HOUSTON — The dual GLP-1/GIP receptor agonist tirzepatide showed significantly greater efficacy than the GLP-1 dulaglutide in the treatment of major kidney outcomes in patients with type 2 diabetes (T2D) and high-risk chronic kidney disease (CKD) in a post-hoc analysis of the phase 3 SURPASS-CVOT trial.

“Tirzepatide slowed the decline in kidney function and reduced the progression of albuminuria,” reported first study author Sophia Zoungas, MBBS, PhD, here at Kidney Week 2025: American Society of Nephrology Annual Meeting.

“If you were to translate these effects over time, you would prevent progression to dialysis probably by about 7-8 years,” said Zoungas, head of the School of Public Health and Preventive Medicine and professor of diabetes, vascular health, and aging at Monash University, Melbourne, Australia.

Once-weekly tirzepatide, with its dual mechanisms, has consistently shown improvements over GLP-1 drugs in general in measures of glucose control and weight loss. The current findings add to the growing body of evidence of the kidney protective effects of tirzepatide in comparison to placebo or other glucose-lowering strategies in patients with T2D, said Zoungas. 

SURPASS-CVOT

In recent results from the SURPASS-CVOT trial, as reported by Medscape Medical News, tirzepatide showed noninferiority but not superiority over dulaglutide in the primary outcome of the three major cardiovascular (CV) events (MACE-3) of CV death, myocardial infarction, or stroke over a median follow-up of 4 years.

The trial included 13,165 patients with T2D and established atherosclerotic CV disease, enrolled at 640 sites in 30 countries across all world regions. 

The trial was notable as being the first of its kind comparing a T2D drug to an active comparator and not just a placebo in measures of CV outcomes.

In secondary outcomes, SURPASS-CVOT also showed that tirzepatide had kidney benefits in the overall population in terms of reduced decline in estimated glomerular filtration rate (eGFR), albuminuria progression, and the risk of the composite major kidney outcome compared with dulaglutide.

High-Risk Patients 

For the current post-hoc analysis, the authors compared kidney outcomes among a subgroup of the most vulnerable patients in the study who had very high-risk CKD, defined as having an eGFR < 30 mL/min/1.73 m²; eGFR ≥ 30 to < 45 mL/min/1.73 m² and micro/macroalbuminuria; or eGFR ≥ 45 to < 60 mL/min/1.73 m² and macroalbuminuria ( based on KDIGO 2025 guidelines). 

Of the 1241 patients in the study who met these criteria, 646 were randomized to tirzepatide, starting at 2.5 mg and escalated up to 5 mg, 7.5 mg, 10 mg, or 15 mg over 24 weeks; and 595 patients were randomized to dulaglutide, with a sham escalation to 1.5 mg.

The patients had a mean age of 68.5 years, mean BMI of 33.0, mean A1c of 8.5%, and a mean duration of diabetes of 19.2 years. About a quarter of patients (24.9%) were treated with SGLT2 inhibitors. 

As many as 85.6% were treated with statins, 68.8% with insulin, 52.1% with ARBs, and 30.9% with ACE inhibitors.

From baseline to week 156 — for the composite kidney outcome of the onset of macroalbuminuria, ≥ 50% reduction in eGFR, onset of end stage kidney disease, or kidney-related death — the rate was 33% lower with tirzepatide vs dulaglutide, at 16.7% vs 23.0%, respectively (hazard ratio [HR], 0.67; P = .002).

Those treated with tirzepatide had significantly lower mean reductions in eGFR, -4.4 compared with -7.5 for dulaglutide, for a significant difference of 3.1 mL/min/1.73 m² (P < .001).

The tirzepatide group also had significantly greater reductions in the mean percentage of urinary albumin/creatinine ratio at week 156, at -41.6 g/kg vs -27.4 g/kg for dulaglutide (-19.7 g/kg difference; P < .05).

There were no significant differences between the groups in terms of serious safety events and adverse events leading to study medication discontinuation, with premature drug discontinuations occurring among 30% in the tirzepatide group and 28.2% with dulaglutide.

 Gastrointestinal adverse events were reported by more participants receiving tirzepatide than dulaglutide (64.6% vs 56.5%).

The results show “tirzepatide compared with dulaglutide reduced the risk of the major kidney composite outcomes,” with the effects most apparent for eGFR decline, Zoungas said.

Mechanisms?

Although teasing out the mechanisms of the benefits is complex, Zoungas noted that data from the SURPASS 4 trial suggested that “about 50% of the effect of tirzepatide on albuminuria is related to a reduction in A1C and body weight, while about 50% is related to other indirect effects.”

“Current literature suggests those are effects on inflammation or other markers that we are actually not measuring, so it's not all the weight loss,” she added.

Meg Jardine, MBBS, PhD, director of the NHMRC Clinical Trials Centre and a professor of medicine at the University of Sydney, Australia, commented that — while the current findings are from a post-hoc analysis of a CV outcome trial — the results offer important new insights on kidney effects of the evolving diabetes/weight loss drugs.

“Before the FLOW trial, we didn’t have proof that weight loss could improve kidney outcomes,” she explained to Medscape Medical News. 

Some smaller trials showed that weight loss through surgical means reduced albuminuria, but kidney endpoints were not definitive.

“Now we have this second study showing a benefit and this is promising. But,” she noted, “this was a secondary outcome.” 

It remains to be seen whether there will be an indication for this drug for prevention of kidney disease, she said. “I think it’s going to be important that each new drug and particularly each new class is tested for kidney outcomes,” she added.

“There are plenty of examples where the hypothesis has not led to proof, so the trials definitely need to be done.”

The study was supported by Eli Lilly and Company. 

Zoungas disclosed relationships with AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly Australia, GSK, Moderna, Novo Nordisk, and Sanofi.Jardine disclosed advisory or other relationships with AstraZeneca, Bayer, Baxter, Boehringer Ingelheim, Chinook, CSL, Janssen, Novartis, OccuRx, Vifor.