The Semaglutide Effect: How Science Is Driving a Weight-Loss Revolution Blog post by Andrew Davies In a recent article , we discussed the increasing popularity and prevalence of semaglutide treatment for weight loss. Here, we explore in more detail the development of semaglutide, review the science behind this and other new weight-loss treatments, and discuss new developments and opportunities in the field.

History of Weight Loss Treatments

We have previously described recent global obesity trends and its classification as a disease as well as some of the different pharmaceutical approaches to treatment ; what remains abundantly clear is that obesity is of increasing concern from a public health perspective. However, although awareness and concern regarding the prevalence of obesity have risen dramatically in recent years, treatments aimed at effecting weight loss were described as far back as the 2nd century AD, in the writings of Soranus of Ephesus (https://pubmed.ncbi.nlm.nih.gov/18386109/). The recommended treatment options described at the time included many that remain familiar today: reduced caloric intake, exercise or physical activity, and water loss via perspiration or diuresis. In the past century, interest in pharmacological methods to achieve weight loss has grown, and beginning in the 1920s and 30s, a number of new approaches achieved transient popularity. Examples included thyroid hormone, amphetamines, diuretics, and laxatives. In more recent years, a combination of fenfluramine and phentermine, more commonly known as fen-phen, achieved widespread use (and ultimately notoriety) in the 1990s before being withdrawn due to harmful side effects. In parallel to pharmacological treatment research, behavioral approaches have long been considered as effective methods to combat obesity. Changes to diet, lifestyle, and activity level were traditionally viewed as effective non-pharmacological treatments, and in many cases continue to be viewed as such, despite more recent evidence suggesting their lack of efficacy. More dramatic surgical and mechanical approaches have also been advocated for at various times. For example, the wiring shut (or nearly so) of the jaw to forcibly reduce caloric intake was explored as a possible weight loss method in the 1980s (CITATION) and onward (https://www.nature.com/articles/s41415-021-3081-1). More recently, bariatric surgery techniques (such as adjustable gastric band or lap-band) have become more common, ultimately achieving a similar effect to jaw wiring by reducing food intake as a consequence of reducing stomach size (in addition to other effects, such as changes in nutrient absorption). In all cases, the goal of these various treatments has remained largely unchanged for decades (or even centuries); namely to effect weight loss. However, in addition to their common goal, they share other key similarities such as lack of efficacy, undesirable and harmful side effects, or a lack of subject adherence. Indeed, even in instances where the treatment proved initially effective, any benefit was often lost following cessation of treatment or intervention. Thus, despite decades, or even millenia, of efforts to identify effective methods of weight loss, the search for a weight loss treatment that is effective, well tolerated, and easy to administer has remained largely unfulfilled. A new class of drugs known as incretin hormones, the most notable of which to date is glucagon-like peptide-1 (GLP-1) receptor agonist (more commonly known as semaglutide), aims to change this.

Glucagon-Like Peptide-1 (GLP-1) and Mimics

The first identification of glucagon-like peptide-1 and its ensuing characterization has been described in detail by Daniel J. Drucker (__https://www.jci.org/articles/view/97233), a Canadian endocrinologist who would subsequently play a pivotal role in the development of related derivative pharmacotherapies. In summary, research on endocrine activity in the gastrointestinal tract revealed the activity of incretins, gut-derived hormones that stimulated insulin release by the pancreas after eating. One of these hormones, GLP-1, demonstrated complete conservation among different mammalian species, and the application of truncated forms (GLP-1 (7-37)) stimulated insulin secretion in isolated mammalian pancreas, with GLP-1 itself secreted in response to glucose in the luminal intestine. Facilitated by advancements in research methods, particularly those related to protein synthesis and characterization, this work eventually led to studies in humans demonstrating that infusion of GLP-1 resulted in stimulation of insulin secretion and inhibition of glucagon secretion. In a series of ensuing studies by Jens Holst and colleagues in Denmark, GLP-1 demonstrated clinical potential as an inhibitor of appetite, reduced food intake, and consequently was identified as a promising new target for the treatment of obesity. However, clinical efficacy appeared limited by a short half life and degradation by endogenous enzymes. Although in vivo inhibition of GLP-1 metabolism and cleavage was possible, attention was turning towards alternative GLP-1 agonists. In addition to some of the previously described effects, Drucker and colleagues used GLP-receptor knockout mice to further explore the function and role of GLP-1. Although GLP-1 agonists have achieved public popularity in recent years, the first related medication to receive clinical approval for the treatment of type 2 diabetes in the US was exenatide, a GLP-1 receptor agonist, in 2005. Bearing considerable homology to GLP-1, one of its key characteristics was a longer half-life, overcoming an important obstacle to earlier GLP-1 treatment efforts. Some of the common features of exenatide and subsequent GLP-1 receptor agonists are the promotion of pancreatic insulin secretion in response to eating, suppression of pancreatic release of glucagon, slowing of digestion in the stomach, and ultimately lowering appetite and promoting satiety. A key advantage of such approaches is the activation of endogenous pancreatic sources of insulin, as opposed to the traditional exogenous introduction of insulin, which, if administered incorrectly, may result in hypoglycemia. Exenatide was originally isolated from lizard venom in 1992, but some of the same challenges remained unsolved at the time of its approval for clinical use some 13 years later. Despite improving on the bioavailability of GLP-1, dosing, optimization of pharmacokinetic profiles, and timing and method of administration remained unsatisfactory. Subsequent efforts to address these limitations culminated in the development of a related drug, and one that is more widely known: semaglutide.[fusion_builder_container type="flex" hundred_percent="no" hundred_percent_height="no" min_height_medium="" min_height_small="" min_height="" hundred_percent_height_scroll="no" align_content="stretch" flex_align_items="flex-start" flex_justify_content="flex-start" flex_wrap_medium="" flex_wrap_small="" flex_wrap="wrap" flex_column_spacing="" hundred_percent_height_center_content="yes" equal_height_columns="no" container_tag="div" menu_anchor="" hide_on_mobile="small-visibility,medium-visibility,large-visibility" status="published" publish_date="" class="" id="" margin_top_medium="" margin_bottom_medium="" margin_top_small="" margin_bottom_small="" margin_top="20px" margin_bottom="20px" padding_top_medium="" padding_right_medium="" padding_bottom_medium="" padding_left_medium="" padding_top_small="" padding_right_small="" padding_bottom_small="" padding_left_small="" padding_top="" padding_right="3%" padding_bottom="" padding_left="3%" link_hover_color="" hue="" saturation="" lightness="" alpha="" link_color="" border_sizes_top="" border_sizes_right="" border_sizes_bottom="" border_sizes_left="" border_color="" border_style="solid" border_radius_top_left="" border_radius_top_right="" border_radius_bottom_right="" border_radius_bottom_left="" box_shadow="no" box_shadow_vertical="" box_shadow_horizontal="" box_shadow_blur="0" box_shadow_spread="0" box_shadow_color="" box_shadow_style=