Metabolic diseases are out of control. In 2024, 42% of Americans have been diagnosed with obesity, and it’s only projected to rise, affecting an estimated 58% of Americans by 2035 – that’s an increase of 70 million people. Beyond the impact on affected individuals, it’s also expensive to manage. The cost of metabolic disease in the US today is $1.1 trillion, and by 2035, the global cost of obesity is expected to be $4.3 trillion or, in more dire terms, 3% of global GDP.

Needless to say, obesity is an important issue affecting millions. Unfortunately, the historically available solutions have been limited. Aside from the classic diet and exercise approach (which often fails), bariatric surgery has been the most effective option. However, it doesn’t come without risks: it is a major surgery that isn’t cheap and requires significant recovery. Additionally, bariatric surgery cannot be scaled to treat the amount of people diagnosed with obesity and, therefore, other solutions are necessary.

Enter: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), more commonly referred to as just GLP-1s, are drugs that mimic the natural form of GLP-1. Natural GLP-1 is an incretin hormone (a gut hormone) that is secreted after ingesting meals that stimulates the release of insulin while also slowing digestion and suppressing appetite. Natural GLP-1 only lasts a short amount of time, on the order of 1-2 minutes, while GLP-1 drugs work for hours or even days.

GLP-1 drugs are receptor agonists. This means that they bind to the receptor site (in this case, GLP-1 receptor sites which are found all over, but most notably in the brain and gut) and enhance the specific GLP-1 cellular activity (i.e. stimulate or “agonize” insulin production and suppress appetite).

Figure 1. How the hormone GLP-1 and how GLP-1 RA drugs work in the body to suppress appetite (i.e. anti-obesity medication mechanism).

But where did they come from? Well, they’ve been around for a while. Originally slated as a diabetes treatment, GLP-1s are really good at stimulating insulin production. While not for everyone, they continue to be an effective diabetes treatment since the first GLP-1 (liraglutide) hit the market in 2010 (as Victoza). While people with diabetes were on these drugs, they realized they were also losing weight, which is often beneficial for those diagnosed with type 2 diabetes. So, in 2014, liraglutide was approved for weight loss (as Saxenda), causing average decreases in body mass of about 8%.

Insulin is a key hormone that helps turn food into energy by converting glucose (sugar) to muscle glycogen (to be stored for use as “quick energy” later). Diabetes is a chronic disease where the body either 1) doesn’t produce enough insulin or 2) becomes resistant to the insulin that is produced, leading to hyperglycemia, or high blood sugar. Hyperglycemia can lead to a host of different pathologies from cardiovascular disease to different skin conditions to depression, so it’s crucial that glucose levels be regulated in the body.
In people with type 1 diabetes, the body doesn’t produce insulin because the immune system incorrectly attacks the insulin producing beta-cells in the pancreas. With no way to dispose of circulating glucose, blood sugar spikes.
In people with type 2 diabetes, the body becomes resistant to insulin or doesn’t produce enough of it. If cells don’t respond appropriately to insulin, glucose is less able to enter cells and stays in the bloodstream.
In people without diabetes, background levels of insulin that are supplemented by insulin spikes after meals.
GLP-1s can be used in people with type 2 diabetes to help regulate blood glucose. GLP-1s work by:
1. Enhancing insulin secretion when blood sugar levels are elevated. This helps regulate blood sugar after eating and, importantly, doesn’t cause insulin to be released when blood sugar is normal, avoiding low blood sugar.
2. Suppressing glucagon release. This slows the liver from releasing stored glucose into the bloodstream (in those with type 2 diabetes, the liver can be too proactive about releasing stored glucose).
3. Slowing gastric emptying. This slows the absorption of glucose into the bloodstream, preventing blood sugar spikes after meals.
4. Promoting satiety and weight loss by increasing the feeling of fullness. This can lead to weight loss, which is beneficial for people with type 2 diabetes because weight loss generally improves insulin sensitivity and blood glucose control.
In all, GLP-1s work by regulating blood glucose. Generally, weight loss and a low-calorie diet can help to reverse type 2 diabetes.
GLP-1s hit the market in the early 2020s and quickly gained traction. These drugs are much safer and more effective than earlier drugs. Metabolic disease continues to plague a growing amount of the global population, and these drugs are a part of the solution.
However, the idea of an anti-obesity medication is not new. Starting in the 1920s, people began taking 2,4-Dinitrophenol (DNP) which caused dramatic weight loss by making mitochondria less efficient (see our Mitochondria May blog post for more information). This drop in efficiency leads to a higher caloric burn, but also results in lots of excess heat. This hyperthermia was dangerous and could be caused by continued use or very slight overdoses. By 1938, it was banned for human consumption. Amphetamines were another favorite in the 1930s. Such “rainbow diet pills” were eventually banned in the 1960s after a series of deaths. In the 1990s fen-phen, a combination drug including fenfluramine and phentermine, was popularized. But just a few years after it gained popularity, it was found to be dangerous, causing valvular heart disease in about a third of its users.

The next generation of GLP-1s came along as Novo Nordisk released semaglutide, which was approved for type 2 diabetes in 2017 (as Ozempic) and for obesity in 2021 (as Wegovy). This drug squashed liraglutide, with its average weight loss coming in at 17-18% body mass. But that wasn’t the end of it. In 2022, Eli Lilly released their dual agonist, tirzepatide, a GLP-1 RA combined with glucose-dependent insulinotropic polypeptide (GIP) (as Mounjaro). And in 2023, it was approved for weight management as well. Tirzepatide has been the most successful GLP-1 for weight loss released to date, with an average weight loss of 20%.

Comparison of popular GLP-1 medications on the market:

Trade name of Saxenda; Prescribed for individuals with obesity; Mimics GLP-1; Administered by injection
7.1% reduction in body weight after 6 months
- Helps stabilize high blood pressure and cholesterol levels.
- Helps improve cardiovascular risk factors.
Trade name of Wegovy; Prescribed for individuals with obesity who may or may not have diabetes; Mimics GLP-1; Administered by injection or oral dose
14.9% reduction in body weight after 68 weeks
- Reduces cholesterol levels
- Improves heart health
- Reduces inflammation
- Helps improve cardiovascular risk factors
Trade name of Zepbound; Prescribed for individuals with obesity; Mimics GIP and GLP-1; Administered by injection
>20% reduction in body weight after 72 weeks
- Helps improve cardiovascular risk factors

But that’s not the end of the story either. There are more drugs to come–triple agonists are being explored, and are showing even more weight loss on shorter time scales. This GLP-1 boom is just the beginning for pharmacological weight management.

So far, 1 in 8 American adults have tried a GLP-1, and that number is only projected to rise. Concerns of production capacity and price are major inhibiting factors, but these drugs have already become significantly cheaper than when they first hit the market. The development of GLP-1 drugs and their success is promising for the future of weight management in America. Both patients and practitioners involved with GLP-1 RAs tend to agree. “The drugs are clearly working on pathways that are dysregulated.” said Katherine Saunders, assistant professor of clinical medicine at Weill Cornell Medicine and cofounder of Intellihealth, a company improving access to medical obesity treatment.

Users often describe the experience of quieting food noise when on a GLP-1. Scientific American published a great article detailing how these drugs make this possible. One woman in the article said, “My whole life has been thinking about food, while I was eating, I’d be thinking about the next meal.” Once starting a GLP-1, these feelings went away. Another woman reported, “All of a sudden it was like some part of my brain that was always there just went quiet. It felt almost surreal to put an injector against my leg and have happen in 48 hours what decades of intervention could not accomplish.”

Where does Calorify fit in?

Throughout the history of obesity, a slow metabolic rate has often been claimed to be a large contributor. However, we’ve known this to be wrong since the ‘80s. Calorify is here to help sort through the weeds. Unlike fad diets, blanket recommendations, and one-size-fits-all programs, a metabolic test can paint a clearer picture of your body’s specific caloric needs in order to reach your unique goals.

Calorify measures total energy expenditure, total energy intake, and body composition, giving us insight into other helpful metrics like energy availability, physical activity level, and more. Having a full picture of your metabolism is incredibly important, especially when thinking about weight loss and energy balance. Order a kit today to gain insight into how your body burns.

References:

London Obesity Clinic. 2024. Semaglutide vs Tirzepatide vs Liraglutide.

Müller et al. 2022. Anti-obesity drug discovery: advances and challenges. Nature Reviews Drug Discovery

Nauck and Meier. 2018. Incretin hormones: Their role in health and disease. Diabetes, Obesity and Metabolism.

Peterson and Shulman. 2018. Mechanisms of Insulin Action and Insulin Resistance. Physiological Reviews.

Phelan. 2024. Winning researchers unlocked GLP-1 drugs for obesity. Science.

Young. 2024. Ozempic Quiets Food Noise in the Brain–But How?. Scientific American.