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Leszek Czupryniak, MD, PhD, is a professor of medicine and head of the Department of Diabetology and Internal Medicine at the Medical University of Warsaw, Poland. His areas of interest are type 1 diabetes, type 2 diabetes, diabetes accompanying other diseases, and chronic complications of diabetes, with special interest in oral antidiabetic agents and insulins.
What are the differences in the efficacy and safety of semaglutide and tirzepatide in patients with obesity and type 2 diabetes? Which drug to choose?
Leszek Czupryniak, MD, PhD: Semaglutide was introduced in 2019 or early 2020, just before the pandemic, and has very quickly become a blockbuster. In 2021 the STEP study results were published, showing how the drug is effective in controlling diabetes, but also in controlling body weight in people with or without diabetes. In June 2021 the American Food and Drug Administration (FDA) registered semaglutide to be used in obesity in any person with a body mass index (BMI) >30 kg/m2 and in the overweight with one obesity-associated ailment such as hypertension, dyslipidemia, whatever. And that started the revolution.
Elon Musk published his impression on Twitter [now X] on how effectively he lost weight with semaglutide. Many people started to use it. Obese people started to chase the drug, hunt for it, because it is apparently—and we see it—very effective, sometimes much more effective than we can see in the studies. There are patients who lose 10, 20, 30, >30 kg of body weight within 1 to 1.5 year, and this is the efficacy that we can compare with bariatric-metabolic surgery. So, semaglutide in a way has become a benchmark drug for obesity treatment today. The preparation of semaglutide for use in obesity is not available everywhere. The drug is called Wegovy and it allows us to reach the dose of 2.4 mg of semaglutide per week in people with obesity. However, everywhere more or less available is the preparation of semaglutide for diabetes, the name is Ozempic, and the studies show the efficacy of the dose of 1 mg/wk. But we do increase the dose using Ozempic because as much as glucose lowering is not so much dose dependent, the body weight lowering is very clearly a dose-dependent effect. So, the higher the dose, the more effective we may be, and a patient may be in treating obesity.
This phenomenon and this blockbuster [effect]—semaglutide being a blockbuster—really happens very rarely in medicine. The drug is so popular and so often used that the patients demand this drug to be prescribed, which of course generated huge interest among the companies to find more drugs in this area, incretin hormones, and to find new preparations that would be more effective, with a more complex way in which the drugs will affect appetite control, body weight, and the whole metabolism.
So, the newest kid on the block is tirzepatide, which was introduced [in 2023]—within 1 to 1.5 year in the USA. In Europe it was introduced in Poland and Switzerland in January 2024, so we do have some experience in Poland with tirzepatide. This is the drug that we call twincretin or dual receptor agonist. Semaglutide is a glucagon-like peptide-1 (GLP-1) produced like the human insulin: produced by organisms, bioengineered, and it’s an original GLP-1 with the same amino-acid sequence as our body produces. Tirzepatide is a compound, a molecule where the company—Eli Lilly company (semaglutide is produced by Novo Nordisk)—they took a glucose-dependent insulinotropic polypeptide (GIP) molecule—GIP is another incretin hormone—they took this molecule and they changed it a little, so the drug stimulates not only the GIP receptor but also the GLP-1 receptor. That’s why we call it twincretin. This led to 2 things. One, greater efficacy. People lose weight to a greater extent when they are treated with tirzepatide. Also, their glucose control is better. With the maximum doses of tirzepatide we can achieve glycated hemoglobin (HbA1c) of 5.8% to 5.6%. This is what we know from the studies, which basically means normal glucose level, and also a little better tolerance, as we see it in patients, because GIP does not act on the stomach as much as GLP-1. So, we have a newer agent, tirzepatide, which is stronger in terms of body weight control and in terms of glucose control, and a little bit better tolerated.
The disadvantage of tirzepatide is that it’s just very, very expensive. It’s 3 times more expensive in Europe than semaglutide. And it’s not reimbursed. Because it’s been on the market for the last 4 or 5 years, semaglutide is reimbursed in some indications in Poland: it is reimbursed in the more advanced diabetes, while tirzepatide has no reimbursement yet because it’s been around only for 5 months. So, if a patient pays 100% for semaglutide, they will have to pay 3 times more for tirzepatide. And in Poland if they have semaglutide reimbursed, tirzepatide is 10 times more expensive than the reimbursed semaglutide. This is something—and I’m not afraid to say this—we look at this price as a sort of unethical behavior because these are not drugs to correct some esthetic problems, like obesity. It’s a drug that is very effective in treating the most challenging-to-treat diseases, very chronic, such as obesity and type 2 diabetes, and this price shouldn’t be that high. But the producer simply, that’s how we understand it, wanted to quench, to decrease the demand and just make the drug available on the market. Not many people simply can afford it, which is bad because we are talking about [a situation, in which] when you’re rich, you’re healthier while if you’re not rich, you’re not so healthy. And we do not like when the drugs are available on the economic basis to our patients. But I’m pretty sure the price will come down soon. The competition is very fierce here, many companies want to introduce new drugs in that area.
Another difference between semaglutide and tirzepatide is the registration. Semaglutide has 2 preparations, Ozempic and Wegovy; one is for diabetes, one is for obesity. Tirzepatide is known under one brand name, Mounjaro, and this has a double registration for both obesity and diabetes, so we do not have to explain the patients, “Look, we prescribe you Ozempic for obesity, but in the leaflet, there will be nothing about obesity, only about type 2 diabetes,” and so on. These are maybe minor differences, but in daily practice they may matter. We’re happy actually to have both of these, we’re looking for more, and we know there will be triple receptor agonists coming within the next 2 to 3 years. The triple receptor agonists will stimulate GIP, GLP-1, and the glucagon receptor, and that will be even more effective than the already very effective tirzepatide. So, if you’ve never heard about it or heard very little, just try to read more because these drugs will come everywhere. I think everyone will be taking it sooner or later. We all fight to control our body weight. And we also see the benefits in cardiovascular risk.
This is probably the last difference here, a meaningful difference. Semaglutide has been repeatedly shown to decrease cardiorenal risk, cardiovascular risk, while with tirzepatide we still await the study results, which should be somewhere in the late 2024, early 2025. We would be hugely surprised if the drug didn’t have any cardiovascular and renal risk protection properties, but it’s formally yet to be shown.
