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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.

Hodge RJ, Paulik MA, Walker A, Boucheron JA, McMullen SL, Gillmor DS, Nunez DJ - PLoS ONE (2016)

Bottom Line: 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)].

View Article: PubMed Central - PubMed

Affiliation: Discovery Medicine, Metabolic Pathways Cardiovascular Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.

ABSTRACT

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.

Nonclinical results: 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.

Clinical 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.

Trial registration: ClinicalTrials.gov NCT01725126.

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Related in: MedlinePlus

Clinical Study Design Schematic.
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pone.0153151.g003: Clinical Study Design Schematic.

Mentions: Part A enrolled healthy subjects. Subjects who passed the Screening procedures were randomized to receive GSK457 or placebo (5:2 allocation, respectively) for 6 weeks to explore safety and tolerability (Fig 3). A single dose of 500mg IR metformin was given just before breakfast on Day 1 and on Day 42 to evaluate the effect of GSK457 on metformin pharmacokinetics. On Day 42, the subjects took metformin followed by GSK457 or placebo, and then breakfast. The subjects were given standardized meals on these days. On Day 1 (the time of randomization), subjects started GSK457 or placebo under the supervision of an unblinded site staff member at dinner, and received study medication for home administration.


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.

Hodge RJ, Paulik MA, Walker A, Boucheron JA, McMullen SL, Gillmor DS, Nunez DJ - PLoS ONE (2016)

Clinical Study Design Schematic.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836696&req=5

pone.0153151.g003: Clinical Study Design Schematic.
Mentions: Part A enrolled healthy subjects. Subjects who passed the Screening procedures were randomized to receive GSK457 or placebo (5:2 allocation, respectively) for 6 weeks to explore safety and tolerability (Fig 3). A single dose of 500mg IR metformin was given just before breakfast on Day 1 and on Day 42 to evaluate the effect of GSK457 on metformin pharmacokinetics. On Day 42, the subjects took metformin followed by GSK457 or placebo, and then breakfast. The subjects were given standardized meals on these days. On Day 1 (the time of randomization), subjects started GSK457 or placebo under the supervision of an unblinded site staff member at dinner, and received study medication for home administration.

Bottom Line: 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)].

View Article: PubMed Central - PubMed

Affiliation: Discovery Medicine, Metabolic Pathways Cardiovascular Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.

ABSTRACT

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.

Nonclinical results: 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.

Clinical 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.

Trial registration: ClinicalTrials.gov NCT01725126.

Show MeSH
Related in: MedlinePlus