Given all the press and popularity of the GLP-1 receptor agonists, it may be good time for a quick review of where we are with this class of medications and what’s ahead in the near future. First thing to remember is that these are not new medications, but have been around for decades, originally to treat adult onset diabetes. It turns out that one of the side effects was weight loss, and that turned out to be the route for true commercial success.
In the many decades I practiced preventive cardiology, getting patients to lose weight was one of the primary cardinal elements in management. Most people prefer lifestyle modification rather than medications to control their diabetes, high blood pressure, blood fat abnormalities, and orthopedic issues
of the weight bearing joints like the back, spine, hips, and knees. Advising patients to lose weight is quite separate from patients actually losing weight. And any success was often followed by recidivism, so that weights would yo-yo, with promises to let them try one more time before incremental or more drastic recommendations were made.
The rise of bariatric surgery in its many iterations provided some patients with morbid obesity a way to actually start making progress. The questions of cost, insurance coverage, medical and psychological suitability, recovery from significant surgery, and long-term support systems were important considerations.
From the medical standpoint, one thing truly impressed me and many of my colleagues about the benefits of marked improvement of a patient’s body-mass-index, even given the known limitations of that metric. That finding was the apparent reversal of type 2 diabetes is some patients if sufficient weight loss was achieved. Significant weight loss became a prime target of the GLP-1 receptor agonist market in patients with diabetes.
Then the influencers began to do their thing. And doctors willing to get “more generous” with writing prescriptions for “patients” especially if those individuals had significant disposable incomes who wanted easier pathways for weight loss than adhering to the discipline required to control the quality and quantity of their diets, engage in exercise programs, or go to and pay for the gym.
A review of 38 randomized clinical trials encompassing almost 26,000 patients on GLP-1 treatment was recently published. The study populations and durations of therapy varied considerably, so direct comparisons are not reasonable and would require bespoke controlled trials. The average placebo-subtracted weight loss was 15% for semaglutide and 19% for tirzepatide, both of which are commercially available. The investigational agent retatrutide had an average weight loss of 22%, and amycretin, which is a combination investigational agent, showed a loss of 24%.
Not included in this review is another promising GLP-1 agent called maritide. Individual clinical trials for these agents have shown even more marked weight loss, approaching those achieved by bariatric surgery. These agents are administered by injection, but there are recently approved oral formulations for semaglutide and another agent called orforglipron, which have also demonstrated significant weight loss in clinical trials.
Other benefits of GLP-1 therapies beside blood sugar control in diabetics and weight loss for medical and cosmetic indications, may include likely class effects for reduction in cardiovascular events, kidney protection, metabolic liver disease, sleep apnea, and possibly neurodegenerative disorders. Perhaps through indirect mechanisms, there may be improvements in blood pressure, blood fats, and inflammation.
But there is the flip side to consider as well. In clinical practice and in our clinical trials, we remind patients that not uncommonly there may be gastrointestinal adverse effects such as nausea, diarrhea, constipation, and vomiting, especially when initiating treatment. Low initial doses and slow incremental dosing are key to enhance tolerability. Gall bladder disease can declare itself with higher doses and longer duration of use. Diabetics on other blood sugar controlling therapies may risk episodes of low blood sugar. Inflammation of the pancreas, which is a serious complication, has been reported.
Risk of excessive weight loss must be monitored. Loss of muscle mass has been a reported adverse effect that deserves closer analysis, but maintaining a resistance exercise regimen and balanced nutrition including high quality protein may mitigate that impact. This may be more important in older individuals and menopausal women since muscle loss may impact strength, movement, and balance. There are physical function and balance tests that can be performed before and during GLP-1 therapy in at risk, especially older, individuals to gauge their suitability for treatment.
And the health-economic 800-pound gorilla in the room is the cost of GLP-1 therapy on the budgets of healthcare systems. Restrictions on availability due to budgets are already issues for those less economically privileged. This becomes a public policy consideration, not a direct medical issue. When finite resources are a reality, the politics of paying for cardiovascular disease, cancer care, neurodegenerative disorders, and children’s health may need to be balanced against the cost of managing obesity. These are just the facts in this era of budgetary constraints exacerbated by our current economic priorities.
Our research site has been engaged in the development of new oral and multimodal GLP-1 agents including those with novel hormonal pathways that may enhance efficacy. There are literally dozens of such new agents on the horizon that hopefully work better with fewer side effects. If you are interested in learning more and possibly participating in some of these programs, drop us a note at careaccess.com.
Irving Kent Loh, M.D., is a preventive cardiologist and the director of the Ventura Heart Institute in Thousand Oaks. Email him at drloh@venturaheart.com.
This article originally appeared on Ventura County Star: Medications for weight loss — a GLP-1 update | Dr. Loh
