A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials

Diabetes Obes Metab. 2019 Jan;21(1):120-128. doi: 10.1111/dom.13494. Epub 2018 Sep 16.


Aims: To evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D).

Methods: Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25-30 kg/m2 ; n = 32) received single-ascending doses (0.01-0.1 mg) of SAR425899 or placebo. In the second, a multiple-ascending-dose trial (NCT02411825), healthy normal- to overweight volunteers (BMI 20-30 kg/m2 ; n = 40) and overweight/obese patients with T2D (BMI 28-42 kg/m2 ; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively.

Results: The most frequently reported adverse events were gastrointestinal; gastrointestinal side effects were less pronounced in patients with T2D compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < 0.05 vs. placebo) and glycated haemoglobin (P < 0.001 versus placebo) in patients with T2D. Additionally, SAR425899 led to reductions in body weight, with a maximal reduction of 5.32 kg in healthy volunteers and 5.46 kg in patients with T2D (P < 0.001 vs. placebo) at end of treatment.

Conclusions: SAR425899 was well tolerated and led to favourable glycaemic effects in patients with T2D and weight reduction in both healthy volunteers and patients. Whether dual GLP-1R/GCR agonism represents a treatment method that is superior to pure GLP-1R agonists for obesity and diabetes treatment remains to be confirmed.

Keywords: GLP-1; clinical trial; dual agonist; glucagon; obesity.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Blood Glucose / analysis
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Humans
  • Hypoglycemic Agents* / adverse effects
  • Hypoglycemic Agents* / pharmacology
  • Hypoglycemic Agents* / therapeutic use
  • Lipids / blood
  • Male
  • Middle Aged
  • Obesity / complications
  • Placebos
  • Receptors, Glucagon / agonists*
  • Young Adult


  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Lipids
  • Placebos
  • Receptors, Glucagon

Associated data

  • ClinicalTrials.gov/NCT02411825