Orforglipron (Foundayo) was able to claim cardiovascular safety based on the ACHIEVE-4 trial, though heart benefits remain unproven.<\/p>\n
Among adults with type 2 diabetes and obesity or overweight at risk for increased cardiovascular risk who were already on contemporary glucose-lowering medications, orforglipron met noninferiority criteria against insulin glargine regarding major adverse cardiovascular events (MACE) over a median 2 years (4.2% vs 5.0%; HR 0.84, 95% CI 0.59-1.20, P<0.0001 for noninferiority).<\/p>\n
Also favoring orforglipron were sustained improvements in glycemic control and body weight over 104 weeks, a drop in albuminuria at week 52 (median change in urinary albumin-to-creatinine ratio -24.2% vs 0%), and slower decline in estimated glomerular filtration rate by cystatin C (estimated treatment difference 2.8 mL\/min\/1.73 m2) compared with insulin glargine. However, gastrointestinal adverse events were unsurprisingly more frequent (62.1% vs 14.2%) and the most common reason for orforglipron treatment discontinuation.<\/p>\n
Klara Klein, MD, PhD, of the University of North Carolina School of Medicine in Chapel Hill, reported the ACHIEVE-4 trial results at the annual meeting of the European Association for the Study of Diabetes<\/a> in Milan. The manuscript was simultaneously published in The Lancet<\/a>.<\/p>\n “These findings support orforglipron as a potential once-daily, oral treatment option with established cardiovascular safety in people with type 2 diabetes and increased cardiovascular risk,” study authors concluded. “The safety profile was consistent with that established for orforglipron in the previous ACHIEVE<\/a> and ATTAIN studies for glycemic control and weight management, respectively.”<\/p>\n Orforglipron is an oral, non-peptide GLP-1 receptor agonist that is FDA approved for the treatment of obesity<\/a>. In contrast with the more well-known oral GLP-1 drug semaglutide (Ozempic, Wegovy), orforglipron’s non-peptide makeup makes it easier to manufacture and is more convenient to use, with no restrictions on time of day for administration.<\/p>\n “The ACHIEVE-4 study reaffirmed the safety of orforglipron while demonstrating clinically meaningful improvements in blood sugar control and weight. Combined with the convenience of a shelf-stable, once-daily oral medication that can be taken without fasting or water restrictions, these results highlight the potential of orforglipron to expand access to effective diabetes treatment globally,” Klein said in a press release.<\/p>\n In any case, the more established peptide GLP-1 receptor agonist drugs are several steps ahead, having achieved proof of cardiovascular benefit and FDA approval for cardiovascular protection<\/a>.<\/p>\n ACHIEVE-4 was not statistically powered for superiority on cardiovascular outcomes, Klein’s team stressed. ATTAIN-Outcomes<\/a> is the ongoing trial that will be powered for superiority in evaluating orforglipron against placebo in people with established atherosclerotic cardiovascular disease or chronic kidney disease with or without type 2 diabetes. That trial is scheduled for completion in 2031.<\/p>\n Klein expressed optimism that the trial will ultimately favor orforglipron. “I personally believe that the cardiovascular benefit\u00a0is largely a class effect. Now, this is a new small molecule … so\u00a0we can’t say definitively until we have a trial that demonstrates this, and that’s coming. But I think these are very encouraging data [from ACHIEVE-4] that this will be in line with the [GLP-1] class,” she said during a press conference.<\/p>\n