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

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.

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 HbA_1c and urinary albumin, were recorded at clinical follow-up.

Significant HbA_1c 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.

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.