SGLT2is, GLP-1s Display Reno-Protective Benefit in Sickle Cell Disease

Preliminary findings support the role of anti-diabetic therapies, including sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1), in providing reno-protective benefits in patients with sickle cell disease (SCD) and type 2 diabetes (T2D).¹

In particular, the retrospective analysis observed improvement in the estimated glomerular filtration rate (eGFR) slope in 80% of patients with GLP-1 agonist treatment and all patients during SGLT2 inhibitor treatment.

“Based upon our results in a small cohort of SCD patients with T2D, the effects of these newer agents on kidney function should be further investigated,” wrote the investigative team, led by Santosh L. Saraf, MD, division of hematology and oncology, University of Illinois Chicago.

Acute and chronic organ damage drive early mortality in SCD—chronic kidney disease (CKD) occurs in nearly half of adults with SCD and a rapid decline in eGFR signals an increased risk of progression to end-stage kidney disease.² Evidence on renin-angiotensin-aldosterone system (RAAS) blocking agents to treat SCD nephropathy is limited to short-term data with mixed results on kidney function preservation.

Large-scale clinical trials have proven the effect of GLP-1 agonists and SGLT2 inhibitors on improving adverse cardiovascular and renal outcomes. These benefits are independent of blood glucose lowering effects in patients with T2D and CKD, indicating these therapies' potential alternative reno-protective mechanisms.

The efficacy of both agents on kidney function and their safety on SCD-related complications, including vaso-occlusive pain episodes (VOEs), remains unknown in current literature. Saraf and colleagues retrospectively assessed adults with SCD treated at their institution who were prescribed GLP-1 agonists or SGLT2 inhibitors as outpatients.

For the analysis, the 2021 creatinine-based CKD Epistemology Collaboration (CKD-EPI) equation was used to calculate CKD and VOEs were defined as pain episodes requiring care in the emergency room, acute care center, or inpatient hospital setting. The eGFR slope was calculated using linear mixed-effects models, with the fixed effects defined as population-level baseline eGFR and time.

Between February 2016 and April 2023, 7 patients with SCD were treated with either a GLP-1 agonist or SGLT2 inhibitor at the investigators’ institution. Patients had a median age of 55 years, 5 were female, and all 7 had hemoglobin SS diseases. The median baseline eGFR before treatment was 76 mL/min/1.73m² and the median urine albumin-to-creatinine ratio was 141 mg/g creatinine.

Among 5 patients treated with a GLP-1 agonist, the median duration of treatment was 21.8 months with liraglutide or dilaglutide. Serum glucose concentrations improved from a median of 213 mg/dL before treatment to 152 mg/dL during treatment. Rates of VOE increased from 1.0 per year to 2.1 per year during GLP-1 agonist treatment.

Upon analysis, the eGFR slope improved from a median of –2.37 mL/min/1.73 m² per year before treatment to +0.49 mL/min/1.73 m² per year during treatment. Four of 5 patients had an improvement in eGFR slope with a median change of +2.36 mL/min/1.73 m² on GLP-1 agonist therapy.

Among 3 patients treated with an SGLT2 inhibitor, the median duration of treatment was 12.6 months with empagliflozin. Serum glucose concentrations were typically stable from a median of 124 mg/dL before treatment to 119 mg/dL during treatment. Rates of VOE increased from a median of 3.0 per year before SGLT2 inhibitor therapy to 6.2 per year after initiation of treatment.

Further, the eGFR slope improved from a median of –0.55 mL/min/1.73 m² per year before treatment to +4.70 mL/min/1.73 m² per year during treatment. All three patients on SGLT2 inhibitor therapy experienced an improvement in the eGFR slope, with a median change of +5.30 mL/min/1.73 m².

“Future prospective studies will be needed to confirm the benefits on kidney function, as well as the potential risks on SCD-related complications, such as VOEs,” they wrote.

References

1. _{Sun R, Srivastava A, Derebail VK, et al. GLP-1 agonists and SGLT-2 inhibitors in adults with sickle cell disease. Am J Hematol. Published online April 24, 2024. doi:10.1002/ajh.27348}
2. _{Ataga KI, Saraf SL, Derebail VK. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol. 2022;18(6):361-377. doi:10.1038/s41581-022-00540-9}
3. _{Rangaswami J, Bhalla V, de Boer IH, et al. Cardiorenal Protection With the Newer Antidiabetic Agents in Patients With Diabetes and Chronic Kidney Disease: A Scientific Statement From the American Heart Association [published correction appears in Circulation. 2020 Oct 27;142(17):e304] [published correction appears in Circulation. 2021 Jun;143(22):e1019-e1020]. Circulation. 2020;142(17):e265-e286. doi:10.1161/CIR.0000000000000920}