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

May 20, 2026Cardiovascular diabetology. Endocrinology reports

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

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Abstract

A 52-year-old man with type 2 diabetes experienced a increase from 6.7% to 8.4% after 22 months on DPP-4 inhibitor therapy despite preserved β-cell function.

Progressive glycemic deterioration occurred despite normal fasting insulin and preserved β-cell function.
Elevations in fasting plasma glucose (168 mg/dL) and postprandial glucose (248 mg/dL) were documented.
Comprehensive evaluations excluded secondary causes of hyperglycemia and autoimmune markers were negative.
Treatment was switched from sitagliptin to low-dose basal insulin, resulting in a decrease in HbA1c to 6.9% after 6 months.
Acquired resistance to may be linked to desensitization of GLP-1 receptor signaling pathways.

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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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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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