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Effect of metformin and insulin vs. placebo and insulin on whole body composition in overweight patients with type 2 diabetes: a randomized placebo-controlled trial

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Abstract

Summary

Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes.

Introduction

Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus.

Methods

This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months.

Results

Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) − 2.4 [− 3.5, − 1.4] kg, p value < 0.001) and FM (− 1.5 [− 2.3, − 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group.

Conclusion

Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

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Acknowledgments

Members of the CIMT trial group—affiliations and e-mails

Trine W Boesgaard (1), Leif Breum (2), Birthe Gade-Rasmussen (3), Simone B Sneppen (4), Christian Gluud (5), Bianca Hemmingsen (5, 6), Tonny Jensen (7), Thure Krarup (8), Sten Madsbad (3, 9, 10), Elisabeth R Mathiesen (7, 9, 10), Hans Perrild (8), Lise Tarnow (6, 14), Birger Thorsteinsson (6, 10), Henrik Vestergaard (10, 11, 12), Søren S Lund (1, 13), Thomas Peter Almdal (7, 10), Louise Lundby-Christensen (14).

Affiliations

(1) Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark

(2) Department of Medicine, Zealand University Hospital, Lykkebækvej 1, Koge, Denmark

(3) Department of Endocrinology, Hvidovre, Copenhagen University Hospital, Kettegaard

Allé 30, 2650 Hvidovre, Denmark

(4) Department of medicine, Gentofte, Copenhagen University Hospital, Kildegaardsvej 28,

2900 Hellerup, Denmark

(5) Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet,

Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark

(6) Department of Cardiology, Nephrology and Endocrinology, Nordsjællands

University Hospital - Hillerød, Dyrehavevej 29, 3400 Hillerød, Denmark

(7) Department of Endocrinology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9,

2100 Copenhagen, Denmark

(8) Department of Endocrinology, Bispebjerg, Copenhagen University Hospital, Bispebjerg

Bakke 23, 2400 Copenhagen, Denmark

(9) Astra – Zeneca, Gothenburg, Sweden

(10) Department of Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

(11) Department of Medicine, Bornholms Hospital, Ullasvej 8, 3700 Rønne, Denmark

(12) The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark

(13) Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Ingelheim, Germany

(14) Steno Diabetes Center Sjælland, Holbæk, Denmark

List of e-mail addresses

Trine W Boesgaard - tweb@novonordisk.com

Leif Breum - lbru@regionsjaelland.dk

Birthe Gade-Rasmussen -Birte.Gade-Rasmussen@regionh.dk

Christian Gluud – cgluud@ctu.dk

Bianca Hemmingsen – biancahemmingsen@hotmail.com

Tonny Jensen - tonny.jensen@regionh.dk

Thure Krarup – Thure.Krarup@regionh.dk

Søren S Lund – sslund@dadlnet.dk

Sten Madsbad – sten.madsbad@regionh.dk

Elisabeth R Mathiesen – elisabeth.reinhardt.mathiessen@regionh.dk

Hans Perrild – hans.perrild@regionh.dk

Simone B Sneppen – simone.sneppen@regionh.dk

Lise Tarnow – lise@vibesholm.dk

Birger Thorsteinsson – birger.thorsteinsson@outlook.dk

Henrik Vestergaard – henrik.vestergaard.01@regionh.dk

Funding

Funding was obtained from Nordsjællands Hospital, the Jascha Foundation, the Osteoporosis Association for patients, the Foundation of A & J C Tvergaard, the Foundation of Captain Lieutenant Harald Jensen and Wife, Inge and Per Refshalls research grant, and Danish Bone Society travel grant.

Author information

Authors and Affiliations

  1. Department of Nephrology and Endocrinology, Nordsjællands University Hospital, Hillerod, Denmark

    A. K. Nordklint, B. Hemmingsen, B. Thorsteinsson & P. Eiken

  2. Department of Ophthalmology, Rigshopitalet – Glostrup, Copenhagen, Denmark

    A. K. Nordklint

  3. Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark

    T.P. Almdal & E.R. Mathiesen

  4. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    T.P. Almdal, S. Madsbad, E.R. Mathiesen, B. Thorsteinsson & H. Vestergaard

  5. Departments of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

    P. Vestergaard

  6. Steno Diabetes Center North Jutland, Aalborg, Denmark

    P. Vestergaard

  7. Steno Diabetes Center Zealand, Holbak, Denmark

    L. Lundby-Christensen & L. Tarnow

  8. Steno Diabetes Center Copenhagen, Gentofte, Denmark

    T.W. Boesgaard & S.S. Lund

  9. Department of Medicine, Zealand University Hospital, Koge, Denmark

    L. Breum

  10. Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark

    B. Gade-Rasmussen & S. Madsbad

  11. Department of Medicine, Gentofte, Copenhagen University Hospital, Hellerup, Denmark

    S.B. Sneppen

  12. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    C. Gluud & B. Hemmingsen

  13. Department of Endocrinology, Bispebjerg, Copenhagen University Hospital, Copenhagen, Denmark

    H. Perrild & P. Eiken

  14. Department of Medicine, Bornholms Hospital, Ronne, Denmark

    H. Vestergaard

  15. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark

    H. Vestergaard

  16. Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

    S.S. Lund

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  1. A. K. Nordklint
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Corresponding author

Correspondence to A. K. Nordklint.

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Conflicts of interest

Pia Eiken is an advisory board member for Amgen and Gedeon Richter Nordic, and on the speakers’ bureau for Amgen, Eli Lilly and AstraZeneca, and own shares in Novo Nordisk A/S.

Louise Lundby-Christensen owns shares in Novo Nordisk A/S.

Thomas Almdal owns shares in Novo Nordisk A/S.

Søren S. Lund has previously published his opinion about the clinical effects of metformin treatment. Søren S. Lund owns shares in Novo Nordisk A/S and shares in dynamically traded investment funds, which may own stocks from pharmaceutical companies. Søren S. Lund has reported former employment at Steno Diabetes Center, which is a diabetes hospital and academic institution previously owned by Novo Nordisk. Søren S. Lund is now employed at Boehringer Ingelheim International GmbH, Ingelheim, Germany. Søren S. Lund’s contribution was his alone and does not necessarily reflect the official position of Boehringer Ingelheim.

Trine W. Boesgaard owns shares in Novo Nordisk A/S. Trine W. Boesgaard has reported former employment at Steno Diabetes Center, which is a diabetes hospital and academic institution previously owned by Novo Nordisk. Trine W. Boesgaard is now employed at Novo Nordisk. Trine W Boesgaard’s contribution was hers alone and does not necessarily reflect the official position of Novo Nordisk.

Azra Karahasanovic Nordklint, Peter Vestergaard, Leif Breum, Birthe Gade-Rasmussen, Simone B Sneppen, Christian Gluud, Bianca Hemmingsen, Tonny Jensen, Thure Krarup, Sten Madsbad, Elisabeth R Mathiesen, Hans Perrild, Lise Tarnow, Birger Thorsteinsson, and Henrik Vestergaard have no known conflicts of interest to declare.

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Nordklint, A.K., Almdal, T., Vestergaard, P. et al. Effect of metformin and insulin vs. placebo and insulin on whole body composition in overweight patients with type 2 diabetes: a randomized placebo-controlled trial. Osteoporos Int 32, 1837–1848 (2021). https://doi.org/10.1007/s00198-021-05870-1

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