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Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial.
- Source :
-
Diabetologia [Diabetologia] 2018 Sep; Vol. 61 (9), pp. 1918-1922. Date of Electronic Publication: 2018 Jul 11. - Publication Year :
- 2018
-
Abstract
- Aims/hypothesis: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m <superscript>2</superscript> ) and type 2 diabetes (HbA <subscript>1c</subscript> 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l).<br />Methods: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug.<br />Results: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA <subscript>1c</subscript> (baseline 67 mmol/mol [8.3%]) was -6.6 ± 2.2 mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2 mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3 mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism.<br />Conclusions/interpretation: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA <subscript>1c</subscript> .<br />Trial Registration: ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.
- Subjects :
- Adolescent
Adult
Aged
Aminopeptidases metabolism
Anti-Obesity Agents therapeutic use
Blood Glucose drug effects
Body Weight drug effects
Double-Blind Method
Female
Glucose metabolism
Glycated Hemoglobin metabolism
Glycoproteins
Humans
Hypoglycemic Agents therapeutic use
Male
Metalloendopeptidases metabolism
Methionyl Aminopeptidases
Middle Aged
Obesity drug therapy
Obesity metabolism
Weight Loss drug effects
Young Adult
Aminopeptidases antagonists & inhibitors
Cinnamates therapeutic use
Cyclohexanes therapeutic use
Diabetes Mellitus, Type 2 drug therapy
Diabetes Mellitus, Type 2 metabolism
Epoxy Compounds therapeutic use
Metalloendopeptidases antagonists & inhibitors
Sesquiterpenes therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0428
- Volume :
- 61
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Diabetologia
- Publication Type :
- Academic Journal
- Accession number :
- 29992370
- Full Text :
- https://doi.org/10.1007/s00125-018-4677-0