Better Than Ozempic?

You probably know about Semaglutide for Weight Loss ← this was our article from back in the day when its popularity was just starting to rise

However, GLP-1 receptor agonists (GLP-1 RAs) like semaglutide (known by such brand names as Ozempic and Wegovy) most certainly have their downsides too, and when it comes to health risks/benefits, there most definitely are trade-offs, such as:

People on Ozempic may have fewer heart attacks, strokes and addictions—but more nausea, vomiting, and stomach pain

So, it’s probably not too surprising that Most People Who Start GLP-1 RAs Quit Them Within A Year (Here’s Why).

However, GLP-1 receptor agonism is only one mechanism of action.

Let’s add a mechanism of action

As well as boosting the action of GLP-1 (glucagon-like peptide 1) receptors, semaglutide’s competitor tirzepatide it also acts simultaneously on GIP (glucose-dependent insulinotropic peptide) receptors, thus adding a second mechanism of action.

For this reason, it is more effective than its predecessors, including Ozempic:

❝The first GLP-1 mimicking drug was exenatide (Bayetta). It’s still available for treating type 2 diabetes, but there are currently no generics. Exenatide does provide some weight loss, but this is quite modest, typically around 3-5% of body weight.

For liraglutide, those using the drug to treat obesity will use the stronger one (Saxenda), which typically gives about 10% weight loss.

Semaglutide, with the stronger formulation called Wegovy, typically results in 15% weight loss.

The newest GLP-1 mimicking drug on the market, tirzepatide (Mounjaro for type 2 diabetes and Zepbound for weight loss), results in weight loss of around 25% of body weight.❞

Read in full: Ozempic’s cousin drug liraglutide is about to get cheaper. But how does it stack up?

You can also read more about tirzepatide in our main feature about it, here: Mounjaro/Zepbound’s Stable Weight Loss Curve

Now for a third mechanism of action

You might have wondered, if GLP-1 is “glucagon-like peptide”, if there’s anything we can do involving glucagon itself.

And the answer is yes, there is! Adding a glucagon receptor agonist to the mix has been done. The drug is called retraglutide. So far, we’re only seeing trials funded by the company that makes the drug in question though, such as:

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

Looking at this and similar studies (also funded by the same company that makes the drug), it seems to only perform (at best) on a par with terzepatide, both for weight loss and in terms of adverse effects.

And most recently, a fourth mechanism of action

Researchers (Dr. Krishna Kumar et al.) have investigated adding a fourth component, an agonist of “peptide YY” (PYY), which reduces appetite and increases fat burn, and/but is quite unrelated to the first three hormones (yes, these are all hormones, by the way).

Bear in mind, these additions have been done not by adding an extra ingredient, but rather by in each case creating a chemical chimera, a single molecule that does the job of each hormone it’s agonizing—think of it like a “master key” that is designed to fit several different (but similar) locks.

Now, the problem of adding a PYY agonist into the mix is that on a molecular level, it’s very different from the first three.

The researchers’ solution? A sort of double-ended molecule that has the previous three actions at one end, and the PYY action at the other end.

Hence the paper title: Molecular Design of Unimolecular Tetra-Receptor Agonists (“tetra-” just means “four” in Greek)

One of the expected outcomes (not yet tested, because the drug is new, so we need people to have time to first be on it and see how much weight is lost in a year, and then discontinue it to see if the weight returns, which realistically means a two-year study minimum) is that there will be little or no weight rebound after discontinuation:

❝One of the limitations of the current drugs is that individual variation, possibly including how people express target receptors or respond to their corresponding hormones, can lead to lesser than desired weight loss outcomes in many patients.

By hitting four different hormone receptors at the same time, we hope to improve the chances of averaging out such variation toward the goal of achieving greater and more consistent overall effectiveness.

“A second issue is that patients tend to regain weight after discontinuing currently available GLP-1 related drugs. Recent studies indicate that weight rebound after drug discontinuation is delayed with the newer, more effective GLP-1 mimetics.

Extending from this observation, one may speculate that multi-chimeras along the lines of the one we discovered could get us closer to the bariatric surgery standard of lasting weight loss.❞

Read in full: Beyond Ozempic: New weight loss drug rivals surgery

Don’t want to wait for that, and/or prefer a more natural approach?

It is possible to get many of the effects of GLP-1 RAs without taking GLP-1RAs, by enjoying foods that increase incretin, a hormone group (the most well-known of which is GLP-1) that slows down stomach emptying, which means a gentler blood sugar curve and feeling fuller for longer. It also acts on the hypothalamus, controlling appetite via the brain too (signalling fullness and reducing hunger).

For what foods to focus on, see:

5 Ways To Naturally Boost The “Ozempic Effect” ← this is from Dr. Jason Fung, who is perhaps most well-known for his work in functional medicine for reversing diabetes, and he’s once again giving us sound advice about metabolic hormone-hacking with dietary tweaks!

You can also check out: Ozempic vs Five Natural Supplements

Enjoy!