I base this post on the SURMOUNT-MAINTAIN (https://doi.org/10.1016/ trials) and ATTAIN-MAINTAIN (https://lnkd.in/gQQEHmFc) trials. Both are rigorous and worth reading but what do they actually tell us about the fundamental challenge of maintaining weight loss? Honestly: not as much as some headlines suggest.

Lesson 1: If you need dose X, don’t expect dose X/2 to do the same job

SURMOUNT-MAINTAIN tested whether tirzepatide at maximum tolerated dose (MTD, 10–15 mg) could be reduced to 5 mg and still maintain weight loss. Continued MTD maintained ~97% of initial weight loss, reduced 5 mg maintained ~68%, and placebo ~43%. Predictable dose-response. We would never expect a patient well-controlled on an ACE inhibitor to stay equally controlled on less than half that dose yet obesity pharmacotherapy apparently needs an RCT to confirm this. The maintenance challenge remains: patients need to stay on the dose that works, indefinitely, like any other chronic, relapsing disease.

Lesson 2: Drug A → Drug C ≈ Drug B → Drug C. So why the detour?

In ATTAIN-MAINTAIN, participants who lost weight on tirzepatide (cohort 1) or semaglutide (cohort 2) during SURMOUNT-5 were switched to oral orforglipron. Both cohorts converged at ~95.9 kg at week 52, which was entirely predictable. The endpoint is determined by the maintenance drug, not the induction drug. If a patient will end up on orforglipron long-term, one could arguably start there directly.

The differential weight change during the switch is also entirely predictable. Tirzepatide (dual GIP/GLP-1) → orforglipron (GLP-1 only): ~5 kg gain. Semaglutide → orforglipron: ~1 kg change. Semaglutide and orforglipron share the same receptor target and comparable efficacy, so trivial changes in weight, cardiometabolic outcomes, and GI adverse events is exactly what you’d expect. Tirzepatide’s superior efficacy means switching to a lower-potency agent naturally produces larger changes. No pharmacological surprise here.

What these trials do not solve

Obesity medications work while you take them, at the dose you need. The real-world maintenance barriers: cost, side effects, mismatched expectations…. remain largely unaddressed (https://lnkd.in/gZf8-Dkx and https://lnkd.in/gzRVRy3D). That is the problem still waiting for a solution.