In my last post, I described how GLP-1s were discovered and how they work.
Now, I want to look at the different options and how they differ from each other.
First, it is important to understand how FDA approval works.
After a medication or treatment has been found to work in animal models, a set of clinical trials may begin.
First, a small Phase 1 study with 20 -100 people is done to make sure the medication is safe to be given to humans.
If the trial proves to be successful, that there are no severe reactions to the medication, the FDA will clear the medication for the Phase 2 clinical trial. About 200-300 people are recruited for this phase of trials and the drug is tested for its ability to work, or in other words, to provide a measurable result that shows its “efficacy”. This involves placebo trials and extensive measurements concerning the results that are intended to occur.
Once the effective dose is determined and the benefits are documented, the medication will be ready for Phase 3.
In Phase 3 a large group of people, maybe 1,000 are recruited from all over the country, with a diversity of age, sex, race, etc. They are tested to generate data on the efficacy and safety of the drug at the dose and usage determined in Phase 2.
The important thing to realize is that, in the three phases of clinical trials, the drug is being evaluated for its ability to treat a specific symptom. The trials are not for ANY use; they are for a SPECIFIC use. Therefore, when the FDA approves the drug after the completion of the Phase 3 trials, they do so specifically for the use for which that drug was tested. And that approval allows physicians to prescribe that drug ONLY for that use, and for the insurance companies to reimburse you ONLY for that use.
Now, Novo Nordisk received approval for Ozempic, for reducing Hba1c in Type II diabetics. That is what physicians are allowed to prescribe it for, and it is what Pharmacy Benefit Managers will allow payment for.
However, semaglutide also showed use for weight loss. Ozempic was not approved for weight loss, so Novo Nordisk had to go through another series of clinical trials with the same medication (semaglutide) testing for weight loss. When that was complete and approved, Novo Nordisk was allowed to market the same molecule, for the physicians to prescribe it for weight loss and the insurance companies to pay for it for weight loss. They named the drug Wegovy when used this way.
The drug is the same and the delivery method is the same (an injection under the skin); however, the dosage needed for weight loss was found to be 3-4 times higher than when used to reduce Hba1c levels. So, the dosage in the delivery pens for Wegovy are higher than those in the Ozempic delivery pens.
Research continues on other uses for semaglutide including Heart Failure, Asthma, neurological disorders, and arthritis. If approved, the market will expand.
Another version of semaglutide is marketed under the name Rybelsus. Rybelsus is not injected, it is a tablet that you swallow. But since it is swallowed, it is more easily broken down by your digestive system. Because of this, Rybelsus requires higher dosages, and you have to follow a very specific routine while taking Rybelsus. You take it every day, and you need to take it on an empty stomach with a sip of water, and then 30 minutes later you need to eat a meal. For some people this is less desirable than a once-a-week injection.
There is another molecule similar to semaglutide called tirzepatide. Both are very similar in that they are amino acid chains of about the same length, with a fatty acid attached. The sequence of amino acids is not the same, and the fatty acid is a little different. It has been observed that tirzepatide has some additional benefits over semaglutide and may result in a little better weight loss.
Tirzepatide is marketed by Lilly under the name Zepbound for diabetes, and Mounjaro for weight loss. I cannot offer an opinion on which might be better for you; you should talk to your physician about the benefits and side effects and make a choice that fits you best.
The most recent study comparing semaglutide and tirzepatide was published on May 11 this year in the New England Journal of Medicine, one of the most prominent journals in the world. It showed a small but significant increased weight loss and waist circumference decrease for tirzepatide over semaglutide.
Other studies showed very comparable measurements for the two molecules, although semaglutide has a slight but significantly longer life in the blood.
The final well-known medication in this group is Jardiance. It is a pill taken once-a-day. It is not in the same category as the medications discussed relating to GLP-1. It’s mode of action is quite different, so I won’t go into it here.
WHAT ABOUT COMPOUNDED VERSIONS OF GLP-1?
The final issue that you might be curious about is “compounding”. Because of the high price of these GLP-1 medications, any way of reducing the costs becomes attractive. And because there is a large market for less expensive versions, there are hundreds of sources focused on getting your business by offering the same medications for a fraction of the cost.
One of the reasons for the high costs of semaglutide is because it is only available in pre-filled injection pens, and these pens are not inexpensive to make and fill. If the drug was available in a vial in which you could remove doses with disposable syringes, the price could be less, but Novo Nordisk does not provide that as an option.
The oldest of the four drugs discussed is Ozempic. Its patent expires in 2032. Novo Nordisk DOES NOT sell bulk amounts of semaglutide to other companies or pharmacies. They are the only source of semaglutide. So how are companies outside of Novo Nordisk able to provide semaglutide to consumers?
Aren’t compounders violating the patent? Well, yes; EXCEPT, the FDA has a provision that allows generic forms of a medication to be sold during the patent protection period, IF there is a SHORTAGE of the medication. In 2022, the FDA issued a formal announcement of a shortage in Wegovy and Ozempic. This allowed companies to purchase generic versions of the drug from other suppliers, to repackage it and then to sell it to patients. However, on February 21st of this year, the FDA formally retracted the shortage. Several patent infringement lawsuits are currently filed.
When considering using a compounded version of one of these drugs, you and your physician should consider these issues (I am not qualified to give you advice on your health maintenance, and you should make an educated choice):
1. Availability
Sometimes your physician will not be able to prescribe a GLP-1 to you because you are either not diabetic, pre-diabetic, or obese. The reason may be because your drug plan will not cover the cost unless you fall within one of those categories. If you and your physician still think you would benefit from it, some compounders will fill the prescription.
2. Cost.
There is a built-in profit for the drug company that holds the patent which is generally higher than the profit collected by the generic manufacturer. Also, the pen is more expensive than the vial.
3. The Base and Salt versions.
I don’t want to get too wonky here, so the point is that there are two ways to package these GLP-1s in solution. One is a “base” form, like baking soda. The other is a “salt” form, like table salt. The reason that this comes up is that only the base version of semaglutide was tested in clinical trials, so it is the only one covered. I have seen no scientific studies comparing the salt and base forms, although some compounding companies site the difference and take positions on one side or the other. It could be argued that the two version SHOULD be similar, but without specific studies it is not possible to decisively make that statement. There is a difference in the “solubility”, the ability to be dissolved in the blood, so that COULD make a difference.
Some compounders use the “salt” form in an attempt to sidestep the patents on the brand-name drugs that were approved as “base” forms.
4. Chemical structure.
As discussed before, Novo Nordisk tried thousands of molecules with changes in amino acids, different fatty acid “feathers” and different attachment points before they found an active drug with a full 7-day life span. The brand name drugs are produced in FDA-regulated manufacturing plants and chemically assayed before packaging and distribution.
Compounded drugs are not necessarily manufactured in facilities regulated by the FDA. I have not seen chemical analyses that confirm that specific ones are identical to the brand-name drug. This is not true for other generic drugs that you may be taking such as SSRIs, or blood pressure drugs, or oral diabetes drugs. Those drugs are produced by Generic drug companies who use FDA-regulated facilities to manufacture, package and ship those drugs.
I do not know what the manufacturers of generic semaglutide actually produce and package for use by compounders. I do not know whether they have made small changes in the amino acid sequence or the structure of the feather or the location the feather is attached. They might do so in order to protect themselves from claims by the Pharma company for patent infringement; but, if they do, then we have no idea of how those changes might affect the effect of the drug, or its lifespan in your body.
Most recently, a study published on April 29th of this year by researchers at Binghamton University in NY, and the Geisinger Medical system in PA, compared compounded and brand-name GLP-1s for safety. They looked at reported adverse events (problems). They found that compounded GLP-1s had higher reports of abdominal pain, nausea, diarrhea, gallbladder inflammation and suicidality. There were reports of more prescribing and preparation errors. Finally, there were more hospitalizations resulting from compounding use.
The bottom line here is that you can save significant money by purchasing generic semaglutide from a compounding pharmacy; but there are open-ended questions that need to be considered between you and your physician before making a choice.