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Background <p>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.</p> Case presentation <p>A 52-year-old non-obese man (body mass index 24.9&#xa0;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&#xa0;mg/dL) and postprandial glucose (248&#xa0;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&#xa0;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.</p> Conclusions <p>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.</p>

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Progressive loss of glycemic control during chronic DPP-4 inhibitor therapy despite preserved β-cell function: a case report suggesting acquired incretin resistance

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  • 发表日期：

    2026年5月20日

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  • Sai Prasad,
  • Aarushi Ahuja,
  • Shreya Sharma,
  • Jay Nagda,
  • Shaily Agrawal,
  • Vidhi Parmar,
  • Harsh Vardhan

摘要

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 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.