seeing a lot of ‘hit onederland on tirz’ posts lately, which is great, but the T2D remission angle doesn’t get enough airtime. here’s what’s actually been useful to me: SURPASS trial series (1-5) - the phase 3 glycemic endpoint data. HbA1c reductions at higher doses have effect sizes that are clinically meaningful, not just statistically real. worth reading the actual numbers instead of summaries. r/diabetes search: “tirzepatide HbA1c target” - filter by past year. better mechanistic discussion than most wellness content, and people are tracking actual lab values. dual agonism mechanism papers - GIP receptor activation on top of GLP-1 is probably why glycemic outcomes look better than sema in head-to-head data. the mechanism is interesting and underexplained in lay coverage. one thing I’ve noticed missing from almost all the lay discussion: “remission” isn’t defined consistently across studies. some require HbA1c under 6.5% off medications for 3+ months, others don’t. that denominator matters a lot before you tell someone tirzepatide reversed their diabetes. the weight loss story is real. the glycemic story is arguably the more important one.
the “remission isn’t defined consistently” point is doing more work than most people realize.
the ADA 2021 consensus uses HbA1c under 6.5% off ALL glycemic medications for at least 3 months, but SURPASS-2 and several tirz observational papers use different cutoffs or don’t specify a medication washout at all, which inflates the headline numbers considerably. the glycemic durability question is also underexplored: how much of the HbA1c improvement tracks weight directly vs. the GIP receptor component independently. that mechanism question seems unresolved in the literature so far.
edit: realized I said that wrong
The “medication washout” framing is the part that actually changes how I read most of the observational remission data, and I think you’re right to flag it. Papers counting people as in remission while still on metformin are measuring something real, but metformin is doing meaningful glycemic work independently, so the denominator problem is worse than the headline numbers suggest. The ADA 2021 criteria as a stricter benchmark does seem more defensible for that reason. Where I’d add a caveat is on calling the mechanism question fully “unresolved.” That might undersell what’s in the literature. The SURPASS subgroup work and some of the adipose tissue GIP receptor studies do suggest the receptor activation contributes to glycemic outcomes beyond what weight loss alone would predict. fwiw The effect size of that independent contribution is still fuzzy, agreed, but “unresolved” reads to me as closer to “no data yet,” when the more accurate framing is probably “directional signal, no clean causal estimate.” Which is a meaningfully different epistemic situation.
Caught on the denominator point specifically, because I’m pre-diabetic range (6.1 at diagnosis, 5.6 now on tirz) and SURMOUNT-4’s discontinuation arm showed meaningful HbA1c rebound at 88 weeks off drug. Most of that cohort was full T2D though, not 6.1 baseline, and whether the reversibility picture looks different at earlier disease stages is the question I haven’t found a clean answer to. The monthly glucose trend I track in CareClinic is honestly my closest proxy for whether the numbers would hold without the drug.
The SURPASS series is the right reading list for glycemic effect size, agreed, but worth flagging that SURPASS isn’t actually a remission trial set. The primary endpoints were HbA1c change and proportion reaching targets while on study drug, not remission defined as A1c under 6.5 off medications for 3+ months. So when you say “the glycemic story is arguably the more important one,” I’d grant that at the surrogate level, but the leap from SURPASS data to remission claims is the bit doing extra work here, because nobody in those trials was off the drug long enough for a remission endpoint to even be measurable. The remission conversation really needs a different study design, and that’s a gap, not a citation.