New players (from oldest to newest). All work. Now it comes down to a cost:benefit analysis.

Not “costs” as in risks or side effects, and mechanisms aside, but literal price. In other words, people who haven’t reached their goal body fat with keto & resistance training and have other options available :)

Semaglutide is a GLP-1Ra, so increased satiety. People literally can’t finish their usual meals and of course lose weight. Metabolic benefits ensue (surprise, surprise... I know)

Tirzepatide: similar to semaglutide but added weight loss benefits via [theorized] GIP signaling. First phase insulin signaling is a strong factor. Keto or mixed diet or whatever, you want a robust first phase insulin response. It’s the best excuse for including some smart carb meals every once in a while. NOT CARB BINGES, AND NOT AT NIGHT WHERE BEDTIME IS THE ONLY THING THAT SHUTS IT DOWN.

In terms of overall efficacy for fat loss and metabolic improvements: tirzepatide > semaglutide > canagliflozin.

Canagliflozin: “liver decreases in proportion to the magnitude of body weight loss IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin [BOOM!], which tended to be greater and occur more often with canagliflozin” (Cusi et al., 2018). #NoShitSherlock

And it seemed to hold it’s own against semaglutide in at least one study: Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial  (McCrimmon et al., 2020)

Bear in mind, context here: semaglutide and tirzepatide are once-weekly subcutaneous injections. Canagliflozin is daily pills. This study kinda surprised me and I don’t think canagliflozin alone is a great fat loss drug… although at its price point… see below

That said, tirzepatide was superior to semaglutide in this study: “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes” (Frias et al., 2021)

My original conclusion wrt efficacy is still: tirzepatide > semaglutide > canagliflozin, but that doesn’t account for costs.

You want adequate glucose control, regardless of mechanism. Keto (low glucose intake), canagliflozin (increased glucose disposal), semaglutide (decreased food intake, increased glucose uptake in the periphery), tirzepatide (similar to semaglutide but also more calorie wasting). In the latter two groups (semaglutide and tirzepatide), people report leaving food on their plate, literally. They spontaneously eat less. Even on low carb.

But back to costs……

Consider this: canafliflozin at a low dose of 100 mg/d costs $0.30/d. If we set that at “1,” semaglutide at 0.25 mg/wk costs “1.4,” or 40% more expensive. Tirzepatide at a similar introductory dose of 5 mg/k costs “12,” or 12x more expensive (~$3.20/d). At max doses: canagliflozin 300 mg/d ($0.90/d or 3x canafliglozin at 100 mg/d); semaglutide 1 mg/wk ($1.65 mg/d or 5.7x canagliflozin at 100 mg/d); and tirzepatide 10 mg/wk ($6.50/d or 23x canagliflozin at 100 mg/d).

THIS ALL DEPENDS ON YOUR DOCTOR AND INSURANCE COVERAGE (in most cases)

But otherwise, if you’re out of pocket, canagliflozin seems like the lowest hanging fruit. Beneficial (albeit not as much as the others), but dirt cheap. Semaglutide is still the cheapest most effective fat loss compound, and if you have the resources, tirzepatide. This is all in the context of not reaching your goals via diet and exercise.

That's all for now!

What do you think? Has anyone tried any of these compounds (or similar)? Let me know in the comments :)

For personalized health consulting services -> email: [email protected].

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