Liraglutide Once a Day Versus Exenatide Twice a Day for Type 2 Diabetes: A 26-week Randomised, Parallel-Group, Multinational, Open-Label Trial (LEAD-6)

Lancet. 2009 Jul 4;374(9683):39-47. doi: 10.1016/S0140-6736(09)60659-0. Epub 2009 Jun 8.

Abstract

Background: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist.

Methods: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882.

Findings: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode.

Interpretation: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.

Funding: Novo Nordisk A/S.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Exenatide
  • Female
  • Glucagon-Like Peptide 1 / adverse effects
  • Glucagon-Like Peptide 1 / agonists
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / chemistry
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glycated Hemoglobin A / drug effects
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemia / chemically induced
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / therapeutic use*
  • Injections, Subcutaneous
  • Linear Models
  • Liraglutide
  • Logistic Models
  • Male
  • Middle Aged
  • Nausea / chemically induced
  • Peptides / adverse effects
  • Peptides / chemistry
  • Peptides / therapeutic use*
  • Treatment Outcome
  • Venoms / adverse effects
  • Venoms / chemistry
  • Venoms / therapeutic use*
  • Weight Loss / drug effects

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Peptides
  • Venoms
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Exenatide

Associated data

  • ClinicalTrials.gov/NCT00518882