Efficacy and safety of linagliptin co-administered with low-dose metformin once daily versus high-dose metformin twice daily in treatment-naïve patients with type 2 diabetes: a double-blind randomized trial

Abstract

Introduction: The aim of this study was to investigate the efficacy and safety of linagliptin + low-dose (LD) metformin once daily versus high-dose (HD) metformin twice daily in treatment-naïve patients with type 2 diabetes.

Methods: Patients (n = 689) were randomized (1:1) to double-blind treatment with linagliptin 5 mg + LD metformin (1000 mg) or HD metformin (2000 mg) for 14 weeks. Metformin was initiated at 500 mg/day and up-titrated within 2 weeks; the dose then remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to Week 14 in patients who tolerated a daily metformin dose of ≥1000 mg after 2 weeks.

Results: At Week 14, HbA1c changed from a mean baseline of 8.0% (64 mmol/mol) by -0.99% (-11 mmol/mol) for linagliptin + LD metformin, and -0.98% (-11 mmol/mol) for HD metformin [treatment difference -0.01% (95% confidence interval -0.13, 0.12) (0 mmol/mol), P = 0.8924]. The proportion of patients who achieved HbA1c <7.0% (53 mmol/mol) without occurrence of moderate or severe gastrointestinal (GI) events (including abdominal pain, nausea, vomiting, diarrhea, and decreased appetite) was the same in both groups (51.3% for both). Although the occurrence of moderate or severe GI events was similar, the linagliptin + LD metformin group had fewer mild GI events (18.5% versus 24.3%). The incidence of hypoglycemia was low in both groups.

Conclusion: Linagliptin + LD metformin combination showed similar efficacy and safety to HD metformin. This combination may be an alternative treatment option in patients who may have difficulty tolerating metformin doses >1000 mg/day.

Funding: Boehringer Ingelheim.

Trial registration: ClinicalTrials.gov NCT01438814.

Figures

Fig. 1

Patient disposition. aAll patients who were treated with ≥1 dose of study medication. bAll patients who had a baseline and ≥1 on-treatment HbA1c measurement. cAll patients who had a baseline and ≥1 on-treatment HbA1c measurement, who tolerated a daily metformin dose of ≥1000 mg at the end of the titration phase. AE adverse event, FAS full analysis set, HbA1c glycated hemoglobin, HD high dose, LD low dose, TS treated set

Fig. 2

Mean changes in HbA1c and FPG over time. a Adjusted mean change in HbA1c from baseline over time from the mixed model repeated measurements analysisa (FAS1000mg; OC). b Adjustedb mean change in FPG from baseline over time up to 14 weeks (FAS1000mg; LOCF). aModel includes treatment, continuous baseline HbA1c in addition to week repeated within patient, week by baseline HbA1c interaction, and week by treatment interaction. bANCOVA model includes treatment, continuous baseline HbA1c, and continuous baseline FPG. FAS1000mg—all patients who had a baseline and ≥1 on-treatment HbA1c measurement, who tolerated a daily metformin dose of ≥1000 mg at the end of the titration phase. ANCOVA analysis of covariance, FAS full analysis set, FPG fasting plasma glucose, HbA1c glycated hemoglobin, HD high dose, LD low dose, LOCF last observation carried forward, OC observed cases, SE standard error