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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

General design of chronic weight loss studies.Baseline body weight and body composition measurements were made during the period Day -18 to -13 (left Black Arrow). Treatment with GSK457 was begun on Day -8 or -7 (Green Arrow). Subcutaneous exendin-4 AlbudAb dosing began on Day 0 (Red Arrow) and ended on Day 28 for the DIO study (right Black Arrow) and on Day 14 for the db/db study (middle Black Arrow); final body composition measurements were also made on that day. Blood was collected on the following day for serum chemistry, HbA1c and hormone analyses, and tissues were collected for histopathology (Blue Arrows).
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pone.0153151.g002: General design of chronic weight loss studies.Baseline body weight and body composition measurements were made during the period Day -18 to -13 (left Black Arrow). Treatment with GSK457 was begun on Day -8 or -7 (Green Arrow). Subcutaneous exendin-4 AlbudAb dosing began on Day 0 (Red Arrow) and ended on Day 28 for the DIO study (right Black Arrow) and on Day 14 for the db/db study (middle Black Arrow); final body composition measurements were also made on that day. Blood was collected on the following day for serum chemistry, HbA1c and hormone analyses, and tissues were collected for histopathology (Blue Arrows).

Mentions: Male DIO C57BL/6 mice, db/db (B6.Cg-m +/+ Lepr db/J) mice and age-matched lean controls were used in these experiments. Fig 2 illustrates the general study designs. The first body weight and body composition measurements were used to randomize the animals to ensure similar baseline weights and percent body fat in each group.


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)

General design of chronic weight loss studies.Baseline body weight and body composition measurements were made during the period Day -18 to -13 (left Black Arrow). Treatment with GSK457 was begun on Day -8 or -7 (Green Arrow). Subcutaneous exendin-4 AlbudAb dosing began on Day 0 (Red Arrow) and ended on Day 28 for the DIO study (right Black Arrow) and on Day 14 for the db/db study (middle Black Arrow); final body composition measurements were also made on that day. Blood was collected on the following day for serum chemistry, HbA1c and hormone analyses, and tissues were collected for histopathology (Blue Arrows).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153151.g002: General design of chronic weight loss studies.Baseline body weight and body composition measurements were made during the period Day -18 to -13 (left Black Arrow). Treatment with GSK457 was begun on Day -8 or -7 (Green Arrow). Subcutaneous exendin-4 AlbudAb dosing began on Day 0 (Red Arrow) and ended on Day 28 for the DIO study (right Black Arrow) and on Day 14 for the db/db study (middle Black Arrow); final body composition measurements were also made on that day. Blood was collected on the following day for serum chemistry, HbA1c and hormone analyses, and tissues were collected for histopathology (Blue Arrows).
Mentions: Male DIO C57BL/6 mice, db/db (B6.Cg-m +/+ Lepr db/J) mice and age-matched lean controls were used in these experiments. Fig 2 illustrates the general study designs. The first body weight and body composition measurements were used to randomize the animals to ensure similar baseline weights and percent body fat in each group.

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