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. 2025 Dec;42(12):e70139.
doi: 10.1111/dme.70139. Epub 2025 Sep 15.

Sulphonylurea efficacy and end-organ outcomes in the management of HNF4A-MODY

M T Crowley  1   2 , N Ng  1 , E Goulden  1 , B Sanchez-Lechuga  1 , S Ludgate  1 , M Burke  1 , K Colclough  3 , S Bacon  1 , M M Byrne  1   2
Affiliations

Sulphonylurea efficacy and end-organ outcomes in the management of HNF4A-MODY

M T Crowley et al. Diabet Med. 2025 Dec.

Abstract

Aims: Sulphonylurea agents are typically used to treat HNF4A-MODY based on the pharmacogenetic aetiology of the condition, although limited evidence exists in the literature for this practice. The aims of this study were to determine the efficacy of sulphonylurea drugs during follow-up, to explore the role of adjunctive therapies in this cohort and to describe micro- and macrovascular complications over longitudinal follow-up.

Methods: Forty-two individuals with an HNF4A mutation were phenotyped in detail, including an oral glucose tolerance test to establish insulin secretory capacity. Subsequent markers, including oral hypoglycaemic usage, end-organ complications, weight, cardiovascular co-morbidity and biochemistry including HbA1c and urinary albumin, were recorded at clinical follow-up.

Results: Significant HbA1c reduction (p = 0.045) was observed in 51.6% of people with an HNF4A gene mutation on sulphonylurea monotherapy, and glycaemic control persisted after 6 years (IQR: 3.5-11) of follow-up. Adjunct agents including insulin are used in 48.4% of the cohort. These individuals have higher BMI (p = 0.037), longer duration of diabetes (p = 0.03) and reduced insulin secretory capacity (AUC C-peptide p = 0.01). Retinopathy was observed in 24.4%, nephropathy in 12.9% and coronary heart disease in 22.6% of the cohort.

Conclusion: Individuals with an HNF4A mutation and normal BMI are likely to respond to sulphonylurea therapy. Avoidance of weight gain is associated with ongoing responsiveness to monotherapy. Adjunct therapies including GLP1RA and SGLT2i may play a role in further glycaemic management in addition to renal protective and cardioprotective effects.

Keywords: HNF4A‐MODY; MODY; sulphonylurea.

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Conflict of interest statement

MMB sat on an advisory board and has received a speaker honorarium and an institutional research grant from Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.

Figures

FIGURE 1
FIGURE 1
Summary of treatment changes following genetic diagnosis to 10‐year (3–11.75) follow‐up. MF = metformin. *1 lost to follow‐up.
FIGURE 2
FIGURE 2
HbA1c change in individuals who successfully transitioned from insulin to sulphonylurea monotherapy. A significant improvement in HbA1c over a duration of 6 years (3.5–11) (58 mmol/mol (49–66) [7.5% (6.6–8.2)] to 45 mmol/mol (42–53) [6.3% (6.0–7.0)]; p = 0.034). The green line indicates target HbA1c 53 mmol/mol [7.0%].
FIGURE 3
FIGURE 3
HbA1c change in 16 people who were successfully treated with sulphonylurea monotherapy. A significant improvement in HbA1c over a duration of 6 years (3.5–11); 55mmol/mol (52–61) [7.2% (6.9–7.7)] to nadir of 42 mmol/mol (39–50) [6.0% (5.7–6.7)] (p = 0.002) and most recent 50 mmol/mol (47–53) [6.7% (6.5–7.0)], p = 0.045). The green line indicates HbA1c of 53 mmol/mol [7.0%]. Asterisk and the round symbols indicate outlier cases.
FIGURE 4
FIGURE 4
Insulin secretory capacity of 14 individuals with diabetes on sulphonylurea monotherapy (black dots) compared with 4 on insulin (black squares).
See this image and copyright information in PMC

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