Sodium-glucose cotransporter 2 (SGLT2) inhibitors and risk of chronic kidney disease-mineral and bone disorders in patients with type 2 diabetes mellitus and stage 1-3 chronic kidney disease

Abstract

Background: In patients with type 2 diabetes mellitus and chronic kidney disease (CKD), sodium-glucose cotransporter 2 (SGLT2) inhibitors improve renal outcomes, but may transiently affect biochemical markers of CKD-mineral and bone disorders (CKD-MBD). We sought to evaluate the long-term risk of CKD-MBD associated with use of SGLT2 inhibitors in this patient population.

Methods: We conducted a retrospective cohort study, employing a target trial emulation framework and using electronic medical records of patients from 9 hospitals in Taiwan (2016-2023). We included adults with type 2 diabetes mellitus and stage 1-3 CKD who had newly started either an SGLT2 inhibitor or, as a comparison group, a glucagon-like peptide-1 receptor agonist (GLP-1 RA). The primary outcome was a composite of incident biochemical abnormalities (serum phosphate > 1.5 mmol/L, serum calcium < 2.1 mmol/L, serum intact parathyroid hormone [iPTH] > 6.9 pmol/L, or serum 25-hydroxyvitamin D < 49.9 nmol/L).

Results: The cohort included 13 379 patients receiving SGLT2 inhibitors (n = 11 920) or GLP-1 RAs (n = 1459) with a median follow-up of 3.3 years. Compared with GLP-1 RAs, SGLT2 inhibitors were associated with a lower cumulative incidence of the composite primary outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.79-0.86), hyperphosphatemia (HR 0.83, 95% CI 0.76-0.91), hypocalcemia (HR 0.82, 95% CI 0.78-0.86), high serum iPTH levels (HR 0.66, 95% CI 0.57-0.78), and low serum 25-hydroxyvitamin D levels (HR 0.65, 95% CI 0.47-0.90).

Interpretation: Use of SGLT2 inhibitors was associated with a lower incidence of biochemical abnormalities related to CKD-MBD than GLP-1 RAs. These agents may be considered to reduce risk of CKD-MBD in patients with type 2 diabetes mellitus and stage 1-3 CKD.

Figure 1:

Flow diagram for patient inclusion in this study. See Related Content tab for accessible version. ^*The numbers represent the total number of patients who met the exclusion criteria. Numbers indicate the exact number of patients excluded because of each criterion, whereby some patients met multiple exclusion criteria. Note: ALT = alanine transaminase, CGRD = Chang Gung Research Database, CKD = chronic kidney disease, GLP-1 RAs = glucagon-like peptide 1 receptor agonists, HbA_1c = glycated hemoglobin, PAOD = peripheral arterial occlusion disease, SGLT2 = sodium–glucose cotransporter 2, UACR = urine albumin-to-creatinine ratio, ULN = upper limit of normal.

Figure 2:

Hazard ratios for the composite primary outcome and its components for patients receiving sodium–glucose cotransporter 2 (SGLT2) inhibitors compared with those receiving glucagon-like peptide 1 receptor agonists (GLP-1-RAs), after application of propensity scores with inverse probability of treatment weighting. See Related Content tab for accessible version. Note: CI = confidence interval, HR = hazard ratio, iPTH = intact parathyroid hormone, IR = incidence rate per 1000 person-years, MBD = mineral and bone disorders.

Figure 3:

Survival curves for patients receiving glucagon-like peptide 1 receptor agonists (GLP-1-RAs) or sodium–glucose cotransporter 2 (SGLT2) inhibitors after application of propensity scores with inverse probability of treatment weighting, showing risk of (A) the composite outcome of all biochemical abnormalities related to chronic kidney disease metabolic and bone disorders, (B) hyperphosphatemia, (C) hypocalcemia, (D) high serum intact parathyroid hormone levels (> 6.9 pmol/L), and (E) low serum 25-hydroxyvitamin D levels (< 49.9 nmol/L) over time. The initial numbers (11 767 and 11 966) refer to the weighted numbers of patients at risk.