Gradual worsening of blood sugar control during long-term DPP-4 inhibitor treatment despite normal insulin-producing cell function: a case suggesting acquired resistance to incretin hormones
A single T2DM case suggests DPP-4 inhibitor failure can occur despite preserved beta-cell function, raising acquired as a hypothesis.
Evidence
This case report tracks one 52-year-old non-obese man whose rose from 6.7% to 8.4% after 22 months on metformin-sitagliptin and fell to 6.9% 6 months after switching sitagliptin to basal insulin.
Caveat
A single uncontrolled case cannot establish GLP-1 receptor desensitisation or rule out all alternative causes of glycemic deterioration.
Simplified
BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed second-line agents for type 2 diabetes mellitus (T2DM). Secondary treatment failure with 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 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 () 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 systematically excluded. Sitagliptin was discontinued and replaced with low-dose basal insulin (insulin glargine 10 units at bedtime) while metformin was continued. At 6-month follow-up, HbA1c decreased to 6.9% without hypoglycemia or weight gain.
CONCLUSIONS: This case raises the hypothesis that acquired resistance to DPP-4 inhibitor therapy, potentially mediated by desensitisation of glucagon-like peptide-1 (GLP-1) receptor signalling pathways, may represent an under-recognised mechanism of secondary treatment failure. Although a single case cannot establish causality, this observation may prompt clinicians to consider DPP-4 inhibitor resistance when encountering unexplained glycemic deterioration in non-obese patients with preserved β-cell function.
Key numbers
1.7%
Increase
increased from 6.7% to 8.4%
168 mg/dL
Fasting Plasma Glucose Level
Elevated fasting plasma glucose at evaluation
248 mg/dL
Postprandial Glucose Level
2-hour postprandial glucose level at evaluation
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