The Development of Glucagon-Like Peptide 1 as a Therapeutic: The Triumph of the Lasker Award for Obesity Is a Victory for Diabetes Research

The recent recognition of Lotte Bjerre Knudsen, Joel Habener, and Svetlana Mojsov with the Lasker Award for their fundamental work underpinning the development of novel and powerful weight loss treatments is timely and worthy of celebration by everyone working in the various fields of metabolic disease. Obesity remains a major scourge of modern societies, with prevalence that has increased 4- to 5-fold over the past 45 years, and is proximate to many of the major causes of mortality.

The generation of medicines based on the glucagon-like peptide 1 (GLP-1) signaling system that result in safe and effective weight loss brings hope and promise to millions of affected people as well as to the medical providers who care for them. Given the centrality of obesity in the pathogenesis of type 2 diabetes, interventions to promote weight loss have long been sought as a means to treat affected patients, and this group is likely to benefit disproportionately from the availability of these novel treatments. However, in the focus on obesity that has surrounded the recent Lasker Award, it is important not to lose sight of the fact that the primary driver in the bench-to-clinic evolution of the GLP-1 system was the treatment of hyperglycemia, a benefit that has been realized through the efforts of these Lasker awardees and many others whose contributions were essential to the whole endeavor. The peer-reviewed journals of the American Diabetes Association, Diabetes and Diabetes Care, have been prominent in reporting the GLP-1 story as it unfolded, and this historic occasion for the field seems like an appropriate time to reflect on its history.

While GLP-1 was not technically discovered until the mid-1980s, its existence had been suspected for many years. It had long been known that factors secreted from the gastrointestinal tract stimulate insulin secretion and promote glucose disposal—a physiologic mechanism termed the incretin effect. The one peptide that was known to conform to this action was glucose-dependent insulinotropic polypeptide (GIP), which had been described by John Brown and Raymond Pederson in 1971 (1), but it did not seem to account for the entirety of the incretin effect. Hence, in 1983 when Habener and colleagues sequenced the proglucagon gene, which encodes a prohormone expressed in the pancreatic islet and intestinal mucosa, they found evidence for a second, glucagon-related peptide and postulated that this might be an intestinal product (2). This finding was confirmed by groups working with Graeme Bell and Linda Lopez who named it GLP-1 (3,4). Working with Mojsov, Habener also demonstrated that truncated GLP-1 was a potent insulinotropin in a perfused rat pancreas model (5)—a finding quickly confirmed by Bernard Kreymann in human subjects (6). Around the same time, Jens Juul Holst and colleagues developed a reliable radioimmunoassay for GLP-1 and showed that the peptide was secreted from the gut (7), supporting its role as the second incretin.

The implications of this initial “discovery” period were followed up by important studies of humans that established the therapeutic potential of the GLP-1 system for type 2 diabetes. Of notable importance was a study published by Michael Nauck and colleagues, which demonstrated that the insulinotropic effect of GLP-1 was retained in individuals with diabetes and was significantly greater than the response to GIP (8). Moreover, this group also showed that short-term infusion of GLP-1 in people with type 2 diabetes and poor glycemic control resulted in near normalization of fasting hyperglycemia by increasing plasma insulin and decreasing circulating glucagon concentrations (9). A subsequent contribution by Holst and colleagues was also critical in supporting the application of GLP-1 as a therapy for diabetes. In the study, patients with type 2 diabetes were administered a continuous subcutaneous GLP-1 infusion for 6 weeks that resulted in substantial improvements in glycemia and β-cell function; modest weight loss was also seen (10). This study demonstrated that continuous stimulation of the GLP-1 receptor was effective for chronic glucose control and that this effect was persistent and not subject to tachyphylaxis. Also important in this early work was the realization that the effects of native GLP-1 on insulin secretion and glucose lowering were very short-lived; subsequent work by Rolf Mentlein, Carolyn Deacon, Holst, and others demonstrated that this was in great part due to enzymatic inactivation by the ubiquitous protease dipeptidyl peptidase 4 (11,12). These studies exemplify how expanding experience with native GLP-1 in humans initiated robust efforts to harness the GLP-1 system for therapeutics.

In parallel to the clinical research, the body of basic and preclinical work expanded through the 1990s and rapidly increased our understanding of the GLP-1 system. Notable advances included the identification of the exendin peptides—reptilian moieties that agonize and antagonize the GLP-1 receptor—by John Eng and colleagues (13), the cloning of the GLP-1 receptor by Bernard Thorens (14), and the demonstration that instillation of GLP-1 into the cerebroventricular system of rats suppresses food intake (15,16). The latter finding prompted several groups to identify and define a GLP-1–GLP-1 receptor system in the central nervous system, expanding the scope of activity beyond the pancreatic islet. Of singular importance to GLP-1 research was the development of a receptor knockout mouse by Daniel Drucker and his team (17). This mouse model has been applied to the understanding of a wide range of GLP-1 physiology and pharmacology by the Drucker laboratory, including roles in the cardiovascular and immune systems as well as in metabolic regulation. Moreover, the GLP-1 receptor knockout has been shared widely with investigators in the field, contributing enormously to the understanding and application of GLP-1–based therapies.

The first GLP-1 receptor agonist reached clinical use in 2005. It was a derivative of exendin-4, or exenatide, which is an injectable peptide that demonstrated reliable glucose-lowering properties and modest reductions in body weight (18); the latter finding was heralded by preclinical work and happily received by patients and prescribers. Soon thereafter, several new modified GLP-1 analogs with improved pharmacokinetics became available. The first was liraglutide, which required daily administration; later came dulaglutide and semaglutide, which could be given once weekly. Liraglutide and semaglutide, developed at Novo Nordisk under the direction of Bjerre Knudsen, had particular impact (19). These longer-acting compounds showed pharmacologic benefits proportional to their circulating half-life, with semaglutide being especially potent. Importantly, they were advanced as weight loss therapies for people with or without diabetes, extending benefits to a large group of people with an important unmet need for treatment. It is this expanded application and its potential impact that were primary factors in this year’s Lasker Award.

Coincident with the development of long-acting GLP-1 receptor agonists was the generation of a new class of monomolecular peptides that activated not only the GLP-1 receptor but also related receptors. Initiated by Richard DiMarchi and Matthias Tschöp, this field has progressed to include dual GLP-1 and GIP receptor agonists, dual GLP-1 and glucagon receptor agonists, and molecules that activate all three receptors (20). The remarkable preclinical effects of these molecules spurred intensified research in the field of G-protein–coupled receptors, which has led to remarkable products for clinical use. This is exemplified by tirzepatide, a dual GLP-1 and GIP receptor agonist that is now approved for treating diabetes and obesity (21). The possibility that multireceptor agonists may be more potent than single GLP-1 receptor agonists has been suggested (22) but not definitively proven, and this class of drugs continues to be heavily investigated. Finally, small-molecule, orally available GLP-1 receptor agonists are also in the pipeline (23), and these present the potential for less expensive and more accessible agents that bring to bear the benefits of GLP-1 signaling for more patients.

The final chapter in the GLP-1 story to date involves the impact and implications of incretin-based drugs on important comorbidities of diabetes. Several GLP-1 receptor agonists have been shown in randomized clinical trials to reduce cardiovascular events in people with diabetes at risk for atherosclerotic vascular disease (24) and, most recently, in individuals with obesity who had underlying cardiovascular disease but did not have diabetes (25). Moreover, a recent trial with semaglutide demonstrated benefits to allay disease progression in people with diabetic nephropathy (26). In addition, GLP-1 receptor agonists have been shown to be beneficial in reducing hepatic steatosis (27,28) and improving sleep apnea (29). A full testimony to the breadth of the potential utility of incretin drugs is the range of clinical studies currently ongoing in Parkinson disease, cognitive dysfunction, suicidal ideation, and alcohol and narcotic use (30).

The progression from the sequencing of proglucagon to the demonstration of physiology in model systems and humans and, finally, to drug development has proceeded relatively rapidly, with steady advances over four decades. The short history provided here is certainly incomplete but describes key events and contributors that drove the project forward. In the field of diabetes research, the GLP-1 system may be the most important discovery since insulin, and the prestigious Lasker Award to Bjerre Knudsen, Habener, and Mojsov is reflective of this. While much of the discussion surrounding this award has focused on the treatment of obesity, these investigators, along with many others, were instrumental in identifying and harnessing a physiological system with the promise to change the life course of the many people suffering from diabetes and its complications.