Anemia (hemoglobin levels <13 g/dL in men and <12 g/dL in women) occurs in 20% to 30% of patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) and is associated with higher mortality and poor health-related quality of life. Current clinical practice guidelines do not offer specific recommendations for preventing the occurrence of anemia.
Recent post hoc analyses of the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) and Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trials indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects for anemia risk. However, their effectiveness in reducing the risk of anemia among patients with T2D and CKD stages 1 to 3 was unclear.
To address this question, a group of researchers led by Jia-Chian Hu, MS, examined anemia incidence associated with initiation of SGLT2 inhibitors in patients with T2D and CKD stages 1 to 3. They compared SGLT2 inhibitors with glucagon-like peptide-1 receptor agonists (GLP-1 RAs); the latter do not exhibit antianemic effects but are similarly situated within the T2D treatment algorithm. The study’s findings were reported in JAMA Network Open.
Data came from the Chang Gung Research Database (CGRD), which collects deidentified electronic medical records from seven Chang Gung Memorial Hospitals, Taiwan’s largest health care system. Diagnoses in the CGRD used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes before 2016 and International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes thereafter.
The study cohort consisted of 13,799 participants with T2D aged >18 years with hemoglobin A1c (HbA1c) levels of ≥6.5% and CKD stages 1 to 3, newly receiving SGLT2 inhibitors or GLP-1 RAs between January 1, 2016, and December 31, 2021. Of the total cohort, 12,331 (89.4%) initiated SGLT2 inhibitors (mean [SD] age, 62.4 [12.3] years; 7548 [61.2%] male, 4783 [38.8%] female; median [IQR] HbA1c level, 8.4% [7.5%-9.7%]; median [IQR] estimated glomerular filtration rate [eGFR], 69.0 [53.0-90.7] mL/min/1.73 m2; and median [IQR] urine albumin-creatinine ratio [UACR], 101.0 [38.5-316.5] mg/g). This was similar to the GLP-1 RA group of 1468 patients (mean [SD] age, 61.5 [13.3] years; 900 male [61.3%], 568 female [38.7%]) after applying the study inclusion and exclusion criteria and propensity scores with fine stratification weights.
To capture more generalizable T2D and CKD populations, the researchers included patients with CKD stages 1 to 3 if their eGFR levels measured between 30 and 60 mL/min/1.73 m2 or were greater than 60 mL/min/1.73 m2 and their UACR was greater than 30 mg/g, using the most recent information recorded within a year before the index date (the first prescription date for SGLT2 inhibitors or GLP-1 RAs). The SGLT2 inhibitors in the exposure group were empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin; the GLP-1 RAs in the comparison group were lixisenatide, liraglutide, dulaglutide, and semaglutide.
Following the CREDENCE and DAPA-CKD trials, the researchers defined the primary incident composite anemia outcomes, including incident anemia events (hemoglobin levels: females, <12 g/dL; males, <13 g/dL; or clinical diagnosis of anemia using ICD-10-CM diagnosis codes), and initiation of anemia treatments (oral or parenteral iron preparations, erythropoiesis-stimulating agents, or red blood cell transfusion).
During the median (IQR) follow-up of 2.5 (1.3-4.1) years, researchers saw 2887 and 429 composite anemia outcomes in patients receiving SGLT2 inhibitors and GLP-1 RAs, respectively. The incidence rate of composite anemia outcomes was lower in patients receiving SGLT2 inhibitors (8.33 [95% CI, 8.03-8.64] per 100 person-years) than in those receiving GLP-1 RAs (10.20 [95% CI, 9.26-11.21] per 100 person-years), yielding a hazard ratio (HR) of 0.81 (95% CI, 0.73-0.90). The number needed to treat for composite anemia outcomes was estimated at 55. Specifically, SGLT2 inhibitors were associated with a reduced risk for incident anemia events (HR, 0.79; 95% CI, 0.71-0.87) but not for initiation of anemia treatment (HR, 0.99; 95% CI, 0.83-1.19).
In the SGLT2 group, the median (IQR) hemoglobin level (13.8 [12.6-15.0] g/dL), hematocrit level (41.0% [37.9%-44.3%]), and red blood cell counts (4.7 [4.3-5.1] × 106/μL) were similar to those in the GLP-1 RA group at baseline. These hematological parameters mostly remained unchanged in the SGLT2 inhibitor group but decreased in the GLP-1 RA group during different follow-up periods. The median (IQR) HbA1c level (8.4% [7.5%-9.75%]), eGFR (69.0 [53.0-90.7] mL/min/1.73 m2), and UACR (101.0 [38.5-316.5] mg/g) in the SGLT2 inhibitor group were also comparable with those in the GLP-1 RA group at baseline after applying propensity scores with fine stratification weights. There were no differences in glycemic control and kidney function changes between the two treatment groups during different follow-up periods.
The study results suggest that SGLT2 inhibitor use was associated with a 19% lower risk of composite anemia outcomes compared with GLP-1 RA use. One additional composite anemia outcome may be prevented among every 55 patients with T2D and CKD stages 1 to 3 who newly receive SGLT2 inhibitors for a 1-year treatment compared with GLP-1 RA use. These findings remained consistent across different individual SGLT2 inhibitors, which implies a class effect of anemia benefits from SGLT2 inhibitors.
The authors acknowledge limitations to their study. Residual confounding may be of concern whenever observational data are analyzed. Due to the reliance on data from the CGRD, it is possible that some data may be missing, including follow-up data. Also, the CGRD does not include comprehensive smoking history information. Lastly, it is possible that misclassification occurred because the validity of the ICD-9-CM and ICD-10-CM anemia codes in the CGRD has not been verified.
“In this retrospective, cohort study emulating the CREDENCE and DAPA-CKD trials and based on multi-institutional routine care data from Taiwan, patients with T2D and CKD stages 1 to 3 and newly receiving SGLT2 inhibitors had a lower incidence of composite anemia outcomes compared with those newly receiving GLP-1 RAs. These results were consistent across several different individual SGLT2 inhibitors, possibly suggesting a drug class benefit with regard to anemia events,” the study authors concluded.
Source: JAMA Network Open
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