Weight and Glucose Reduction Observed with a Combination of Nutritional Agents in Rodent Models Does Not Translate to Humans in a Randomized Clinical Trial with Healthy Volunteers and Subjects with Type 2 Diabetes.
BACKGROUND
Nutritional agents have modest efficacy in reducing weight and blood glucose in animal models and humans, but combinations are less well characterized. GSK2890457 (GSK457) is a combination of 4 nutritional agents, discovered by the systematic assessment of 16 potential components using the diet-induced obese mouse model, which was subsequently evaluated in a human study.
In the diet-induced obese mouse model, GSK457 (15% w/w in chow) given with a long-acting glucagon-like peptide -1 receptor agonist, exendin-4 AlbudAb, produced weight loss of 30.8% after 28 days of treatment. In db/db mice, a model of diabetes, GSK457 (10% w/w) combined with the exendin-4 AlbudAb reduced glucose by 217 mg/dL and HbA1c by 1.2% after 14 days.


RESULTS
GSK457 was evaluated in a 6 week randomized, placebo-controlled study that enrolled healthy subjects and subjects with type 2 diabetes to investigate changes in weight and glucose. In healthy subjects, GSK457 well tolerated when titrated up to 40 g/day, and it reduced systemic exposure of metformin by ~ 30%. In subjects with diabetes taking liraglutide 1.8 mg/day, GSK457 did not reduce weight, but it slightly decreased mean glucose by 0.356 mmol/L (95% CI: -1.409, 0.698) and HbAlc by 0.065% (95% CI: -0.495, 0.365), compared to placebo. In subjects with diabetes taking metformin, weight increased in the GSK457-treated group [adjusted mean % increase from baseline: 1.26% (95% CI: -0.24, 2.75)], and mean glucose and HbA1c were decreased slightly compared to placebo [adjusted mean glucose change from baseline: -1.22 mmol/L (95% CI: -2.45, 0.01); adjusted mean HbA1c change from baseline: -0.219% (95% CI: -0.910, 0.472)].


CONCLUSIONS
Our data demonstrate remarkable effects of GSK457 in rodent models of obesity and diabetes, but a marked lack of translation to humans. Caution should be exercised with nutritional agents when predicting human efficacy from rodent models of obesity and diabetes.


BACKGROUND
ClinicalTrials.gov NCT01725126.
Discovery Medicine, Metabolic Pathways Cardiovascular Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Rebecca J
RJ
Hodge
Biology, Metabolic Pathways Cardiovascular Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Mark A
MA
Paulik
Quantitative Sciences - Clinical Statistics, R&D Projects Clinical Platforms and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Ann
A
Walker
Biology, Metabolic Pathways Cardiovascular Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Joyce A
JA
Boucheron
Clinical Pharmacology Science and Study Operations, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Susan L
SL
McMullen
Clinical Pharmacology Science and Study Operations, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Dawn S
DS
Gillmor
Discovery Medicine, Metabolic Pathways Cardiovascular Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
Derek J
DJ
Nunez
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015431:Weight Loss / Q000187:drug effects; D055815:Young Adult
D001685:Biological Factors; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D008687:Metformin