How they came about: from a lizard to obesity treatment
The story begins far from any gym. Starting in the 1980s, researchers such as Jean-Pierre Raufman and, later, John Eng studied the venom of the Gila monster, a lizard from the southwestern United States, and identified in it a substance called exendin-4. It was very similar to a human hormone, GLP-1, but with one advantage: it lasted hours in the body, while natural GLP-1 degrades within one or two minutes. From that finding came exenatide (Byetta), the first GLP-1 analogue, approved by the FDA in 2005 for type 2 diabetes.
The class evolved. Semaglutide was approved first for type 2 diabetes (Ozempic, injectable, December 2017; Rybelsus, oral, September 2019). Only afterwards, once appetite reduction and weight loss were consistently observed, came approval for obesity: Wegovy, also semaglutide, was cleared by the FDA in June 2021. Next came tirzepatide, a dual agonist that activates two receptors at the same time, GIP and GLP-1: approved as Mounjaro for diabetes in May 2022 and as Zepbound for obesity in November 2023.
Drugs.com, FDA approval history (Wegovy 2021, Zepbound 2023); VA Research, "Diabetes drug from Gila monster venom"
How they work in the body
GLP-1 is a hormone the gut releases when you eat. The pens mimic this hormone and act on two main fronts. In the stomach, they slow gastric emptying, so food stays longer and the feeling of fullness lasts longer. In the brain, in areas that regulate appetite, they signal satiety and reduce hunger. Tirzepatide adds to this the effect of GIP, another hormone linked to appetite control. The result is eating less without the same sense of deprivation as a conventional restrictive diet.
The magnitude of weight loss in the studies is large. With semaglutide, the STEP program showed expressive reductions with the obesity dose plus lifestyle change (in STEP 1, about 14.9% weight loss over 68 weeks, against 2.4% with placebo). With tirzepatide, the SURMOUNT-1 trial recorded up to about 22.5% body weight loss over 72 weeks at the highest dose, against 2.4% with placebo. These are high numbers, and that is exactly why caring about what is lost matters.
The risks: what the label and the studies show
Like any medication, the pens have adverse effects and contraindications. The most common are gastrointestinal: nausea, vomiting, diarrhea and constipation, usually more intense at the start and at dose increases. Beyond those, studies and labels point to less frequent but serious risks that require medical assessment.
- Pancreatitis. Cases of acute pancreatitis have been reported. Anyone with a history of pancreatitis needs careful assessment before any decision.
- Gallbladder disease. Increase in events such as stones and cholecystitis, which in turn can be related to pancreatitis, especially with rapid weight loss.
- Thyroid contraindication. In rodent studies, semaglutide increased thyroid C-cell tumors. That is why it is contraindicated for anyone with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2). The relevance of this finding for humans is not yet defined.
Look et al., "Body composition changes... SURMOUNT-1", Diabetes, Obesity and Metabolism, 2025
Care before starting
Before is where it is decided whether the medication makes sense for you, and that decision belongs to medicine. The assessment includes personal and family history (thyroid, pancreatitis, gallbladder), a real indication according to clinical criteria, result expectations and a follow-up plan. None of this is settled by a friend's recommendation, a clandestine compounding pharmacy or an online purchase. A prescription-only medication without a prescription and without follow-up is a risk not worth taking.
Care during use
If a physician has prescribed and follows up, the use phase is where you protect what is most valuable to you: muscle. Losing weight while losing lean mass leaves you weaker, with a lower metabolism and more prone to regaining weight afterwards. Three pillars sustain lean mass during use, and two of them are within our scope.
- Adequate protein. With reduced appetite, it is easy to eat too little protein. The daily protein target, set with your dietitian, needs to be prioritized even while eating less overall.
- Strength training. Mechanical stimulus is the signal that tells the body to preserve muscle while you lose fat. Without it, the body treats muscle as expendable.
- Hydration and follow-up. Gastrointestinal effects can lead to dehydration; medical follow-up adjusts whatever is needed.
Care afterwards: the rebound effect
This is the most honest point of the whole conversation. The pens control appetite while you use them. When use stops, appetite comes back. In the STEP 1 extension, participants regained about two-thirds of the weight lost one year after stopping semaglutide. The medication did not rewrite your behavior; it created a window. What sustains the result in the long run is the habit built inside that window: a strength training routine, protein intake and an eating pattern you can maintain without the pen.
The role of training and protein
What remains
The pen solves the calorie equation; it does not choose what leaves your body and does not guarantee the result stays. In SURMOUNT-1, one quarter of the weight lost was muscle. In the STEP 1 extension, two-thirds of the weight came back one year after stopping. The two numbers tell the same story: without strength training and enough protein, the medication lowers the number on the scale and hands back a weakened body, ready to regain. The pen is a medical decision, from start to discontinuation, and that does not change. But what survives after it, the muscle you build while appetite is controlled, is your territory. Use the window to train, not only to eat less.
