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Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study

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Abstract

Aims/hypothesis

Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (−7.7% vs −3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.

Methods

This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40–70 years old, overweight (BMI 27–40 kg/m2) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.

Results

Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs −4% [−11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs −0.5% (−15, 14]), and decreased insulin clearance rate (−3.5% [−11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (−8.2% [−11, −6] vs −0.1 [−3, 2]) and NEFA concentrations (−14 [−20, −8] vs −2.1 [−10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.

Conclusions/interpretation

A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.

Trial registration

ClinicalTrials.gov NCT01784965

Funding

The study was funded by the ADA.

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Abbreviations

GGIT:

Graded-glucose infusion test

GLP-1:

Glucagon-like peptide 1

IFG:

Impaired fasting glucose

IGT:

Impaired glucose tolerance

MMTT:

Mixed-meal tolerance test

SSPG:

Steady-state plasma glucose

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Acknowledgements

The authors thank P. Schaaf, the research dietitian, and the staff and nurses in the Stanford Clinical and Translational Research centre for their invaluable assistance with the study.

Funding

The study was funded by the ADA (7-09-NOVO-15 to GR). Liraglutide and matching placebo were provided by Novo Nordisk. The ADA and Novo Nordisk were not involved in the design or conduct of the study, the collection, management, analysis and interpretation of the data or the preparation, review or approval of the manuscript.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

SHK and GR conceptualised and designed the study and interpreted the analyses. SHK performed data analysis and drafted the manuscript. GR revised the manuscript for critical intellectual content. AL, DA, FA, CL, KG and VT helped acquire the data and edited the manuscript. All authors approved the final version of the manuscript. SHK is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

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Authors and Affiliations

  1. Department of Medicine, Stanford University School of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305-5103, USA

    Sun H. Kim, Alice Liu, Danit Ariel, Fahim Abbasi, Cindy Lamendola, Kaylene Grove, Vanessa Tomasso & Gerald Reaven

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  1. Sun H. Kim
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  2. Alice Liu
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  3. Danit Ariel
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  8. Gerald Reaven
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Corresponding author

Correspondence to Sun H. Kim.

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Kim, S.H., Liu, A., Ariel, D. et al. Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study. Diabetologia 57, 455–462 (2014). https://doi.org/10.1007/s00125-013-3134-3

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