Another Win for GLP-1 Agonists

Patients with chronic kidney disease (CKD) continue experience unsatisfactory outcomes, with a significant number of patients progressing to end-stage kidney disease. ACE inhibitors and angiotensin receptor blockers were the first major drug therapy breakthrough, with both drugs demonstrating an ability to attenuate progression of CKD.

More recently, the SGLT2 inhibitors have demonstrated a marked ability to slow progression of CKD, and both empagliflozin and dapagliflozin are FDA approved for patients with CKD (with and without diabetes).

The GLP-1 agonists are a rising class of medications. These agents have been shown to reduce the rates of major adverse cardiac events in patients with type II diabetes, and to produce profound weight loss in obese patients. More recently, these agents demonstrated the potential to reduce rates of adverse cardiac outcomes in obese patients with heart failure and a preserved ejection fraction.

In this week’s issue, we cover the latest new on the potential for the GLP-1 agonists to slow the progression of CKD in patients with diabetes.

Point 1: Trial Stopped Early

The FLOW trial was a randomised, double-blind, placebo-controlled trial comparing injectable semaglutide 1.0 mg with placebo in over 3,500 patients with CKD from over 28 countries at more than 400 investigator sites.

The key objective of the FLOW trial is to demonstrate delay in progression of CKD and to lower the risk of kidney and cardiovascular mortality. To test this aim, the authors used a composite primary endpoint consisting of the following five components:

• onset of persistent ≥ 50% reduction in eGFR¹ according to the CKD-EPI² equation compared with baseline
• onset of persistent eGFR¹ (CKD-EPI²) < 15 mL/min/1.73 m2
• initiation of chronic kidney replacement therapy (dialysis or kidney transplantation)
• death from kidney disease or death from cardiovascular disease in people with type 2 diabetes and chronic kidney disease.

The company who manufactures semaglutide announced that the trial was stopped early due to demonstrated efficacy of semaglutide versus placebo.

Point 2: Potential for a Strong Combination

These data will have to be reviewed once the trial is published, but they indicated that GLP-1 agonists may offer a power new options to delay progression of CKD in patients with diabetes. Given that these agents also reduce weight and prevent major adverse cardiac events in these patients, the renal protective effects would establish these drugs even more strongly as the standard of care. Future studies should evaluate if the GLP-1 agonists can be combined with the SGLT2 inhibitors to provide synergistic protection from CKD progression.