Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial

• Published in: Diabetologia Vol. 56; no. 7; pp. 1503 - 1511
• Main Authors: Charbonnel, B., Steinberg, H., Eymard, E., Xu, L., Thakkar, P., Prabhu, V., Davies, M. J., Engel, S. S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-07-2013; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Clinical trials; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Drug dosages; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucagon; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - adverse effects; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - therapeutic use; Glucose; Glycated Hemoglobin A - metabolism; Human Physiology; Humans; Hypoglycemia; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Internal Medicine; Liraglutide; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metformin - therapeutic use; Middle Aged; Peptides; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - therapeutic use; Sitagliptin Phosphate; Sulfonylurea Compounds - administration & dosage; Sulfonylurea Compounds - adverse effects; Sulfonylurea Compounds - therapeutic use; Treatment Outcome; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - therapeutic use; Young Adult; United States > US; Type 2 diabetes; Glimepiride; Antihyperglycaemic agents; HbA; Treatment intensification; Sitagliptin; Metformin; Liraglutide; Endocrinopathy; Human; Metabolic diseases; Intensification; Biguanides; Treatment; Sulfonamides; Sulfonylureas; Clinical trial; Safety
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-2905-1

Aims/hypothesis
The aim of this work was to compare treatment intensification strategies based on orally administered vs injectable incretin-based antihyperglycaemic agents in patients with type 2 diabetes mellitus on metformin monotherapy.
Methods
In a 26 week, open-label study, 653 patients (baseline HbA
1c
 = 8.2% [66 mmol/mol]) were randomised at 111 sites in 21 countries in a 1:1 ratio to a strategy using oral agents (starting with sitagliptin 100 mg/day) or a strategy using the injectable drug liraglutide starting at a dose of 0.6 mg/day, up-titrated to 1.2 mg/day after 1 week. The following patients with type 2 diabetes mellitus were recruited for the study: those aged 18–79 years, on a stable dose of metformin monotherapy ≥1,500 mg/day for ≥12 weeks, with an HbA
1c
≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) and a fasting fingerstick glucose (FFG) <15 mmol/l (<270 mg/dl) at the randomisation visit, deemed capable by the investigator of using a Victoza pen injection device (containing 6 mg/ml liraglutide; Novo Nordisk, Bagsværd, Denmark). Women taking part in the study agreed to remain abstinent or use an acceptable method of birth control during the study. Randomisation was performed via a computer-generated allocation schedule using an interactive voice response system. After 12 weeks, patients on sitagliptin with HbA
1c
 ≥ 7.0% (53 mmol/mol) and fasting glucose >6.1 mmol/l had their treatment intensified with glimepiride; patients on liraglutide with HbA
1c
 ≥ 7.0% (53 mmol/mol) had the dose up-titrated to 1.8 mg/day. The primary analysis assessed whether the strategy using oral drugs was non-inferior to that using an injectable drug regarding HbA
1c
change from baseline at week 26 using a per-protocol (PP) population and a non-inferiority margin of 0.4%.
Results
In the PP population (522 patients included: oral strategy,
n
 = 269; injectable strategy,
n
 = 253) antihyperglycaemic therapy was intensified at week 12 in 50.2% and 28.5%, respectively. HbA
1c
decreased over 26 weeks in both treatment strategy groups, with a larger initial reduction at week 12 in the injectable strategy group. The LS mean change in HbA
1c
at week 26 was −1.3% (95% CI −1.4, −1.2) in the oral strategy group and −1.4% (95% CI −1.5, −1.3) in the injectable strategy group; the study met the non-inferiority criterion. Both treatment regimens were generally well tolerated; hypoglycaemia was reported more often with the oral strategy, while nausea, vomiting, diarrhoea and abdominal pain were reported more often with the injectable strategy.
Conclusions/interpretation
An oral, incretin-based treatment strategy with sitagliptin and, if needed, glimepiride may be a good approach in many patients with type 2 diabetes mellitus for managing inadequate glycaemic control on metformin monotherapy, as compared with an injectable treatment strategy with liraglutide. The oral and injectable strategies had similar effects on HbA
1c
and had good overall tolerability.
Trial registration
ClinicalTrials.gov NCT01296412
Funding
The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA.