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

<div><p>Background</p><p>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.</p><p>Nonclinical Results</p><p>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 <i>db/db</i> 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.</p><p>Clinical Results</p><p>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)].</p><p>Conclusions</p><p>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.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/results?term=NCT01725126&Search=Search" target="_blank">NCT01725126</a></p></div

CONSORT flow diagram.

<p>CONSORT flow diagram.</p

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.

<p>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.</p

Clinical Study Design Schematic.

<p>Clinical Study Design Schematic.</p

Clinical Study Design and Main Inclusion-Exclusion Criteria.

<p>Clinical Study Design and Main Inclusion-Exclusion Criteria.</p

General design of chronic weight loss studies.

<p>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 <i>db/db</i> 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).</p

GSK457 + exendin-4 AlbudAb combination treatment reduced glucose and HbA1c levels in <i>db/db</i> mice after 14 days.

<p>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).</p

Adverse Events during the Treatment Period Reported by More than 1 Subject.

<p>Adverse Events during the Treatment Period Reported by More than 1 Subject.</p

Clinical Study: Demographic and Baseline Characteristics.

<p>Clinical Study: Demographic and Baseline Characteristics.</p

GSK457 + exendin-4 AlbudAb combination treatment returned DIO C57BL/6NTac mice to the body weight of age-matched lean control mice after 28 days.

<p>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.</p