Tirzepatide reduces albuminuria among adults with type 2 diabetes in SURPASS trials
Key takeaways:
- Adults receiving tirzepatide in the SURPASS trials had significant decreases in urine albumin-to-creatinine ratio.
- Those with CKD receiving tirzepatide had larger urine albumin-to-creatinine ratio reductions.
Adults with type 2 diabetes receiving tirzepatide had significantly greater declines in urine albumin-to-creatinine ratio than those receiving comparators such as placebo or another therapy, researchers reported.
In a post hoc analysis of the SURPASS trials published in Diabetes Care, adults receiving 5 mg, 10 mg or 15 mg tirzepatide (Mounjaro, Eli Lilly) had reductions in urine albumin-to-creatinine ratio at about 40 weeks, with greater decreases observed for those with chronic kidney disease at baseline. Hiddo J. L. Heerspink, PhD, professor and clinical pharmacologist in the department of clinical pharmacy and pharmacology at the University Medical Center Groningen in the Netherlands, said the magnitude of the reductions in urine albumin-to-creatinine ratio shows the potential renal benefits tirzepatide could provide.
“Tirzepatide will likely slow the decline in kidney function and reduce the risk of kidney failure in patients with type 2 diabetes,” Heerspink told Healio. “Previous large meta-analyses have demonstrated that therapies reducing urinary albumin-to-creatinine ratio by at least 25% are highly likely to confer clinical benefit. The achieved reductions with tirzepatide, in particular in patients with higher baseline urinary albumin-to-creatinine ratio, indicate that a 25% reduction can be achieved.”
Researchers collected data from the five SURPASS trials, which assessed the effects of tirzepatide among people with type 2 diabetes. Tirzepatide was compared with placebo in SURPASS-1 and SURPASS-5, once-weekly semaglutide 1 mg (Ozempic, Novo Nordisk) in SURPASS-2, daily insulin degludec (Tresiba, Novo Nordisk) in SURPASS-3 and titrated insulin glargine (Lantus, Sanofi) in SURPASS-4. Percent change in urine albumin-to-creatinine ratio was collected from baseline to 40 weeks for all trials except SURPASS-4, in which the final measure was collected at 42 weeks.
Compared with the comparator group, tirzepatide 5 mg conferred a 19.3% greater decline, tirzepatide 10 mg was linked to a 22% greater reduction and tirzepatide 15 mg was tied to a 26.3% larger decrease in urine albumin-to-creatinine ratio (P < .001 for all). The greatest differences in urine albumin-to-creatinine ratio were observed in the two trials comparing tirzepatide with placebo.
Reductions in urine albumin-to-creatinine ratio with tirzepatide were larger for adults with CKD. Among adults with a urine albumin-to-creatinine ratio of 30 mg/g or higher at baseline, those receiving tirzepatide 5 mg had a 31.3% greater urine albumin-to-creatinine ratio reduction, the tirzepatide 10 mg group had a 42.2% larger decline and the tirzepatide 15 mg group had a 47.3% greater decrease than adults in the pooled comparator group.
Of adults with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2, those receiving tirzepatide 5 mg had a 26.6% greater urine albumin-to-creatinine ratio decrease, the 10 mg tirzepatide group had a 23.6% greater decline and adults receiving tirzepatide 15 mg had a 49.2% larger reduction than the comparator group.
Researchers found tirzepatide reduced urine albumin-to-creatinine ratio through direct and indirect means. Reductions in HbA1c and body weight induced by tirzepatide mediated 45.9% of the decline in urine albumin-to-creatinine ratio, with the remaining 54.1% of the decrease being explained by the direct effects of the tirzepatide doses and other variables.
“[The mediation analysis] suggests that other direct effects of tirzepatide on the leakage of albumin through the glomeruli are involved as well,” Heerspink said. “This could be direct effects on the glycocalyx/endothelial function or potential anti-inflammatory effects.”
Heerspink noted most adults enrolled in the SURPASS trials had preserved kidney function, and additional studies enrolling adults with type 2 diabetes plus CKD with longer follow-up are needed.
For more information:
Hiddo J. L. Heerspink, PhD, can be reached at h.j.lambers.heerspink@umcg.nl.
Perspective
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Albuminuria, often measured by urinary albumin-to-creatinine ratio, is as an important marker of kidney function and a predictor of cardiovascular risk, particularly in patients with diabetes. In the SURPASS randomized clinical trials, which evaluated the efficacy and safety of tirzepatide, a GIP/GLP-1 dual agonist, in patients with type 2 diabetes, urinary albumin-to-creatinine ratio reduction emerged as a noteworthy secondary endpoint, suggesting potential kidney benefits of this novel therapy.
SURPASS trials enrolled adults with type 2 diabetes or overweight or obesity and without contraindications for GIP/GLP-1 use. About two-thirds of the participants were on renin-angiotensin-system inhibitors and about 15% on SGLT2 inhibitors. About 70% of them had normal urinary albumin-to-creatinine ratio. Estimated glomerular filtration rate was higher than 60 mL/min/1.73 m2 in more than 90% of the study participants.
Tirzepatide use was associated with urinary albumin-to-creatinine ratio reduction vs. placebo or insulin. It is important to note that urinary albumin-to-creatinine ratio reduction was not different between participants randomly assigned to tirzepatide or semaglutide (SURPASS-2), except for those with urinary albumin-to-creatinine ratio of 30 mg/g or higher who received 15 mg tirzepatide. Notably, urinary albumin-to-creatinine ratio reduction with tirzepatide was similar among participants receiving or not receiving renin-angiotensin-system inhibitors or SGLT2 inhibitors. Estimated glomerular filtration rate changes were not different between tirzepatide and comparators in this group of study participants with mostly normal estimated glomerular filtration rates.
By targeting glucose and weight, and potentially by other indirect and direct renal protective mechanisms, tirzepatide could play a critical role not only in managing blood glucose levels and weight, but also in improving long-term kidney outcomes. The results of the mechanistic TREASURE-CKD trial to be completed in 2026 will shed light into tirzepatide’s potential kidney protective mechanisms.
Importantly, the results of these analyses add to the growing body of evidence that therapies targeting multiple pathways may offer sizeable kidney protection. Further studies focusing on long-term kidney outcomes are needed to confirm and extend these findings.
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