Sodium glucose transporter 2 inhibitors (SGLT2 Inhibitors) are FDA approved medications for diabetes mellitus type II (DMII), chronic kidney disease (CKD), and heart failure with reduced ejection fraction (HFrEF). The 2012 KDIGO guidelines recommend SGLT2 inhibitors for their cardiovascular and kidney protective benefits in CKD patients (1). The CREDENCE (2), EMPA-Kidney (3), and DAPA-CKD (4) trials added to this body of evidence by demonstrating a lower risk of disease progression, kidney failure, and glomerular filtration rate (GFR) decline. The guidelines also recommend SGLT2 inhibitors for CKD patients with an estimated GFR (eGFR) > 25 mL/min/1.73m ².

SGLT2 inhibitors offer kidney protective benefits due to a variety of mechanisms, such as lowering glomerular capillary hypertension and hyperfiltration (5). This alleviates stress on the filtration barrier, lessens albuminuria, and reduces oxygen demand. Through these mechanisms, CKD patients can have a reduced risk of progression to end-stage kidney disease (ESKD). Efficacy of these mechanisms is generally measured via eGFR, degree of albuminuria, and urine albumin creatinine ratio (UACR) (6).

The benefits of SGLT2 inhibitors on kidney function have been demonstrated in multiple trials. The DAPA-CKD trial was a randomized control trial that sought to assess the renal and cardiovascular protective benefits of the SGLT2 inhibitor dapagliflozin (4). The primary outcome assessed was a composite of a decline in eGFR of at least 50%, ESKD, or death from renal or cardiovascular causes. This outcome only occurred in approximately 9.2% of the dapagliflozin group compared to 14.5% of the placebo group. Death occurred in 4.7% of the dapagliflozin group and 6.8% in the placebo group. The EMPA-Kidney study was another trial conducted in both diabetic and non-diabetic patients administered empagliflozin and produced similar results to DAPA-CKD (3). Notably, fewer than half of the participants (46%) had diabetes. The primary outcome was a composite of progression of kidney disease with a decrease in eGFR <10 mL/min/1.73m², a decrease in eGFR ≥ 40% from baseline, or death as deemed from renal causes. This outcome occurred in approximately 13.1% of the empagliflozin group compared to 16.9% in the placebo group. Furthermore, the effects were similar in both diabetic and non-diabetic patients with CKD regardless of initial GFR. Lastly, the CREDENCE trial evaluated canagliflozin and investigated a primary outcome of ESKD, doubling of serum creatinine (SCr), or death from renal or cardiovascular causes (2). This trial was stopped early as the results indicated a 30% improvement in the primary outcome from placebo. Based on these trials, it was concluded that SGLT2 inhibitors provided renal protective benefit via a reduction in the decline of eGFR, progression into ESKD, and death by renal causes (2-4).

Furthermore, SGLT2 inhibitors may be used in patients experiencing albuminuria as they have shown benefit in reducing these levels. It has been observed among the various SGLT2 inhibitor clinical trials that because the risk of CKD progression increases with increasing albuminuria, the effective benefit of SGLT2 inhibitors is therefore greater in those with high levels of albuminuria despite any similarities in relative risk. Moreover, although patients may not see any additional HbA1c lowering while transitioning towards ESKD, kidney protective benefits have still been observed via decreased albuminuria and decreased rate of eGFR decline (7). Similarly, one study was performed to determine dapagliflozin’s effects on UACR (6). Data from 3,820 patients was analyzed from the DAPA-CKD trial and found an overall reduction in stage of UACR. Geometric mean UACR reduction was 29.3% compared to placebo. Further analysis found associations between a reduction in UACR and eGFR, providing additional support for UACR as a strong marker of kidney function.

While SGLT2 inhibitors are recommended in CKD patients with an eGFR > 25 mL/min/1.73m², initiation of SGLT2 inhibitors has been strongly discouraged in CKD patients with an eGFR < 25 mL/min/1.73m² (7). This is due to the nature of SGLT2 inhibitor naive patients who may experience acute increases in SCr possibly leading to an acute kidney injury and a lowering of eGFR. However, if a dialysis patient is already taking an SGLT2 inhibitor experiences a decline to an eGFR of < 25 mL/min/1.73m², they may continue the SGLT2 inhibitor, but some dose adjustments may be required based on decreased renal function. These patients often experience macroalbuminuria of up to ≥ 300 mg/day, but the benefit of reducing progression into kidney failure may be justified (6).

Regarding adverse effects associated with SGLT2 inhibitors, there is a risk for acute kidney injury at the initiation of therapy (1,8). The 2012 KDIGO guidelines define acute kidney injury as an increase in SCr by ≥ 0.3 mg/dL within 48 hours, or an increase in SCr > 1.5 times baseline which has occurred within the past seven days, or a urine volume < 0.5 mL/kg/h for 6 hours (9). If this occurs, SGLT2 inhibitors should be discontinued immediately and treatment for acute kidney injury should be initiated. Volume status and perfusion pressure should be maintained, monitoring for functional status, SCr and urine output monitoring, hyperglycemia avoidance, and avoidance of contrast media. In higher stages of acute kidney injury, ICU admission along with renal replacement therapy should be strongly considered.

Additionally, SGLT2 inhibitors include a risk of decreased eGFR in addition to acute kidney injury in the first few weeks of therapy, but overall renal protective benefits have been observed with consistent use (8). Genitourinary fungal infection is the most common adverse effect associated with SGLT2 inhibitors. This occurs due to the drug’s mechanism of action which leads to decreased blood glucose and glucosuria. Hyperkalemia has been observed, but generally under instances when SGLT2 inhibitors are used concomitantly with electrolyte altering medications such as potassium sparing diuretics, angiotensin- converting enzyme inhibitors, and angiotensin receptor blockers (8,10). The SGLT2 inhibitor mechanism also lends itself to diuretic-like effects where hypovolemia and hypotension adverse effects have been reported (8). Hypersensitivity reactions have been observed, but no cross-sensitivity has been reported between agents. Based on these potential adverse effects, patients should continue to be monitored for infection, electrolyte imbalances, hypersensitivity reactions, and volume status (8,10).

While SGLT2 inhibitors were originally developed with the intention of treating diabetes mellitus type II, additional cardiovascular and kidney protective benefits have been identified through meticulous study and multiple randomized control trials (1). CKD is a progressive and irreversible disease, so the mainstay of treatment is to prevent patients from progressing to ESKD. SGLT2 inhibitors are a pharmacologic option for slowing CKD progression into ESKD and have shown consistent benefit at reducing the rate of eGFR decline, albuminuria, UACR, and death by renal causes (1-6). While patients may not receive glycemic control from SGLT2 inhibitors in later stages of CKD, patients will continue to reap their renal protective benefits as their disease progresses for years following diagnosis (7). Therefore, CKD patients with an eGFR > 25 mL/min/1.73² may be considered for initiation of a SGLT2 inhibitor for its renal protective benefits, slower disease progression, and higher quality of life as a result (1,5).

References:

1. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2022;102(5S):S1-S127. doi:10.1016/j.kint.2022.06.008
2. Perkovic V, Jardine MJ, Neal B, et Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744
3. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233
4. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816
5. Vallon V, Verma Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function. Annu Rev Physiol. 2021;83:503-528. doi:10.1146/annurev-physiol-031620-095920
6. Jongs N, Greene T, Chertow GM, et Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis f rom the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(11):755-766. doi:10.1016/S2213- 8587(21)00243-6
7. Dekkers CCJ, Wheeler DC, Sjöström CD, Stefansson BV, Cain V, Heerspink Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b-4 chronic kidney disease [published correction appears in Nephrol Dial Transplant. 2018 Jul 1;33(7):1280]. Nephrol Dial Transplant. 2018;33(11):2005-2011. doi:10.1093/ndt/gfx350
8. In: Lexi-Drugs. Lexi-Comp, Inc. Updated May 5, 2023. Accessed May 17, 2023. https://online-lexi-com.eu1.proxy.openathens.net/lco/action/doc/retrieve/docid/patch_f /4230722
9. Khwaja KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-c184. doi:10.1159/000339789
10. Weir MR, Kline I, Xie J, Edwards R, Usiskin Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular f iltration rate (eGFR). Curr Med Res Opin. 2014;30(9):1759-1768. doi:10.1185/03007995.2014.919907

GMO-000825  Rev A  09/2023