Orforglipron and kidney protection in type 2 diabetes: Insights from the ACHIEVE-4 trial

Findings from the ACHIEVE-4 trial suggest that orforglipron may help protect kidney function in people with type 2 diabetes and high cardiovascular risk, highlighting the need for dedicated kidney outcomes trials to confirm its long-term renal benefits.

In this interview at the EASD 2026 meeting, Katherine Tuttle (University of Washington School of Medicine, WA, USA) discusses findings from the ACHIEVE-4 trial, which investigated the effects of orforglipron compared with insulin glargine on kidney outcomes in people with type 2 diabetes and high cardiovascular risk. The results showed a 26% lower event rate for major adverse kidney outcomes with orforglipron, including new-onset macroalbuminuria, a 40% or greater decline in glomerular filtration rate, kidney failure, or kidney death. These findings provide encouraging evidence of the potential renal benefits of orforglipron, an oral, small-molecule, non-peptide GLP-1 receptor agonist, and align with previous evidence of kidney protection from injectable GLP-1 receptor agonists. Tuttle discusses the clinical implications of these findings for glucose-lowering therapy, the potential role of orforglipron in preserving kidney function in people with type 2 diabetes, and the limitations of interpreting secondary kidney outcomes. She also highlights the need for dedicated kidney outcomes trials to establish whether the observed benefits translate into sustained long-term renal protection.

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What are the key kidney findings from the ACHIEVE-4 trial?

We were really very pleased with the kidney protection we observed with orforglipron compared with insulin glargine in people with type 2 diabetes at high cardiovascular risk. We saw a 26% lower event rate for major adverse kidney outcomes, including new-onset macroalbuminuria, a 40% or greater decline in GFR, kidney failure, or kidney death.

The event rates were actually quite high, at nearly 13% in the insulin glargine group compared with only 9% in the orforglipron group. These were clinically meaningful findings that provide a strong signal of kidney protection in a population at high risk of kidney disease.

What do these results tell us about the potential renal benefits of orforglipron in people with type 2 diabetes?

I think these findings provide a strong signal that orforglipron is likely to be kidney protective. Orforglipron is an oral, small-molecule, non-peptide GLP-1 receptor agonist, and the results align very well with what we know from the FLOW trial of injectable semaglutide 1 mg once weekly, which demonstrated kidney protection.

These findings extend those observations and suggest that an oral agent such as orforglipron may also provide long-term benefits for kidney outcomes.

How might these findings influence the choice of glucose-lowering therapy for people at high cardiovascular and kidney risk?

I think we have to stay within the current approved indications, which are for type 2 diabetes and weight management. In ACHIEVE-4, the primary cardiovascular outcome showed that orforglipron was non-inferior to insulin glargine, the gold-standard comparator. However, the trial was designed as a safety and non-inferiority study, so these findings alone will not lead to a specific kidney-related indication.

The secondary kidney outcomes showed evidence of kidney protection. So, I think the clinical takeaway is that, when choosing orforglipron to treat diabetes or manage weight in an appropriate patient, there is a potential additional benefit in terms of preserving kidney function. Preventing the loss of kidney function and maintaining kidney health are important goals for people with diabetes, given their implications for overall health.

What are the key questions that remain about the longer-term renal effects of orforglipron?

Ideally, we would want a dedicated kidney outcomes trial to move from a strong hypothesis to a definitive conclusion. I think the hypothesis is strong, but we need more evidence to confirm the long-term renal effects of orforglipron.

I hope we can return to conducting dedicated kidney outcomes trials, rather than relying on kidney outcomes as secondary endpoints in trials designed to investigate something else. This is really important because kidney disease is a serious complication that many people fear, and it is treatable. We need more robust evidence from clinical trials specifically designed to test whether a drug provides kidney protection. That is my plea to the community.

Abstract details: Tuttle KR, Lambers Heerspink H, Klein K, Cox D, Chen J, Liu R, Meskimen E, Ludwig L. Effects of orforglipron versus insulin glargine on kidney outcomes in people with type 2 diabetes and high cardiovascular risk: results of the ACHIEVE-4 trial. LBA Oral presentation 05. Presented at: 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD); September 28–October 2, 2026; Milan, Italy.