AMPLITUDE-O

AMPLITUDE-O tested efpeglenatide, a long-acting GLP-1 receptor agonist, in 4,076 adults with type 2 diabetes at high cardiovascular risk. Participants were assigned two-to-one to efpeglenatide or placebo and followed for a median of 1.81 years. Gerstein and colleagues published it in the New England Journal of Medicine in 2021.

Major adverse cardiovascular events occurred in 7.0% of the efpeglenatide group versus 9.2% on placebo — 3.9 versus 5.3 events per 100 person-years, a hazard ratio of 0.73 that was significant for superiority, not just noninferiority. A composite kidney outcome (declining kidney function or macroalbuminuria) fell further still: 13.0% versus 18.4%, hazard ratio 0.68. Diarrhea, constipation, nausea, vomiting and bloating were all more frequent on the drug.

That is one of the larger effect sizes in the class, and it arrived over a notably short follow-up. It also arrived with an unusual feature: many participants were already taking an SGLT2 inhibitor, and the benefit appeared to hold in that group — relevant because most earlier GLP-1 trials predate widespread SGLT2 use.

And then nothing happened. Efpeglenatide was never brought to market in the United States. Development was discontinued for commercial reasons, not because of a safety signal. This is the confusion worth naming: a positive trial is not a product. Drugs are withdrawn or shelved because of manufacturing economics, competitive positioning and portfolio decisions, and patients are left reading results for a medication they cannot obtain. Albiglutide has a nearly identical story.

Worth asking your clinician: which GLP-1 drugs are actually available and covered for you this year, rather than which have the most impressive published numbers. Our AMPLITUDE-O deep dive, pipeline tracker, and cardiovascular study roundup keep track of what is real and what is still in trials.