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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

Mean weight, weighted mean glucose AUC (0–24 h), mean % HbA1c and mean fasting plasma glucose in T2D subjects taking liraglutide and GSK457 or placebo in Part B of the clinical study.Panel A shows the mean weight (± SE) from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. Panels B and C show the weighted mean glucose AUC (0–24 h) and % HbA1c (± SE), respectively, at Baseline (Day -1) and at the end of the 6-week Treatment period (Day 42). Panel D shows the mean fasting plasma glucose (± SE) from the safety labs from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. In all panels, the GSK457 group is shown as red symbols and lines and the placebo group as blue symbols and lines.
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pone.0153151.g006: Mean weight, weighted mean glucose AUC (0–24 h), mean % HbA1c and mean fasting plasma glucose in T2D subjects taking liraglutide and GSK457 or placebo in Part B of the clinical study.Panel A shows the mean weight (± SE) from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. Panels B and C show the weighted mean glucose AUC (0–24 h) and % HbA1c (± SE), respectively, at Baseline (Day -1) and at the end of the 6-week Treatment period (Day 42). Panel D shows the mean fasting plasma glucose (± SE) from the safety labs from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. In all panels, the GSK457 group is shown as red symbols and lines and the placebo group as blue symbols and lines.

Mentions: Body weight: At the start of the liraglutide Stabilization phase, mean body weight was slightly higher in subjects who were later randomized to GSK457 than to Placebo. There was a trend for a reduction in mean body weight during the 12-week Stabilization phase in both groups of subjects [mean ± SD GSK457 (−1.29kg ± 2.593) and placebo (−2.55kg ± 4.428)]. The mean (SE) body weight versus time is plotted in Fig 6.


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)

Mean weight, weighted mean glucose AUC (0–24 h), mean % HbA1c and mean fasting plasma glucose in T2D subjects taking liraglutide and GSK457 or placebo in Part B of the clinical study.Panel A shows the mean weight (± SE) from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. Panels B and C show the weighted mean glucose AUC (0–24 h) and % HbA1c (± SE), respectively, at Baseline (Day -1) and at the end of the 6-week Treatment period (Day 42). Panel D shows the mean fasting plasma glucose (± SE) from the safety labs from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. In all panels, the GSK457 group is shown as red symbols and lines and the placebo group as blue symbols and lines.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153151.g006: Mean weight, weighted mean glucose AUC (0–24 h), mean % HbA1c and mean fasting plasma glucose in T2D subjects taking liraglutide and GSK457 or placebo in Part B of the clinical study.Panel A shows the mean weight (± SE) from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. Panels B and C show the weighted mean glucose AUC (0–24 h) and % HbA1c (± SE), respectively, at Baseline (Day -1) and at the end of the 6-week Treatment period (Day 42). Panel D shows the mean fasting plasma glucose (± SE) from the safety labs from the Screening visit to the Follow-up visit and it includes the 3-month liraglutide Stabilization period and the 6-week Treatment period. In all panels, the GSK457 group is shown as red symbols and lines and the placebo group as blue symbols and lines.
Mentions: Body weight: At the start of the liraglutide Stabilization phase, mean body weight was slightly higher in subjects who were later randomized to GSK457 than to Placebo. There was a trend for a reduction in mean body weight during the 12-week Stabilization phase in both groups of subjects [mean ± SD GSK457 (−1.29kg ± 2.593) and placebo (−2.55kg ± 4.428)]. The mean (SE) body weight versus time is plotted in Fig 6.

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