Welcome back to another article looking at clinically and scientifically important GLP-1 news!
This morning Eli Lilly released top line data around one of the most critically important trials for orforglipron(Foundayo) This trial going by the name ACHIEVE-4 and it was a 2 year long trial looking at cardiovascular safety and outcomes of orforglipron compared once daily insulin glargine:
This trial in the last week took on an imminent importance as the FDA essentially called out Eli Lilly saying the FDA needed to see the cardiovascular and hepatic safety data from this trial as it relates to the approval of orforglipron. I don’t want to digress too much, but this was a somewhat messy situation that is partially the FDA’s own fault. With the new accelerated approval program that the current FDA is using, orforglipron was approved in only 50 days. This left an odd gap as the FDA mandates that drug makers run cardiovascular outcome trials for all new anti-diabetic agents and even though this initial FDA approval is for obesity WITHOUT diabetes, the FDA is requesting this data for orforglipron for weight loss. As we’ll see the cardiac safety and benefit of the drug has been confirmed and while not providing specific data Lilly’s own press release says:
ACHIEVE-4 included a thorough analysis of potential drug-induced liver injury (DILI), and these analyses confirmed there was no hepatic safety signal, consistent with all prior studies in the ACHIEVE and ATTAIN programs.
All that to say, if the FDA had simply delayed approval by a couple weeks none of the bad press would have happened, the drug would still be approved, and we’d have a better idea of cardiac and hepatic safety.
Anyways, to the results!
I want to use oral semaglutide as a comparison here because Novo Nordisk ran nearly the exact same trial in a trial called PIONEER-6 that was published in 2019.
That’s a BIG drop in all-cause death! 57%
Primary outcome= MACE-3, expanded outcome=MACE-4
This is something that you absolutely LOVE to see in science, replication of results! While these trials were set up differently, PIONEER was an event driven trial that lasted 16 months and ACHIEVE was a planned 2 year long trial with an active comparator instead of placebo. We see almost exactly the same level of reduction in MACE-3 (HR 0.77 vs 0.79) & MACE-4 (HR 0.84 vs 0.82)
Orforglipron had superior efficacy in terms of A1c reduction -1.6% vs 1.0% and weight loss -8.1kg vs -4.2kg.
It also had superior reduction in all-cause mortality (57% vs 49%) but it’s likely in a head-to-head trial that difference would not be statistically significant. The A1c and weight loss are consistent with other orforglipron trials, the discontinuation rate is also very similar. All of this is extremely exciting news!
And yes, comparing different trials set multiple years apart is difficult and oftentimes unwise, but I want to explain my excitement as a clinician. This proves that the cardiovascular benefits and mortality benefits of GLP-1 medications extend to the small molecule realm, which until today was an open question. Would a small molecule have the same benefits? Today’s trial results are a resounding yes. Whether by peptide or small molecule, hitting the GLP-1 receptor seems to work magic in the body.
Of course, there are still other open questions about these trial results because these are merely the topline results, we don’t have it broken down by rates of heart attack, stroke, etc. We don’t know the changes in renal function, cholesterol and blood pressure. We also need to see the liver data from this trial instead of just a statement from Lilly. Rest assured that data is coming rapidly, it’ll be presented the first week of June at the ADA 2026 conference and I’ll be at the conference and plan to report on it. Stay tuned!
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