Type 2 diabetes (T2D) is clinically heterogeneous, and the biological determinants of this heterogeneity remain poorly defined in East Asian populations. Polygenic risk scores (PRS) quantify inherited susceptibility to T2D and may inform individualized management. We assessed whether genetic predisposition—captured by T2D pathway-based PRS (pPRS)—relates to medication use and complications among individuals with T2D.

Electronic medical records from a medical center in Taiwan were analyzed using data drawn from a subset of the Taiwan Precision Medicine Initiative (TPMI). A total of 19,734 patients with T2D were included in the analysis (6,121 without diabetes medication, 10,142 receiving oral therapy and 3,471 receiving injectable therapy), and their genetic and clinical characteristics were compared. We applied the pPRS strategy described by Suzuki et al. (Nature, 2024) to evaluate associations with use of oral and injectable medications, as well as with clinical traits such as hypertension, cardiovascular disease, heart failure, and end-stage kidney disease. Injectable therapy is treated as a marker of clinical severity rather than a direct cause of complications, so our models further adjust for treatment class to estimate the contribution of genetic susceptibility (pPRS) independently of this marker.

Overall, the injection group had the highest pPRS and a less favorable clinical profile. All the pPRS were significantly associated with more frequent use of injectable therapies, with the strongest association observed for Residual glycaemic (OR 1.24, 95% CI 1.19-1.29) and beta cell dysfunction with a positive association with proinsulin (Beta cell +PI) (OR 1.22, 95% CI 1.17-1.27). Obesity pPRS were associated with higher proportion of hypertension (OR 1.06, 95% CI 1.02-1.09), kidney disease (OR 1.05, 95% CI 1.02-1.09) and end-stage kidney disease (OR 1.16, 95% CI 1.08-1.24), while Beta cell +PI pPRS were associated with lower proportion of HTN (OR 0.91, 95% CI 0.88-0.94), heart failure (OR 0.90, 95% CI 0.86-0.95) and chronic kidney disease (OR 0.94, 95% CI 0.92-0.97).

In patients with T2D, pPRS are associated with subsequent medication use. Even after adjustment for medication class, these pPRS show distinct effects on complication risk. Obesity promotes complications, whereas genetic susceptibility to impaired insulin secretion tends to show the reverse pattern. These findings could lead to more effective therapeutic interventions, thereby improving outcomes for individuals affected by T2D.