The trials of the least favourite sibling
Do you have any siblings? If you do, were you the favourite child? Likely, the favourite child is now saying, “No, my parents loved my siblings and me equally!” However, the non-favourite children know this was not the case.
My mother always said she loved my brother and me equally, but actions speak louder than words. My brother got more attention and always seemed to get better presents at Christmas because, “Danny, you are hard to shop for.” It’s not my fault I didn’t know what I wanted, and I always realized I would have happily taken whatever my brother got after seeing him play with it and how much fun he had! I am kidding, kind of, and I am being dramatic again. My mother still loved me very much, just a little less. Anywho! This seems like an appropriate introduction to today’s topic about a new medication on the market called Rybelsus!
Is Rybelsus the least favourite sibling compared to Ozempic?
Have you heard of it? Probably not. I am sure you have heard of oral Ozempic, though! That is because that is what Rybelsus is. Oral Ozempic is what everyone refers to it as, in typical least favourite sibling fashion. Rybelsus contains semaglutide, just like Ozempic. However, Rybelsus comes as an oral formulation instead of as an injectable. It also needs to be taken once a day vs. the once-a-week Ozempic dose. Rybelsus is a new medication for managing diabetes, and it does an OK job.
Sorry my drug rep friends, but let me explain! PS. When you start paying me the big pharma money, I might change my tune. I mean, probably not, but we won’t know until you do! 🙂
Semaglutide as an oral tablet?
So one of the first issues the drug company had to overcome was how do we get a massive molecule like GLP-1 from the intestines into the body so it can work its magic on blood sugars?
You see, with an injectable, the needle does all that work and puts the drug directly into the system bypassing the whole stomach, acid, and digestion thing. However, with oral medications, they have to find a way to essentially break into Fort Knox, all the while having enough remaining concentration to have some actual effect in the body. So what they did is attached semaglutide to an absorption enhancer called SNAC.
Now, SNAC has been around for a while and is commonly found in Vitamin B12 supplements to allow for their absorption. SNAC works because it essentially creates a temporary change in the acidity of your GI tract, and through ‘magic and wishes,’ this allows semaglutide to cross the cell layer and into the bloodstream. It is a pretty neat technology despite my somewhat lack of knowledge of how it actually works.
One of the obvious concerns was if we are creating this hole or pathway from our GI tract to the bloodstream allowing a big ass molecule like semaglutide through, does that enable pathogens, food and other drugs to be better absorbed too? While that is a very fair point, it does not seem to be the case. It looks like the SNAC and semaglutide are so tightly knit together that the pathway is quite small and does not lead to other issues. Now in saying that, the drug company does recommend taking Rybelsus on a completely empty stomach (no food or drugs) and no more than 4oz of water for at least 30-60 minutes to avoid any issues. Talk about a royal pain in the ass. Similarly, that was likely one of the reasons I was not the favourite child.
One strike against Rybelsus. How did it manage blood sugars?
I’m going to refer to the PIONEER 6 trial by Husain and friends. This was a trial to assess the safety of Rybelsus in not causing nasty things like heart attacks and strokes compared to placebo. Every diabetes medication needs to have this trial completed in order to come to market. The good news: Rybelsus did not cause any cardiovascular issues. However, it also did not provide any cardiovascular benefit like the golden child Ozempic. Another point in the disappointment column.
In terms of blood sugar lowering, Rybelsus did a decent job leading to an A1C decrease of ~1%. This was comparable to Victoza but not quite as good as Ozempic, which led to an A1C lowering of ~1.5%. Similarly, in the weight-loss category, Rybelsus did OK. Leading to an average loss of 4-5kg at the highest dose of 14mg daily. However, again compared to the Ozempic, it still did not stack up. Ozempic at 1mg once weekly averages 5-6kg depending on the study you read. At 2.4mg once a week, Ozempic can lead to a whopping ~15kg or nearly 20% loss from baseline body weight. Crazy, I know!
Side effects were pretty standard, primarily GI in nature, such as nausea, vomiting, and diarrhea. The risk of low blood sugars was near nil and occurred when participants were on other medications such as insulin which is at a much higher risk of causing low blood sugars. Again, the mechanism by which semaglutide reduces blood sugars shuts off when blood sugars are within the normal range!
So, if Rybelsus is not that great, why did it get made?
The drug company asserts that it is what people wanted – they prefer an oral pill over an injectable. There are certainly a few individuals who are very needle phobic, so an oral formulation is preferred. However, a vast majority of people are actually quite OK with injecting Ozempic. Especially when they see the needle is no bigger than the whiskers on my face and the fact they only need to do an injection once a week!
Personally, I think it is more that healthcare professionals don’t like injectables, and it is their discomfort that led to the development of an inferior oral product. Which in one regard, I can understand, it might be easier to counsel on an oral medication vs. an injectable, and I may be biased as I do this all day long, but I don’t really see it as all that hard, especially when I know I am providing a great benefit to my patient. Another thing to consider is that more and more medications will come in an injectable formulation as our treatments become more complex in managing chronic diseases. Now, this is just my opinion, of course.
In conclusion, I am not super impressed with Rybelsus. Again, sorry to my drug rep pals, but the drug offers no significant benefits outside of blood sugar lowering. Dosing is going to be a pain in the ass and likely not realistic for many individuals – leading to possible treatment failure. I don’t see this medication getting pushed for obesity treatment as the weight-loss effects aren’t spectacular, and better agents are available. Unlike myself, I can certainly see why someone would consider it the least favourite child compared to Ozempic. So if you are extremely needle phobic, did not tolerate Ozempic, or can’t do injections for any other reasons, then Rybelsus might be an option for you. If not, I prefer the injectable formulation of Ozempic!
– Dr. Dan