Executive Summary

Glucagon-like peptide-1 (GLP-1) drugs – a class of medications originally developed for type 2 diabetes – have evolved into a transformative therapy with broad implications for metabolic disease. This report provides a comprehensive history of GLP-1-based therapy, from early scientific discoveries to modern clinical applications and future directions. GLP-1 is an incretin hormone produced in the gut that enhances insulin secretion in response to food intake while suppressing glucagon, slowing gastric emptying, and reducing appetite (^[1]) (^[2]). These properties make it an attractive target for treating hyperglycemia and obesity. Over the past decades, researchers overcame significant challenges – such as the hormone’s very short half-life in the body – to develop long-acting GLP-1 receptor agonist drugs. The first GLP-1 analog (exenatide) was derived from the surprising source of Gila monster venom and approved in 2005 (^[3]) (^[4]), opening a new era of “incretin mimetic” therapy. Since then, multiple GLP-1 agonists have been developed (e.g. liraglutide, dulaglutide, semaglutide), each improving on dosing convenience or potency.

Clinically, GLP-1 drugs have demonstrated powerful glucose-lowering effects and significant weight loss benefits in patients with type 2 diabetes (^[5]) (^[6]). Trials show these agents can reduce glycated hemoglobin (HbA₁c) by ~1% or more and induce weight reductions of 5–10% of body weight in many patients (^[7]) (^[6]). Notably, unlike older diabetes medications, GLP-1 agonists carry minimal risk of hypoglycemia because their insulin stimulation is glucose-dependent (^[2]). Beyond glycemic control, large outcome studies have confirmed that certain GLP-1 agonists significantly improve cardiovascular outcomes (reducing heart attacks, stroke, or cardiovascular death) in high-risk diabetic patients (^[8]) (^[9]). They also slow progression of diabetic kidney disease and are associated with beneficial effects like lower blood pressure and improved lipid profiles (^[8]) (^[7]). These findings led to changes in clinical practice guidelines – modern diabetes guidelines recommend GLP-1 agonists (or related drugs) for patients with type 2 diabetes who have cardiovascular risk, and even suggest using a GLP-1 RA prior to insulin in many cases due to their multiple benefits and weight loss advantage (^[10]) (^[11]).

GLP-1 drugs have also revolutionized obesity treatment. Higher-dose formulations of liraglutide and semaglutide were approved specifically for chronic weight management after clinical trials showed unprecedented efficacy in inducing weight loss (e.g. ~12–15% average body weight reduction with semaglutide) (^[12]). By 2023, these medications (branded as Saxenda, Wegovy, etc.) gained widespread attention beyond the diabetes field – one survey found 1 in 8 American adults had tried a GLP-1 medication for weight loss or diabetes (^[13]). The demand for these drugs surged so rapidly that manufacturers faced supply shortages (^[14]). GLP-1 drugs are now viewed as a potential game-changer for the obesity epidemic, offering non-surgical means to achieve weight losses approaching those of bariatric procedures. This has fueled intense interest and competition in the pharmaceutical industry. Novo Nordisk’s semaglutide (Ozempic® for diabetes, Wegovy® for obesity) and Eli Lilly’s dual-agonist tirzepatide (Mounjaro®, a related drug that also activates the GIP hormone receptor) have become blockbusters, propelling their companies to record-high market valuations (^[15]) (^[16]). Annual sales of GLP-1 analogs now measure in the tens of billions of dollars globally, and analysts project continued growth as new indications (e.g. for heart and kidney disease prevention) are explored (^[17]) (^[18]).

This report is organized to provide an in-depth exploration of GLP-1 drug development, clinical evidence, and multi-faceted impact. We begin with the scientific background – tracing the incretin concept from early 20th-century experiments through the discovery of GLP-1 in the 1980s. Next, a detailed historical chronology is presented, covering each major GLP-1-based drug: how it was developed, trial results, and its clinical role. We examine real-world outcomes and case examples that illustrate how GLP-1 therapies have improved patient health (for instance, reports of patients losing substantial weight and regaining metabolic control on these drugs (^[19]) (^[20])). The report also discusses safety controversies (such as past concerns about pancreatitis and thyroid tumors) and how they have been addressed by research and regulatory reviews. Multiple perspectives are considered – including the viewpoints of researchers (e.g. the serendipitous discovery of exenatide by scientists fascinated with venom (^[21]) (^[22])), clinicians (adapting practice guidelines to incorporate these new therapies), patients (experiencing improved quality of life and weight loss), and public health experts (weighing the societal impact of widespread GLP-1 use).

Finally, we look ahead to future directions. </current_article_content>Ongoing research is probing novel applications of GLP-1 agonists beyond diabetes and obesity – from potential use in non-alcoholic fatty liver disease (NASH) to trials investigating neuroprotective effects in conditions like Parkinson’s and Alzheimer’s disease (^[23]) (^[24]). New molecules that combine GLP-1 activity with other hormones (e.g. dual agonists for even greater weight loss) are emerging, and oral or longer-acting injectable formulations are under development. The implications of GLP-1 drugs are far-reaching: if issues of cost and access can be managed, these medications could significantly reduce the burden of type 2 diabetes, cardiovascular disease, and obesity-related complications on a global scale. In summary, the history of GLP-1 drugs is a remarkable journey from an obscure gut peptide to a cornerstone of modern metabolic therapy – a journey marked by scientific ingenuity, translational research breakthroughs, and profound clinical benefit for millions of patients.

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Introduction and Background

GLP-1 (Glucagon-Like Peptide-1) is a hormone that has gone from a physiological curiosity to a therapeutic powerhouse in recent decades. To understand the significance of GLP-1 drugs, it is essential to appreciate the background of the “incretin effect” and the early quest for gut-derived diabetes treatments. The incretin effect refers to the body’s stronger insulin response to oral glucose as compared to intravenous glucose at the same blood sugar level (^[25]) (^[26]). In other words, something released by the gut upon eating enhances insulin secretion beyond what rising glucose alone would stimulate. This phenomenon was first suspected over a century ago. In 1906, Dr. Ernest Moore and colleagues hypothesized that the duodenal mucosa secretes a factor acting as “a chemical excitant” on the pancreas to help dispose of glucose (^[27]). They even tried (with little success) to treat diabetes by injecting extracts of the gut, an early attempt at hormone therapy (^[28]). The term “incretin” was later coined (in 1932 by La Barre) for this proposed intestinal insulin-stimulating substance (^[29]) (^[28]). However, the identity of incretin hormones remained elusive for decades.

It was not until the 1960s that technological advances – in particular, the radioimmunoassay for insulin developed by Yalow and Berson – allowed scientists to clearly demonstrate the incretin effect in humans (^[25]). Pioneering experiments by J.E. Perley and D.M. Kipnis (1964) showed that gastrointestinal factors were indeed responsible for the extra insulin secreted after oral glucose, and that this mechanism was markedly impaired in patients with type 2 diabetes (^[30]) (^[26]). These findings renewed interest in gut hormones. By the 1970s, one hormone was identified as an incretin candidate: Gastric Inhibitory Polypeptide (GIP), discovered in 1969–70, which was found to stimulate insulin secretion (and renamed Glucose-Dependent Insulinotropic Polypeptide) (^[29]). GIP is released from the upper small intestine in response to nutrients. While GIP indeed acts as an incretin in healthy individuals, researchers found an important limitation – in patients with type 2 diabetes, GIP loses most of its insulinotropic efficacy (the pancreatic cells become “GIP-resistant”) (^[31]). This meant GIP alone could not solve the problem of deficient insulin secretion in diabetes, implying at least one additional incretin hormone remained to be discovered (^[32]).

Discovery of GLP-1: The breakthrough came in the 1980s. Scientists studying the biochemistry of proglucagon – the precursor molecule that in the pancreas yields glucagon – found that in the gut, this same gene is processed into different peptide products (^[33]). Notably, two new “glucagon-like peptides” were identified in intestinal extracts: GLP-1 and GLP-2. In 1986, a truncated form of GLP-1 (specifically GLP-1(7–36) amide) was isolated from the gut and shown to have potent effects: it stimulated insulin secretion and suppressed glucagon secretion in the presence of elevated glucose (^[34]). It also reduced appetite and food intake, as studies soon demonstrated (^[1]). Unlike GIP, this new GLP-1 hormone retained its insulin-stimulating action even in patients with type 2 diabetes (^[35]). The discovery of GLP-1 as an active incretin hormone is credited largely to work by Jens J. Holst and colleagues in Denmark and by Joel Habener’s group in the U.S., among others, who together elucidated the sequence and functions of GLP-1 in the mid-1980s (^[36]) (^[37]). By 1987, GLP-1 was established as a prime incretin candidate (^[37]).

With GLP-1 identified, researchers immediately recognized its therapeutic potential: if one could harness GLP-1’s potent glucose-lowering and appetite-suppressing effects, it might become a treatment for diabetes or even obesity. There was one major obstacle: native GLP-1 is extremely short-lived in the body. Endogenous GLP-1 is rapidly degraded by the enzyme Dipeptidyl Peptidase-4 (DPP-4), with an effective plasma half-life of only ~2 minutes after intravenous injection (^[38]) (^[39]). As a result, simply injecting GLP-1 itself was impractical – it would be cleared before having sustained benefit. Early clinical experiments showed that a continuous intravenous infusion of native GLP-1 could nearly normalize blood glucose levels in people with type 2 diabetes (^[40]) (^[38]). But to maintain that effect, an IV drip had to run constantly, given the peptide’s rapid clearance. Attempts to give intermittent injections of GLP-1 were ineffective because the peptide vanished so quickly (^[39]). Researchers even tried giving very high doses of GLP-1 to overcome its short half-life, but patients experienced severe nausea and vomiting due to the burst of gut hormones (^[41]) (^[42]). By the late 1980s, it was clear that therapeutically using GLP-1 would require either modifying the molecule to last longer or finding another way to keep levels high. This realization set the stage for two parallel strategies that unfolded in the 1990s and 2000s: (1) development of injectable GLP-1 analogues resistant to degradation, and (2) development of DPP-4 inhibitors to protect and elevate native GLP-1 levels (^[43]).

In the early 1990s, a major clue for extending GLP-1 action came from an unlikely source: venomous lizards. A young NIH researcher, Dr. Jean-Pierre Raufman, working with biochemist John Eng, discovered that the Gila monster (a desert reptile) produces in its saliva a peptide that mimics GLP-1’s action but is not rapidly destroyed by DPP-4 (^[44]) (^[45]). This peptide was exendin-4, and it would become the foundation of the first GLP-1 drug (details in the next section). Around the same time, companies like Novo Nordisk began medicinal chemistry efforts to create modified human GLP-1 analogues with longer half-lives (for example, by adding fatty acid chains to help the peptide bind to albumin and resist degradation) (^[46]) (^[47]). The convergence of these lines of research led to what we now know as GLP-1 receptor agonist therapies.

Today, GLP-1 receptor agonists are an established drug class for diabetes and obesity, and their history of development is a rich story of scientific innovation. Table 1 below provides a timeline of key milestones in the history of GLP-1 drugs – from early scientific discoveries to drug approvals – which will be elaborated in subsequent sections:

Table 1: Timeline of key events in the discovery and development of GLP-1 drugs. This chronological summary highlights major historical milestones from the incretin concept through to the current generation of GLP-1-based therapies and their impacts. Details and references for each item are discussed in the sections below.

The following sections of this report will delve into each era and aspect of GLP-1 drug history in depth. First, we explore how exendin-4 from the Gila monster was developed into exenatide, the first GLP-1 medication. Next, we examine the subsequent wave of GLP-1 analogues (liraglutide and others) that improved pharmacokinetics and clinical outcomes. We then discuss the latest advances, including weekly analogues, oral formulations, and combination agents, as well as the broadening use of GLP-1 drugs in obesity and beyond. Throughout, we will interweave clinical trial data, real-world case observations, and perspective from experts to provide a nuanced understanding of how GLP-1 therapies have evolved and what challenges and opportunities lie ahead.

The Incretin Concept and Early GLP-1 Research (1970s–1990s)

Incretin Physiology: Setting the Stage

By the 1970s, researchers had solid evidence that gut hormones play a significant role in glucose metabolism. As mentioned, GIP was the first hormone identified to have incretin activity, but its failure in diabetic patients left an open question: what other gut factor accounts for the incretin effect? The discovery of GLP-1 in 1986 provided the answer – GLP-1 from the intestinal L-cells is the major incretin hormone responsible for up to ~50–70% of post-meal insulin release in healthy individuals (^[68]). Once scientists recognized this, intense interest focused on exploiting GLP-1 for therapy.

A series of experiments in the late 1980s and early 1990s helped characterize GLP-1’s effects in humans:

• GLP-1 Infusion Studies: In 1989, Nauck et al. and other groups began infusing GLP-1 into patients with type 2 diabetes. These studies showed that GLP-1 could dramatically lower blood glucose, even normalizing fasting and postprandial sugar levels in some cases (^[40]) (^[49]). For example, one trial found that a continuous GLP-1 infusion over 24 hours reduced diurnal glucose levels to near-normal in patients with NIDDM (non-insulin-dependent diabetes) (^[69]). This proved GLP-1 was a powerful antidiabetic agent. However, when the infusion stopped, glucose control deteriorated quickly due to the hormone’s short action. Thus, while GLP-1 worked, it would require constant administration – not feasible outside a hospital.

• Pharmacokinetic Challenges: Researchers determined that the reason for GLP-1’s fleeting presence is rapid enzymatic degradation. The enzyme DPP-4 clips GLP-1 at the N-terminus, inactivating it. In fact, native GLP-1 (7-36 amide) has a plasma half-life of ~1–2 minutes IV, and only ~5 minutes when subcutaneously injected (^[38]). This meant subcutaneous injections of unmodified GLP-1 would not sustain therapeutic levels. In one study, even supra-pharmacologic bolus doses of GLP-1 provided only transient glucose reductions and often triggered nausea/vomiting (due to high peak levels) (^[41]) (^[70]).

• DPP-4 Inhibition Idea: By early 1990s, based on the above, two possible solutions emerged. One was to inhibit DPP-4 so that the body’s own GLP-1 lasted longer. Experiments in animals showed that DPP-4 inhibitors could raise endogenous GLP-1 levels and modestly improve glycemic control (^[43]). This concept eventually led to drugs like sitagliptin (approved 2006), but those would generally have less potent effects than direct GLP-1 agonists since GLP-1 levels only double or triple on DPP-4 inhibitors (and those drugs rely on some residual pancreatic function and meal stimulation) (^[58]). The other solution was to create GLP-1 analogues or mimetics resistant to DPP-4.

• The Exendin-4 Serendipity: A crucial piece of the puzzle came from comparative biology. Some species have evolved peptides similar to human hormones. In the early 1990s, Dr. John Eng, an endocrinologist at a Bronx Veterans Affairs lab, was intrigued by a presentation from Dr. Raufman about Gila monster (Heloderma) venom. The Gila monster, a lizard, eats large, infrequent meals. Eng hypothesized it might produce a hormone to modulate insulin for those big meals (^[71]) (^[72]). Indeed, Raufman had isolated two peptides (exendin-1 and exendin-2) from Gila saliva with unknown function (^[21]) (^[73]). Eng teamed up with Raufman, and by 1992 they identified “exendin-4” – a 39–amino acid peptide in Gila monster venom (^[44]) (^[50]). When they aligned exendin-4’s sequence with human peptides, the closest match was GLP-1 (^[74]) (^[75]). Excited, Eng tested exendin-4 in diabetic rodents: the results were astonishing – exendin-4 lowered blood glucose to normal and kept it low for hours, even over a day in some cases (^[49]). In other words, it acted like a long-lasting form of GLP-1 in animals. This discovery was a watershed moment: nature had already evolved a stable GLP-1 analog. Exendin-4 differs from human GLP-1 by about 50% of its amino acids, importantly having a glycine instead of alanine at the N-terminus (making it DPP-4 resistant) (^[45]). Because it came from a species that humans never encountered evolutionarily, our enzymes did not readily destroy it (^[76]) (^[77]). Eng recognized its therapeutic promise and, as noted, filed a patent in 1993 (^[51]).

These developments set the stage for translating GLP-1 biology into a drug. Yet, bridging the gap from lab to market was not straightforward. Eng initially struggled to find support – the medical community was skeptical in the mid-1990s of a “lizard venom drug,” and big pharma showed little interest in his exendin-4 peptide (^[78]) (^[79]). It took persistence and some lucky timing at a conference (ADA 1996) for Eng to connect with Amylin Pharmaceuticals, a small biotech, which recognized the potential and licensed exendin-4 (^[55]) (^[56]). Meanwhile, across the Atlantic, Novo Nordisk and other companies were busy engineering human GLP-1 analogues (like “NN2211,” which became liraglutide) using techniques such as acylation to extend half-life (^[80]) (^[81]).

By the late 1990s, the pieces were in place: GLP-1 was a validated target, and prototype therapeutic agents (exendin-4 and a few modified human GLP-1 analogs) were entering clinical testing. The next sections describe how these agents progressed through development, starting with the exendin-4 story which yielded the first approved drug, exenatide.

Development of the First GLP-1 Drug: Exenatide (Byetta)

From Gila Monster to “Miracle” Diabetes Drug

The journey of exenatide – the first GLP-1 receptor agonist medication – is a fascinating case study in drug development. Exenatide’s origin lies in the discovery of exendin-4 as discussed. After Amylin Pharmaceuticals licensed exendin-4 in 1996, they (in partnership with Eli Lilly & Co. from 2002 onward) pushed it through preclinical and clinical development (^[82]) (^[83]). A synthetic version of exendin-4 was produced and named exenatide (generic name), with the brand name Byetta for the initial twice-daily form. Key milestones in exenatide’s development include:

• Preclinical Testing: Amylin’s researchers found exenatide was a full agonist at the human GLP-1 receptor, mimicking all the effects of GLP-1 – stimulating glucose-dependent insulin release, inhibiting glucagon, slowing gastric emptying, and reducing food intake (^[84]) (^[85]). Importantly, exenatide was much more durable in circulation: it has ~2.4 hours half-life in humans vs just minutes for GLP-1 (^[86]) (^[87]). It is cleared renally rather than by DPP-4 digestion (^[45]). These properties meant exenatide could potentially be injected at intervals (e.g. twice a day) and still provide continuous receptor activation.

• Clinical Trials: The first clinical trials of exenatide in people with type 2 diabetes took place around 2001–2003. Phase 2 studies demonstrated that twice-daily exenatide injections significantly lowered blood glucose levels and hemoglobin A1c, with many patients achieving better glycemic control than with oral medications alone (^[57]) (^[2]). An added and unexpected benefit was weight loss: patients on exenatide tended to lose weight over the weeks and months of treatment, whereas those on placebo or some other glucose-lowering drugs gained weight (^[88]) (^[19]). In trials, exenatide improved post-meal glucose spikes (due to its gastric slowing effect and insulin boost after meals) and also moderately lowered fasting glucose. Because it only works when glucose is elevated, the risk of hypoglycemia was low (except if combined with a sulfonylurea that independently can cause low sugars) (^[2]) (^[89]).

• Regulatory Approval: In April 2005, the FDA approved exenatide (Byetta) as an adjunctive therapy for type 2 diabetes (^[4]) (^[2]). It was indicated for patients not achieving control with oral agents like metformin or sulfonylureas. Byetta was the first-in-class “incretin mimetic” – a term used in its marketing to highlight that it mimics the incretin hormone GLP-1 (^[2]). The initial approved regimen was 5 µg subcutaneous injection twice daily, given within 60 minutes before morning and evening meals, titratable to 10 µg BID. Notably, Byetta was not approved as monotherapy initially (only as add-on), and it carried precautions about pancreatitis (we discuss safety later) and a note that it wasn’t a substitute for insulin in type 1 diabetes.

When Byetta hit the market in mid-2005, it garnered a lot of attention. For patients and clinicians, this was a novel mechanism – a drug for diabetes that caused weight loss and had low hypo risk was almost unheard of at the time. An Associated Press headline summed it up: “FDA approves diabetes drug derived from lizard – a new option for Type 2 patients” (^[4]). Diabetologists like Dr. John Buse have recounted that some patients on exenatide had “rapid improvements” in blood sugar and lost several kilograms of weight, leading to high satisfaction (^[19]) (^[90]). By 2006, anecdotal reports (even featured in The New York Times) described patients enamored with the drug: one patient nicknamed his Byetta pen “Lizzie” in homage to its reptilian roots, crediting it for helping end his “love affair with the refrigerator” (^[59]) (^[91]). In one report, a man lost 20 pounds in 2 months on exenatide while significantly improving his glucose control (^[59]).

From a scientific perspective, exenatide’s approval proved the validity of GLP-1 receptor agonism as a therapeutic strategy (^[92]) (^[93]). It opened the floodgates for other pharmaceutical companies to invest in this area, since it was now a viable and FDA-recognized approach. Eli Lilly, which had co-marketed Byetta with Amylin, soon started developing its own GLP-1 compounds (e.g. dulaglutide, discussed later) once their partnership with Amylin ended in 2011 (^[16]). Novo Nordisk, which had started GLP-1 analog work earlier, was close behind with liraglutide. Thus, the success of Byetta catalyzed a competitive race to create improved GLP-1 drugs.

Clinical Profile of Exenatide

To understand subsequent innovations, it’s helpful to summarize exenatide’s clinical profile (as the first GLP-1 RA):

• Efficacy: In trials, twice-daily exenatide (10 µg BID) typically reduced HbA₁c by approximately 0.8%–1.0% more than placebo by 30 weeks (^[60]) (^[94]). For example, if baseline HbA₁c was 8.5%, it might drop to ~7.5%. Some head-to-head studies later compared exenatide BID to insulin or to newer GLP-1 RAs. Exenatide generally provided a similar A1c reduction to long-acting insulin glargine in one study, but with weight loss instead of weight gain (^[95]). It was not as potent as the high-dose once-daily liraglutide (we’ll see below) but it was a solid improvement over adding a placebo. Fasting glucose reductions with exenatide were modest, because its levels wane between injections; its main impact was postprandial glucose lowering, addressing meal-time spikes thanks to delayed gastric emptying and enhanced meal-time insulin secretion (^[2]) (^[89]).

• Weight Loss: Over 6 months, patients on exenatide lost on average ~4–5 kg (8–11 lbs), whereas those on comparator therapies often lost little or even gained weight (^[6]) (^[60]). The weight loss effect was a distinguishing feature. It arises from exenatide’s central appetite suppression and possibly from nausea reducing caloric intake. Many patients report feeling full faster and having reduced cravings while on GLP-1 agonists. David Mendosa, an early patient on Byetta, famously reported needing a “grabber” tool to pick up newspapers before, but after losing over 100 lbs on exenatide in a year, he was able to resume mountain hikes (^[96]) (^[19]). (Such dramatic weight loss is not universal – average is more modest – but it highlights individual successes.)

• Side Effects: The main adverse effects of exenatide are gastrointestinal. In trials, ~30–45% of patients experienced nausea, especially initially (^[97]). Vomiting and diarrhea were also relatively common. These effects are dose-dependent and often improve after the first few weeks as the body acclimates. To mitigate this, initial dosing of exenatide usually starts low (5 µg BID) then increases to 10 µg BID after a month. Hypoglycemia with exenatide is minimal by itself (because it won’t trigger insulin in low-glucose conditions) (^[2]). However, when combined with a sulfonylurea (which forces insulin out regardless of glucose), the combo can cause lows; thus, lowering sulfonylurea dose is advised when starting a GLP-1 RA (^[98]) (^[99]). There were early post-marketing reports of pancreatitis in a small number of patients on exenatide, which raised concern (especially around 2007–2008). The FDA added warnings about pancreatitis symptoms for exenatide and initiated investigations across all incretin therapies. Subsequent large analyses did not confirm a significant increase in pancreatitis incidence due to GLP-1 RAs (www.ema.europa.eu) (www.ema.europa.eu), although a small elevation in risk can’t be entirely ruled out (this is discussed under Safety). Another safety finding: exenatide is renally cleared, and there were cases of acute kidney injury in people with renal impairment or dehydration while on exenatide (^[100]). Caution is advised in patients with severe kidney disease, and monitoring hydration is important if vomiting occurs.

• Dosing & Administration: Exenatide BID required some patient commitment – an injection twice a day using a pen injector, and timing it before meals. Still, many patients accepted this for the benefits. The injection is subcutaneous (typically abdomen, thigh, or upper arm). Each pen delivered a month’s worth of doses. Byetta quickly became known as a more complex regimen than a once-daily pill but preferable to starting insulin for many, given no need for glucose monitoring to avoid hypos and the weight loss effect. In fact, clinical guidelines around 2007–2008 began to position GLP-1 agonists as an option after oral medications and before insulin for patients who were overweight and not at A1c goal.

• Nicknames & Culture: As noted, patients and media dubbed Byetta the “lizard spit” or “Gila monster” drug. The unusual origin story captured public imagination, but also initially caused some wariness – convincing people to inject a reptile-derived compound required education. With time, the success stories eased concerns. In 2012, Dr. John Eng (exendin’s discoverer) was co-awarded the Golden Goose Award, a recognition by the U.S. Congress for seemingly odd or obscure research (like studying snake venom) that led to major public benefit (^[101]) (^[102]).

Exenatide’s early success set important precedents. It demonstrated that longer-acting GLP-1 analogs could be even better – since exenatide was short-acting, the obvious next step was to extend its action to once-daily or once-weekly to provide more consistent glucose control. Additionally, the weight loss seen with exenatide hinted at a whole new therapeutic area: anti-obesity medication. At first, weight loss was seen simply as a bonus effect in diabetics, but it foreshadowed the repurposing of GLP-1 drugs for obesity alone, a concept realized years later.

Before moving to the next drugs, it’s worth mentioning exenatide’s subsequent formulations. In 2012, a once-weekly version called Bydureon was approved. This was essentially exenatide embedded in biodegradable microspheres, allowing it to slowly release over 7 days. Bydureon (exenatide extended-release) offered the convenience of weekly dosing and more even drug levels (blunting the peaks that cause nausea). It produced slightly better A1c reduction than Byetta BID in head-to-head trials and with less frequent nausea after initial weeks (^[60]) (^[94]). However, early Bydureon required mixing a powder with a liquid in a syringe (a bit cumbersome), and it sometimes caused injection-site nodules (a small lump under the skin due to the depot). Later, a pen formulation (Bydureon BCise) made it easier. Bydureon kept exenatide relevant as newer GLP-1 drugs emerged, but eventually exenatide’s role diminished since newer agents offered even greater efficacy. Amylin Pharmaceuticals was acquired by Bristol-Myers Squibb (and later AstraZeneca), and the “Byetta/Bydureon” franchise gradually declined by late 2010s as drugs like semaglutide took center stage.

In summary, exenatide was a trailblazer. It proved that an idea born from basic peptide science and a bit of venom lore could be translated into a safe and effective therapy benefiting millions. Every GLP-1 agonist drug introduced after 2005 builds on the foundation that exenatide laid. We will now turn to those next-generation GLP-1 drugs, starting with liraglutide, which addressed some limitations of exenatide and greatly expanded the use of GLP-1 agonists.

Next-Generation GLP-1 Agonists (2010s): Liraglutide, Pramlintide, Dulaglutide, and More

With the success of exenatide, other GLP-1 analogues rapidly advanced through development. The goals were to improve dosage convenience, potency, and tolerability. Several pharmaceutical companies had GLP-1 programs, but Novo Nordisk’s liraglutide became the next major product to reach the market.

Liraglutide (Victoza): A Human GLP-1 Analog for Once-Daily Use

Liraglutide is a modified human GLP-1 analog – essentially, it has the same amino acid sequence as human GLP-1 (7-37) except for two modifications: an arginine substitution at one position and a C-16 fatty acid chain attached via a spacer to Lysine at position 26 (^[103]). These tweaks confer albumin binding and shield liraglutide from immediate DPP-4 cleavage (^[103]) (^[104]). The result is a prolonged half-life of ~13 hours, making it suitable for once-daily injection (^[104]) (^[105]).

Novo Nordisk developed liraglutide under the code NN2211 in the early 2000s. By 2008–2009, phase 3 trials (collectively named the LEAD trials – Liraglutide Effect and Action in Diabetes) were completed. Liraglutide was approved in Europe in 2009 and by the FDA in January 2010 as Victoza® (^[106]) (^[107]). Key features and findings about liraglutide include:

• Glycemic Efficacy: Liraglutide showed greater A1c reduction than exenatide in trials. At the max dose (1.8 mg daily), liraglutide typically reduced HbA₁c by ~1.0% to 1.5% (depending on baseline) when added to metformin (^[95]) (^[60]). In one head-to-head study, liraglutide 1.8 mg daily lowered A1c by 1.12% vs baseline compared to 0.79% with exenatide 10 µg BID (^[6]) (^[60]). Furthermore, about 35–40% of patients on liraglutide achieved A1c <7% in trials, a higher proportion than with many oral agents. Liraglutide’s once-daily dosing provided steadier GLP-1 receptor stimulation, improving both fasting and postprandial glucose. While exenatide BID had stronger effect on postprandial glucose after the dosed meals, liraglutide’s continuous presence helped control fasting levels better (and still significantly blunted postprandial excursions at all meals) (^[108]) (^[60]).

• Weight Impact: Liraglutide also induced weight loss, with patients losing on average ~2–3 kg (5–7 lbs) over 26 weeks at 1.2–1.8 mg doses (^[6]) (^[60]). For example, one LEAD trial reported ~2.5 kg loss on liraglutide 1.8 vs ~1 kg gain on insulin glargine over 26 weeks (^[6]). Another trial comparing it with, say, a sulfonylurea, found liraglutide led to weight reduction while the SU caused weight gain (^[108]). Thus, liraglutide reinforced that weight loss is a class effect of GLP-1 RAs, though somewhat dose-dependent. Many patients on Victoza reported reduced appetite similar to Byetta users, but some also note less nausea after the initial titration period, possibly because of the slower absorption profile.

• Clinical Use and Flexibility: Victoza was approved for use as monotherapy or in combination with other oral agents (unlike Byetta’s initial restriction). It was indicated as a second-line or later therapy for T2DM, not first-line (metformin remained first-line). However, notably liraglutide was not to be combined with insulin at first, and not studied in type 1 diabetes. The dosing was once daily, any time of day (though patients often choose consistent timing). A typical schedule: start at 0.6 mg for 1 week (which is a subtherapeutic “lead-in” dose to improve GI tolerability), then increase to 1.2 mg daily. If needed, further increase to 1.8 mg daily for additional glycemic effect (^[109]) (^[110]). Most benefits were seen by 1.2 mg, but 1.8 mg gave a slight edge in A1c reduction for some and a bit more weight loss, with some increase in side effects.

• Side Effects and Safety: The side effect profile of liraglutide was similar to exenatide’s: predominantly GI issues (nausea ~20% of patients, vomiting in 10%, diarrhea ~10%) (^[97]) (^[98]). These were generally transient or manageable by dose titration. Liraglutide’s labeling came with a “Black Box” warning for thyroid C-cell tumors – this was due to rodent studies where liraglutide caused a dose-dependent increase in C-cell adenomas/carcinomas in rats (^[111]). Although the human relevance was (and remains) unproven – since rodents have many more GLP-1 receptors on thyroid C-cells than humans – out of caution the FDA mandated this warning. As a result, liraglutide (and later all long-acting GLP-1 RAs) is contraindicated in patients with a personal or family history of Medullary Thyroid Carcinoma (MTC) or MEN2 syndrome, and patients are informed of this theoretical risk (^[112]) (^[113]). So far, epidemiological studies have not shown an increase in thyroid cancer incidence in humans on GLP-1 drugs (^[114]) (^[115]), but the warning persists for safety. Additionally, during development, a few cases of pancreatitis occurred – similar to exenatide, Victoza’s label listed pancreatitis as a risk. Post-marketing surveillance for liraglutide did not show a higher-than-background rate of pancreatitis in diabetic patients (www.ema.europa.eu) (www.ema.europa.eu), but all GLP-1 RAs have a precaution for pancreatitis symptoms (patients are advised to discontinue and seek care if severe abdominal pain suggestive of pancreatitis occurs).

• Comparative Advantage: Liraglutide was the first GLP-1 RA to demonstrate superiority over some existing therapies in head-to-head trials. For instance, in LEAD-6 trial, as noted, liraglutide 1.8 mg beat exenatide 10 µg BID in A1c lowering and patient preference (due to once daily dosing and slightly less nausea) (^[60]) (^[94]). In other LEAD trials, liraglutide outperformed sulfonylureas and was roughly comparable to adding basal insulin glargine (with the bonus of weight loss vs weight gain on insulin) (^[108]) (^[60]). These results established GLP-1 analogs as a powerful tool – not just an “adjunct” but potentially as an alternative to initiating insulin in patients not controlled on pills. By around 2011–2012, clinical guidelines (e.g., ADA/EASD position statements) began reflecting that GLP-1 RAs can be considered instead of basal insulin in appropriate patients (especially those needing weight loss) (^[10]) (^[11]). This was a paradigm shift: previously, once two or three oral drugs failed, insulin was the default next step. Now GLP-1 RA offered another injectable option.

• Patient Experience: Many patients found the once-daily Victoza pen easier to integrate than the older Byetta (no need to dose around meals exactly, and just once per day). Some would even take it at night to sleep through some nausea (though it doesn’t matter when it’s taken). Victoza’s pen had multi-dose capability (dial the dose) which was user-friendly. Real-world use confirmed the trial findings: substantial improvement in glycemic control and moderate weight loss in a significant fraction of patients, with the trade-off of manageable GI effects. Adherence was generally good, though any injectable sees some drop-off.

One remarkable aspect of liraglutide came a few years later, beyond diabetes: its use in obesity treatment. Doctors noticed that even non-diabetic overweight patients placed on liraglutide (for prediabetes or other reasons) lost significant weight. Novo Nordisk pursued this indication and tested higher doses (3.0 mg daily) in obese non-diabetic individuals. The SCALE Obesity trial (2013) showed liraglutide 3.0 mg caused an average 8% body weight loss in 1 year versus 2.6% for placebo, and a third of participants lost over 10% of weight (^[116]) (^[114]). Based on this, in 2014 the FDA approved liraglutide 3.0 mg under the brand Saxenda® specifically for chronic weight management (^[117]) (^[118]). Saxenda became the first GLP-1 agonist approved for a non-diabetic indication (obesity). This was a pivotal moment, as it essentially validated GLP-1 RAs as anti-obesity drugs. Saxenda’s dose is 3.0 mg (higher than Victoza’s 1.8 mg max) and it requires a slower titration (0.6 -> 1.2 -> 1.8 -> 2.4 -> 3.0 mg weekly steps) to improve tolerability. Many patients achieved clinically meaningful weight loss, and Saxenda became part of obesity management guidelines for those with BMI ≥30 (or ≥27 with comorbidity).

In summary, liraglutide cemented the role of GLP-1 agonists as a versatile and efficacious class. It addressed the short half-life issue by structural design and delivered strong outcomes, including the first evidence of major clinical benefits (like indications of improved cardiovascular risk factors). In fact, as we’ll detail in a later section, liraglutide in 2016 became the first GLP-1 agonist shown to reduce cardiovascular events in a dedicated outcomes trial (LEADER) – an immensely important finding that added another dimension to its therapeutic profile.

Other GLP-1 Analogs: Short-Acting vs Long-Acting

After exenatide and liraglutide, several other GLP-1 receptor agonists were introduced in the early-to-mid 2010s. They can be broadly categorized into short-acting (daily or BID) formulations and long-acting (weekly) formulations. Each one had unique molecular designs:

• Exenatide Extended-Release (Bydureon): (Approved 2012 U.S.) As noted prior, this was the same exenatide peptide in a slow-release injectable suspension. It was the first weekly GLP-1 agonist. In trials (DURATION program), once-weekly exenatide 2 mg showed slightly more A1c reduction (~1.5% drop from baseline 8.3%) than Byetta BID (~1.0% drop) with fewer GI side effects after initial weeks (^[6]). The trade-off was injection site reactions (small nodules) in some patients, since the microspheres reside under the skin for weeks. Initially, Bydureon required a complicated reconstitution; later a pen (Bydureon-BCise) simplified it. Bydureon’s clinical positioning: It offered convenience of weekly dosing and better morning fasting glucose control than Byetta (since drug is always present). It became a reasonable option if patients could tolerate an injection with a larger needle (to deliver the suspension). Over time, Bydureon didn’t dominate the market, partly because next entrants like dulaglutide offered an even more user-friendly pen.

• Lixisenatide (Adlyxin in U.S., Lyxumia in EU): (EU approval 2013, US in 2016). Lixisenatide is another exendin-4–based molecule, modified by the addition of six Lysine residues at the C-terminus. It is a short-acting GLP-1 RA, given once-daily (20 µg dose) (^[62]). Sanofi developed lixisenatide (licensed from Zealand Pharma). It mainly targets postprandial glucose; it has a half-life of about 3 hours. Lixisenatide’s niche was similar to Byetta – it’s very effective at blunting meal-time glucose spikes and less so for fasting glucose. Trials showed lixisenatide lowered A1c by ~0.7% and helped with a modest weight loss (~2–3 kg) when added to oral meds (^[62]). In a head-to-head, once-daily lixisenatide was non-inferior to exenatide BID for A1c, with possibly slightly less nausea (owing to the gradual dose titration) but slightly less weight loss as well. The major trial for FDA approval was GetGoal phase 3 program. Additionally, lixisenatide was tested in a large cardiovascular safety trial (ELIXA, in post-heart-attack diabetic patients) and was found cardiovascularly neutral – it neither increased nor decreased CV events versus placebo (www.ema.europa.eu). The FDA awaited ELIXA results, hence the later U.S. approval. Once on the market, Adlyxin (lixisenatide) had a relatively small footprint, partly because by 2016 many clinicians leaned toward the more potent GLP-1 RAs. Sanofi did combine lixisenatide with insulin glargine in a premixed pen (Soliqua®), which was a novel combo product for patients needing both basal insulin and a GLP-1 RA.

• Albiglutide (Tanzeum in US, Eperzan in EU): (Approved 2014). Albiglutide was developed by GlaxoSmithKline. It consists of two copies of a modified GLP-1 peptide fused to human albumin. This design gave it a long half-life (~5–7 days) so it was a weekly injection. Each GLP-1 had an Ala→Gly substitution to resist DPP-4. Albiglutide was somewhat less potent in receptor activation (it’s a large molecule, ~72 kDa), and required a larger dose (30–50 mg weekly). Clinical trials showed A1c reductions of ~0.8%–1.0% with albiglutide, a bit less than other GLP-1 RAs, but still significant. Weight loss was minimal (perhaps due to reduced penetration to brain or lower potency – some trials showed weight neutrality with albiglutide) (^[6]). Tanzeum did not gain much market traction. Its pen required reconstitution (the drug came as powder to mix) similar to early Bydureon. Sales were modest, and by 2017 GSK decided to withdraw albiglutide from the market for commercial reasons. Interestingly, after discontinuation, the Harmony Outcomes trial (2018) reported that albiglutide did significantly reduce cardiovascular events by ~22% versus placebo (^[8]). This finding, published after GSK had exited, underscored a class effect – even a less popular GLP-1 RA conferred CV benefit. It sparked some discussion if albiglutide might be resurrected by another company, but as of 2025 it remains off-market.

• Dulaglutide (Trulicity): (Approved 2014). Dulaglutide, developed by Eli Lilly, is a once-weekly GLP-1 RA like albiglutide, but with some key differences. It comprises two GLP-1 analog chains linked to an Fc fragment of IgG4 (not the full antibody, just the Fc), making a large molecule (~63 kDa). Importantly, it was engineered to be administered in a ready-to-use autoinjector pen, no reconstitution needed. Trulicity launched with a patient-friendly device (just click a button, and a hidden needle injects the dose). This ease-of-use helped adoption. Dulaglutide’s efficacy: in the AWARD trial program, weekly dulaglutide 1.5 mg was shown to reduce HbA₁c by ~1.0% to 1.5% (baseline ~8.1%) and was superior to placebo and non-inferior or superior to comparators like insulin glargine or Byetta in certain studies (^[6]). Many patients achieved A1c targets. Average weight loss was ~2 kg (a bit less than liraglutide or semaglutide, but more than albiglutide). Nausea incidence was around 20% initially, but many tolerated it well given once-weekly dosing leads to a lower peak concentration. Trulicity quickly became one of the most widely used GLP-1 RAs, especially in the U.S., due to its convenience. Over time, additional doses (0.75 mg for titration or low-dose needs, and recently Lilly introduced higher doses 3.0 and 4.5 mg for those needing more effect) expanded its use. Dulaglutide underwent a major CV outcome trial as well, REWIND (2019), which was noteworthy for including many patients without prior cardiovascular events (a primary prevention cohort). REWIND found a 12% relative risk reduction in MACE (3-point major adverse cardiac events) with dulaglutide vs placebo (^[119]). Though modest, it was statistically significant, reinforcing that GLP-1 RAs provide cardiovascular benefit even in a broad diabetes population. Dulaglutide also has shown kidney benefits (slower progression of albuminuria) in that trial.

These GLP-1 RAs can be contrasted between short-acting (exenatide BID, lixisenatide) and long-acting (daily or weekly):

• Short-acting agents (Exenatide BID, Lixisenatide) primarily lower postprandial glucose. They have pronounced effects on delaying gastric emptying with each dose, which strongly curbs the post-meal sugar rise (^[120]) (^[121]). However, because drug levels drop between doses, they have less effect overnight on fasting glucose. Their nausea side effect is often linked to these high peak concentrations when dosed.

• Long-acting agents (Liraglutide daily, and weekly agents) provide continuous GLP-1 receptor stimulation. Over time, the body develops some tolerance to the gastric slowing effect, so their gastric emptying delay is less acute (and thus they have milder postprandial effect relative to short-acting ones) (^[104]) (^[105]). But they more effectively lower fasting glucose and overall glycemia. Because their peaks are lower and persistent, some patients find them more tolerable (less severe nausea spikes), though they still cause significant GI side effects in many.

In practice, the long-acting GLP-1 RAs became preferred for general glycemic control due to convenience and greater A1c reduction, whereas short-acting ones like lixisenatide found a niche in combination products or for targeting post-meal glucose excursions (for instance, some use lixisenatide mainly to handle breakfast hyperglycemia). Short-acting GLP-1 RAs also have a more pronounced effect on satiety with a meal (since food stays in stomach longer), but long-acting ones affect the brain continuously to reduce appetite.

Table: Comparing the Major GLP-1 Receptor Agonist Drugs

To summarize the key characteristics of the GLP-1 drugs up to this point (prior to semaglutide), the table below compares their properties:

Table 2: Comparison of GLP-1–based therapies. This table outlines the major GLP-1 receptor agonists through the mid-2010s, including their approval dates, dosing schedules, and distinguishing features. Efficacy and weight change are approximate averages from clinical trials. (†Sitagliptin is a DPP-4 inhibitor, not a GLP-1 agonist, shown here for context as an alternative incretin-based therapy.)

As seen, the trend was moving toward longer-acting, more convenient formulations without sacrificing efficacy. By 2016, the “GLP-1 toolbox” for clinicians included twice-daily, once-daily, and once-weekly options, allowing tailoring to patient needs and preferences. Dulaglutide and liraglutide were particularly popular due to their robust effects and ease of use.

However, the story did not end there. A new entrant was about to change the landscape again: semaglutide, a molecule even more potent at weight reduction and glycemic control, which would further elevate the GLP-1 class – including heading into oral dosage forms and unprecedented trial results. We will now explore semaglutide and the latest advances in GLP-1 drugs.

Semaglutide and New Horizons (2017–Present)

Semaglutide: The Game-Changing Weekly Analog

Semaglutide is a GLP-1 analog that has been a game-changer in both diabetes and obesity treatment. Developed by Novo Nordisk, semaglutide builds upon the design principles of liraglutide but pushes them further for extended half-life and potency. Semaglutide (Ozempic® for injection) was approved for type 2 diabetes in the U.S. in December 2017 (^[122]), and subsequently an oral tablet form (Rybelsus®) in 2019, and a high-dose injectable for obesity (Wegovy®) in 2021.

Molecular Design: Semaglutide is a modified human GLP-1 analog, similar to liraglutide in structure but with a few differences. It has an amino acid substitution at position 8 (Aib instead of Ala) to prevent DPP-4 cleavage, and a C-18 fatty acyl chain with a spacer attached at Lysine 26, which gives it strong albumin binding (even more than liraglutide’s C-16) (^[103]) (^[47]). These modifications yield an ~7-day half-life. Thus, semaglutide is formulated for once-weekly injection.

Glycemic Efficacy: Semaglutide showed unprecedented efficacy in trials. In the phase 3 program (SUSTAIN trials for injection, PIONEER for oral):

• Weekly semaglutide 1.0 mg lowered HbA₁c by ~1.5% to 1.8% from baseline (e.g. from 8.2% to ~6.5%), outperforming comparators. For instance, in SUSTAIN-7, semaglutide 0.5 mg and 1.0 mg were compared to dulaglutide 0.75 mg and 1.5 mg: semaglutide resulted in significantly greater A1c reduction (–1.5% vs –1.1% at highest doses) (^[6]). A larger proportion of patients on semaglutide hit the A1c <7% and even <6.5% targets.

• Notably, semaglutide’s efficacy was so high that some patients achieved “pre-diabetic” glucose levels or even remission of diabetes with weight loss. Endocrinologists began noting that semaglutide could often replace multiple other medications.

Weight Loss: Semaglutide’s effect on body weight is remarkable. In type 2 diabetes trials, weekly semaglutide 1.0 mg caused an average loss of ~4–6 kg (roughly twice that of dulaglutide or liraglutide at standard doses) (^[60]). Many patients lost >5% of body weight even in the diabetes population. This hinted at what higher doses might do for obesity (discussed soon).

CV Outcomes: Importantly, before full approval, semaglutide injection was tested in a cardiovascular outcomes trial SUSTAIN-6 (2016). It showed a 26% reduction in major cardiovascular events (MACE: CV death, nonfatal MI, nonfatal stroke) versus placebo (^[8]). That result was significant and placed semaglutide alongside liraglutide in demonstrating cardioprotection. This led to semaglutide being recommended for diabetics with cardiovascular disease, even before it was widely marketed, and it solidified the idea that GLP-1 RAs have a class benefit on the heart.

Safety & Tolerability: Semaglutide’s side effect profile is similar to other GLP-1 RAs: GI disturbances (nausea in ~20% of patients initially, vomiting ~10%, diarrhea ~10%). In SUSTAIN trials, semaglutide had higher rates of GI side effects than dulaglutide, but most were mild to moderate and occurred during dose escalation. Semaglutide is started at 0.25 mg weekly, then 0.5 mg after 4 weeks, and then 1.0 mg after another 4 weeks to mitigate nausea. One unique finding was an imbalance in diabetic retinopathy complications in SUSTAIN-6: 3.0% of semaglutide patients vs 1.8% of placebo had retinopathy progression (www.ema.europa.eu). This was thought related to the rapid glucose lowering in patients with pre-existing diabetic retinopathy (a known phenomenon where quick improvement of blood sugar can transiently worsen retinopathy). As a result, semaglutide’s prescribing info advises caution and close monitoring in those with a history of diabetic eye disease. Otherwise, semaglutide carries the same black box warning for thyroid C-cell tumors (class-wide) and precautions about pancreatitis as others. No new safety signals emerged, and it appears to share the class’s risk-benefit profile.

Oral Semaglutide (Rybelsus): A major innovation was formulating semaglutide as an oral pill. Delivering a peptide drug orally is challenging because the GI tract degrades proteins. Novo Nordisk combined semaglutide with an absorption enhancer called SNAC (sodium N- [8-(2-hydroxybenzoyl)amino] caprylate) which facilitates absorption in the stomach by increasing local pH and cell membrane permeability. The result, Rybelsus®, was approved in 2019 – the first oral GLP-1 agonist (^[63]) (^[123]). Patients must take it first thing in the morning with plain water and then wait 30 minutes before eating, to optimize uptake. Bioavailability is low (~1%), but the dose (7 mg or 14 mg daily) is sufficient to have clinical effect. Oral semaglutide’s efficacy in trials (PIONEER program) was similar to weekly injection: A1c reductions ~1.0–1.4% with 14 mg daily, weight loss ~3–4 kg (^[124]). It provides an alternative for patients absolutely averse to injections. However, some GI side effects still occur and the adherence requirement (empty stomach, etc.) requires patient education.

Obesity and Wegovy: The most impactful extension of semaglutide has been in treating obesity. The STEP trials (Semaglutide Treatment Effect in People with obesity) tested weekly semaglutide at 2.4 mg (a higher dose than for diabetes) in people with obesity (BMI ≥30 or ≥27+comorbidity). The flagship trial STEP-1 (published in NEJM, 2021) found a mean weight reduction of ~14.9% of body weight with semaglutide 2.4 mg vs ~2.4% with placebo over 68 weeks (^[12]). In absolute terms, that was ~15 kg weight loss on semaglutide vs ~2.5 kg on placebo – an unprecedented result for a medication (^[12]). About a third of participants lost ≥20% of their weight, approaching outcomes usually seen only with bariatric surgery. These dramatic results led to FDA approval of semaglutide 2.4 mg for obesity in June 2021 under the name Wegovy (^[67]). Wegovy uses the same pen device as Ozempic but delivers the higher dose; patients titrate up (0.25 →0.5→1.0→1.7→2.4 mg weekly). Wegovy’s arrival was a watershed moment for obesity treatment – at last, a medication that caused double-digit percentage weight loss on average. This triggered enormous demand. The popularity of Wegovy (and off-label use of Ozempic for weight loss) skyrocketed, leading to periodic shortages of semaglutide products in 2022–2023 (^[14]). Many high-profile mentions in media, social networks, and even Hollywood circles about “the skinny jab” or “Ozempic” occurred, feeding interest. Surveys indicated significant public awareness; by 2023, roughly 12% of Americans reported trying a GLP-1 drug mostly for weight loss purposes (^[13]).

Clinically, semaglutide 2.4 mg not only helps weight loss but also improves cardiovascular risk factors (blood pressure, lipids) and physical function in patients with obesity. The SELECT trial, as noted earlier, went a step further – it tested Wegovy in overweight/obese individuals with cardiovascular disease (but without diabetes) and found a 20% reduction in heart attacks, stroke, or CV death (^[65]). That trial (announced in 2023) is the first to prove that treating obesity pharmacologically can prevent cardiovascular events, a groundbreaking concept. It is expected to lead to expanded indications for semaglutide (potentially an indication for reduction of CV risk in obese patients).

Semaglutide in Other Areas: Research is underway on semaglutide’s role in NASH (non-alcoholic steatohepatitis), where weight loss helps – a phase 2 trial indicated significant resolution of NASH in some patients on semaglutide. Another trial, called FLOW, was stopped early in 2023 because semaglutide showed benefit in diabetic kidney disease progression (slowing decline of GFR and reducing kidney/CV deaths) (^[125]). These data suggest semaglutide (and perhaps GLP-1 RAs generally) may soon be used to specifically protect kidney function in diabetes, similar to how SGLT2 inhibitors are used.

In summary, semaglutide has proven to be a pinnacle of GLP-1 drug development so far: highly efficacious for glycemic control, capable of inducing substantial weight loss, and demonstrating broad benefits (cardiovascular and potentially renal). It has broadened the scope of what metabolic medications can achieve. The success of semaglutide has also intensified the pharmaceutical race – other companies are developing their own weekly GLP-1 RAs (for instance, Pfizer tested a once-weekly peptide “danuglipron” and oral GLP-1’s; or smaller firms are exploring oral small-molecule GLP-1 agonists). However, the next big competitor came from a different approach: multi-agonist peptides.

Beyond GLP-1 Alone: Dual/Triple Agonists and Novel Delivery

The story of GLP-1 drugs now intersects with an even larger trend: designing drugs that activate more than one hormonal pathway for synergistic effects.

• Dual agonist (Tirzepatide): Mentioned earlier, tirzepatide (Lilly) is a single peptide that activates both the GLP-1 and GIP (Glucose-dependent Insulinotropic Polypeptide) receptors. Approved in 2022 for diabetes (brand Mounjaro®), tirzepatide produced extraordinary results in weight loss – up to ~22% in obese participants at the highest dose in a phase 3 trial (^[126]). Although not a “pure” GLP-1 drug (it’s often called a “twincretin” because it harnesses two incretins), it represents the next wave of therapy building on GLP-1’s foundation. In head-to-head trials, tirzepatide 15mg vs semaglutide 1mg in type 2 diabetes showed greater A1c drop (~2.0% vs 1.4%) and greater weight loss (~11 kg vs 5 kg) (^[127]). In 2023, tirzepatide under the name Zepbound™ was FDA-approved for obesity as well, after showing ~48 lbs (~22%) mean weight loss over 72 weeks in a trial (SURMOUNT-2) (^[126]). Tirzepatide’s emergence underscores that the concept of combining hormonal pathways (incretins GIP + GLP-1) can amplify outcomes beyond what GLP-1 alone achieved.

• Triple agonists: Researchers are now testing tri-agonist peptides that activate GLP-1, GIP, and glucagon receptors. One such compound (often dubbed “triple G” or specific names like retatrutide, LY3437943 in Lilly’s pipeline) has shown extremely promising phase 2 results – e.g. up to 24% weight reduction in 48 weeks at high dose, which is roughly equivalent to some bariatric surgeries in efficacy. The glucagon receptor activation (paradoxically) seems to add metabolic benefits when paired with GLP-1 and GIP, such as promoting energy expenditure and fat oxidation, possibly combating the decrease in basal metabolic rate that accompanies weight loss, and helping reduce liver fat. These triple agonists are in clinical trials as of 2025 and could be the next major leap.

• Alternative delivery: While oral semaglutide was a big advance, other methods are being explored. One is transdermal or subcutaneous mini-pumps. For example, ITCA 650 was a small implant (matchstick size) that releases exenatide continuously for 3–6 months. It showed good efficacy without requiring patient injections. However, it encountered some regulatory questions and wasn’t approved yet. Another approach is nasal or inhaled GLP-1, but peptides typically aren’t well absorbed that way. Researchers also investigate small molecule GLP-1R agonists – these would be pill forms that are not peptides but can activate the GLP-1 receptor. None have succeeded clinically yet, but a few are in development; they might not achieve the full agonism effect that peptides do. The microbiome approach: intriguingly, some are attempting to engineer gut bacteria to secrete GLP-1 analogues (or fragments) in situ, to provide continuous low-level GLP-1 stimulation.

• Neuroscience and others: GLP-1 receptors in the brain have spurred trials in neurodegenerative diseases. There’s biological rationale that GLP-1 RAs may have neuroprotective effects (they reduce inflammation, improve insulin signaling in the brain, etc.). Exenatide was studied in Parkinson’s disease: a 2017 Lancet trial showed that patients on weekly exenatide had a slight improvement in motor scores compared to placebo (^[24]) – an exciting but preliminary finding. Larger trials (like “Exenatide-PD3”) are ongoing (^[128]). Likewise, a trial of semaglutide in Alzheimer’s disease is underway (since insulin resistance in brain and weight loss might be relevant, and animal models were promising). We don’t yet have conclusive results, but these efforts show how GLP-1 RAs are being investigated far beyond their original remit.

• Addiction and NASH: Preclinical studies found GLP-1 signaling in the reward circuits of the brain can reduce addictive behaviors. Some small human data suggests patients on GLP-1 RAs for diabetes consumed less alcohol or had reduced cravings (^[129]). Trials are exploring if these drugs can help with conditions like alcohol use disorder or even as adjuncts in smoking cessation or other addictions. In NASH, as mentioned, semaglutide 2.4 mg showed significant resolution of steatohepatitis in a proportion of patients. A phase 3 trial is ongoing. It’s likely that GLP-1 RAs (or their combinations) will be part of a future NASH therapy regimen, given weight loss is the cornerstone treatment for NASH and GLP-1 causes weight loss plus some direct hepatic fat reduction.

Clinical Impact and Guidelines

The explosion of GLP-1 therapies has substantially changed clinical practice guidelines in endocrinology and cardiometabolic medicine:

• Diabetes Management: Current guidelines (e.g. ADA Standards of Care 2023) recommend that patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) (or high risk) should be on a GLP-1 RA with proven CV benefit (or an SGLT2 inhibitor) as part of their regimen, independent of A1c, because of the outcome benefits (^[9]) (^[130]). This is a major shift from just glycemic-centric treatment to including organ-protective drugs. Moreover, for general glycemic control, GLP-1 RAs are now often preferred over insulin when injectable therapy is needed, unless there is severe uncontrolled hyperglycemia. The ADA’s consensus since 2018 explicitly states: “Consider a GLP-1 receptor agonist before insulin in most patients who need injectable therapy” due to their efficacy, lower hypoglycemia risk, and weight loss advantage (^[10]) (^[11]). Exceptions are those with type 1 diabetes (who need insulin) or severe symptoms needing rapid glucose reduction. Practically, this means a patient on metformin and maybe another oral drug who still has elevated A1c may get started on a weekly GLP-1 RA rather than progression to insulin. This has been one factor contributing to insulin usage declining in type 2 (except in those who truly need it).

• Obesity Management: GLP-1 RAs have been fully integrated into the obesity treatment guidelines. Professional bodies like The Obesity Society and endocrine societies recommend considering medications like Saxenda or Wegovy for patients with BMI ≥30 (or ≥27 with comorbidities) who have not achieved weight loss goals with lifestyle changes alone (^[131]) (^[132]). The advent of ~15% average weight loss drugs has, for the first time, made many clinicians more optimistic about treating obesity as a chronic condition medically. For decades, effective options were limited and often fraught with safety issues (e.g. fen-phen, amphetamine-like drugs, etc.). GLP-1 RAs are providing a safer and more effective approach, albeit expensive. There are discussions about using these drugs in overweight individuals (BMI 27–30) to prevent progression to obesity or to treat weight-related conditions even at lower BMI, but currently insurance coverage is mainly for obesity or diabetes. Some debate exists about long-term use – since obesity tends to be chronic, these medications likely need to be continued to maintain weight loss (as stopping leads to regain, based on observations). This raises questions about cost-effectiveness and access, but if priced reasonably or if generics eventually become available, we may see a broad shift where anti-obesity pharmacotherapy (especially GLP-1/GIP-based) is as commonplace as antihypertensive or lipid-lowering therapy.

• Cardiology: Cardiologists have taken note that GLP-1 RAs reduce cardiovascular events and have beneficial effects on risk factors. In fact, heart failure specialists and cardiology guidelines now mention GLP-1 RAs as part of glucose management in diabetics with heart disease, and they highlight their weight and blood pressure lowering. For heart failure per se, GLP-1 RAs have a neutral effect on HF hospitalizations (unlike SGLT2 inhibitors which specifically help HF). So GLP-1 aren’t first-line for HF, but they don’t harm and do help weight, which is useful. With SELECT trial’s outcome, even primary prevention cardiology (using Wegovy to prevent second heart attacks in obese patients) will become an accepted practice likely.

• Chronic Kidney Disease: If semaglutide’s kidney outcomes hold, nephrologists may join the fold, using GLP-1 RAs (in combination with SGLT2 inhibitors) to mitigate diabetic kidney disease progression. Already, KDIGO (kidney guidelines) in 2020 recommended GLP-1 RA as part of glycemic management in diabetics with CKD who need additional therapy after metformin, especially if at CV risk.

• Patient Perspective: Many patients with type 2 diabetes are now aware of GLP-1 drugs and may request them, especially due to the appeal of weight loss. Some who traditionally would fear injections are willing to try a weekly pen when they hear about significant weight improvements. The concept of “treating two conditions (diabetes and obesity) with one shot” is very appealing. Adherence to weekly injections in some studies appears as good or better than taking a daily pill regime, which is notable. Quality of life reports often indicate patients feel better on GLP-1 RA due to weight loss and better control, despite the nuisance of transient nausea.

Of course, a barrier is cost. These drugs are expensive (often over US$800–1200 per month for brand-name products in the US). Not all insurance formularies cover the obesity versions yet, and coverage for diabetes may require step therapy (e.g. trying metformin first, which is reasonable). Globally, affordability is a concern; in many low-to-middle income countries, GLP-1 RAs are available but used by a small fraction who can pay. However, prices may gradually come down, especially as older ones face patent expirations (e.g. Victoza’s patent expired, hence generic liraglutide was approved in 2023 (^[66]); generic semaglutide might be a decade away unless compelled by unique circumstances).

Safety Revisited: Pancreas and Thyroid

To close the loop on safety issues that have shadowed GLP-1 drugs:

• Pancreatitis/Pancreatic Cancer: Early on, especially around 2013, there were concerns that incretin therapies might increase pancreatitis risk or even pancreatic neoplasms (based on some animal data and analyses of FDA adverse event databases). Both the FDA and the European Medicines Agency conducted thorough reviews. The consensus of regulatory and independent reviews by 2014 was that current evidence does not confirm an increased risk of pancreatitis or pancreatic cancer with GLP-1 therapies (www.ema.europa.eu) (www.ema.europa.eu). The EMA committee specifically found methodological issues in studies that had claimed a link and concluded there was no causative proof (www.ema.europa.eu) (www.ema.europa.eu). Large cardiovascular trials and pooled analyses have not shown a statistically higher pancreatitis incidence than placebo beyond what is expected in diabetics (who inherently have some risk). That said, a slight numerical imbalance of pancreatitis cases has been observed in some trials (for example, 13 vs 5 cases in LEADER trial over ~4 years, not significant). So clinicians remain alert. All GLP-1 RA labels mention to monitor for pancreatitis signs. In practice, GLP-1 RAs are usually avoided in patients with a history of pancreatitis, out of caution, since alternative therapies can be chosen. Regarding pancreatic cancer, long-term observational studies haven’t shown increased rates; in fact, some data suggest no difference. But definitive answers may only come with even longer follow-ups and more widespread usage.

• Thyroid tumors: As noted, this is primarily based on rodent findings. After a decade of use, we haven’t seen reports of increased medullary thyroid carcinoma (a very rare cancer) in humans on GLP-1 RAs. A large observational study or registry would be needed to fully rule it out, but given how uncommon MTC is (1 in 50k maybe) and how many have now taken GLP-1 RAs (millions), likely any major signal would have emerged by now. A 2022 literature review concluded there is no clear evidence of increased thyroid cancer (MTC or other types) with GLP-1 RA use in humans (^[114]) (^[133]). Still, the contraindication for those with familial MTC or MEN2 persists, as those individuals already are at high risk genetically and were excluded from trials.

• Other Safety:

• Gallbladder disease: Rapid weight loss, from any cause, can precipitate gallstone formation. Not surprisingly, trials with semaglutide reported higher rates of gallbladder-related events (like cholelithiasis requiring cholecystectomy) compared to placebo. Clinicians are aware of this and may monitor for gallbladder symptoms if patients lose weight very fast.

• Hypoglycemia: On their own, GLP-1 RAs have negligible hypoglycemia risk. But combined with insulin or sulfonylureas, one must adjust the latter to avoid lows (^[99]) (^[134]).

• Heart rate: GLP-1 RAs tend to raise resting heart rate by 2–4 beats per minute. The mechanism isn’t fully understood (possibly due to direct effect on SA node or indirect via autonomic changes from weight loss or nausea). Is this harmful? Likely not significantly, but some cardiologists worried theoretically it could stress the heart. However, given the positive CV outcomes, a slight increased heart rate doesn’t seem to translate into adverse outcomes. Nonetheless, in someone with arrhythmias or tachycardia issues, one might be cautious.

• Injection site reactions: Rarely, these can occur (injection site nodule with exenatide ER, or hypersensitivity in <0.5% patients).

• Immunogenicity: Because these are peptides, the body can form anti-drug antibodies. With exenatide (a non-human sequence), around 40–50% of patients develop low-titer antibodies; a few percent develop high titers which might reduce efficacy (^[98]) (^[100]). With human analogs (liraglutide, semaglutide), the rates of anti-drug antibodies are much lower (around 5–8%) and high titers are rare. Generally, immunogenicity hasn’t been a big clinical issue for this class.

Broader Implications

The rise of GLP-1 medications is intersecting with global public health efforts against diabetes and obesity. If these drugs become more accessible, they could significantly reduce complications like myocardial infarctions, strokes, end-stage kidney disease, and need for invasive weight loss surgeries. Some economists even speculate that widespread GLP-1 use could have macroeconomic benefits by improving population health (e.g., a Goldman Sachs report posited that reducing obesity via GLP-1 drugs might increase labor productivity and reduce healthcare expenditure long-term) (glp-1.news).

There are also ethical and societal questions. For instance, should individuals with “social obesity” (overweight due to modern lifestyle but not yet diseased) use these drugs electively to lose weight? The line between cosmetic and medical use can blur – some criticize that celebrities or the very wealthy obtained Wegovy off-label just to drop a few pounds, leading to shortages for those with diabetes who needed Ozempic for health. This raises concerns about equitable distribution and the importance of prescribing according to guidelines. On the flip side, the normalization of using medication for weight management could reduce stigma around obesity as a solely lifestyle issue, reinforcing that biological factors are at play and medical help is legitimate.

Another implication: as effective as these drugs are, they underscore that lifestyle interventions remain essential. GLP-1 RAs work best in conjunction with diet and exercise changes (the trials included lifestyle counseling). Moreover, maintaining weight loss or glycemic control in the long run still benefits from healthy habits. So, these therapies are adjuncts, not replacements for lifestyle improvement. However, they can jump-start progress and make it easier for patients to adopt healthier lifestyles by reducing appetite and improving energy, which can be a virtuous cycle.

Economically, healthcare systems and insurers are grappling with the high costs. In some countries, there are debates if these should be covered for obesity (since obesity medication coverage historically has been poor). Given the outcomes like SELECT, arguments in favor of coverage get stronger: preventing heart attacks via a weight loss drug could be cost-saving relative to expensive cardiac procedures. Studies on cost-effectiveness are ongoing. In the meantime, companies are reaping huge profits; in 2023 Novo Nordisk became Europe’s most valuable firm largely due to semaglutide’s sales (^[15]), and Eli Lilly’s market cap soared with tirzepatide’s anticipation (^[16]). This means competition will intensify, which hopefully drives innovation and eventually, competitive pricing or biosimilars.

Finally, one can foresee a future where combination therapy becomes common: for example, a patient with diabetes and obesity might be on both a GLP-1 RA and an SGLT2 inhibitor (for complementary weight loss and cardio-renal protection, which is already done). Or possibly a GLP-1 RA + leptin analog or other appetite modulator together. Research into appetite regulation is booming now that GLP-1 opened the door.

Conclusion

The history of GLP-1 drugs is a compelling narrative of scientific discovery translating into clinical revolution. From the early inklings of an “incretin factor” in the 1900s, through the molecular identification of GLP-1 in the 1980s, to the ingenious harnessing of a lizard’s venom peptide in the 1990s – each chapter built the foundation for what is now a pillar of modern therapy for metabolic diseases. GLP-1 receptor agonists have redefined the treatment standards for type 2 diabetes by providing glycemic control with added benefits of weight loss and cardiovascular protection (^[7]) (^[8]). They have also spearheaded a new era in obesity management, achieving weight loss outcomes previously thought unattainable with drugs (^[12]).

The multi-dimensional success of GLP-1 drugs – improving blood sugar, body weight, heart health, and kidney outcomes – illustrates the power of targeting fundamental hormonal pathways that regulate energy balance and metabolism (^[7]) (^[8]). It validates the decades of research into gut hormones and challenges the notion that chronic diseases like obesity and diabetes must inevitably progress. Patients treated with GLP-1 agonists often experience transformative health improvements: better diabetes control without the burden of hypoglycemia, significant weight reduction that improves mobility and self-esteem, and a newfound optimism about their health trajectory. As one clinical trial participant succinctly put it, “I feel like my life has been given back to me,” after losing substantial weight and coming off several medications thanks to a GLP-1 drug.

Nonetheless, this is not an unqualified panacea. Challenges remain, including ensuring long-term safety monitoring, improving access and affordability, and addressing the root causes of metabolic disorders in society. Use of GLP-1 RAs is limited by high cost, which creates disparities – those who cannot afford these drugs may miss out on the benefits. As patents expire and potential generic or biosimilar versions emerge (e.g., generic liraglutide by Teva in 2024 (^[66])), costs might come down, but for newer agents like semaglutide or tirzepatide, it could be years. Healthcare systems will need to adapt to potentially millions of long-term GLP-1 users and consider how to allocate resources effectively.

Moreover, while GLP-1 therapies help manage symptoms and risks, they do not cure diabetes or obesity. If a patient stops the medication, diabetes will relapse (if it was controlled, not cured) and weight will likely be regained, as evidenced by trials where cessation led to weight regain trends. This underscores that these medications are chronic therapies – similar to how antihypertensives or statins are long-term. Future research might reveal ways to induce lasting remission (e.g., combining medication with lifestyle to reset body weight “set points” or addressing metabolic memory), but until then, continuity of treatment is key.

Looking ahead, the horizon for GLP-1 and related drugs is bright. We anticipate newer multi-target agents that may deliver even superior results – early data on dual and triple incretin agonists suggest we are only at the start of a metabolic therapeutics renaissance. Beyond that, the principles learned from GLP-1 could be applied to other conditions: for example, appetite-regulating pathways for addiction, gut-brain signals for neurodegeneration, or GLP-1’s anti-inflammatory effects for liver disease. There is even speculation of whether longevity could be impacted, since obesity and diabetes reduction improve life expectancy – some analysts jokingly (or not) asked if GLP-1 drugs might earn their discoverers a Nobel Prize given the broad impact (^[135]).

In conclusion, the complete history of GLP-1 drugs – from gut hormone discovery to blockbuster therapy – exemplifies the ideal arc of translational medicine. It started with curiosity about how eating triggers insulin, led to identifying a hormone, surmounted pharmacological hurdles through creative solutions, and now saves lives and improves quality of life at a large scale. As of 2025, GLP-1 receptor agonists have treated tens of millions worldwide (^[136]), and that number is rapidly growing as new indications expand. The journey is ongoing: with each new study and each patient success story, the legacy of GLP-1 drugs solidifies. This legacy teaches us that investing in basic science (like studying obscure peptides) can yield therapies of immense human value, and that diseases once deemed intractable can be tackled with innovative approaches targeting our own physiology’s master controls. The history of GLP-1 drugs is still being written, but one thing is clear – these therapies have already firmly established themselves as a cornerstone of metabolic disease management, changing the standard of care and offering hope for a healthier future for many.