c) level by treatment and kidney function group at week 24. The analysis used a mixed-effects repeated-measures model that included region, insulin-treated status, baseline estimated glomerular filtration rate, treatment, visit, treatment-by-visit interaction, and baseline HbA1c value as a fixed-effect covariate. An unstructured covariance matrix was assumed. Data from weeks 6, 12, and 24 were used in the model. The last postbaseline observation before rescue medication was carried forward. Figure 2 from Allegretti et al, AJKD © National Kidney Foundation.

The most common side effect observed was hypoglycemia, but this was not different from the control placebo group. Other adverse events that were higher in the treatment group included diuretic effects (11.5% vs 3.2%), urinary tract and genital mycotic infections (3.2% vs 0%), as well as AKI (5.1% vs 3.9%).

A frequently cited explanation for the renoprotective effect of SGLT2 inhibitors is that they decrease intraglomerular pressure, which is critical in the pathogenesis of diabetic kidney disease. By increasing distal sodium delivery to the macula densa, tubuloglomerular feedback is activated, thereby resulting in afferent arteriolar vasoconstriction. This is reflected in an acute ‘dip’ in eGFR, similar to that which is seen with RAAS inhibition. An increase in serum creatinine of 0.08 mg/dL and a decrease in eGFR of 2.41 mL/min/1.73 m² were also observed at week 24 in those who received bexagliflozin.

When extrapolating the applicability of the study findings into clinical practice, one has to consider the limitations of this study, especially the small sample size (n=312 randomized). Other dedicated CKD outcome trials are forthcoming, including EMPA-KIDNEY and DAPA-CKD. Given the putative mechanism for renoprotection, both of the above trials are enrolling participants with and without T2DM, and thus it remains to be determined whether the benefits from SGLT2 inhibitors apply similarly to patients with CKD without diabetes.

– Post prepared by Claudia Rodriguez @clau_rdgz, AJKDBlog Guest Contributor, and Edgar Lerma @edgarvlermamd, AJKD Social Media Advisory Board member.

To view Allegretti et al (subscription required), please visit AJKD.org.

Title: Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD
Authors: A.S. Allegretti, W. Zhang, W. Zhou, T.K. Thurber, S.P. Rigby, C. Bowman-Stroud, C. Trescoli, P. Serusclat, M.W. Freeman, and Y.-D.C. Halvorsen
DOI: 10.1053/j.ajkd.2019.03.417