THE STORY OF GLP-1
A Historical Journey in the Treatment of Diabetes and Obesity
Jens Juul Holst
FADL’s Forlag
The Story of GLP-1
A Historical Journal in the Treatment of Diabetes and Obesity
Jens Juul Holst
Co-authors Mads Krogsgaard Thomsen, Sten Madsbad & Jens Meldgaard Bruun
1st edition, 1st print run
© FADL’s Forlag A/S, Copenhagen 2024
ISBN: 978-87-7625-042-3
Translated by Billy O’Shea
Thanks to Carolyn Deacon for reviewing the manuscript
Project manager and publisher’s editor: Joachim Sømark
Graphic typesetting: Grafiliokus/Anne-Mette Thomsen
Cover: Julie Panton | Panton Studio’s
Illustrations: Birgitte Lerche
Printed by: ADverts SA
Printed in Latvia 2024
Mechanical, photographic or other reproduction of this book or parts thereof is permitted only by agreement between the Danish Ministry of Children and Education and Copy-Dan Tekst & Node. Any other use is prohibited under Danish copyright law without the written consent of the publisher.
5.1
5.2
Biography
Jens Juul Holst, MD, DMSc
Jens Juul Holst is Professor of Medical Physiology at the Department of Biomedical Sciences, University of Copenhagen. He is also Senior Group Leader at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
Professor Holst’s scientific work has focused on the regulatory peptides of the pancreas and the gut and their importance in the regulation of the functions of the GI-tract and metabolism, with particular focus on blood glucose and appetite regulation, obesity and diabetes. A particular emphasis has been on the role of the incretin hormones of the gut (GLP-1 and GIP).
Professor Holst great scientific achievements include the discovery of GLP-1 (glucagon-like peptide 1), a gut hormone regulating insulin secretion and appetite and food intake, and his subsequent both basic and translational research in this field.
Photo by Lars Svankjær, The Royal Danish Academy of Sciences and Letters
SHORT BIOGRAPHY – JENS JUUL HOLST,
MD., DMS c
With an H-index of 161 (WoS, October 2024), he is among the most cited European scientists in his field. He has authored more than 1900 publications (about 1759 listed in PubMed) that have received more than 109,075 citations in Web of Science as of October 2024. According to PubMed he has 119 new titles in 2023 and 2024.
Foreword
There have been considerable advances in the treatment of overweight and diabetes in recent years, but nevertheless, the prevalence of two conditions keep increasing. In Denmark there are now more people who are overweight or obese than of normal weight, and since type 2 diabetes is largely associated with obesity, this means that there are also more patients with diabetes.
Until recently, treating these groups has been difficult. A weight loss of 10-12% could be achieved within a few months with low-calorie diets, but it proved almost impossible to maintain the weight loss afterwards. Diabetes treatment has so far focused on getting blood sugar levels under control, but this is in itself a difficult task (even with insulin), and the question is whether better blood sugar control has an impact on what is really important for patients: obtaining control over complications such as eye problems, kidney disease, blood clots, amputation and ultimately excess mortality.
Some years ago, a number of very extensive international studies, into which many resources were invested, investigated whether improved blood sugar control could be shown to have a clear effect on the above complications. This was not the case. A large and costly project aimed at clarifying the beneficial effects of lifestyle changes on patients was closed down after almost ten years due to a lack of results. On this background, it was sensational news in 2015-16, when it was documented that the frequency
THE STORY OF GLP- 1
FOREWORD
of cardiovascular complications (blood clots in the heart, stroke, and death from heart disease) could be reduced by treatment with new medications for diabetes. One of the medications studied was liraglutide, an analogue of one of the body’s own hormones: GLP-1 (‘glucagon-like peptide-1’). GLP-1 is a so-called incretin hormone, a hormone from the gastrointestinal tract, which is essential for the secretion of insulin in connection with meal consumption. GLP-1 – and thus also liraglutide – also had an appetite suppressant and weight-reducing effect, and subsequent studies with a second-generation version of the drug, semaglutide, which requires only weekly injections, showed very good effects on blood sugar levels as well as on appetite and food intake. With semaglutide, weight loss of between 15-18% could be achieved in 68 weeks. Subsequent GLP-1 based drugs, which are also predominantly based on the effect of GLP-1, have shown weight loss of up to 25% in persons who are overweight/obese (without diabetes), while in diabetic patients, up to half have achieved completely normal blood sugar levels. This is a milestone and has never been seen before. Most recently, semaglutide has been shown to reduce the number of cardiovascular complications by 20% in obese people with an elevated risk of cardiovascular disease. However, these striking results have also created a set of new problems. The medicine is expensive and is only available to a limited extent. So who should receive treatment, and who should pay for it? The new medications raise a number of societal issues that will hopefully be solved in the future.
I was fortunate enough to be involved at the forefront of the discovery of the glucagon-like peptides in the mid-1980s, as well as in
the subsequent exploration of the many effects and significance of these hormones. I am often asked to describe the discovery and development of the glucagon-like substances, and it is indeed an exciting story. The development largely follows the evolution of research into metabolic diseases and in this book, I have attempted to describe it in a, hopefully, not too inaccessible manner. The book describes the historical development, but also, when this is necessary for understanding, the physiological background to the individual developmental steps. It is not, for example, fruitful to discuss diabetes without knowledge of the nature and development of the disease, for which reason I have also described the underlying metabolic processes in both the healthy body and in diabetes patients. To facilitate understanding, I have - to a limited extent - dealt with the anatomical, biochemical and physiological aspects of normal food intake and digestion. To conclude the book, I have asked two experts in diabetes and obesity treatment, Prof. Sten Madsbad of Hvidovre Hospital, University of Copenhagen, and Prof. Jens Meldgaard Bruun of the Steno Diabetes Centre in Aarhus, to share their experiences with the medications. To an important extent, the success of the GLP-1 based therapies has depended on developments and studies by the pharmaceutical industry. This development is also described, and one of the key persons from Novo Nordisk, who was the first to develop a GLP-1 analogue and to engage in obesity therapy with the GLP-1 analogues, Prof. Mads Krogsgaard Thomsen has contributed with a description of the journey of these compounds (liraglutide and semaglutide) to the market.
The book is equipped with an index in which you can quickly look up mentions of specific topics or people. There is also a brief
THE STORY OF GLP- 1