Eli Lilly's new oral weight loss pill works as well as injectables: Why this could be better than oral semaglutide?
The blockbuster weight loss drug, semaglutide, now has competition in orforglipron, which is just as safe as injectable alternatives and more effectively lowers HbA1c (average blood sugar count of three months) in patients with type 2 diabetes and obesity. The best part. No injections required — just a daily pill.
The investigational once-daily pill by US manufacturer Eli Lilly lowered HbA1C by an average of 1.3% to 1.6% across doses, with improvements seen as early as four weeks, in adults with type 2 diabetes, according to Phase 3 results of the ACHIEVE-1 trials, published in The New England Journal of Medicine. Orforglipron also led to an average weight loss of 16.0 lbs or 7.3 kg (7.9%) at the highest dose by week 40. 'The efficacy, safety, and tolerability are really consistent with the very best injectable GLP-1s,' Kenneth Custer, president of cardiometabolic health at Eli Lilly, was quoted as saying.
Why is orforglipron effective?
Orforglipron and semaglutide are both GLP-1 receptor agonists, which mimic the effects of the naturally occurring hormone GLP-1, which helps regulate blood sugar, reduce appetite and slow down gastric emptying. But while orforglipron is non-peptide, semaglutide is a peptide. Peptides are smaller than proteins, while non-peptides encompass a wider range of chemical compounds with diverse structures and functions.
'Orforglipron, being a non-peptide, is a smaller molecule. This allows better absorption of the drug through the gut. They don't get broken down as easily by digestive enzymes. Hence the efficacy,' says Dr Anoop Misra, chairman, diabetes and endocrinology, Fortis C-Doc.
What are the advantages of orforglipron over semaglutide?
Orforglipron is an oral pill taken once daily, while semaglutide is available as both an oral tablet (Rybelsus) and a subcutaneous injection (Ozempic, Wegovy).
'Previous oral GLP-1s like semaglutide (Rybelsus) are peptide-based and have significant limitations — they must be taken on an empty stomach with minimal water and have much lower bioavailability than injectable form. Orforglipron is a small molecule that doesn't require food or water restrictions, so it is very convenient and is absorbed easily,' says Dr Misra.
What about the trial results?
At 40 weeks, all three doses (3 mg, 12 mg, 36 mg) of orforglipron achieved the primary goal of superior HbA1C reduction. Improvements in HbA1C were observed as early as four weeks and were accompanied by similar reductions in fasting serum glucose.
'The early onset of glycemic improvement, observed as soon as four weeks, reinforces the therapeutic potential of orforglipron as an effective, oral GLP-1 therapy for early type 2 diabetes treatment. These findings support further investigation in broader populations and longer-duration studies,' said Dr Julio Rosenstock, senior scientific advisor for Velocity Clinical Research at Medical City Dallas, clinical professor of medicine, University of Texas Southwestern Medical Center, and lead trial investigator.
What about side effects?
In the study, orforglipron had a safety profile similar to the established GLP-1 class of medication. The most frequently reported adverse events were gastrointestinal-related.
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