Emerging evidence for GLP-1 agonists in slowing CKD progression

Abstract

Purpose of review:

Diabetic kidney disease continues to increase, and several novel therapeutic agents have been shown to slow the progression of chronic kidney disease in those with diabetes. This review summarizes more recent data on the role of GLP-1 receptor agonists and kidney outcomes.

Recent findings:

Post-hoc analysis of cardiovascular outcome trials, as well as several retrospective studies, demonstrate benefits of GLP-1 receptor agonist therapy for chronic kidney disease progression in diabetics. While limited randomized clinical trials evidence assessing the effects of GLP-1 receptor agonists on kidney outcomes in diabetic chronic kidney disease patients have been published, FLOW-CKD trial was halted based on interim data for efficacy, and results are awaited.

Summary:

GLP-1 receptor agonism is a promising therapy for slowing the progression of diabetic chronic kidney disease. Recent studies support kidney benefits GLP-1 receptor agonists over insulin and DPP4-inhibitors, and the FLOW-CKD trial would inform the potential benefits for reducing the need for dialysis and kidney-disease related mortality in those with kidney disease.

Introduction

Unlike the improvements in cardiovascular disease (CVD) mortality achieved over the recent decades [1], chronic kidney disease (CKD), with increasing prevalence coincident with that of diabetes mellitus and obesity, persists as a leading cause of death worldwide [2]. The ongoing deployment of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on top of RAAS antagonism has ushered a new era in both diabetic and non-diabetic proteinuric kidney disease management [3,4], raising the question of whether some other classes of anti-diabetic medications may benefit kidney-related mortality outcomes for diabetic and non-diabetic CKD patients. Glucagon-like peptide-1 (GLP-1) agonists (including GLP-1 analogs, GLP-1 receptor agonists, and others) exhibit multiple beneficial metabolic effects, including stimulating pancreatic insulin release and slowing gastric emptying (effects that underpin the current accelerating utilization for obesity [5]).

From 2005, GLP-1 receptor agonists have been an option for patients with uncontrolled hyperglycemia in type 2 diabetes mellitus and are a recommended option for patients with diabetes and atherosclerotic cardiovascular disease or kidney disease [6,7]. Both SGLT2 inhibitors and GLP-1 receptor agonists improve cardiovascular outcomes in diabetic patients with increased cardiovascular risk [8]; however, unlike the conclusive role for SGLT2i in CKD, the effects of GLP-1 agonism on the need for renal replacement therapy and kidney disease-related mortality are less clear in diabetic patients, and remain unstudied in patients with non-diabetic CKD. Existing data supporting a role for GLP-1 receptor agonism in slowing the progression of kidney disease in patients with diabetes derive from cardiovascular outcome trials (CVOT) with their subsequent meta-analyses or post-hoc studies [9,10], a limitation hopefully to be remedied by ongoing trials. In this review, we briefly review the mechanism of action, and discuss most recent clinical trial and observational evidence on the subject (Table 1).

Table 1:

Recent clinical studies reporting kidney outcome of GLP-1 agonists

Title	Type of study	Country	N	Comparator	Conclusions
Heerspink et al (21)	RCT	14 countries	2002	Tirzepatide SC vs. SC insulin glargine	eGFR decline: −1.4 (SE 0.2) mL/min per 1.73 m2 (Tirzepatide) vs −3.6 (SE 0.2) mL/min per 1.73 m2 (Insulin glargine) Change in albuminuria: −6.8% (95% CI −14.1 to 1.1) (Tirzepatide) vs. 36.9% [95% CI 26·0 to 48·7] increase in Insulin glargine
Shaman et al (19)	RCT	7 countries	12637	Semaglutide 0.5 mg and 1.0 mg SC and liraglutide 1.8mg SC vs placebo	eGFR decline: −0.87 mL/min/1.73m2 (semaglutide) vs. and −0.26 mL/min/1.73m2 (liraglutide) Reduction in albuminuria: Semaglutide 0.5 mg: −20% (95% CI, 10%–28%) Semaglutide 1.0 mg: −33%, (95% CI, 24%–40%) Liraglutide: −23% (95% CI, 18%–27%)
Schechter et al (25)	Observational study	Israel	6848	Exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide vs basal insulin	eGFR decline: A difference of 0.42 mL/min/1.73 m2/year [95% CI 0.11–0.73 as compared to basal insulin, 95% CI Albuminuria: Lower risk for categorical progression of UACR compared with basal insulin (HR 0.90, 95% CI 0.830 0.97)
Peng et al (26)		Taiwan	14558	Liraglutide and dulaglutide vs long acting insulin	Significantly decreased the risk of composite kidney outcome (eGFR <15 mL/min/1.73 m2, ESRD or renal death) HR 0.39, 95% CI (0.30–0.51).
Lin et al (28)		Taiwan	8922	Liraglutide and dulaglutide vs DPP-4i	>50% decline in EGFR: HR 0.74 (95% CI 0.60–0.91) ESKD: HR 0.71 (95%CI: 0.57–0.88)

RCT: Randomized controlled trial; SC: subcutaneous; eGFR- estimated glomerular filtration rate; UACR- urine albumin:creatinine ratio; HR- hazard ratio; NR- Not reported; ESRD- end stage renal disease

Mechanism of action

GLP-1 is an incretin hormone secreted after ingestion of glucose and food nutrients stimulates the release of insulin from pancreatic islet cells [11]. By slowing gastric emptying and reduced appetite stimulation, it also facilitates weight loss [12,13]. These effects were attributed to the overall cardiovascular benefits noted in the studies of the general population with GLP-1 receptor agonists. These agents also have kidney protective effects through direct and indirect effects. Known direct effects include the beneficial glomerular hemodynamic effects, reduced inflammatory burden, oxidative stress, and lower reactive oxygen species in the kidneys [14]. Indirect effects include the improvement in glycemic control and weight loss which reduced urinary albumin excretion and eventual impact on the decline in kidney function. Such renal-specific effects support the likelihood for a significant benefit of GLP-1 agonism in slowing CKD progression with a resultant improvement for diabetic patients in the need for renal replacement therapy and kidney disease-related mortality. The viability of this role for GLP-1 receptor agonists will hopefully be solidified by ongoing trials, but in the interim, recent observational studies using real world data further lend some support for the kidney benefits noted in CVOTs (Table 1).

Side effects

Based on clinical trial and real-world experience, the most common side effects of GLP-1 receptor agonists include various gastrointestinal symptoms such as nausea, vomiting and diarrhea which occurs early during drug initiation and tend to diminish with continuation of treatment [15]. It is also associated with an increased risk of gall bladder and biliary diseases, and monitoring of symptoms related are warranted. There was no increased risk of pancreatitis, pancreatic cancer or medullary thyroid cancer, with GLP-1 receptor agonists; however, they are contraindicated among those at risk of medullary thyroid cancer. Clinicians caring for those with CKD on GLP-1RA should counsel patients about these discussed side effects and monitor for development of these adverse effects.

Post-hoc analyses of cardiovascular outcome trials

More recent post-hoc analyses of prior cardiovascular outcome trials further highlight the renoprotective role of GLP-1 receptor agonists through examination of eGFR change and proteinuria but are limited by the paucity of renal events that would inform assessment of risk for kidney replacement therapy and kidney mortality. A 2021 meta-analysis of 6 cardiovascular outcome trials (that reported kidney outcomes) with established or high CVD risk disclosed a non-significant trend for benefit of eGFR change (hazard ratio [HR] for worsening kidney function 0.86 [0.72–1.02]), that improved (OR 0.82 [0.69–0.98]) with exclusion of a trial that studied patients with a recent acute coronary episode [16]. A subsequent post-hoc analysis of pooled secondary outcome data from LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [17]) and SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide [18]) in Subjects With Type 2 Diabetes) showed improvements in proteinuria and GFR decline [19]. In the pooled analysis, there was a 24% (95% CI, 20%−27%; P<0.001) reduction in albuminuria with semaglutide/liraglutide (vs. placebo) from baseline to 2 years. They also reported that with semaglutide 1.0 mg and liraglutide (vs. placebo), eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m²/year (P<0.0001 and P<0.001), respectively. Notably, the effects were larger in those with eGFR <60 ml/min/1.73 m² compared to those with higher eGFR.

The SURPASS-4 (Tirzepatide Versus Insulin Glargine in Type 2 Diabetes and Increased Cardiovascular Risk) trial assessed antihyperglycemic efficacy and safety of tirzepatide (a peptide dual agonist of GLP-1 and gastric inhibitory polypeptide receptors, the latter with added benefits to glucagon and lipid regulation) versus insulin glargine in diabetic patients with high CVD risk, including 342 subjects having eGFR < 60 (mL/min/1.73m²) [20]. Recently in a post-hoc, exploratory study of SURPASS-4 trial data, Heerspink and colleagues [21] reported that during 104 weeks of follow up, eGFR declined at a slower rate in the tirzepatide (n=995) group when compared to the insulin (n=1000) group (difference between groups 2.2 [mL/min/1.73m² per year], 95% CI 1.6–2.8), regardless of SGLT2i use, and with the most difference in patients with an eGFR of less than 60 (mL/min/1.73m²). Albuminuria was also stabilized in tirzepatide treated patients when compared to insulin treated, a benefit that largely contributed to a reduction in the composite kidney outcome. Of note, among patients with an eGFR < 60 (mL/min/1.73m²), only 15 patients had a decline in eGFR > 40% from baseline, two progressed to ESKD, and there were no renal deaths, yielding the composite outcome of limited utility.

The AMPLITUDE-O trial enrolled 4076 participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor to study the effects of efpeglenatide on major atherosclerotic cardiovascular events [22]. Over 1/3^rd of the study population had kidney disease at baseline. During a median follow-up of 1.81 years, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo (HR, 0.73; 95% CI, 0.58 to 0.92; P<0.001 for noninferiority; P=0.007 for superiority). Further, composite renal outcome event defined as a decrease in kidney function or macroalbuminuria occurred in 13% of participant in the efpeglenatide group and in 18.4% of participants who received placebo (HR, 0.68; 95% CI, 0.57 to 0.79; P<0.001).

Recent observational study evidence

GLP-1 receptor agonists versus insulin

Patients with diabetes and an eGFR of 20–60 (mL/min/1.73m²) or proteinuria (albumin to creatinine ratio [ACR] ≥ 30 mg/g) but without atherosclerotic cardiovascular disease, heart failure, or high-risk indicators, and who are on maximally tolerated ACEI/ARB and metformin, are recommended for SGLT2 inhibitor initiation regardless of hemoglobin A1C [6,23]. GLP-1 receptor agonists with demonstrated benefits for CVD are recommended in this scenario if SGLT2 inhibitors are contraindicated or not tolerated [24]. Apart from this latter caveat, GLP-1 receptor agonists may also be added as an alternative to insulin (for CVD benefit) when hemoglobin A1C is above goal, and injection therapy is needed. The recommendation to initiate specifically for kidney benefit may follow reporting by ongoing trials, but recently, real world studies have compared GLP1 receptor agonists to other anti-diabetic agents in large populations of lower cardiovascular risk CKD patients with notable results.

In an observational cohort study utilizing 10 years of data across a healthcare system database, Schechter and colleagues [25] examined longer-term kidney outcomes with GLP-1 receptor agonist use as compared to insulin. The study evaluated 11,634 patients treated with primarily injection GLP-1 receptor agonists and 22,598 patients treated with basal insulin, that after propensity-score matching yielded 3424 participants in each group. Patients were 45% female, with a mean age of 59 years, a 9.7-year history of diabetes, and average hemoglobin A1C of 9.0%. Ninety-one percent of patients at an eGFR of ≥ 60 (mL/min/1.73m²) at baseline, with 61% of patients having ACR ≤ 30 (mg/g). ACEi/ARBs were employed in 75% of patients, and 14% were treated with SGLT2 inhibitors. When analyzed as-treated, average follow up was 22 months, and the composite kidney outcome (eGFR loss of ≥ 40% or ESKD) occurred in 194 patients with a resultant HR with GLP-1 receptor agonists of 0.71 (0.54–0.95). Further, patients treated with GLP-1 receptor agonists in the as-treated group had reduced eGFR decline at all time points after 12 months and had lower risk for confirmed categorical increase in albuminuria (HR 0.75 [0.64–0.89], consistent with prior studies).

Uncontrolled diabetes is a leading risk factor for development and progression of CKD. In a retrospective, exploratory study utilizing a national healthcare database, Peng and colleagues [26] evaluated renal outcomes among patients requiring intensive glycemic control and receiving either GLP-1 receptor agonist or insulin therapy. Utilizing propensity-score matched pairs of 7279 patients, within which 25% had preexisting diabetic nephropathy, over an average follow up of 2.6 years, the HR for dialysis-requiring ESKD and renal death were 0.29 (95% CI 0.2–0.4) and 0.28 (95% CI 0.15–0.5; 0.07). In the GLP-1 receptor agonist group, 35 patients were declared ESKD (versus 119 in insulin group), and there were 13 renal deaths (versus 14 in the insulin group). While the examined population was identified based on diabetes status and not cardiovascular risk, a 29% reduction in the rate of major adverse cardiovascular events was observed, a result consistent with prior reports. Although the study is notable for the number of kidney events, the underlying study design and data sources remain only suggestive that GLP-1 receptor agonists will benefit hard kidney outcomes in a clinical trial setting.

These more recent studies do support findings observed in CVOTs, and notably the populations studied were more enriched in patients with mild-moderate chronic kidney disease at baseline. While the kidney benefit of GLP-1 receptor agonist is suggested for patients with established diabetic nephropathy, whether such benefits are attained in diabetic patients without existing kidney disease had been unclear. In the GRADE trial (Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes) [27], patients without kidney disease on metformin were randomized to insulin, glimepiride, liraglutide or sitagliptin to benefit glycemic control. Over 5 years of follow up, no significant differences were found in CKD progression among the agents.

GLP-1 agonists versus dipeptidyl peptidase-4 inhibitors in advanced CKD

Data on the effects of GLP-1 agonists in advanced chronic kidney disease has also been lacking. In a retrospective cohort study, Lin and colleagues [28] compared cardiovascular mortality and kidney outcomes in diabetic patients with an eGFR < 30 (mL/min/1.73m²) at baseline via a propensity-score matched (1:4) cohort, with 602 patients treated with GLP-1 receptor agonists and 1479 patients treated with dipeptidyl peptidase-4 inhibitors (DPP4i). Patients were on average 66 years old with an eGFR of 20 (mL/min/1.73m²). Although no significant difference was observed in the composite cardiovascular outcome (CV death, myocardial infarction or stroke), authors reported significant reductions in the risk for eGFR decline greater than 50% (HR 0.74 [95% CI 0.6–0.91]), progression to ESKD/dialysis (HR 0.72 [95% CI 0.56–0.93]), and all-cause death (HR 0.71 [95% CI 0.57–0.88]). The reported benefit to all-cause mortality is of similar magnitude to an earlier retrospective cohort study of GLP-1 receptor agonist versus DPP4I in patients with CKD stage 5 or ESKD. [29]

FLOW-CKD trial

Signals from the CVOT post-hoc analyses and retrospective cohort studies point to a benefit of GLP-1 agonists in patients with diabetic kidney disease and reinforce the need for a clinical trial to assess for kidney-related outcomes. The FLOW trial [30] is a randomized, placebo-controlled, double-blind parallel-group trial assessing once-weekly Semaglutide injection in addition to standard of care therapy. The inclusion criteria for the study included diabetic patients with an eGFR between 50 and 75 (mL/min/1.73m²) with an ACR > 300 to < 5000 (mg/g) or an eGFR between 25 and 50 (mL/min/1.73m²) with an ACR > 100 to < 5000 (mg/g). A majority of the 3534 participants were high risk for CKD progression, with an average age of 66 years and average eGFR of 47 (mL/min/1.73m²). The authors will assess endpoints of kidney disease progression, need for renal replacement therapy, and kidney and cardiovascular related mortality. In October 2023, the manufacturer of Semaglutide reported that the trial would be stopped early based meeting criteria for early efficacy [31].

Clinical Practice Guideline recommendations

Recently updated 2022 KDIGO guidelines for those with diabetes and kidney disease recommend the use of GLP-1 receptor agonists for those who have not achieved individualized glycemic targets despite the use of metformin and SGLT2i treatment, or who are unable to use those medications (Level 1B) (7). The 2023 American Diabetes Association Standards of Care recommends that in people with type 2 diabetes and diabetic kidney disease, consider use of a GLP-1 receptor agonist (A).

Conclusions

Although no clinical trials examining the benefits of GLP-1 receptor agonists specifically in CKD patients have been published within the last year, we await the upcoming release of FLOW trial results. Recent post-hoc analyses of CVOTs and retrospective cohort studies have demonstrated GLP-1 benefits to CKD progression, the need for dialysis and mortality. Compared to insulin and DPP4 inhibitors, GLP-1 receptor agonists, in addition to proven cardiovascular benefits, may reduce the risk for CKD progression and kidney related mortality in patients with existing diabetic chronic kidney disease.

Key Points.

• Secondary analyses of cardiovascular outcome trials demonstrate the kidney benefits (albuminuria reduction and slower decline in eGFR) of GLP-1 receptor agonists.

• Recent retrospective cohort studies also show benefits of GLP-1 receptor agonists over insulin and DPP4 inhibitors in improving kidney outcomes.

• Large randomized, placebo- controlled clinical trial of once-weekly Semaglutide in diabetic chronic kidney disease patients has been halted based on interim data demonstrating efficacy.