In:
Diabetes, Obesity and Metabolism, Wiley, Vol. 19, No. 12 ( 2017-12), p. 1762-1772
Abstract:
To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF ‐05231023, a long‐acting fibroblast growth factor 21 ( FGF 21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes. Methods Participants received PF ‐05231023 or placebo intravenously once weekly for 4 weeks. Safety (12‐lead ECG s, vital signs, adverse events [ AEs ], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure ( BP ; mean, systolic and diastolic) and ECGs were monitored. Results A total of 107 people were randomized. PF ‐05231023 significantly decreased mean placebo‐adjusted fasting triglycerides (day 25, 33%‐43%) and increased HDL cholesterol (day 25, 15.7%‐28.6%) and adiponectin (day 25, 1574 to 3272 ng/mL) across all doses, without significant changes in body weight (day 25, −0.45% to −1.21%). Modest decreases from baseline were observed for N‐terminal propeptides of type 1 collagen (P1NP) on day 25, although C‐telopeptide cross‐linking of type 1 collagen (CTX‐1) increased minimally. Systolic, diastolic BP , and pulse rate increased in a dose‐ and time‐related manner. There were 5 serious AE s (one treatment‐related) and no deaths. Three participants discontinued because of AE s. The majority of AE s were gastrointestinal. PF ‐05231023 increased BP and heart rate in rats, but not in monkeys. Conclusions Once‐weekly PF ‐05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long‐acting FGF 21 molecule.
Type of Medium:
Online Resource
ISSN:
1462-8902
,
1463-1326
DOI:
10.1111/dom.2017.19.issue-12
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2004918-3
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