Predictors of Glycemic Response to Sulfonylurea Therapy in Type 2 Diabetes Over 12 Months: Comparative Analysis of Linear Regression and Machine Learning Models

Background: Sulfonylureas are commonly prescribed for managing type 2 diabetes, yet treatment responses vary significantly among individuals. Although advances in machine learning (ML) may enhance predictive capabilities compared to traditional statistical methods, their practical utility in real-world clinical environments remains uncertain. Objective: This study aimed to evaluate and compare the predictive performance of linear regression models with several ML approaches for predicting glycemic response to sulfonylurea therapy using routine clinical data, and to assess model interpretability using Shapley Additive Explanations (SHAP) analysis as a secondary analysis. Methods: A cohort of 7557 individuals with type 2 diabetes who initiated sulfonylurea therapy was analyzed, with all patients followed for 1 year. Linear and logistic regression models were used as baseline comparisons. A range of ML models was trained to predict the continuous change in hemoglobin A1c (HbA1c) levels and the achievement of HbA1c <58 mmol/mol at follow-up. These models included random forest, extreme gradient boosting, support vector machines, a conventional feedforward neural network, and Bayesian additive regression trees. Model performance was assessed using standard metrics including R² and root mean squared error for regression tasks and area under the receiver operating characteristic for classification. In a subset of 2361 patients, nonfasting connecting peptide (C-peptide) was analyzed as a proxy for β-cell function. SHAP analysis was performed to identify and compare key predictors driving model performance across methods. Results: All models exhibited similar performance, with no significant advantages of ML techniques over linear regression. For continuous outcomes, Bayesian additive regression trees demonstrated the highest R² (0.445) and lowest root mean squared error (0.105), though the differences among models were minimal. For the binary outcome, extreme gradient boosting achieved the highest area under the receiver operating characteristic curve (0.712), with CIs overlapping those of other models. Across all models, baseline HbA1c was consistently the primary predictor, explaining the majority of the variance. SHAP analyses confirmed that baseline HbA1c, age, BMI, and sex were the most influential predictors. Sensitivity analyses and hyperparameter tuning did not significantly improve model performance. In the C-peptide subset, higher C-peptide levels were associated with greater glycemic improvement (β=-3.2 mmol/mol per log(C-peptide); P<.001). Conclusions: In this large, population-based cohort, ML models did not outperform traditional regression for predicting glycemic response to sulfonylureas. These findings suggest that limited gains from ML likely reflect an absence of strong nonlinear or high-order interactions in routine clinical data and that available features may not capture sufficient biological heterogeneity for complex models to confer added benefit. The inclusion of a C-peptide subset provides additional mechanistic insight by linking preserved β-cell function with treatment response.

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