Efficacy and Safety of Glimepiride With or Without Linagliptin Treatment in Patients With HNF1A Diabetes (Maturity-Onset Diabetes of the Young Type 3): A Randomized, Double-Blinded, Placebo-Controlled, Crossover Trial (GLIMLINA)

Abstract

Objective: Sulfonylureas are first-line treatment of hepatocyte nuclear factor 1-α (HNF1A) diabetes (maturity-onset diabetes of the young type 3), but many patients do not achieve optimal glycemic control without episodes of hypoglycemia. We investigated the combination of the sulfonylurea glimepiride and the dipeptidyl peptidase 4 inhibitor linagliptin versus glimepiride monotherapy with respect to glycemic variability, glycemic control, and risk of hypoglycemia.

Research design and methods: In a randomized, double-blinded, crossover trial, patients with HNF1A diabetes (n = 19; mean ± SD age 43 ± 14 years, BMI 24.8 ± 2.8 kg/m², and glycated hemoglobin [HbA_1c] 7.4 ± 0.2% [57.1 ± 7.3 mmol/mol]) were randomly assigned to treatment with glimepiride + linagliptin 5 mg (16 weeks), washout (4 weeks), and glimepiride + placebo (16 weeks) (or vice versa). Glimepiride was titrated targeting a fasting plasma glucose of 4.5-6.0 mmol/L without hypoglycemia. Treatments were evaluated by continuous glucose monitoring (CGM), HbA_1c, and meal test.

Results: Compared with glimepiride + placebo, glimepiride + linagliptin did not significantly improve the primary end point, mean amplitude of glycemic excursions (MAGE) (mean difference -0.7 mmol/L, P = 0.1540), but displayed significant reductions in coefficient of variation on CGM (-3.6%, P = 0.0401), HbA_1c (-0.5%, P = 0.0048), and glimepiride dose (-0.7 mg/day, P = 0.0099). β-cell glucose sensitivity (assessed as C-peptide-to-glucose ratio) during meal test improved with glimepiride + linagliptin. Incidences of hypoglycemia were similar with both treatments.

Conclusions: Linagliptin as add-on treatment to glimepiride improved glycemic variability and control without increasing risk of hypoglycemia in patients with HNF1A diabetes.

Figure 1

CGM and meal and bicycle test. A: Mean ± SD values from CGM during 24 h at baseline and at the end of two 16-week treatment periods of glimepiride + linagliptin and glimepiride + placebo in 19 patients with HNF1A diabetes. B: Differences in means and 95% CI in glycemic variability calculated from CGM data between glimepiride + linagliptin and glimepiride + placebo. C: Mean percent time spent in different plasma glucose (PG) ranges, calculated from CGM. D–H: Combined meal and bicycle test concentration versus time for plasma/serum glucose (D), C-peptide (E), C-peptide–to–glucose ratio (F), glucagon (G), and acetaminophen (H). Graphics data are mean ± SEM if not otherwise indicated. Orange circle, baseline; red square, glimepiride + placebo; blue triangle, glimepiride + linagliptin. *P < 0.05.