Close-up image of a Gila Monster lizard crawling over a rock

From Gila Monsters and Type 2 Diabetes to Alzheimer’s Disease and Beyond: The Story of Ozempic & GLP-1 Drugs

Over the last several years, Ozempic has permeated conversations in pop culture, news, and beyond, becoming a shorthand for dramatic weight loss. While often used colloquially to refer to the entire class of drugs, Ozempic is one of three FDA-approved forms of semaglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist originally developed for the treatment of type 2 diabetes (T2D). This class of drugs is not new; exanatide, the first GLP-1 receptor agonist (GLP-1 RA) indicated for T2D, was approved in 2005 under the brand name Byetta. Three more compounds entered the U.S. market before the approval of Ozempic in 2017, which ultimately kickstarted GLP-1 receptor agonists’ meteoric rise in popularity.

With nearly $50 billion in anticipated sales in 2024, GLP-1 RAs are on track to become the best-selling drug class of the year. So how did a game-changing T2D drug come to dominate the pharmaceutical industry, and what’s in store for GLP-1 drugs in the years to come?

 

The GLP-1 story begins

The development of GLP-1 RAs began when scientists reached an understanding of the role of GLP-1 in normal blood glucose regulation. Type 2 diabetes, which affects roughly 35 million Americans, is caused by an impairment of insulin release from the pancreas in combination with insulin resistance, a failure of cells to respond normally to insulin. This inhibits cellular uptake of glucose for energy, leading to glucose accumulating in the blood. GLP-1 is an endogenous hormone released by endocrine cells of the intestine and certain neuronal populations in the brainstem after food consumption. GLP-1 signaling helps control blood sugar by stimulating insulin secretion from pancreatic beta cells and inhibiting glucagon release. Additionally, it helps to regulate further food intake by slowing gastric emptying and promoting satiety via activation of GLP-1 receptors in the brainstem and hypothalamus.

Until recently, metformin, sulfonylureas, and insulin were the only treatment options for T2D not controlled by lifestyle modifications. The discovery that GLP-1 accounts for up to 70% of insulin release solidified its potential as a therapeutic target in T2D. While modulation of GLP-1 could therapeutically regulate blood glucose, it had the additional advantage of not “overshooting” and causing hypoglycemia, as is possible with insulin injections. However, the path to leveraging its potential was less straightforward. GLP-1 has a short half-life when administered intravenously or subcutaneously, making it difficult to maintain a high, stable plasma concentration in a therapeutic context.

Initial research into GLP-1-focused drugs was thus aimed at identifying analogs that could have a longer half-life in vivo than endogenous GLP-1. The first successful candidate was discovered in an unlikely place: the saliva of a large, venomous reptile. After noting that the Gila monster could maintain stable blood glucose levels even in long periods of fasting, Dr. John Eng identified a more long-acting GLP-1 variant, exendin-4, in the reptile’s saliva. He was granted a patent for pharmaceutical compositions of exendin-4 as a treatment for T2D in 1995. Ten years later, the drug was approved by the FDA under the name exenatide (Byetta). However, exenatide inconveniently required twice-daily injections, leading researchers to seek even longer-lasting alternatives.

 

A growing wave of GLP-1 RA drugs

Researchers at Novo Nordisk identified various candidate GLP-1 analogs that could bind to serum albumin and maintain sufficient plasma concentrations for once-daily dosing. These efforts produced liraglutide (Victoza), a daily GLP-1 RA approved in the U.S. for T2D in 2010. Eli Lilly then responded with the launch of dulaglutide (Trulicity), a once-weekly subcutaneous injection approved by the FDA in 2014. But liraglutide had another unexpected advantage: weight loss. After clinical trials of a higher liraglutide dose revealed that 63% of participants lost >5% of their body weight, the drug was approved for weight loss in 2014 under the name Saxenda.

As the GLP-1 RA market slowly chugged along, Novo Nordisk continued exploring longer-acting GLP-1 analogs for T2D. Researchers eventually developed semaglutide, a once-weekly injectable GLP-1 RA approved in 2017 under the now-ubiquitous name Ozempic. After trials revealed that participants taking the drug forT2D lost roughly 6% of their body weight on average, it quickly became evident that semaglutide also had powerful potential as a weight loss drug. While it was not approved for weight loss until its release under the name Wegovy in 2021, off-label prescribing for non-diabetic patients became common, further driven by social media buzz and Novo Nordisk’s marketing efforts. Thus began a broader surge of interest in GLP-1 drugs for weight loss and beyond, leading to new players entering the market, persistent shortages, and a seemingly endless social commentary on who’s losing weight and how.

As of June 2024, these GLP-1 agonist drugs are approved in the United States for the following indications:

 

Additionally, tirzapetide, a member of a novel and closely related class of drugs that are dual agonists for GLP-1 and gastric inhibitory polypeptide (GIP) receptors, has been FDA-approved for diabetes and chronic weight management under the names Mounjaro and Zepbound, respectively.

 

Game-changing effects for type 2 diabetes and weight loss

With ten GLP-1 analogs on the market and dozens more in the development pipeline, it’s natural to wonder why these drugs are so popular. A comprehensive discussion of all GLP-1 RA trials (or even semaglutide trials alone) is beyond the scope of this article, but if you’re interested in a more thorough overview of major diabetes and weight loss trials across GLP-1 drugs, I recommend this page. As type 2 diabetes treatments, they’re impressively effective at achieving glycemic control with, in most cases, the added convenience of once-weekly administration. For example, a randomized multinational study of 1,089 patients whose blood glucose was poorly controlled with metformin alone or paired with a sulfonylurea compared weekly semaglutide to a daily insulin regimen over 30 weeks. Patients taking semaglutide had a significantly greater reduction in HbA1c (1.21% and 1.64% for 0.5 and 1.0 mg semaglutide vs. 0.83% with insulin) and a weight loss of 3.47 kg and 5.17 kg for each dose. Conversely, patients taking insulin actually experienced a mean weight gain of 1.15 kg.

The landmark STEP 1 trial, which explored the efficacy of high-dose (2.4 mg) semaglutide plus lifestyle intervention for weight loss in adults who were overweight or obese revealed an average weight reduction of 14.9% over 68 weeks in the treatment group vs. 2.4% in the placebo group. Eighty-six percent of patients on semaglutide lost at least 5% of their body weight. Work exploring the mechanisms driving semaglutide-induced weight loss found the drug reduced food intake by 24% and was associated with less hunger and food cravings as well as a lower preference for high-fat foods. Further studies examined the durability of this weight loss, demonstrating that patients on semaglutide tended to lose weight for up to ~60 weeks and maintain that weight loss for their remaining time on the drug. However, an extension of the STEP 1 trial found that, within one year after treatment discontinuation, patients regained two-thirds of their weight loss.

While semaglutide and other GLP-1 RAs can be a game-changer for patients looking to lose weight, side effects, high costs, and supply issues limit the success of long-term treatment and, in turn, sustained weight loss. A recent study of nearly 200,000 patients taking GLP-1 RAs for diabetes or weight loss found discontinuation rates of 26.2% at three months and 36.5% at one year, with higher odds of discontinuation among Black and Hispanic patients, Medicare and Medicaid enrollees, and patients taking the drug for obesity only. GLP-1 RAs are also linked to gastrointestinal side effects ranging from unpleasant to severe, which can also impact adherence. Milder side effects like nausea, vomiting, dizziness, and constipation are relatively common, but patients on GLP-1 RAs are also at risk for more serious side effects such as bowel obstruction, gastroparesis, and pancreatitis.

Despite these limitations, GLP-1 prescriptions for weight loss have skyrocketed, including off-label prescribing of drugs not approved for weight loss and prescribing outside of indicated BMI criteria. The explosion of interest in these drugs has led to persistent shortages, driven largely by supply chain issues associated with the autoinjector pens used for injectable versions. Online pharmacies have capitalized on this unmet demand for cosmetic weight loss by offering compounded semaglutide and tirzapetide. This has raised a host of new concerns over the quality and safety of compounded GLP-1 RAs, the potential harm of their advertisement on TikTok and other platforms, and the potential for serious side effects in this population.

 

What’s on the horizon for GLP-1 agonists?

With 6% of U.S. adults currently prescribed a GLP-1 drug and 1 in 8 having taken one at some point in their life, it’s safe to say these drugs are a defining feature of today’s healthcare landscape. A growing number of drug makers have contributed to the 124 drugs currently in active development, encompassing everything from more GLP-1 agonists to RNA interference (RNAi) therapies that aim to produce more durable effects. But some of the most promising GLP-1 RA data aren’t just about weight loss – the drugs have shown immense potential in addressing conditions with limited existing treatment options.

A growing number of patients have had success in using GLP-1 agonists to manage the metabolic symptoms of polycystic ovarian syndrome (PCOS), a poorly understood condition that can cause excess production of testosterone in women. The effects of GLP-1 agonists on food cravings may also translate into effective treatments for addiction to alcohol and other drugs. While evidence is currently limited to preclinical findings and anecdotal data, several randomized clinical trials are now underway to explore the impact of semaglutide treatment on alcohol and nicotine use. GLP-1 agonists even have promising effects for neurological conditions such as Parkinson’s and Alzheimer’s disease. A substantial body of preclinical research has demonstrated the neuroprotective effects of GLP-1 and GLP-1 agonists, but these findings have only recently translated into human studies. A 2024 trial of lixisenatide in patients with early Parkinson’s disease found a slight improvement in scores of motor symptoms at 12 months among those taking the drug compared to a worsening of symptoms in the placebo group. Ongoing studies of GLP-1 agonists for neurological conditions include two Phase III trials evaluating the effects of semaglutide in patients with Alzheimer’s disease.

GLP-1 agonist drugs have progressed far beyond their origins as a treatment for type 2 diabetes, changing not only the way we address diabetes and weight loss but also transforming possibilities for addiction, neurological disease, and more. While this class of drugs has skyrocketed in popularity over the last decade, the growing body of research exploring the effects of GLP-1s in various facets of health has made it clear that their impact is only getting started.

 

Author’s note:

GLP-1 drugs have generated a fascinating and dynamic area of drug development. But like most things worth talking about, the issue of weight and health deserves more nuance, which I don’t always see in the discourse around weight loss drugs.

I appreciate how groundbreaking these drugs are for managing T2D, reducing cardiovascular risk, and helping people lose weight, especially for those who struggle with binge eating. I’m interested to see where they go in the future. But I can’t help but think that, when it comes to weight loss, the conversation around GLP-1 receptor agonists often faces the same flaws that tend to color our conversations around weight and health. Weight is by no means a perfect indicator of health or habits, and I fear that having a more clinically accepted “miracle drug” for weight loss will only exacerbate issues that individuals in larger bodies already face in seeking medical care. And it’s introduced a new catch-22: while this population is regularly subjected to fatphobic attitudes and actions, many losing weight with GLP-1 RAs are also stigmatized for taking a “shortcut.”

Focusing directly on weight loss to improve health isn’t the same as emphasizing nutrition, movement, and holistic well-being. I also worry, in turn, about what it means for the level of entitlement we feel to comment on others’ bodies and make assumptions about their lifestyle or health, viewing size solely as a problem to be solved rather than another variable in the spectrum of human phenotypes.

This issue is well beyond the scope of an author’s note (or a corporate blog, to be honest), but I want to encourage readers to approach it with the care it deserves. We’re going to be talking about these drugs for a while, so I hope others in our industry can do so with discretion and respect.