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Clinical Appropriateness of GLP-1RAs in Patients with Declining Kidney Function

By Judith Councell posted 02-22-2021 13:03

  
Clinical Appropriateness of GLP-1RAs in Patients with Declining Kidney Function
Author: Judy Councell, PharmD
Reviewed for Accuracy By: Leanne Ertle, PharmD
Reviewed for Readability By: Amber Fisher, PharmD, BCACP

 

Clinical Question:

    • What is the evidence surrounding the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with respect to renal protection and up to what point, with respect to eGFR, do renal and/or glycemic benefits continue?


Objectives:

    1. Differentiate the elimination of incretin-mimetic GLP-1RAs from human GLP-1RAs.
    2. Describe the mechanism by which human GLP-1RAs may provide renal benefits.
    3. Understand the results of the cardiovascular outcomes trials (CVOTs) with respect to renal outcomes for three of the human GLP-1RAs: dulaglutide, liraglutide and semaglutide.
    4. Review additional available evidence surrounding the use of human GLP-1RA use in DKD and hemodialysis.


Background:

Diabetic kidney disease (DKD) develops in ~40% of patients with type 2 diabetes mellitus (DM2), and is the leading cause of end-stage renal disease (ESRD) in the United States.2 ESRD is kidney failure treated by dialysis or transplantation, typically occurring once eGFR <15 mL/min/1.73m2. The two most prominent risk factors are hyperglycemia and hypertension. While we have a number of pharmacotherapy options for the treatment of diabetes, the advent of the SGLT-2 inhibitors and the GLP-1RAs have shown us that these agents may work through additional mechanisms to slow the progression of kidney dysfunction.

  1. Differentiate the elimination of incretin-mimetic GLP-1RAs from human GLP-1RAs.

There are two different types of GLP-1RAs: the incretin-mimetics (i.e. exenatide, lixisenatide) and the human GLP-1RAs (i.e. dulaglutide, liraglutide, semaglutide), and there is a difference in how these two types of GLP-1RAs are eliminated.  Human GLP-1RAs are not cleared by the kidneys, while the incretin-mimetics are.3 Human GLP-1RAs are protected from renal clearance because the molecules are too large to be cleared by the kidneys. Instead, human GLP-1RAs are metabolized locally in their target tissues (pancreas, gut, heart, muscle, kidney, etc.) by way of typical protein degradation. Therefore, the human GLP-1RAs generally do not have dose adjustments for patients with renal impairment (Table 1). The incretin-mimetics, however, are mainly eliminated by the kidneys, thereby necessitating renal dose adjustments at much higher eGFR/CrCl cut-offs than the human GLP-1RAs. As the scope of this article is to cover the limits surrounding the use of GLP-1RAs in patients with a reduced eGFR, from this point further, only the human GLP-1RAs will be discussed.


  1. Describe the mechanism by which human GLP-1RA’s may provide renal benefits.

Although not completely understood, it is thought that there are multiple mechanisms by which the GLP-1RAs may offer nephroprotection. Importantly, the mechanisms of nephroprotection lie beyond reduction in hyperglycemia. They also provide benefits through a variety of renal and cardiac effects. These include increased natriuresis, reduced hyperfiltration, reduced renal and systemic inflammation, improved tubule-glomerular feedback, a reduction in angiotensin II and renin concentrations, etc.8-10 Now, let’s review what the literature has shown regarding how these effects have played out in clinical trials examining renal benefits.

 

  1. Understand the results of the cardiovascular outcomes trials (CVOTs) with respect to renal outcomes for three of the human GLP-1RAs: dulaglutide, liraglutide and semaglutide.

Before we dive in, it’s important to establish that there have been no published GLP-1RA trials with a primary endpoint of kidney events or that have enrolled only patients with DKD. However, we do have data from the CVOTs for each of these agents. Each of the respective CVOT trials examined renal outcomes as composite secondary endpoints, which included new onset macroalbuminuria, loss of eGFR and initiation of renal replacement therapy (RRT). The LEADER and SUSTAIN-6 trials also included renal death in their composite outcomes (Table 2).


As shown in Table 3, the REWIND, LEADER and SUSTAIN-6 trials all showed significant reductions in their secondary composite renal endpoints.11-14 In the three trials, this finding was primarily driven by significant reductions in new onset macroalbuminuria. Significant reductions were not found with respect to loss of eGFR, initiation of RRT or renal death in any of the trials. Renal outcomes were not evaluated in the PIONEER 6 trial.15

Recall from Table 2, however, that the REWIND trial examined eGFR loss specifically through a sustained decreased eGFR <30%. When the researchers performed additional sensitivity analyses examining how their results might change with higher thresholds of change, they found that dulaglutide was associated with a reduced incidence of sustained eGFR decline of 40% or more (HR 0.70 (95% CI 0.57-0.85, p=0.004) and 50% or more (HR 0.56 (95% CI 0.41-0.76, p=0.0002).16



4. Review additional available evidence surrounding the use of human GLP-1RA use in DKD and hemodialysis. 

Notably, there were limited numbers of patients with severely reduced kidney function included in the aforementioned trials (Table 4). About 20-26% of patients in each trial had an eGFR <60 mL/min/1.73m2 at baseline, with only ~1-3% of patients having an eGFR <30 mL/min/1.73m2, thereby limiting the generalizability of their findings to those specific groups of patients.


In 2018, however, the AWARD-7 trial was published.17 This trial was the first clinical trial that examined the use of GLP-1RAs specifically in patients with reduced kidney function. It examined the efficacy and safety of dulaglutide in 577 patients with T2DM and CKD stages 3-4. The average eGFR was 38 mL/min/1.73m2, and 30% of patients had an eGFR <30 mL/min/1.73m2. The primary outcome was a reduction in A1C. Secondary outcomes included eGFR decline, urine albumin-to-creatinine ratio, hypoglycemia and weight changes. They found dulaglutide to be non-inferior to insulin glargine with respect to A1C reduction, while also demonstrating weight loss, lower rates of hypoglycemia, reductions in albuminuria, and reduced rates of decline in eGFR. 

The results of the AWARD-7 trial are significant for a number of reasons. First, they suggest that dulaglutide may be associated with renal benefits beyond a reduction in albuminuria, as reductions in rates of eGFR decline were also shown. Second, the AWARD-7 trial provides supporting evidence to a growing body of literature suggesting the glycemic efficacy of GLP-1RA’s is maintained in patients with renal impairment. Finally, the AWARD-7 trial adds to our understanding of how patients with reduced kidney function at baseline are likely to experience higher rates of gastrointestinal side effects, particularly nausea, vomiting and diarrhea.

In 2016, the first RCT of a GLP-1RA in patients with ESRD was conducted. This trial examined the use of SQ liraglutide, titrated up to a dose of 1.8 mg daily, in twenty patients with T2DM receiving hemodialysis or peritoneal dialysis who had documented β-cell function.18 Although dose-corrected liraglutide concentrations were significantly higher in patients with ESRD, progressive accumulation did not occur. This finding suggested that although the kidneys may play some role in the elimination of liraglutide, they were not the main contributors to its elimination and/or degradation. Additionally, use of liraglutide allowed for reduced doses of basal insulin to be used without compromising glycemic control. Patients with ESRD, however, were more likely to experience gastrointestinal side effects compared to the control group. The authors suggested considering lower doses with prolonged titration in patient’s with ESRD as a result.

In 2018, an observational trial evaluated the efficacy and safety of dulaglutide 0.75 mg SQ once weekly when added to bolus-containing insulin regimens in fifteen Japanese patients with T2DM receiving hemodialysis.19 Dulaglutide significantly reduced total daily doses of insulin while simultaneously significantly decreasing glucose concentrations without affecting the incidence of hypoglycemia. Additionally, dulaglutide was well tolerated. Loss of appetite was experienced by nine patients and self-limiting nausea and vomiting by one. No diarrhea was reported.

While no trials of PO or SQ semaglutide have been performed in patients with ESRD, one study demonstrated that the PK of PO semaglutide were not affected by ESRD.20 Similar findings have been seen in a PK study with SQ semaglutide in patients with ESRD.21

Conclusion:

 The GLP-1RAs have been shown to provide beneficial effects on kidney function, primarily through a reduction in new onset macroalbuminuria. Although albuminuria is a well-established biomarker that may reflect the risk of DKD, ultimately it remains a surrogate marker. Recently, however, the AWARD-7 trial also demonstrated a reduction in eGFR decline with dulaglutide in a population of patients with T2DM and CKD stages 3-4.

The AWARD-7 trial also supported the idea that GLP-1RAs help maintain glycemic efficacy in patients with poor kidney function while reducing the risk of hypoglycemia when compared to insulin therapy. This has been corroborated in available trials of human GLP-1RAs in ESRD. It should be noted, however, that gastrointestinal side effects may be more common in this population. As a result, providers should have a low threshold to more closely monitor kidney function, especially if severe nausea, diarrhea or vomiting occur in these types of patie