Recently, I posted a thread about my use of semaglutide for weight loss, and was given the idea by @recessedmandibleHTN III to create a thread comparing semaglutide and tirzepatide. First, I'll go over both briefly and explain what they do, and then I will compare the two, and give my opinion on which is better.

Semaglutide

What is it?

To put it as simply as possible, it's just an apatite suppressant. It is a GLP-1 receptor agonist medication used to treat type 2 diabetes and obesity. It works by mimicking the natural hormone GLP-1. Semaglutide is a single agonist. It only effects GLP-1R (GLP-1 receptors). It has the highest affinity for its target site. Semaglutide is about 94% identical to human produced GLP-1. GLP-1 has multiple effects. To mention a few it decreased hunger and food noise, delayed gastric emptying, increased satiety, decreased glucagon secretion, increased pancreatic beta cell function.

Effects on muscle mass

Out of the 3 main GLP-1 Agonists, Semaglutide has the worst muscle wastage to fat loss ratio compared to the other agonists. This is because it doesn't have the other methods of action that will help to relieve side effects and improve nutrient partitioning (amongst other things) to preserve lean mass. The muscle mass loss can be mitigated to a large degree by making sure you continue to have a high protein diet (which may be hard if you want to puke every time you eat), and continue weight training. The drug itself is not muscle wasting like some people seem to believe. The muscle loss is a direct cause of the aggressive deficit.

The side effects of Semaglutide

The most common would be Nausea which is experienced by around 43.9% of users on this highest dosage of Semaglutide (2.4mg). Vomiting, Diarrhoea, Abdominal pain and constipation are amongst the most common side effects. You may feel sick every time you think about eating, which is a large reason why it works, but obviously this is not ideal. Semaglutide has the harshest side effects out of the 3.

Who should use Semaglutide?

If your sole goal is just straight up weight loss, Semaglutide is the way you should go since it is the strongest at stimulating GLP-1. You are guaranteed to lose wight if the thought of eating makes you want to puke.

Tirzepatide

What is it?

Tirzepatide isn’t actually GLP-1. It’s actually a 39 amino acid modified GIP molecule that has GLP-1 activity added to the molecule. That is why we call it a dual agonist. It’s having an effect on two incretin receptors. That means Tirzepatide is binding to the native GIP-R (GIP receptor) with essentially equal affinity as our body’s own GIP molecule. However, the GLP-1 binding is about 5 times weaker than what our body creates. It is an imbalanced dual agonist with preferential activity at GIP over GLP-1. This means that mg for mg, compared to Semaglutide, it will reduce apatite to a much greater degree than Tirzepatide since the drug is a full agonist of GIP-R, and only a partial agonist of GLP-1R. That partial agonist effect means you’re not fully saturating the receptor site, which means you don’t get the full effect.

The benefits of being a GIP Agonist

There are multiple benefits to GIP (glucose-dependent insulinotropic polypeptide) Agonism that Semaglutide don't produce. GIP is another hormone involved in glucose metabolism. It has an anti-emetic/anti-nausea effect which explain why some people experience less side effects. Like GLP-1, it promotes insulin secretion in response to high blood glucose levels. However, GIP has also been shown to have effects on fat metabolism and energy balance. It also has other effects, it is neuroprotective, increases bone formation, decreases stomach acid secretion, increases insulin release.

Effects on muscle mass and bodyweight

In a study comparing the weight loss effects of Semaglutide and Tirzepatide, it was found that a larger proportion of patients on Tirzepatide achieved significant weight loss.

In terms of lean mass preservation Tirzepatide does seem to preserve more than Semaglutide users.

The side effect of Tirzepatide

The side effect profile is very much the same as Semaglutide. The side effects are typically less severe than Semaglutide allowing it to be a much more sustainable to run long term. The main side effects still are Nausea, Vomiting, Diarrhoea, Abdominal pain and constipation.

Who should run Tirzepatide?

If your are going to a run a GLP-1 year round and you cannot get your hands on retatrutide for whatever reason, Tirzepatide is your best bet.

WHATS THE DIFFERENCE

Both are both widely used for weight loss, but they differ in how strongly they tend to work and why. Semaglutide helps reduce appetite and slow digestion by mimicking one hormone (GLP-1), leading to steady, significant weight loss. Tirzepatide activates two hormones (GLP-1 and GIP), which can further suppress appetite and improve how the body uses energy, and in clinical trials it has generally led to greater average weight loss than semaglutide.

WHICH DO I RECOMMEND?

Personally, I only have experience with using semaglutide for weight loss. What I can tell you is that you won't want to eat ANYTHING. It's just an appetite suppressant. For me, I wasn't exactly avoidant towards food, but the idea of eating wasn't very appealing to me most days and I have to force feed myself sometimes. The results speak for themselves, I've lost a ton of weight and leaned down. Tirzepatide, from others' anecdotes, helps preserve muscle more than semaglutide does (this was found to be the same in studies.) In my opinion, I've gained muscle on semaglutide by staying consistent with the gym, and eating right and ensuring I have enough protein every day. Essentially, don't be a fucking moron and starve yourself.

Availability

Currently, for people just getting into peptide and drug use, semaglutide will be more available and easy for consumption than Tirzepatide. This is because Semaglutide can be taken orally. Now when taking orally, doses must be larger and daily rather than weekly, so this might be costly. However, if you are scared of needles like me lol, semaglutide is the way to go. If you're used to peptides and care a lot about your muscle mass being preserved, go with Tirzepatide. It all depends on what YOU want out of the drug.

THanks for reading

-rky