Background
People with type 2 diabetes are at increased risk of both cardiovascular disease and chronic kidney disease. Over time, diabetes can damage the tiny blood vessels in the kidneys, leading to albumin leaking into the urine, falling kidney filtration, and eventually kidney failure. Because kidney disease often progresses silently, treatments that can slow this process are especially important.
Tirzepatide and dulaglutide are injectable medicines used to improve blood glucose control in type 2 diabetes. Dulaglutide is a glucagon-like peptide-1 receptor agonist, or GLP-1 receptor agonist. Tirzepatide is a newer dual incretin agonist that acts on both glucose-dependent insulinotropic polypeptide, or GIP, and GLP-1 receptors. Both drugs can reduce blood sugar and body weight, and both have shown cardiovascular benefits in large trials. The key question addressed here was whether tirzepatide also offers kidney advantages compared with dulaglutide.
This article reports pre-specified exploratory kidney analyses from SURPASS-CVOT, a large cardiovascular outcomes trial in people with type 2 diabetes and established atherosclerotic cardiovascular disease.
How the study was designed
SURPASS-CVOT was a randomized, double-blind, active-comparator trial conducted at 640 sites in 30 countries. Adults aged 40 years or older with type 2 diabetes and atherosclerotic cardiovascular disease were eligible if their hemoglobin A1c was between 7.0% and 10.5% and their body mass index was at least 25 kg/m2.
Participants were randomly assigned in a 1:1 ratio to receive either tirzepatide, titrated up to 15 mg once weekly, or dulaglutide 1.5 mg once weekly, both given as blinded subcutaneous injections. Because the trial was double-blind, neither participants nor investigators knew which treatment was being given.
Kidney monitoring was built into the study. Annual visits included measurements of serum creatinine, cystatin C, and urine albumin-to-creatinine ratio, or UACR. These tests help assess kidney filtration and detect protein leakage into the urine, an early sign of diabetic kidney disease.
The investigators pre-specified a composite kidney outcome that counted the first occurrence of any of the following: persistent macroalbuminuria, persistent reduction in estimated glomerular filtration rate, or eGFR, of at least 50%; end-stage kidney disease, defined as eGFR below 15 mL/min per 1.73 m2 or chronic dialysis or kidney replacement therapy; or death from kidney disease.
The researchers also separated participants into chronic kidney disease risk groups. High-risk chronic kidney disease was defined by one of three patterns: eGFR of 60 mL/min per 1.73 m2 or higher with UACR above 300 mg/g; eGFR between 45 and less than 60 mL/min per 1.73 m2 with UACR above 30 mg/g; or eGFR below 45 mL/min per 1.73 m2. Kidney function was estimated using the CKD-EPI creatinine-cystatin C equation, which improves accuracy compared with creatinine alone.
Who took part
Between May 29, 2020, and June 27, 2022, 16,979 people were screened and 13,299 were randomized, including 2,948 with high-risk chronic kidney disease. After excluding 134 people who had been assigned in error, 6,586 participants received tirzepatide and 6,579 received dulaglutide.
At baseline, kidney disease was common. Among 12,954 participants with available albuminuria data, 4,142 people, or 32.0%, had microalbuminuria, and 1,491 people, or 11.5%, had macroalbuminuria. Among 13,004 participants with available eGFR data, 2,928 people, or 22.5%, had eGFR below 60 mL/min per 1.73 m2, indicating reduced kidney function.
These figures show that the trial population already had a substantial burden of kidney risk, making it well suited to examine whether one therapy might better protect kidney health than the other.
Main kidney results
After a median follow-up of 4.0 years, with an interquartile range of 3.7 to 4.4 years, tirzepatide was associated with a significantly lower risk of the primary composite kidney outcome than dulaglutide.
In the overall study population, the composite kidney outcome occurred in 396 participants, or 6.0%, in the tirzepatide group and 498 participants, or 7.6%, in the dulaglutide group. This corresponded to a 23% relative risk reduction, with a hazard ratio of 0.77 and a 95% confidence interval of 0.68 to 0.88. The p value was 0.0002, indicating a statistically significant difference.
The benefit was also seen in both chronic kidney disease subgroups:
– In participants with low-to-moderate-risk chronic kidney disease, the outcome occurred in 195 people, or 4.0%, with tirzepatide and 283 people, or 5.6%, with dulaglutide. The hazard ratio was 0.70, with a 95% confidence interval of 0.58 to 0.84, and p = 0.0001.
– In participants with high-risk chronic kidney disease, the outcome occurred in 185 people, or 12.2%, with tirzepatide and 203 people, or 14.5%, with dulaglutide. The hazard ratio was 0.79, with a 95% confidence interval of 0.64 to 0.96, and p = 0.018.
These findings suggest that tirzepatide may offer kidney protection across a broad range of kidney risk, not only in people with early kidney damage but also in those with more advanced disease.
What drove the benefit?
The pattern of benefit differed by kidney risk group.
In people with low-to-moderate-risk chronic kidney disease, the main driver was a lower rate of new-onset persistent macroalbuminuria. Macroalbuminuria means a high level of albumin in the urine and is a strong marker of diabetic kidney damage and future kidney decline. Preventing progression to macroalbuminuria can be clinically meaningful because it may reflect earlier interruption of the kidney injury process.
In people with high-risk chronic kidney disease, the main driver was a slower decline in eGFR. In practical terms, this means kidney filtration function fell more slowly over time with tirzepatide than with dulaglutide. Slowing eGFR loss is important because it may delay kidney failure and the need for dialysis or transplantation.
The annual rate of eGFR decline was lower with tirzepatide than with dulaglutide in the overall population. The between-group difference was 0.29 mL/min per 1.73 m2 per year, with a 95% confidence interval of 0.17 to 0.41 and p < 0.0001. In the high-risk chronic kidney disease group, the difference was even larger at 0.93 mL/min per 1.73 m2 per year, with a 95% confidence interval of 0.65 to 1.22 and p < 0.0001.
Although these annual differences may appear modest, even small slowing of kidney function loss can accumulate over years and may translate into meaningful clinical benefit.
Safety and tolerability
The safety profile was broadly consistent with what is already known about incretin-based therapies. Nausea, vomiting, and diarrhea were more common with tirzepatide than with dulaglutide.
These gastrointestinal side effects are important because they can affect treatment adherence and quality of life, especially during dose escalation. In practice, they are often most pronounced early in treatment and may improve over time. Careful dose titration and patient counseling can help many people stay on therapy.
The abstract does not provide a detailed breakdown of severe adverse events in this exploratory kidney analysis, so the kidney findings should be interpreted together with the parent cardiovascular trial and the full safety dataset.
How to interpret these findings
This analysis adds to the growing evidence that newer incretin-based therapies may protect kidney health beyond their glucose-lowering effects alone. Several mechanisms could contribute, including improved glycemic control, weight loss, lower blood pressure, reduced inflammation, and possible direct effects on kidney hemodynamics and albuminuria.
The results are especially notable because tirzepatide was compared not with placebo, but with dulaglutide, an established GLP-1 receptor agonist already known for cardiometabolic benefit. Showing a kidney advantage over an active comparator strengthens the clinical relevance of the findings.
That said, this was an exploratory analysis of a cardiovascular outcomes trial, not a kidney-outcomes trial designed primarily to prove renal superiority. The kidney endpoints were pre-specified, which increases credibility, but the findings still need confirmation in dedicated renal trials and in routine practice settings.
Clinical implications
For clinicians caring for people with type 2 diabetes and atherosclerotic cardiovascular disease, the results suggest that tirzepatide may be a strong option when kidney protection is an important treatment goal, especially in patients with albuminuria or declining eGFR.
For people with earlier chronic kidney disease, the reduction in progression to persistent macroalbuminuria may be particularly meaningful. For those with more advanced kidney impairment, slowing eGFR decline may help preserve kidney function longer.
These findings do not replace standard kidney-protective therapies such as blood pressure control, use of renin-angiotensin system blockers when indicated, sodium-glucose cotransporter 2 inhibitors for eligible patients, and comprehensive cardiovascular risk reduction. Rather, they suggest that tirzepatide may be an additional tool in a layered approach to diabetic kidney protection.
Treatment decisions still need to be individualized. Factors such as gastrointestinal tolerability, cost, access, weight-loss goals, glycemic targets, and coexisting cardiovascular or kidney disease should all be considered.
Strengths and limitations
This study had several strengths. It was large, international, randomized, double-blind, and used an active comparator. Kidney data were collected prospectively, and the analyses were pre-specified rather than purely post hoc. The inclusion of people with a wide range of kidney risk makes the findings relevant to many patients seen in real-world diabetes care.
There are also limitations. The kidney analysis was exploratory, which means it was not the main endpoint of the parent trial. The trial compared two active drugs rather than a drug versus placebo, which is useful clinically but can make effect sizes appear smaller than placebo-controlled comparisons. In addition, albuminuria and eGFR were assessed at annual visits, so more frequent measurements might have captured kidney changes in greater detail.
Another important point is that the study population had type 2 diabetes and established cardiovascular disease, so the results may not apply equally to people without cardiovascular disease or to those with different clinical backgrounds.
Bottom line
In people with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was associated with fewer major kidney events than dulaglutide. The benefit appeared to arise in different ways depending on kidney risk: less progression to macroalbuminuria in those with lower-to-moderate kidney risk, and slower decline in kidney function in those at high kidney risk.
Taken together, these findings suggest that tirzepatide may offer meaningful kidney protection in addition to its glucose-lowering and weight-reducing effects. While the results are promising, they should be confirmed by dedicated kidney outcome studies before being considered definitive evidence of renal superiority.
