Why are SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors and GLP-1 (Glucagon-Like Peptide-1) agonists used to treat diabetes in patients with End-Stage Renal Disease (ESRD)?

From the Guidelines

SGLT2 inhibitors and GLP-1 agonists can be used in patients with End-Stage Renal Disease (ESRD) for diabetes management, but with careful consideration of their potential benefits and risks, as recommended by the 2022 KDIGO clinical practice guideline 1. The use of these medications in ESRD patients is supported by recent studies, which suggest that they can provide cardiovascular and kidney benefits, even in patients with severely impaired kidney function 1. Some key points to consider when using SGLT2 inhibitors and GLP-1 agonists in ESRD patients include:

• SGLT2 inhibitors can be continued in patients with eGFR below 30 mL/min/1.73 m2, as long as they are well tolerated and kidney replacement therapy is not imminent 1.
• GLP-1 agonists can be used in patients with T2D and CKD who have not achieved individualized glycemic targets despite use of metformin and SGLT2i treatment, or who are unable to use those medications 1.
• The choice of GLP-1 agonist should prioritize agents with documented cardiovascular benefits, and the dose should be titrated up slowly to minimize gastrointestinal side effects 1.
• The risk of hypoglycemia is generally low with GLP-1 agonists when used alone, but risk is increased when used concomitantly with other medications such as sulfonylureas or insulin 1. Overall, the decision to use SGLT2 inhibitors and GLP-1 agonists in ESRD patients should be made on a case-by-case basis, taking into account the individual patient's clinical status, potential benefits, and risks, as recommended by the 2022 KDIGO clinical practice guideline 1.

From the FDA Drug Label

To reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression (1) To reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ( 1)

SGLT2 inhibitors are used in patients with diabetes and End-Stage Renal Disease (ESRD) to reduce the risk of cardiovascular death and hospitalization for heart failure. However, the labels note that these medications are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2 for dapagliflozin 2 and less than 30 mL/min/1.73 m2 for canagliflozin 3.

• The use of GLP-1 agonists in ESRD for diabetes is not directly supported by the provided drug labels.
• Key considerations for the use of SGLT2 inhibitors in patients with ESRD include the potential benefits of reducing cardiovascular risk and slowing kidney disease progression.

From the Research

Use of SGLT2 Inhibitors and GLP-1 Agonists in ESRD for Diabetes

• SGLT2 inhibitors and GLP-1 receptor agonists are used in patients with type 2 diabetes as glucose-lowering therapies, with additional benefits of weight loss and blood pressure reduction 4.
• These drugs have been shown to confer protection against major cardiovascular disease, reduce the risk of admission to hospital for heart failure, and reduce cardiovascular and all-cause mortality 4, 5, 6.
• SGLT2 inhibitors may exert nephroprotective effects beyond glycemic control, including reducing glomerular hyperfiltration, inflammation, and oxidative stress 5, 7.
• GLP-1 receptor agonists have also been shown to have renoprotective effects, including reducing macroalbuminuria and slowing the progression of renal disease 8, 6.
• The combination of SGLT2 inhibitors and GLP-1 receptor agonists may produce additive cardiovascular and renal benefits, making them a potential therapeutic option for patients with type 2 diabetes and chronic kidney disease 8, 6.

Mechanisms of Action

• SGLT2 inhibitors work by reducing sodium reabsorption in the proximal tubule, causing afferent arteriole vasoconstriction and reduction in hyperfiltration 5, 7.
• GLP-1 receptor agonists work via anti-atherogenic/anti-inflammatory mechanisms, raising the possibility that combined therapy with SGLT2 inhibitors may produce additive cardiovascular benefits 8.
• The nephroprotective effects of SGLT2 inhibitors and GLP-1 receptor agonists are thought to be mediated by several mechanisms, including attenuation of glomerular hyperfiltration, inflammation, and oxidative stress 5, 7, 6.

Clinical Implications

• SGLT2 inhibitors and GLP-1 receptor agonists are now considered second-line or even first-line glucose-lowering therapies in patients with cardiorenal disease, irrespective of glycemic control 4.
• These drugs should be prioritized according to existing evidence, with GLP-1 receptor agonists considered in patients at high risk of or with established cardiovascular disease, and SGLT2 inhibitors considered for patients with heart failure or chronic kidney disease 4.
• The use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with end-stage renal disease (ESRD) may provide additional benefits beyond glycemic control, including cardiovascular and renal protection 6.