Professor Sophia Zoungas
An Australian-led trial has shown tirzepatide reduced major kidney events and slowed renal decline more than dulaglutide in adults with type 2 diabetes and cardiovascular disease, strengthening evidence that dual incretin therapy may confer kidney benefits beyond conventional GLP-1RA treatment.
Researchers say the findings are likely to intensify interest in whether tirzepatide can help address the substantial residual kidney risk that persists in many patients with type 2 diabetes despite modern kidney-protective therapy.
Published in The Lancet Diabetes & Endocrinology [link here], the pre-specified exploratory analysis of the SURPASS-CVOT trial found tirzepatide reduced the risk of a composite kidney outcome by 23% compared with dulaglutide in patients with type 2 diabetes and established atherosclerotic cardiovascular disease.
Led by endocrinologist and Executive Director of The George Institute for Global Health, Professor Sophia Zoungas and colleagues, the study analysed outcomes from 13,165 participants randomised to weekly tirzepatide or dulaglutide across 640 sites in 30 countries. Participants had type 2 diabetes, established cardiovascular disease, HbA1c between 7% and 10.5%, and BMI of at least 25 kg/m². Median follow-up was four years.
The primary composite kidney endpoint included persistent macroalbuminuria; sustained eGFR decline of at least 50%; end-stage kidney disease; or death from kidney disease.
Across the overall study population, the primary kidney outcome occurred in 6.0% of tirzepatide-treated participants compared with 7.6% of those receiving dulaglutide, translating to a hazard ratio of 0.77.
Much of the apparent benefit reflected lower rates of persistent macroalbuminuria, which the investigators explained is an important marker of future kidney disease progression, while harder renal endpoints such as end-stage kidney disease remained uncommon during follow-up.
The pattern of benefit also differed according to baseline kidney risk.
In patients with low-to-moderate-risk chronic kidney disease, tirzepatide reduced the primary kidney outcome by 30%, largely through lower rates of new persistent macroalbuminuria.
Among those with high-risk chronic kidney disease, the signal shifted towards preservation of kidney function, with fewer sustained eGFR declines of both 40% and 50%.
At three years, the between-group difference in eGFR decline in the high-risk CKD subgroup reached 3.17 mL/min/1.73m².
Investigators also reported greater reductions in HbA1c, bodyweight, systolic blood pressure and albuminuria with tirzepatide compared with dulaglutide. At 36 months, UACR fell by 47.5% in the high-risk CKD group receiving tirzepatide compared with 32.1% in the dulaglutide arm.
The authors said the findings suggested tirzepatide’s dual-hormone mechanism – targeting both GIP and GLP-1 receptors – may provide kidney benefits beyond conventional GLP-1 therapies.
That signal appeared to differ according to baseline kidney risk, with tirzepatide reducing progression of albuminuria earlier in CKD and slowing loss of kidney function in patients with more advanced disease.
“The greater improvement seen with tirzepatide compared with dulaglutide in albuminuria, in addition to reduced decline in kidney function and a range of composite kidney outcomes, suggests a potential additional benefit of dual agonism on clinically meaningful kidney events,” the investigators wrote.
The investigators also noted the findings extended earlier observations from SURPASS-4, where tirzepatide slowed eGFR decline despite an early reversible dip in kidney function consistent with reduced hyperfiltration.
An accompanying comment [link here], researchers said the findings were particularly notable because the benefit emerged against an active comparator already known to provide cardiovascular and renal protection, rather than against placebo or insulin.
Professor Janaka Karalliedde
Professor Janaka Karalliedde, Professor of Diabetes in the School of Cardiovascular Medicine and Metabolic Sciences, King’s College London, said the renal signal was especially impressive given the trial population was already receiving substantial background kidney-protective therapy, including renin–angiotensin system blockade, SGLT2 inhibitors and mineralocorticoid receptor antagonists.
The commentators noted that many patients with type 2 diabetes continue to experience progressive kidney decline despite widespread use of SGLT2 inhibitors, renin–angiotensin system blockade and other established kidney-protective therapies.
“In the context of addressing residual renal risk, the results reported by Zoungas and colleagues are potentially impactful,” Professor Karalliedde wrote.
Professor Karalliedde also highlighted the degree of kidney function preservation seen in the high-risk CKD subgroup.
“It is remarkable that participants in the high-risk chronic kidney disease group treated with tirzepatide lost only approximately 1 mL/min per 1·73 m² per year,” he wrote.
“This is equivalent to age-related background loss in eGFR.”
However, both the study authors and commentators cautioned the kidney analyses were exploratory and not adjusted for multiplicity, meaning the findings should be interpreted as supportive rather than definitive proof of renal benefit.
The linked comment also argued it remained unclear how much of the apparent kidney protection was directly attributable to tirzepatide itself, versus the greater reductions in bodyweight, HbA1c and blood pressure seen with the drug. Previous mediation analyses from earlier SURPASS studies suggested roughly 45% of albuminuria reduction could be explained by improvements in glycaemia and weight.
Gastrointestinal adverse events, including nausea, vomiting and diarrhoea, were more common with tirzepatide, although no major differences in serious adverse events were reported between groups.
Professor Karalliedde said the findings nevertheless highlighted the growing number of therapeutic options emerging for diabetic kidney disease.
“As clinicians, we now have several more treatments to offer people with type 2 diabetes and chronic kidney disease,” he wrote.
“But real-world use of guideline-directed and evidence-based medications for chronic kidney disease remains suboptimal.”