Early identification of suboptimal responders to metformin in type 2 diabetes using long-term real-world HbA1c trajectories.

Authors

Eunsol Yang, Andrew Riselli, Fei Xu, Sneha B Sridhar, Mark Kvale, Kathleen M Giacomini, Monique M Hedderson, Sook Wah Yee, Rada M Savic

Published in

medRxiv : the preprint server for health sciences. Jul 20, 2026. Epub Jul 20, 2026.

Abstract

Metformin remains the primary treatment for type 2 diabetes, yet over 40% of patients fail to maintain glycaemic control. We aimed to identify patients unlikely to respond to metformin prior to treatment initiation and to evaluate whether on-treatment management can improve glycaemic outcomes in suboptimal responders, informing early treatment decisions.
We analyzed 59,881 longitudinal HbA1c measurements from 7,105 patients with type 2 diabetes receiving metformin monotherapy using real-world electronic health records from Kaiser Permanente Northern California with up to six years of follow-up. We integrated demographic, clinical, genetic, and pharmacological factors to characterize metformin responder phenotypes and quantify the impact of adherence and weight control on time to glycaemic failure.
Three distinct trajectory-based phenotypes were identified: good (63.6%), poor (8.9%), and non-responders (27.5%). Poor responders initially achieved glycaemic targets but lost control within 2.5 years, while non-responders showed minimal HbA1c reduction and failed within 1 year. Five baseline factors-HbA1c, age at diagnosis, body mass index, sex, and estimated glomerular filtration rate-classified phenotypes with good discrimination (area under the receiver operating characteristic curve = 0.84). Incorporating on-treatment HbA1c further enhanced identification of non-responders. Among suboptimal responders, weight control and improved adherence delayed glycaemic failure by approximately 7 months; however, eventual glycaemic failure remained likely.
We characterized three clinically relevant metformin responder phenotypes and showed that suboptimal responders can be identified early using baseline features. Poor and non-responders are unlikely to achieve durable glycaemic control with metformin alone and may require alternative treatment strategies.

PMID:
42539052
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.

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