SGLT2 Inhibitors and CKD

From the Chair

 Sodium-glucose cotransporter 2 (SGLT2) inhibitors are impressively effective in patients with chronic kidney disease (CKD)—treating hyperglycemia in those patients with type 2 diabetes, reducing blood pressure, slowing kidney progression, and reducing the risk of heart failure.^1,2 SGLT2 inhibitors are well tolerated and on the cusp of becoming generic medications, which could make them much less expensive and much more available.

In a recent article published in Nature titled “SGLT2 inhibitors breathe life into kidney-disease care,”³ Amanda Keener reviews the potential use of SGLT2 inhibitors in all patients with CKD, from children to adults, and potentially even in high-risk CKD patients with type 1 diabetes. Can SGLT2 inhibitors be used in all patients with CKD?

The most important group of patients who should receive treatment with SGLT2 inhibitors is patients with CKD and type 2 diabetes. These patients represent 30% to 40% of all patients with CKD. Multiple trials have demonstrated benefit in slowing progression of kidney disease and reducing the rate of heart failure hospitalization.^1,2,4 However, the evidence that all patients, including those with normo- or microalbuminuria have renoprotective benefits from SGLT2 inhibitors is quite limited.⁵

Should all patients across the etiologic spectrum of CKD be treated? The evidence from both the DAPA-CKD and EMPA-Kidney studies suggest that the answer is probably yes. Approximately 25% of patients recruited in the DAPA-CKD trial and about 66% of patients in the EMPA-Kidney trial did not have diabetes and yet showed renal and cardiovascular benefit from SGLT2 inhibitors. However, there is no definitive evidence that patients with transplant immunosuppression-related CKD benefit from SGLT2 inhibitors,⁶ largely because renal transplant patients were excluded from the pivotal SGLT2 inhibitor trials. A retrospective study in transplant recipients supported efficacy in treating hyperglycemia and hypomagnesemia but did not evaluate renal or cardiovascular end points.⁷ Likewise, it is not clear whether patients with autosomal-dominant polycystic kidney disease and other renal genetic disease would benefit from SGLT2 inhibitors.⁸

Whether SGLT2 inhibitors can be used in children is also a bit uncertain. While type 2 diabetes mellitus (T2DM) is not common in children and adolescents, the number of patients with T2DM in this age group is increasing. Further, SGLT2 inhibitors are effective in slowing nondiabetic CKD. In 2021, the European Medicines Agency approved SGLT2 inhibitors in children older than 10 years of age. In the United States, approval for use of SGLT2 inhibitors in children with CKD is pending.

There are patients in whom SGLT2 inhibitor treatment is contraindicated. Patients with CKD from type 1 diabetes mellitus (T1DM) should not receive SGLT2 inhibitor treatment. This is due to the risk of euglycemic ketoacidosis (commonly defined as ketoacidosis with a blood sugar <250 mg/dL). The mechanism is thought to involve insulinopenia and increased glucagon secretion, both leading to increased lipolysis and ketogenesis.⁹

Trials studying SGLT2 inhibitors in T1DM patients show an increased risk of diabetic ketoacidosis (DKA). In the inTANDEM trial in T1DM, the SGLT2i inhibitor sotagliflozin was effective in treating hyperglycemia but associated with a dose-dependent three- to five-fold higher rate of DKA.¹⁰ Similar results were observed in the DEPICT-2 trial using dapafliglozin.¹¹ The US Food and Drug Administration estimates that for every 26 patients with T1DM receiving treatment with an SGLT2 inhibitor, there will be one case of DKA, translating into 16 additional deaths in the United States each year.¹² Ultimately, it is likely that the risk-benefit of SGLT2 inhibitors in patients with CKD will need to be weighed. Whether the trade-offs for treatment favor SGLT2 inhibitor use in patients with CKD with T1DM remains uncertain.³

SGLT2 inhibitors are contraindicated in pregnancy, especially during the second and third trimesters, because of concerns about toxicity observed in animal studies. Some concern has also been expressed about using SGLT2 inhibitors in breastfeeding mothers, although the evidence for harm is more theoretical because SGLT2 inhibitors are not secreted into breast milk. Nonetheless, the manufacturer of dapafliglozin, among others, does not recommend use in breastfeeding mothers.

In addition to specific subpopulations of patients with CKD, SGLT2 inhibitors should be used cautiously in patients who are sick or have limited oral intake. Wang et al⁹ reinforce guideline recommendations¹³ that SGLT2 inhibitors be held at least 24 hours before and for at least 3 to 4 days after elective surgery, invasive procedures, and anticipated severe stressful physical activity. This is because the pharmacologic effects of SGLT2 inhibitors persist beyond five half-lives of elimination (2-3 days).

The bottom line is that SGLT2 inhibitors are breathing life into slowing kidney progression and reducing cardiovascular complications in patients with CKD. However, more research is needed to demonstrate their efficacy and safety in key subpopulations.

References

1. The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233
2. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816
3. Keener AB. SGLT2 inhibitors breathe life into kidney-disease care. Nature. 2023;615(7951):S2-S4. doi:10.1038/d41586-023-00648-3
4. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744
5. Singh AK, Farag YMK, Agarwal R. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(24):2301. doi:10.1056/NEJMc2301923
6. Ujjawal A, Schreiber B, Verma A. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in kidney transplant recipients: what is the evidence? Ther Adv Endocrinol Metab. 2022. doi:10.1177/20420188221090001
7. Afsar B, Afsar RE, Demiray A, et al. Sodium-glucose cotransporter inhibition in polycystic kidney disease: fact or fiction. Clin Kidney J. 2022;15(7):1275-1283. doi:10.1093/ckj/sfac029
8. Song CC, Brown A, Winstead R, et al. Early initiation of sodium-glucose linked transporter inhibitors (SGLT-2i) and associated metabolic and electrolyte outcomes in diabetic kidney transplant recipients. Endocrinol Diabetes Metab. doi:10.1002/edm2.185
9. Wang KM, Isom RT. SGLT2 inhibitor-induced euglycemic diabetic ketoacidosis: a case report. Kidney Med. 2020;2(2):218-221. doi:10.1016/j.xkme.2019.12.006
10. Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 study. Diabetes Care. 2018;41(9):1970-1980. doi:10.2337/dc18-0343
11. Mathieu C, Rudofsky G, Phillip M, et al. Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial. Diabetes Obes Metab. 2020;22(9):1516-1526. doi:10.1111/dom.14060
12. Taylor SI, Blau JE, Rother K, Beitelshees AL. SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks. Lancet Diabetes Endocrinol. 2019;7(12):949-958. doi:10.1016/S2213-8587(19)30154-8
13. Kumar S, Bhavnani SP, Goyal P, Rich MW, Krishnaswami A. Preoperative cessation of SGLT2i. American College of Cardiology. October 7, 2022. Accessed June 18, 2023. https://www.acc.org/Latest-in-Cardiology/Articles/2022/10/07/17/21/Preoperative-Cessation-of-SGLT2i