Oleanolic Acid‐Enriched Olive Oil Attenuates Kidney Function Decline in Patients With Type 2 Diabetes: Results From the OLTRAD Randomised Controlled Trial

Aims Chronic kidney disease (CKD) is a major complication of type 2 diabetes mellitus (T2DM), driven in part by oxidative stress and the accumulation of advanced glycation end products (AGEs). Oleanolic acid (OA), a natural triterpene present in olive‐derived matrices, may modulate AGE metabolism. In this prespecified, exploratory secondary analysis of the OLTRAD trial, we evaluated whether long‐term intake of OA‐enriched olive oil attenuates kidney function decline in patients with T2DM. Methods In the OLTRAD randomised controlled trial, 97 patients with T2DM were assigned to consume OA‐enriched olive oil (600 mg OA/kg) or control olive oil for 12 months, alongside standard therapy. Kidney outcomes included estimated glomerular filtration rate (eGFR) and urinary albumin‐to‐creatinine ratio (uACR). Circulating AGEs (methylglyoxal [MG], carboxymethyllysine [CML]), enzymes involved in AGE metabolism (aldose reductase [AR], glyoxalase‐I [GloxI]), and oxidative stress markers (ROS and MDA) were assessed. Results OA‐enriched olive oil attenuated eGFR decline relative to control, an effect restricted to participants with mildly impaired eGFR at baseline (60–90 mL/min/1.73 m 2 ; time × group interaction p = 0.010), with no significant interaction among participants with normal baseline eGFR. OA‐enriched oil also prevented the rise in uACR observed with control oil. Mechanistically, OA reduced AR concentration and increased GloxI activity, resulting in lower circulating MG, whereas CML remained unchanged. OA‐enriched oil further reduced ROS and MDA levels, while MDA increased with control oil. Conclusions In this exploratory, hypothesis‐generating secondary analysis, long‐term consumption of OA‐enriched olive oil was associated with attenuated kidney function decline in patients with T2DM, an effect limited to those with baseline mildly impaired eGFR. These changes were associated with modulation of AGE‐related pathways and reduced oxidative stress. As the trial was powered for glycemic control rather than renal outcomes, larger, adequately powered studies are needed to confirm these findings before their clinical relevance can be established. Trial Registration: Clinicaltrials.gov identifier: NCT06030544; https://clinicaltrials.gov/study/NCT06030544