As the new GLP-1 receptor anti-obesity drugs are increasingly recognized for their positive effects on infertility, the latest news
NORBERT GLEICHER, MD, is Medical and Laboratory Director as well as Chief Scientist at the Center for Human Reproduction (CHR) in NYC
September 9, 2024, Revised with permission from the September 2024 issue of the CHR VOICE.
Briefing: The new GLP-1 receptor agonists, after years of use as anti-diabetic drugs, only recently fully recognized for their ability to result in highly significant weight loss with a remarkably good safety profile, are revolutionizing health care. Though their safety in pregnancy is not yet fully confirmed, early data suggest that they will likely demonstrate a similar safety profile in pregnancy. Therefore, it is likely they will be increasingly integrated into fertility treatments of obese women as well as men. Here are the newest developments regarding this astonishing family of drugs.
Common sense would suggest that any significant weight loss will be associated with secondary health benefits. Such an assumption follows pretty automatically from the long-known association of obesity with poor health. Removal of obesity from consideration, therefore, would be expected to lead to improvements in general health. But not every obese person has metabolically bad obesity; some obese individuals, indeed, are metabolically very healthy, while some very skinny people may be metabolically in quite poor shape. Some older data, indeed, have demonstrated that mortality in very low-weight individuals is greater than in slightly chunky people.
In a study of 50,000 Canadian women, skinniest women, with a BMI of less than 22.5, which included underweight as well as normal weight women, demonstrated a 44% higher risk of dying during approximately seven-years of follow-up, while at the other end of the spectrum, women with more than 38.7% total body fat had only 19% higher death rates. For men with a BMI below 23.8 the death rate in the follow-up period was 45% higher, whereas men in the highest body fat group (more than 36% body fat) had a 59% higher death rate.1
All of this, of course, does not negate beneficial effects of weight loss on general health, but demonstrates that weight, of course, is not the only determining factor of health and that – like almost every medical treatment – weight loss may also have negative effects. And this is exactly what makes new discoveries on how drugs like semaglutide and other GLP-1 receptor-agonists affect not only weight, but also individual organ systems so interesting and, as a recent paper in Nature Medicine noted, why cardiologists and other clinicians – including fertility specialists – must start familiarizing themselves with prescribing them.2
So, what else beyond weight loss can we expect from these drugs? An excellent summary was recently offered in Science magazine: 3 GLP-1s directly activate T cells through their GLP-1 receptor (GLP-1R), thereby reducing inflammation. As noted above, they at least partially indirectly of course induce weight loss through PGP-1 receptors (Rs) in the brain, and – through loss of fat cells – weight loss also reduces inflammation. Consequently, there already exists evidence that GLP-1s reduce the risk of myocardial infarction, atherosclerosis, diabetic kidney disease, and metabolic liver disease.
A reduction in inflammation, however, also benefits the brain. In other words, GLP-1s are also neuroprotective with already established declines in stroke risk and several studies underway to confirm preliminary suggestions that these drugs may also have beneficial effects on Parkinson’s disease and Alzheimer’s disease. And the same also applies to several neuropsychiatric diseases, including substance use disorders and compulsive behavior, including several additions beyond substance abuse. Yale University’s F. Perry Wilson, MSCE, MD, in his excellent weekly commentary, the Impact Factor, recently noted that data also demonstrated that the drug Ozempic (and other GLPs) not only reduced calories but also alcohol consumption, compulsive shopping (any family members as treatment candidates?) and could be viewed as “fundamentally anti-consumption drugs in a society that may be considered plagued by overconsumption.” A small study also suggested a potential beneficial effect on smoking cessation.4
A significant concern in using GLP-1s for weight loss has been that significant weight loss can induce muscle wasting, physical frailty and/or sarcopenia. A recent Viewpoint article in JAMA, however, did not support this notion based on so-far published data.5 That is good news, but should not prevent people (especially older people) from exercising their muscles when taking these medications.
Another concern with these drugs has been that, once stopped, much of the lost weight appears to return. A recent paper investigating long-term weight loss from semaglutide treatment, therefore, was timely.6 Weight loss continued over 65 weeks and was sustained for up to 4 years. By 208 weeks mean reduction in weight had fallen to a level of -10.2%, reflecting a waist circumference of -7.7cm, a still highly significant level vs. placebo (P<0.0001). Whether and how GLP-1s should be discontinued to maintain maximum weight loss, however, remains unresolved.
Despite resistance from the insurance industry, use of GLP-1s for weight loss has, of course, exploded. This was confirmed by a recent Research Letter in JAMA Health Forum investigating national U.S. data over all payment methods (commercial insurance, Medicaid, Medicare Part D, and cash), representing 92% of prescriptions for semaglutide (in the form of 3 brands) in retail pharmacies between January 2021 and December 2023.7 Interestingly, persistently, a majority of all such prescriptions were filled through commercial insurance.
This, of course, should not surprise, considering how expensive these drugs are. Unfortunately, those high prices have also given rise to a rapidly growing industry which offers the public a whole variety of generic GLP-1s, with often false claims of 100% mimicking the expensive brand names. Indeed, almost half of all online pharmacies have started selling weight loss drugs.8 Many, indeed, do so without requiring prescriptions or with virtual prescribers offering prescriptions through the seller. The Food and Drug Administration (FDA) and other international regulatory authorities, moreover, have warned the public about fake version of these drugs. In response, Eli Lilly and Company, one of the main manufacturers of these drugs, just announced an at least 50% price reduction for the lowest dosage (2.5mg) of their drug, Zepbound®(tirzepatide) in flasks (higher dosages are still at old prices and delivered through s.c. pen). The company also sells Tizepatide under the brand name Munjaro®.
Another Research Letter, this time in JAMA Network Open, therefore, was extremely timely, well describing the dangers of what is going on in this relatively new marketplace.9 The study confirmed that semaglutide products are actively sold without prescriptions, often by illegal online pharmacies. Products sold are often unregistered and/or fake. U.S. poison centers, moreover, registered a 1,500% increase in semaglutide-related calls.
This, of course, does not mean that there are not legitimate pharmacies, licensed and capable of compounding GLP-1s properly; but pharmacies willing to dispense these medications without prescriptions should be suspect. In other words, obesity is a disease and requires medications, and these medications should be prescribed by licensed physicians and produced by licensed manufacturers or compounding pharmacies.
The original studies of GLP-1s, of course, go back decades and started with investigators trying to determine how peptides could help regulate glucose levels after food intake in diabetic patients. That these medications could also be helpful in fighting obesity came into focus only relatively recently. An article in Science magazine offers a detailed history on occasion of the awarding the Mani L. Bhaumik Breakthrough of the Year Award to Lotte Bjerre Knudsen (chief scientific adviser at Novo Nordisk) and Richard DiMarchi (Distinguished Professor of Biochemistry and Gill Chair in Biomolecular Sciences at Indiana University) for their role in ensuring that GLP-1R agonists were developed beyond diabetes.10 As the article noted, both awardees “stayed strong in the face of critics who doubted that obesity was a disease at all.”
And, finally, a little bit of new science: At least with initial use, GLP-1s can cause side effects, including, on rare occasions, severe nausea. Investigators now discovered in a mouse model that the neurons that produce this sick feeling are distinct from those which – after food intake – provide the feeling of fullness.11 In the process, they also discovered that GLP-1Rs in the so-called hindbrain were responsible for the weight loss, though not for the nausea. As research in this area is extremely active, one can expect quick progress. Several next generations of these drugs are already under study and can be expected to lead to even more weight loss than current drugs. Moreover, preliminary results from at least one oral medications have been also reported to be positive.
Several companies are also investigating spontaneous pregnancies that occurred in their already existing data sets of long-term use of these drugs in an attempt to determine whether these drugs should still be withheld from pregnant women (which also, of course, means women attempting to conceive). Preliminary results have been reassuring but until more solid data are available, their use should still be considered contraindicated, with a wash-out period of at least one month before start of fertility treatment. Reports in women have also suggested unplanned pregnancies in women on these medications who were on oral contraceptives. These pregnancies have been attributed to slower gastric emptying with use of these drugs and, therefore, declining protection by oral contraceptives. But some very preliminary data suggests, somewhat unsurprisingly, that these medications may improve fertility directly, and not only through weight loss.
And to conclude, here is a very simple diagram to explain how these GLP-1Rs work for weight loss, extracted from beautiful graphics in an excellent article in Scientific American.12
REFERENCES
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