The Diabetogenic Burden of Modern Pharmacotherapy: A Review of High-Risk Medication Classes

Drug-induced hyperglycemia and the subsequent development of medication-related diabetes represent significant clinical challenges that often complicate the treatment of primary conditions. This phenomenon occurs through diverse pathophysiological pathways, including the exacerbation of peripheral insulin resistance, suppression of pancreatic beta-cell function, and stimulation of hepatic gluconeogenesis. While glucocorticoids remain the most common cause of iatrogenic diabetes, inducing a unique circadian hyperglycemic pattern in approximately 30% of patients, second-generation antipsychotics like clozapine and olanzapine pose a 2- to 3-fold increased risk of type 2 diabetes through multireceptor interactions and metabolic inflammation. In addition, medications that include thiazide diuretics and beta-blockers negatively affect insulin production through electrolyte imbalance and autonomic nervous system interference, while statins increase the risk of new-onset diabetes through disruption of the mevalonate pathway (dose-dependent). Modern antineoplastic therapies, particularly immune-checkpoint inhibitors, activate new mechanisms that cause autoimmune destruction of pancreatic beta-cells, while somatostatin analogs (e.g., pasireotide) produce severe glucose elevations as a result of their inhibition of incretin hormone release. Furthermore, immunosuppressants, particularly calcineurin inhibitors (CNIs), and antiretroviral therapies contribute to impaired glucose metabolism and an increased risk of diabetes. Other agents, including fluoroquinolones, theophylline, niacin, and phenytoin, further highlight the broad spectrum of pharmacological triggers for glycemic dysregulation. Due to this potential for the development of permanent damage to glucose homeostasis, early detection and management of patients’ metabolic health through comprehensive monitoring and provision of systemic electrolyte stabilization are necessary. This review aims to summarize how these drugs affect blood sugar to improve early risk identification and the use of metabolic-neutral strategies.