There has been an explosion in popularity of weight-loss drugs like Ozempic and Wegovy recently, leading to manufacturing shortages and delays as well as off-label prescriptions. When one medication becomes unavailable, patients frequently ask their doctors about similar drugs that provide them with the same outcome—which is, in most cases, rapid and significant weight loss.
There are a number of drugs that have been FDA approved for obesity and/or diabetes management. Many of them, like Ozempic and Wegovy, have the same active ingredient: semaglutide.
But there are also other active ingredients that result in weight loss, and studies are currently being conducted to see which ingredient works faster or better and why certain medications seem to be more effective on some patients versus others.
Below, experts explain the differences between these buzzy weight-loss drugs in terms of function, effectiveness, and known side effects.
Ingredient: semaglutide
Found in: Ozempic, Wegovy, Rybelsus. Compounded semaglutide, which is commonly mixed with a base of sodium or acetate plus B12 or L-carnitine, has also become a popular (and often more affordable) option for those who can’t get the name-brand medication.
What it is: Semaglutide was developed in 2012 and released for the treatment of type 2 diabetes in 2017. “Ozempic is semaglutide injected weekly, sold for the treatment of diabetes, with a maximum dose of 2 mg,” explains Dr. Rosen. “Wegovy is semaglutide injected weekly for the treatment of obesity with a maximum dose of 2.4 mg. Rybelsus is semaglutide administered through daily pills and is marketed for the treatment of diabetes.”
Dosage: Patients start Wegovy at 0.25 mg and, every four weeks, have the option to increase to 0.5 mg, 1.0 mg, and 1.7 mg, with a maximum dose of 2.4 mg. Dosages for compounded semaglutide vary.
How it works: Semaglutide is in a group of medications classified as GLP-1 (glucagon-like peptide 1) agonists. “An agonist is something that activates a receptor,” explains Dr. Daniel Rosen, a board-certified bariatric surgeon in New York City. “A GLP-1 agonist activates a GLP receptor by mimicking the biological peptide GLP-1. In contrast, an antagonist would block a receptor without activating it, effectively preventing the biologic hormone from doing its job.” When the GLP-1 receptors in the pancreas are activated by the medication, it results in reduced appetite and delayed glucose absorption due to slower gastric emptying.
In layman’s terms, GLP-1 is a hormone that your body produces to help it process food for energy. It lowers the amount of sugar (glucose) in your bloodstream and slows your digestion. This helps you feel fuller longer and results in eating less. This, in turn, aids in weight loss.
Ingredient: liraglutide
Found in: Saxenda, Victoza
What it is: “Liraglutide is a GLP-1 receptor agonist, similar to semaglutide, but it requires daily, rather than weekly, injections. Saxenda is the branded version of the medication liraglutide, marketed for the treatment of obesity. Under the brand name Victoza, liraglutide is marketed for the treatment of diabetes,” explains Dr. Rosen.
Victoza was FDA approved in 2010 for the treatment of type 2 diabetes, so it’s been around significantly longer than semaglutide and tirzepatide.
Dosage: Patients start at a daily dose of 0.6 mg for the first week, then increase the dosage by 0.6 mg each week until they reach 3 mg, at which point they continue to maintain on that dose.
Ingredient: tirzepatide
Found in: Mounjaro and Zepbound
What it is: “Mounjaro is a dual agonist, or an analogue of two weight-regulating hormones—GLP and GIP [gastric inhibitory peptide],” says Dr. Rekha Kumar, an endocrinologist in New York City and Chief Medical Officer at the medically assisted weight-loss program Found. It was FDA approved in 2022 for people with type 2 diabetes.
On November 8, 2023, the drug received FDA approval for chronic weight management in adults with obesity under the name Zepbound. It’s the second drug after Wegovy to receive approval for weight loss. According to Eli Lilly’s press release, Zepbound is expected to be available by the end of the year at a list price of $1,059.87.
Dosage: Mounjaro and Zepbound patients start with a weekly injection of 2.5 mg for four weeks. You can increase to 5 mg for the following four weeks. If you need more glycemic control, doses can be increased to 7.5 mg, then 10 mg, 12.5 mg, and the maximum of 15 mg, with at least four weeks at each strength.
How it works: Like Ozempic and Wegovy, it’s a once-weekly injection to help patients feel full by regulating glucose levels. However, since it’s a dual agonist that activates GIP in addition to GLP-1 receptors, “it tends to work better [than semaglutide],” says Dr. Kumar.
In semaglutide trials, patients showed an average weight loss of 14.9% after 68 weeks, whereas “tirzepatide trials showed weight loss of 26% on average, for adults receiving it for 88 weeks,” adds Dr. Rosen. In Zepbound clinical trials, people taking the drug on the highest dose (15 mg) lost on average 48 pounds, while at the lowest dose (5 mg), people lost on average 34 pounds (compared to 7 pounds on placebo) over the course of 72 weeks.
Ingredient: retatrutide
Found in: This medication is still in clinical trials. “No release date has been set for retatrutide; it has not yet been granted FDA approval,” says Dr. Rosen. “As of now, no brand name has been released by Eli Lilly for retatrutide.”
What it is: “To date, it is the most effective medication to have been developed for the treatment of obesity, but it has not yet been released,” says Dr. Rosen. “Phase 2 trials have shown better weight loss with retatrutide than with tirzepatide or semaglutide.” This is because it’s not a single or dual agonist but a triple agonist (and the only one of its kind).
How it works: “Retatrutide is a triple agonist peptide, acting on the receptors for GLP-1, GIP, and glucagon,” explains Dr. Rosen. Although he has not been able to prescribe it since it is still in clinical trials, he has high hopes for this medication. “Retatrutide trials showed weight loss of 17.5% at 24 weeks and 24.2% at 48 weeks, respectively. It is reasonable to extrapolate that when studies for retatrutide extend beyond one year, weight loss from retatrutide will likely exceed weight loss from tirzepatide,” he says.
Why choose one weight-loss drug over another?
In terms of semaglutide vs. retatrutide, semaglutide vs. tirzepatide, and semaglutide vs. liraglutide, it’s hard to say with certainty which is most effective, since results vary with each patient.
“Determining what medication to prescribe a patient involves many factors, including the patient’s insurance coverage and their ability to have a certain medication approved and covered, the cost (if insurance coverage is not an option), the potential for side effects, and the patient’s tolerance for the different options for medication administration,” says Dr. Rosen. “All in all, it is an individual decision that the doctor makes with each patient.”
All of these medications have side effects that can include nausea, constipation, and/or vomiting. Serious but rare side effects include pancreatitis and gallbladder disease. If you are pregnant or have a history of medullary thyroid cancer, you should not be prescribed any of these medications, says Dr. Kumar.
“One medication could work better than another because of the number of hormones involved in their mechanism of action,” explains Dr. Kumar. “Retatrutide is a ‘triple G’ because it works on three hormones, tirzepatide works on two hormones, and semaglutide works on one hormone. The efficacy is directly related to the number of weight-regulating hormones it mimics, which is why we see tirzepatide outperform semaglutide and retatrutide outperform tirzepatide in clinical trials.”
Dr. Kumar notes that, in real life, people also respond differently to medications due to their genetics and biology. Further testing is needed to see why someone would respond better to a certain medication and why.
It’s hard to compare these ingredients head-to-head, since they are still relatively new, but they are being studied. “Currently, a trial is underway comparing Mounjaro head-to-head with Wegovy in overweight and obese patients,” says Dr. Rosen.
“In my experience, patients lose weight better and faster with Mounjaro compared to Wegovy,” says Dr. Rosen. “I often treat patients whose weight loss has plateaued on the maximum dose of Wegovy, and I find that by changing them over to a less than maximum dose of Mounjaro, they are able to start losing weight again.”
Why would I choose compounded semaglutide over a brand-name form?
Many people are choosing the compound version simply because there is a backorder on brand-name medications. Others want other ingredients added to ensure they don’t lose muscle mass alongside fat.
Joe Baczewski, RN, founder of LIVation in Madison, Connecticut, compounds semaglutide with carnitine. “Semaglutide has the intended effect of stabilizing blood sugar and reducing food intake. The problem that all GLP-1 peptides have is, there is no control over where you pull from for the lost caloric intake. For energy, your body breaks down glucose, followed by lean mass [muscle], then fat. Carnitine helps our patients to skip glucose and lean mass and primarily break down fat.” Baczewski adds that a keto-style diet in conjunction with the medication can help you achieve better weight-loss results.
Can anyone use any of these medications?
“It’s best to try to stay on label,” says Dr. Kumar. “Medications that are FDA approved for diabetes should be prescribed for diabetes, and medications that are FDA approved for weight loss should be prescribed for weight loss.” Currently, Ozempic, Rybelsus, Mounjaro, and Victoza are approved for the treatment of type 2 diabetes.
Saxenda and Wegovy have been approved for weight loss, and you do not need a diabetes diagnosis to get a prescription, although some doctors may require a certain BMI and a comorbidity like high blood pressure or high cholesterol.
However, there are always exceptions, to see how well someone can tolerate a certain medication. “Sometimes there’s some trial and error in figuring out what works best for someone, and medications can be prescribed off label,” adds Dr. Kumar.
Do these medications work for things other than weight loss and diabetes?
“There are a number of studies being done on the effects of GLP-1 agonists on addiction, depression, mental health, and chronic inflammatory illnesses,” says Baczewski. “Our clinic, with full disclosure to our patient, has been able to use semaglutide off label to help with alcohol cravings. The control it provides these patients is exceptional and will need to be further evaluated by research.”
Are there any over-the-counter pills that work like these medications?
Thanks to TikTok and a nationwide shortage of some of these drugs, some influencers have started touting over-the-counter supplements, such as berberine, as a substitute. It’s not, according to our experts. “No over-the-counter supplements have the same efficacy as these medicines,” says Dr. Kumar. “Some supplements could show very mild similarities—but not to the degree of these pharmaceutical agents. For example, research has shown that berberine also can reduce blood sugar [fasting blood/plasma glucose] in some people with prediabetes and/or type 2 diabetes, however, it is unlikely to suppress appetite or be helpful for weight loss.”
So no, berberine does not work like a weight-loss drug. And as with anything you inject or ingest, you need to be aware of side effects, contraindications, and potentially dangerous interactions.
“Dietary supplements do not need to be FDA approved, which means their safety and efficacy is not always known. Supplements should not be taken in lieu of medicine. People interested in weight loss should consult a doctor specialized in obesity medicine first, to discuss safe and effective options,” says Dr. Kumar.
