Dr. Michael Fulks reviews recent breakthroughs in GLP-1–based therapies, including emerging combinations and convenient oral options that are reshaping the treatment landscape for obesity, type 2 diabetes, and related metabolic conditions.
Semaglutide and tirzepatide have become first-line therapy for several cardiovascular and metabolic conditions of life underwriting concern. Four recent articles in the NEJM provide guidance over the expanding pool of GLP-1 agonists, some of which have other hormonal effects enhancing weight loss. Tirzepatide (Zepbound, Mounjaro), a GLP-1 agonist as well as being a “GIP” further suppressing appetite, was recently compared head-to-head in a NEJM article to semaglutide (Ozempic, Wegovy) which is only a GLP-1 agonist. Both arms had appropriate dose escalation to usual max dosages as once-weekly SubQ injections for 16 months resulting in an average of 20% weight loss for tirzepatide and 14% for semaglutide. A 2-inch greater reduction in waist circumference (which may better reflect the real target of central fat loss) was noted for tirzepatide as well.
BUT, Novo Nordisk (semaglutide) understands that experience is showing rival tirzepatide to be superior and has come up with a combo of semaglutide and cagrilinitide, an analogue of the hormone amylin which also regulates appetite in the brain. An article on this combination for treating T2 diabetes and a separate article on treating those obese without DM just appeared in NEJM. The semaglutide arm in the obesity study achieved about 15% weight loss but the combination arm hit 20% with an almost 7-inch decrease in waist circumference. In the DM study, almost 3/4 of those in the combination arm dropped their HbA1c to ≤6.5%. Adverse effects are primarily gastrointestinal with the combination possibly slightly worse but still close to the range seen for tirzepatide.
A potential alternative to weekly SubQ shots is daily oral Rx with orforglipron, a small molecule GLP-1 agonist with good bioavailability via the oral route in contrast to oral semaglutide (Rybelsus) which has food and timing restrictions. A recent orforglipron study in NEJM compared various doses to placebo for 9 months (7 months shorter than the studies noted above so substantially smaller effect expected) in participants with T2DM generating an almost 8% weight loss at highest dose with about 60% ending with a HbA1c of ≤6.5%. Gastrointestinal adverse effects were not totaled but nausea, which is a common one, was less common than for the subQ drugs above.
For now, initial therapy of obesity and/or T2DM with SubQ tirzepatide may be most effective but the semaglutide-cagrilinitide combination may prove a match depending on how side effects and pricing play out with further experience. Oral orforglipron may fill the role of maintenance therapy once desired weight or HbA1c is achieved as there is no reason to believe more than a small minority of users will be able to stop therapy and maintain weight loss. Depending on pricing and degree of weight loss needed, orforglipron might be the initial choice for some when it comes to market. New variations and combinations are being explored including semaglutide with bimagrumab, a monoclonal antibody, which has a protective effect on loss of lean body mass which may be a substantial and of concern, especially at older ages.
These drugs all show marked improvement in metabolic conditions including DM, NASH, hypertension, and unfavorable lipids with impact dependent on the degree and persistence of weight loss (the key to reduced mortality). Persistent weight loss consisting of mostly fat, convenience, cost to consumer, and any reduction in GI side effects will determine which agents win out.
About the Author
Michael Fulks, MD, Consulting Medical Director, is board-certified in internal and insurance medicine. After leaving practice, he served as a medical director, creating or editing several underwriting manuals and preferred programs. More recently, Mike has consulted for CRL participating in its mortality research on laboratory test results, BP and build, and in the development of risk-scoring tools for laboratory and non-laboratory data.