Progressive loss of glycemic control during chronic DPP-4 inhibitor therapy despite preserved β-cell function: a case report suggesting acquired incretin resistance
Abstract
BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed second-line agents for type 2 diabetes mellitus (T2DM). Secondary treatment failure with DPP-4 inhibitors is conventionally attributed to progressive β-cell dysfunction. Acquired resistance to DPP-4 inhibitor therapy, characterised by progressive glycemic deterioration despite preserved endogenous insulin secretion, remains an under-recognised and poorly documented clinical phenomenon. We report a case of secondary DPP-4 inhibitor failure with preserved β-cell function, raising the hypothesis of acquired incretin resistance as an alternative mechanism of treatment failure. CASE PRESENTATION: A 52-year-old non-obese man (body mass index 24.9 kg/m²) with a 4-year history of T2DM developed progressive glycemic deterioration after 22 months of stable glycemic control with metformin and sitagliptin combination therapy. His glycated haemoglobin (HbA1c) increased from 6.7% to 8.4% over an 8-month period, with corresponding elevations in fasting plasma glucose (168 mg/dL) and postprandial glucose (248 mg/dL). Comprehensive evaluation revealed preserved β-cell function with normal fasting insulin (14 µIU/mL), C-peptide (2.1 ng/mL), and homeostatic model assessment of β-cell function (HOMA-β) of 68%. Insulin resistance was mild (HOMA-IR 2.3). Autoimmune markers were negative, hepatic and renal function were normal (AST 28 U/L, ALT 32 U/L, eGFR 92 mL/min/1.73 m²), and secondary causes of hyperglycemia were…
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