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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

GSK457 + exendin-4 AlbudAb combination treatment returned DIO C57BL/6NTac mice to the body weight of age-matched lean control mice after 28 days.GSK457 administration began on Day -7 (baseline) and exendin-4 AlbudAb SC dosing began on Day 0. An asterisk (*) indicates a significant difference from vehicle (p < 0.05). The small dots/dashed line indicates the additive weight loss.
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pone.0153151.g004: GSK457 + exendin-4 AlbudAb combination treatment returned DIO C57BL/6NTac mice to the body weight of age-matched lean control mice after 28 days.GSK457 administration began on Day -7 (baseline) and exendin-4 AlbudAb SC dosing began on Day 0. An asterisk (*) indicates a significant difference from vehicle (p < 0.05). The small dots/dashed line indicates the additive weight loss.

Mentions: In the DIO mouse, GSK457 treatment alone produced a vehicle-subtracted weight loss of 12.7% (p<0.05). DIO mice treated with the exendin-4 AlbudAb (ED20 dose for weight loss = 0.03 mg/kg) had a vehicle-subtracted weight loss of 5.0% (p<0.05). Pre-dosing GSK457 for a week followed by a combination of GSK457 and the exendin-4 AlbudAb for 28 days resulted in a vehicle-subtracted weight loss of 30.8%, far exceeding the sum of the exendin-4 AlbudAb and GSK457 effects, p < 0.001 (Fig 4). The final body weight (32 ± 0.8 g) of the GSK457 + exendin-4 AlbudAb combination group was not different from the final body weight of the lean control group (31.7 ± 0.6 g) (p = 0.68), reflecting a complete reversal of the diet induced obesity.


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)

GSK457 + exendin-4 AlbudAb combination treatment returned DIO C57BL/6NTac mice to the body weight of age-matched lean control mice after 28 days.GSK457 administration began on Day -7 (baseline) and exendin-4 AlbudAb SC dosing began on Day 0. An asterisk (*) indicates a significant difference from vehicle (p < 0.05). The small dots/dashed line indicates the additive weight loss.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153151.g004: GSK457 + exendin-4 AlbudAb combination treatment returned DIO C57BL/6NTac mice to the body weight of age-matched lean control mice after 28 days.GSK457 administration began on Day -7 (baseline) and exendin-4 AlbudAb SC dosing began on Day 0. An asterisk (*) indicates a significant difference from vehicle (p < 0.05). The small dots/dashed line indicates the additive weight loss.
Mentions: In the DIO mouse, GSK457 treatment alone produced a vehicle-subtracted weight loss of 12.7% (p<0.05). DIO mice treated with the exendin-4 AlbudAb (ED20 dose for weight loss = 0.03 mg/kg) had a vehicle-subtracted weight loss of 5.0% (p<0.05). Pre-dosing GSK457 for a week followed by a combination of GSK457 and the exendin-4 AlbudAb for 28 days resulted in a vehicle-subtracted weight loss of 30.8%, far exceeding the sum of the exendin-4 AlbudAb and GSK457 effects, p < 0.001 (Fig 4). The final body weight (32 ± 0.8 g) of the GSK457 + exendin-4 AlbudAb combination group was not different from the final body weight of the lean control group (31.7 ± 0.6 g) (p = 0.68), reflecting a complete reversal of the diet induced obesity.

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