The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2–3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.
Obesity, diagnosed as a body mass index (BMI) ≥ 30 kg/m 2, is a progressive, chronic disease that has grown to pandemic prevalence over the past decades. Obesity substantially increases the risk of type-2 diabetes (T2D), cardiometabolic diseases, osteoarthritis, neurological and mental disorders as well as several forms of cancer, resulting in premature disability and demise. Depending on the severity of the disease and the age at diagnosis, long-term health complications may last a lifetime and worsen the therapeutic outcome for multiple associated chronic diseases. Unsurprisingly, obesity leads to excess medical costs and imposes a large economic burden on individuals, families, health care systems, and societies.
While traditionally recognized primarily as a disease of the elderly, T2D is currently one of the most frequently diagnosed preventable chronic diseases in middle age, as well as children and adolescents. Excess body fat along with age constitute the two most important risk factors for the premature development of T2D. Some studies report that >80% of youth and ~50% of adults with T2D are overweight or obese at point of diagnosis. Early onset T2D relative to late-onset disease is associated with a more rapid deterioration of β-cell function, emphasizing the importance for early diagnosis and treatment initiation. Obesity-related mechanisms that are potentially linked to the severity of the disease include adipocyte lipid spillover, ectopic fat accumulation and tissue inflammation. Sizeable weight loss not only improves glucometabolic health, it may also reduce the risk for obesity-linked co-morbidities, increase life expectancy, and improve quality of life. Therapies aiming to decrease body weight are consequently a valuable strategy to delay the onset and decrease the risk of T2D, as well as managing established disease.
Lifestyle modifications, such as balanced nutrition, calorie restriction and physical exercise, remain the cornerstone of any weight loss intervention. However, lifestyle changes alone are insufficiently efficacious and sustainable as a stand-alone therapy, possibly because physiological adaptations conspire to promote weight regain following diet-induced weight loss. Genetic and environmental factors may further undermined treatment efficacy. Polygenetic gene variants, each accounting for only a small difference in body weight, may sum up to sizably affect body mass and may hinder susceptibility of an individual to respond to a weight loss intervention. There are also less frequent variants with larger effects leading to early onset of severe obesity in humans. Several syndromic and monogenic disorders of obesity that have been identified include Prader–Willi syndrome, Bardet–Biedl syndrome, and loss-of-function mutations in the genes encoding for pro-opiomelanocortin (POMC), leptin, leptin receptor (LEPR) or the melanocortin-4 receptor (MC4R).
Pharmacotherapy as an adjunct to lifestyle adjustments is often used to enhance weight loss efficacy. However, a key obstacle in the development of anti-obesity medication is that rodent studies proved largely incapable to predict cardiovascular safety in humans. Also, the heterogeneity of patient cohorts, with many individuals being of advanced age and at high risk for development of cardiovascular diseases (CVD), represents an obstacle that is not easy to address with pharmacotherapy. Consistent with this, a series of previously employed anti-obesity medications were withdrawn soon after approval due to unforeseen adverse effects on the cardiovascular system. Furthermore, when given at tolerable doses, pharmacotherapy rarely decreases body weight >10%. Notable exceptions are semaglutide 2.4 mg (Wegovy® Novo Nordisk, Copenhagen, Denmark), a long-acting agonist at the glucagon-like peptide-1 receptor (GLP-1R), and the experimental drug candidate tirzepatide, a dual-agonist at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Each of these peptides decrease body weight with a favorable safety profile in the majority of patients by >10%. While the clinical success of these drugs sets the stage for a new era in anti-obesity medication, there remains considerable controversy as to how GIP regulates metabolism and whether GIP receptor agonism or antagonism is a preferred treatment for obesity and T2D. In this manuscript, we provide an overview of the mechanistic biology and in vivo pharmacology of GLP-1 and GIP. We summarize recent clinical results with molecules that target each receptor and discuss recurrent questions related to their mode-of-action.
GLP-1 is encoded by proglucagon, a 158 amino acid precursor protein, that is predominantly expressed in the gut, pancreas, and distinct neuronal populations of the hindbrain. In the brain and the intestine, proglucagon is cleaved by the action of the prohormone convertase 1/3 (PC1/3) into GLP-1, GLP-2, glicentin, glicentin-related polypeptide (GRPP), and oxyntomodulin (OXM). In the pancreatic α-cells, proglucagon is cleaved by PC2 into glucagon, GRPP and the major proglucagon fragment (MPGF). In the intestine, GLP-1 is secreted from enteroendocrine L-cells located in the gut epithelium. The density of the L-cells is low in the duodenum and jejunum and it is high in the ileum and colon. Nutrients stimulating the secretion of GLP-1 in the intestine include monosaccharides such as glucose, galactose, fructose, fatty acids, as well as proteins and amino acids, particularly glutamine and glycine. The relevance of endocrine factors to promote GLP-1 secretion seem to vary across species and may include acetylcholine, insulin, ghrelin, GIP, and gastrin-releasing peptide. Circulating levels of total GLP-1 are low during fasting (~5 pmol/l) and rapidly rise up to 40 pmol/l shortly after a meal. Consistent with the ability of GLP-1 to accelerate glucose-stimulation of insulin secretion (GSIS), the meal-induced rise in plasma GLP-1 is paralleled by enhanced insulin immunoreactivity.
GLP-1 promotes its biological action through binding to the GLP-1 receptor (GLP-1R), a 7 transmembrane G protein-coupled receptor of the class B family. GLP-1R signals primarily via the Gαs pathway, and hence accelerates intracellular levels of cAMP. GLP-1R can also recruit, and induce signaling, via the Gαq and β-arrestin pathways and knockdown of β-arrestin-1 in rat insulinoma (INS1) cells decreases the ability of GLP-1 to promote GSIS. Immunohistochemical studies in tissues from humans and non-human primates show widespread distribution of GLP-1R in the brain and in the periphery. These data largely align with studies in rodents in which the abundance of the GLP-1R transcript was assessed using mice that express green fluorescent protein (GFP) under control of the GLP-1R promoter. Consistent with the ability of GLP-1R agonists to decrease homeostatic and hedonic food intake, expression GLP-1R is found in the rodent hypothalamus (ARC, VMH, DMH, PVH, LH), hindbrain (AP, NTS, ventrolateral medulla) and telencephalon (amygdala, olfactory bulb, preoptic area, nucleus accumbens). In the pancreas, GLP-1R is solidly expressed in the β- and δ-cells but is only found in a small portion of α-cells. No expression of GLP-1R is found in the liver and the thyroid gland.
Albeit best known for its glycemic effects, GLP-1 is a pleiotropic hormone with a series of metabolic effects beyond the regulation of glucose metabolism.
