Semaglutide vs Danuglipron

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In the realm of GLP-1 pills, Pfizer has recently entered the fray with their own innovative contender. They’ve initiated trials for danuglipron, another oral GLP-1 agonist, which has shown some promising results.

Currently, Ozempic has a pill alternative called Rybelsus, which you might already be familiar with as the only oral GLP-1 agonist currently on the market. However, it’s about to get a lot more company.

Novo Nordisk currently has the edge. Ozempic and Mounjaro, two popular GLP-1 agonist drugs used for weight loss, are given as injections.

However, there is a growing effort to transform these types of drugs into pill form, catering to the preferences of individuals who would rather swallow a pill than give themselves injections. They’re actively pursuing the introduction of a pill version of their injectable weight loss drug, Wegovy.

Essentially, this pill will be Rybelsus given at a much higher dose and targeted specifically towards weight loss.

Challenges of GLP-1 pills

When it comes to weight loss, the mechanism behind all these GLP-1 agonists are generally the same. These compounds operate by slowing down the digestive system and triggering sensations of fullness, effectively reducing the amount of food you can eat.

What sets these GLP-1 agonists apart is the fact they can be taken in pill form, eliminating the need for injections like most others in their class. You see, GLP-1 agonists are intricate molecules, vulnerable to damage caused by the acidic environment and enzymes found in the stomach and gut.

Hence, it comes as no surprise that many GLP-1 agonists such as Bydureon, Mounjaro, and Ozempic require injections to safeguard these delicate molecules from the harsh effects of stomach acids and enzymes.

How semaglutide pills work

Now, you might wonder: how is Novo Nordisk or Pfizer able to deal with this issue? The answer is that each drug takes two distinct approaches.

In Novo Nordisk’s case, while the injectable form of semaglutide is vulnerable to destruction in the stomach, the oral form of semaglutide introduces an intriguing element: the addition of a compound known as SNAC (sodium N-(8-[2-hydroxybenzoyl]amino) caprylate).

SNAC acts as an absorption enhancer, and plays a crucial role in protecting the delicate semaglutide molecule from the harsh gastric environment. It also helps the drug’s absorption through the stomach lining. This helps ensure the safe journey of semaglutide from the pill into the bloodstream.

It is this integration of SNAC with semaglutide that enables Rybelsus to function as a pill. This technology is also being employed in the development of the pill form of Wegovy.

How danuglipron pills works

In Pfizer’s case, the molecule itself seems to be able to withstand the destruction of the stomach, and is able to make it to the bloodstream without any specialized help.

It’s hard to say exactly why, however I do notice that semaglutide is a much larger and more complex molecule, while danuglipron is a smaller and simpler molecule.

Perhaps a smaller and simpler molecule has less areas for enzymes or other chemicals to attack it, making it less prone to damage from the surrounding environment.

Semaglutide vs danuglipron

But how do these GLP-1 pills compare to each other? Novo Nordisk’s Rybelsus and Pfizer’s danuglipron initially target diabetes, although Pfizer likely plans to branch out with a separate brand for obesity treatment once their drug gains approval for diabetes. However, Novo Nordisk’s upcoming pill form of Wegovy, already has a distinct focus on obesity treatment.

While they all share the commonality of being pills, there are some noteworthy differences.

Semaglutide only needs to be taken once a day, whereas danuglipron likely needs to be taken twice a day. However, semaglutide must be taken on an empty stomach, whereas danuglipron may offer more flexibility in this regard.

How about effectiveness for weight loss? While direct head-to-head comparisons are lacking, we can draw some indirect comparisons.

Individuals using Rybelsus achieved an average weight loss of approximately 3.4 kg. Those on danuglipron experienced a slightly higher average weight loss of 4.2 kg. However, the pill form of Wegovy has individuals shedding an impressive average of around 13 kg.

Thus, danuglipron seems to show promise in closely matching Rybelsus in weight loss, but falls significantly short of the pill version of Wegovy.

Caveats to the comparison

However, there are a few problems with this surface-level comparison. Firstly, we must consider the different time frames for these studies.

Rybelsus and the pill form of Wegovy underwent testing for a year or even longer, whereas danuglipron’s trials were limited to 16 weeks.

As a result, danuglipron’s long-term effectiveness remains unproven. Some speculate that this shorter duration could indicate faster results, as it achieved in four months what Rybelsus accomplished in a year.

But this speculation is incorrect. Weight loss with these medications is not a linear journey. The first few months often yield the fastest progress, after which weight loss slows down or even plateaus.

At this stage, the medication’s ability to sustain and maintain weight loss in the long run becomes more important, or else it could run into the issue of weight regain commonly associated with short-term drugs like phentermine.

Additionally, the number of studies conducted on Rybelsus far surpasses those done on the other drugs. The PIONEER trials, consisting of 10 studies, compared Rybelsus against other medications and under different conditions. Consequently, the results from these trials carry greater reliability.

The pill form of Wegovy currently only has two published studies, namely the PIONEER PLUS and OASIS 1 trials, with more OASIS trials planned in the near future.

On the other hand, danuglipron has relatively limited trial data, with only one phase 2 trial, making the reliability of its results less robust.

Lastly, it’s worth noting that danuglipron’s current focus is solely on diabetes treatment. Once Pfizer shifts its attention to weight loss, they may explore the possibility of increasing the dosage to maximize its weight loss potential.

So until then, it may not be entirely fair to directly compare danuglipron to the pill form of Wegovy, as they technically target different conditions.

GLP-1 pills vs injections

Amidst the rise of all these GLP-1 pills, do injections hold any advantages or are they doomed to disappear?

A common misconception some people have is that injections may offer greater effectiveness than pills. In clinical practice, the injectable Ozempic is often regarded as equivalent in therapeutic efficacy to its oral form, Rybelsus.

However, when we look into comparative studies examining the weight loss achieved with these drugs at their maximum recommended doses for diabetic patients, an intriguing pattern emerges.

On average, Ozempic seems to do better than Rybelsus at these doses, implying that the injectable form of semaglutide might be more effective for weight loss when compared to its oral counterpart.

However, this might just be a dosing issue. It’s obvious that the oral formulations are not as well absorbed as their injected counterparts.

But the solution seems to be to simply increase the dose until you get the desired absorption. Ozempic is injected at a 1 mg dose, while Rybelsus is taken at a 14 mg dose—equivalent to a fourteenfold increase. Similarly, Wegovy is injected at 2.4 mg, whereas the pill form of Wegovy necessitates 50 mg for comparable benefits—more than a twentyfold increase.

So pill formulations are meticulously designed to achieve similar effectiveness to their injected counterparts.

Any differences in effectiveness is likely to be more influenced by patient compliance. For example, for some individuals, giving yourself an injection once a week may be easier than daily pill consumption, especially if you need to take it on an empty stomach every time.

Skipping days due to forgetfulness or taking the pills with food due to convenience can reduce the efficacy of the pills, making injections more effective for certain people due to their lifestyle. So both the pills and injections will be useful for different individuals.

Another reason why injections will continue to hold their own is because most other GLP-1 agonists, such as Mounjaro, are still vulnerable to stomach acid and enzyme breakdown.

Absorption enhancers and protective molecules, such as SNAC, are limited to just semaglutide and cant be applied to other GLP-1 agonists at the moment.

However, it is highly likely that pharmaceutical companies in possession of these drugs are actively pursuing the development of SNAC-like absorption enhancers to market their injectable medications in pill form, to cater to a wider audience.

So despite the upcoming rise of GLP-1 pills, injections will continue to persist and offer unique advantages compared to their pill forms.

Learn more about

• Semaglutide vs Tirzepatide
• What Forms of Semaglutide are Available?
• What to Expect With Wegovy
• Comparing other GLP-1 Agonists for Weight Loss
• Other weight loss medications

See also

• 
  3 Tips to BEST Use Rybelsus
  It’s more important than you might think to take Rybelsus with minimal water on an empty stomach and waiting at least 30 minutes before eating.
• 
  Comparing Weight Loss Drugs in 2024
  Ozempic and Mounjaro are highly effective at treating obesity, however there are many other approved and off-label options that also work.
• 
  Bupropion vs Contrave vs Naltrexone
  Contrave is a synergistic combination of buproprion and naltrexone, which can be replicated to some degree using the generics individually.
• 
  New Obesity Drugs in 2024
  New obesity drugs target more than just GLP-1 and do much more than suppress appetite for a more nuanced approach to weight loss.
• 
  Mounjaro: Who Loses the Most Weight?
  White or Asian younger women who use metformin and have lower sugar and lipid levels tend to experience more weight loss with Mounjaro.