GLP-1 Receptor Agonists and Next-Generation Metabolic Hormone Therapies for Chronic Kidney Disease

Clinical Investigations of Incretin Therapies Across Cardiovascular-Kidney-Metabolic Conditions

Currently available GLP-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1RA products have received FDA approval for several indications. The supporting evidence for these approvals and relevant clinical practice guidelines are outlined below.

Multiple clinical trials with agents from both the GLP-1RA and GIP-GLP-1RA classes have reported secondary outcomes related to chronic kidney disease (CKD).

Evidence from Key Cardiovascular Outcome Trials

The LEADER cardiovascular outcome trial enrolled 9,340 individuals with type 2 diabetes (T2D) at elevated cardiovascular risk. This study included a pre-specified secondary kidney composite outcome consisting of new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, kidney failure, or death from kidney disease. Treatment with liraglutide resulted in fewer kidney disease events compared to placebo (268 versus 337 events; hazard ratio 0.78; 95% CI 0.67-0.92), independent of HbA1c levels. A smaller investigation involving 84 patients linked liraglutide treatment with preserved estimated glomerular filtration rate (eGFR) and reduced albuminuria.

The LIRA-RENAL trial recruited 279 patients with T2D and baseline eGFR of 30-59 ml/min/1.73 m². Although this 26-week study did not demonstrate reduced eGFR decline, its duration was likely insufficient to properly assess this outcome.

Evidence regarding liraglutide's effect on kidney outcomes in T2D patients without baseline CKD remains inconsistent. An analysis of the GRADE trial reported no differences in mean composite kidney outcomes over five years between treatment groups including DPP-4 inhibitors, sulfonylureas, GLP-1RAs, and insulin glargine. Conversely, a target trial emulation study using insurance claims data found that GLP-1RA use reduced the risk of primary kidney composite outcomes compared to DPP-4 inhibitor treatment among T2D patients with moderate cardiovascular risk. These conflicting findings may reflect variations in baseline CKD risk.

Albuminuria Reduction Across Therapies

The ELIXA trial included 6,068 participants with T2D and a history of myocardial infarction or unstable angina. An exploratory analysis found that lixisenatide reduced albuminuria progression in a graded manner across increasing urinary albumin-to-creatinine ratio (UACR) categories, though benefits for those with normoalbuminuria and moderately increased albuminuria became non-significant after adjustment for HbA1c.

The EXSCEL cardiovascular outcome trial enrolled 14,752 patients with T2D, with or without previous cardiovascular disease. A secondary analysis did not show significant effects on kidney disease outcomes. Another post hoc analysis comparing twice-daily exenatide versus titrated insulin glargine found no effect on eGFR or albuminuria in T2D patients.

The REWIND CVOT enrolled 9,901 participants with T2D who had either previous cardiovascular events or cardiovascular risk factors. Approximately 22% had baseline eGFR <60 ml/min/1.73 m² and 35% had UACR >30 mg/g. After mean follow-up of 5.4 years, significantly fewer participants treated with dulaglutide experienced kidney outcome events compared to placebo.

Dulaglutide in Moderate-to-Severe CKD

The AWARD-7 trial included 577 participants with T2D and moderate-to-severe CKD. After 52 weeks, mean eGFR decline was significantly improved with both dulaglutide doses compared to insulin glargine. This benefit was most pronounced in participants with baseline UACR ≥300 mg/g. Glycemic control was similar across all treatment groups, indicating kidney benefits were independent of glucose-lowering effects.

The Harmony Outcomes CVOT with albiglutide enrolled 9,463 participants with T2D and established cardiovascular disease. Approximately 18% had nephropathy at baseline. Kidney impairment was included as a prespecified adverse event, with a trend toward benefit observed in those receiving albiglutide versus placebo.

Additional GLP-1RA Evidence

The AMPLITUDE-O trial assessed cardiovascular safety and efficacy of the long-acting GLP-1RA efpeglenatide in 4,076 patients with T2D and either established cardiovascular disease or CKD. After median follow-up of 1.8 years, efpeglenatide treatment resulted in fewer composite kidney outcome events than placebo.

The SUSTAIN-6 trial enrolled 3,297 participants with T2D and established cardiovascular disease and/or CKD. Rates of new or worsening nephropathy were lower in the semaglutide group versus placebo, with this effect primarily driven by reduction in new-onset macroalbuminuria.

The SELECT trial enrolled 17,604 patients with preexisting cardiovascular disease, BMI ≥27 kg/m², and without diabetes. Treatment with semaglutide reduced the risk of the primary cardiovascular outcome by 20% and the nephropathy outcome by 22%, suggesting kidney-protective effects extend to populations with obesity but without T2D.

The SOUL study showed that oral semaglutide reduced major adverse cardiovascular events risk by 14%. The impact on secondary kidney composite outcomes was not statistically significant, though the CKD subgroup had very low kidney outcome risk at baseline.

A post hoc analysis of the Semaglutide STEP trials assessed albuminuria changes in STEP 2 and eGFR in STEP 1-3. Although no eGFR difference was reported between semaglutide and placebo, albuminuria decreased significantly with semaglutide treatment compared to placebo.

Tirzepatide Kidney Protection Evidence

Post hoc analyses of the SURPASS phase III clinical program trials indicate kidney protection with tirzepatide treatment. An analysis of SURPASS-4 found tirzepatide-treated participants had lower risk of composite kidney outcomes compared to insulin glargine. Another analysis reported tirzepatide slowed eGFR loss relative to insulin glargine independently of weight changes.

In a post hoc analysis of adults with obesity from SURMOUNT-1 and SURMOUNT-2 trials, tirzepatide was associated with albuminuria reduction, particularly among individuals with baseline albuminuria.

The Landmark FLOW Trial

While secondary and exploratory kidney outcomes from large trials suggested kidney protection by GLP-1RAs and dual GIP-GLP-1RAs, publication of the FLOW trial in 2024 solidified this drug class as standard-of-care for CKD in T2D. FLOW was a dedicated kidney outcome trial that enrolled 3,533 participants with T2D and established CKD.

Treatment with subcutaneous semaglutide 1 mg once-weekly reduced relative risk of the primary kidney outcome by 24% versus placebo. Semaglutide also reduced major adverse cardiovascular events and all-cause mortality in hierarchical testing as confirmatory secondary outcomes. Based on these findings, semaglutide became the first incretin therapy approved by FDA and EMA to improve kidney, heart, and mortality outcomes in people with T2D and CKD.

Meta-Analyses and Pooled Data

A pooled analysis of SUSTAIN-6 and LEADER found GLP-1RA therapy lowered albuminuria from baseline to 2 years by 24% versus placebo. GLP-1RA therapy additionally slowed eGFR decline based on pooled analyses of SUSTAIN-6 and PIONEER-6. Benefits for CKD progression were consistent across all HbA1c, blood pressure, BMI, and UACR subgroups. Tirzepatide treatment was also associated with UACR reduction versus comparators in pooled analysis of SURPASS-1-5 trials.

In a meta-analysis of cardiovascular outcome trials, GLP-1RA treatment compared with placebo lowered risk of three-point major adverse cardiovascular events composite by 14%, all-cause mortality by 12%, and hospital admission for heart failure by 11%. This meta-analysis also reported 21% lower relative risk of composite kidney outcome.

An updated meta-analysis including SELECT and FLOW data reported 18% relative risk reduction for composite kidney outcome without albuminuria outcome and 16% relative risk reduction for kidney failure outcome with GLP-1RA treatment versus placebo. Other meta-analyses reported 16-17% risk reduction for worsening kidney function with GLP-1RAs compared to placebo.

Real-World Evidence

Real-world studies provide complementary information about uptake, effectiveness, and safety of incretin therapies in routine clinical practice. A 2024 retrospective observational study emulating an idealized target trial found GLP-1RA initiation was associated with lower risk of primary composite kidney outcome compared to DPP-4 inhibitor initiation among people with T2D and moderate cardiovascular risk.

Another retrospective analysis comparing addition of GLP-1RA versus basal insulin in T2D patients with CKD already treated with SGLT2 inhibitors found GLP-1RA addition was associated with greater HbA1c reduction, greater weight loss, and attenuated eGFR decline. Another clinical trial emulation found GLP-1RA initiation in people with T2D and CKD was associated with lower annual rates of acute healthcare utilization and all-cause mortality.

Prescribing Patterns and Adherence

Beyond validating GLP-1RA therapy benefits, real-world evidence provides important insight into prescribing and utilization patterns. A study from the CURE-CKD Registry found only 6.8% of patients with T2D and CKD were prescribed GLP-1RAs, dropping to 6.3% when assessing persistence for ≥90 days.

A 2024 nationwide registry study from Denmark found approximately 20% of users discontinued GLP-1RA therapies within the first 12 months, with only half adherent to therapy. Similar findings were reported in other real-world studies. Possible reasons for discontinuation include side effects, cost, or inadequate therapeutic response. Health tracking apps like Shotlee can help monitor medication adherence and treatment response patterns.

Limited studies point to economic benefit of semaglutide use in patients with obesity and cardiovascular disease, and in those with T2D and established cardiovascular disease or CKD, though more comprehensive cost-effectiveness analyses are needed.

Additional Clinical Benefits and Safety

Real-world data studies also identify additional clinical benefits or safety signals in large populations. A study using US Veterans Affairs health system data identified incident GLP-1RA users between October 2017 and December 2023. This study systematically mapped associations of GLP-1RA use versus other glucose-lowering agents on 175 different health outcomes.

Notably, GLP-1RA treatment decreased risk of CKD and acute kidney injury relative to usual care with other glucose-lowering agents. GLP-1RA use was also associated with reduced risks of various conditions including other cardiometabolic, coagulation, substance use, and psychotic and neurocognitive disorders. Several population-based cohort studies have additionally reported lower hyperkalemia risk with GLP-1RAs compared to DPP-4 inhibitors in people with T2D.

Combination Therapy Approaches

Combination therapy addressing totality of kidney and cardiovascular risks in people with CKD represents an area of active interest. Although no prospective trials have tested GLP-1RAs in combination with other therapeutic classes in CKD, a prespecified analysis of the FLOW trial found benefits of semaglutide for improving kidney outcomes, major cardiovascular events, and all-cause death were consistent regardless of background SGLT2 inhibitor use.

A post hoc analysis from the FIDELITY program testing finerenone for CKD in T2D found larger albuminuria reduction among participants on baseline GLP-1RA therapy, suggesting additional kidney protection with this therapeutic combination.

Ongoing and Future Research

Clinical trials are underway to further evaluate efficacy, safety, and mechanisms of kidney protection of GLP-1RAs, dual GIP-GLP-1RAs, and next-generation dual and triple agonists consisting of incretin and metabolic hormone therapies.

The REMODEL trial is a 52-week mechanistic study examining subcutaneous semaglutide's effect on measures of kidney oxygenation, perfusion, inflammation, and fibrosis. This trial completed in November 2024, though results have not yet been reported.

The TREASURE-CKD trial is an ongoing 52-week investigation examining tirzepatide's effect on kidney oxygenation by MRI in addition to measured GFR, eGFR, and UACR outcomes, estimated to complete in 2026. These trials will provide critical mechanistic and clinical insights into incretin therapies in CKD.

Ongoing research will additionally evaluate if CagriSema, combining cagrilintide and semaglutide, can reduce kidney damage in people with obesity, CKD, and T2D.

Developmental Pipeline

Multiple other incretin and metabolic hormone therapies are in developmental pipeline for cardiovascular-kidney-metabolic conditions. Orforglipron is an oral small-molecule GLP-1 with weight-loss efficacy in adults with obesity and glucose-lowering efficacy in initial phase III trials for T2D. A dedicated cardiovascular outcome trial is underway with orfloglipron.

Another investigational agent, amycretin, is a novel, unimolecular GLP-1 and amylin receptor agonist showing promise in early clinical studies for weight loss and glycemic control. Upcoming clinical trials will test amycretin efficacy and safety in obesity-related CKD with a companion trial for heart failure with preserved ejection fraction in obesity with or without T2D.

The TRIUMPH-Outcomes trial is testing triple GLP-1-GIP-glucagon agonist retatrutide's effect on dual primary cardiovascular and kidney outcomes in participants with obesity, T2D, and atherosclerotic cardiovascular disease or CKD.

Early evidence also supports kidney benefits of GLP-1-glucagon receptor co-agonism. A phase IIb trial with once-daily GLP-1-glucagon receptor co-agonist cotadutide in patients with T2D and CKD found dose-dependent UACR reduction compared to placebo. Although cotadutide development was stopped, another once-weekly GLP-1-glucagon receptor co-agonist AZD9550 is currently being studied in people with T2D and overweight or obesity.