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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 reduced glucose and HbA1c levels in db/db mice after 14 days.GSK457 treatment began on Day -8 and exendin-4 AlbudAb SC dosing began on Day 0. Blood was collected on Day 15 to measure (A) serum glucose levels (mg/dL) and (B) HbA1c (change (Δ) in %, normalized to control). An asterisk (*) indicates a significant difference from vehicle (p < 0.05).
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pone.0153151.g005: GSK457 + exendin-4 AlbudAb combination treatment reduced glucose and HbA1c levels in db/db mice after 14 days.GSK457 treatment began on Day -8 and exendin-4 AlbudAb SC dosing began on Day 0. Blood was collected on Day 15 to measure (A) serum glucose levels (mg/dL) and (B) HbA1c (change (Δ) in %, normalized to control). An asterisk (*) indicates a significant difference from vehicle (p < 0.05).

Mentions: In db/db mice, 14-day administration of 10% GSK457 and exendin-4 AlbudAb in combination significantly reduced serum glucose (change from baseline -217mg/dL; p<0.001) and HbA1c levels (change from baseline -1.2%; p<0.001), while the pair-fed animals lost more weight without a statistically significant improvement in glucose or HbA1c (Fig 5). This demonstrates glycemic improvement in the combination treatment beyond that achieved by weight loss alone. In addition, the reduction in glucose (-217 mg/dL) and HbA1c (-1.2%) demonstrates effects of the combination that are greater than the sum of effects of each component (-142 mg/dL for glucose additivity; -0.7% for HbA1c additivity) (p<0.05).


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 reduced glucose and HbA1c levels in db/db mice after 14 days.GSK457 treatment began on Day -8 and exendin-4 AlbudAb SC dosing began on Day 0. Blood was collected on Day 15 to measure (A) serum glucose levels (mg/dL) and (B) HbA1c (change (Δ) in %, normalized to control). An asterisk (*) indicates a significant difference from vehicle (p < 0.05).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153151.g005: GSK457 + exendin-4 AlbudAb combination treatment reduced glucose and HbA1c levels in db/db mice after 14 days.GSK457 treatment began on Day -8 and exendin-4 AlbudAb SC dosing began on Day 0. Blood was collected on Day 15 to measure (A) serum glucose levels (mg/dL) and (B) HbA1c (change (Δ) in %, normalized to control). An asterisk (*) indicates a significant difference from vehicle (p < 0.05).
Mentions: In db/db mice, 14-day administration of 10% GSK457 and exendin-4 AlbudAb in combination significantly reduced serum glucose (change from baseline -217mg/dL; p<0.001) and HbA1c levels (change from baseline -1.2%; p<0.001), while the pair-fed animals lost more weight without a statistically significant improvement in glucose or HbA1c (Fig 5). This demonstrates glycemic improvement in the combination treatment beyond that achieved by weight loss alone. In addition, the reduction in glucose (-217 mg/dL) and HbA1c (-1.2%) demonstrates effects of the combination that are greater than the sum of effects of each component (-142 mg/dL for glucose additivity; -0.7% for HbA1c additivity) (p<0.05).

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