Hype around new weight loss drugs (glucagon-like peptide 1 (GLP-1) agonists) is soaring. And who wouldn't be interested in a drug that can reduce body weight by 20% and curb hunger? Some experts see these drugs as the holy grail, but others are advising caution. So, are these drugs the right for you?
Obesity (BMI is 30.0 or higher) has reached epidemic levels among children and adults in the United States. The CDC notes that in the last 20 years, U.S. obesity prevalence increased from 30.5% to 41.9%. Another 31% of Americans are overweight (BMI is 25.0 to <30). Obesity contributes to serious medical conditions, including heart disease, type 2 diabetes, and some cancers. The estimated annual medical cost of obesity in the U.S. was nearly $173 billon in 2019. Research suggests that 80–90% of adults who have type 2 diabetes also are overweight or obese.
GLP-1 is a hormone made in the intestine and brain, which is secreted when food is consumed. GLP-1 agonist drugs were designed to treat diabetes by imitating the action of GLP-1 to stimulate insulin release from the pancreas, which lowers blood sugar levels after meals. In instances of low insulin, blood sugar rises above normal levels and can lead to diabetes. GLP-1 drugs also decrease glucagon production. Glucagon is a hormone that increases blood sugar levels. The FDA has approved several GLP-1 agonist drugs to treat Type 2 diabetes. For example, semaglutide (Ozempic) was FDA-approved in 2017 to lower hemoglobin A1C for the treatment of type 2 diabetes.
During clinical trials and in clinical usage, it was noted that patients taking GLP-1 agonist drugs experienced significant weight loss and reported feeling less hungry. Drugs companies quickly started clinical trials to obtain FDA approval for their drugs specifically to treat for weight loss. In a study of 175 overweight or obese patients who were given the drug semaglutide, patients lost an average of 5.9% of their total body weight in three months and 10.9% in six months. A separate study demonstrated that another drug taken by people with diabetes, dulaglutide, experienced an average weight loss of 6.8 lbs, 8.8 lbs, or 10.4 lbs, depending on dose, in 8 months. Today, there are several GLP-1 agonist drugs that are FDA-approved for weight loss, including liraglutide (Saxenda) and semaglutide (Wegovy), which is Ozempic at a higher dose . Other GLP-1 agonist drugs which have been approved for type 2 diabetes but are being prescribed off-label for weight loss include semaglutide (Ozempic/Rybelsus), dulaglutide (Trulicity), liraglutide (Victoza), lixisenatide (Adlyxin), and exenatide (Byetta/Bydureon BCise).
A new class of drugs called GIP/GLP-1 agonists that also has been approved for type 2 diabetes and demonstrate significant impact on weight loss include tirzepatide (Mounjaro.) Glucose-dependent insulinotropic polypeptide (GIP) is another hormone responsible for blood sugar regulation The average weight loss with the maximum recommended dose of Mounjaro was 12 pounds more than semaglutide. It appears that adding additional sites of actions for these drugs against blood sugar regulation can improve their efficacy. For example, recent results from clinical trials with retatrutide, a drug that acts on three receptors, GIP/GLP-1 and glucagon, suggest that it results in more weight loss than any other drug in use in obese people. Nearly 70 new obesity treatments are in development, with 2/3 of them being some version of a GLP-1 agonist.
With weight loss results like those reported in clinical trials, it's easy to see why people would be flocking to these GLP-1 agonists drugs for weight loss. But hold on a minute. As with everything that seems too good to be true, there are some downsides. All of the GLP-1 drugs are available only as an injection except Rybelsus, which is taken orally. Additionally, they are incredibly expensive (on average $900-$1300/month), likely so much so that many patients will not be able to afford them. Many insurance companies, including Medicare, will not cover the cost except in cases of type 2 diabetes. Medicaid coverage depends on each state's rules but, in general, it does not cover the cost of these drugs for weight loss. Data suggests that when patients stop taking the medication, they gain weight, suggesting that taking the drugs may be necessary for the rest of your life. The rollercoaster of fluctuating weight loss and gain can cause more serious health conditions than maintaining a weight slightly above average so it’s important that you don’t get into a cycle of taking the drug, losing weigh, stopping the drug, gaining weight, and repeat.
There also are a host of side effects associated with GLP-1 drugs, including nausea, vomiting, stomach pain, headache, dizziness, constipation or diarrhea, heartburn, indigestion, or GERD (gastroesophageal reflux disease), and low blood sugar in people with type 2 diabetes. More serious side effects include acute pancreatitis, acute gallstones, acute kidney injury, diabetic retinopathy in people with type 2 diabetes, changes in heart rate, suicidal behavior or ideation, stomach paralysis, bowel obstruction, and risk of thyroid C-cell tumors. Additionally, women who are pregnant or breastfeeding should not take GLP-1 drugs because the effects on the fetus have not been studied. Similarly, reproductive age women should consider contraception to avoid pregnancy if they are taking GLP-1 drugs.
Given the side effects, complexity of delivering the drug via injection, and cost of the drug, the current first line treatment for type 2 diabetes remains a drug called metformin, not GLP-1 drugs. GLP-1 drugs are only recommended for patients with type 2 diabetes who are allergic to metformin or who do not respond medically to metformin. Additionally, GLP-1 drugs are intended to be used in addition to changes in diet and exercise for best results. The FDA currently approves use of GLP-1 drugs for weight loss only in people who are obese or in overweight people who have coexisting conditions, like high blood pressure or high cholesterol. There is no clear understanding of risks and benefits for people who want to take GLP-1 drugs to lose weight for aesthetic reasons. GLP-1 drugs should be avoided by people who have a history of kidney disease, thyroid conditions or cancer, gallbladder disease, gastrointestinal disease, or pancreatitis.
One quick comment on something I've been seeing more lately - patients taking compounded versions of GLP-1 drugs instead of the FDA-approved versions because they are cheaper. Major medical societies including the Society of the National Academies of Sciences, Engineering, and Medicine (NASEM) agree that compounded drugs should be considered in only two situations - the patient is allergic to one or more of the ingredients used in an FDA-approved product or available FDA-approved products don’t offer a certain dosage level of a medication. Neither of those conditions exist in this instance. NASEM recommendations stem from the fact that compounded drugs have not been tested in clinical trials so the efficacy and safety cannot be evaluated. Also, compounded drugs are more likely to contain more or less of the active ingredient (and extra ingredients) than intended due to errors during compounding. FDA-approved drugs face a much more rigorous production process designed to ensure that the dose and ingredients are exactly what they are intended to be. This is true for all compounded medications, not just GLP-1 agonist drugs.
One side effect of rapid weight loss should be of particular concern to menopausal women - muscle mass loss. When people lose a substantial amount of weight over a short period of time, they don't just lose fat but also muscle. And menopausal women are already dealing with the consequences of significant muscle loss. Compared with early peri-menopausal women, mean muscle mass is 10% lower in late peri- and post-menopausal women. Sarcopenia, a musculoskeletal disease wherein muscle mass, strength, and performance are significantly compromised, is as much as 32% more prevalent in post-menopausal women. There is concern that rapid weight loss caused by GLP-1 drugs could significantly worsen the already significant loss of muscle mass that menopausal women experience. It seems clear that menopausal women who decide to use GLP-1 should simultaneously engage in a weight lifting program that prioritizes lifting heavy weights in order to protect against significant muscle mass loss.
GLP-1 agonists drugs are not the only way to lose weight. Interestingly, some diets, in particular those with low glycemic load that restrict carbohydrates, have shown an average weight loss of 12% in one year among patients with type 2 diabetes, suggesting that changes in diet can be as effective as using GLP-1 drugs. Other changes in lifestyle, like increasing the intensity of your workouts, adding stress relieving activities like yoga to reduce cortisol, and even spending time with friends to reduce symptoms of depression can be inexpensive, but evidence-based effective ways to loss weight.
Studies have shown that menopausal women primarily experience fat redistribution as a result of decreased sex hormones. To date, data does not support that weight gain by midlife women is a consequence of menopause. Instead, other factors that can be changed seem to be responsible. For example, many menopausal women have disrupted sleep because of night sweats, which often leaves them too tired to exercise or results in a lower intensity workout. Similarly, menopausal women have a higher incidence of depression and anxiety, which can lead to additional food intake. And the decreased muscle mass experienced by midlife women burns fewer calories, which means that eating like you did when you were 30 or 40 may no longer be appropriate.
With regard to hype - don't forget that it behooves the pharmaceutical industry to spend lots of money to convince you that their new weight loss drugs are a miracle cure. GLP-1 drugs are very expensive and have to be taken for a lifetime. Don't get me wrong, data and personal experience make clear that some obese and overweight people cannot lose weight only with changes to their diet and exercise. Additionally, the health consequences of being obese, particularly if you have type 2 diabetes are dire. The benefits of rapid weight loss, even at a high financial cost, may well justify the risks. But for those who are within a healthy weight range (or overweight but with no other qualifying health conditions) but not pleased with their body aesthetic as a result of menopause, the risk/benefit assessment is more complicated. For my patients who are not overweight (with other health concerns)/obese and who do not have type 2 diabetes, I recommend that they carefully examine their lives - keep a food log for a week to monitor food intake and talk with a nutritionist about possible changes, use technology like a sports watch to monitor sleep to identify how much disruption actually happens and get treated as appropriate, add weight lifting and HIIT to their exercise plan, get therapy and/or medication to manage mood changes, and find ways - yoga, breathwork, meditation, quiet time in the bath, etc - to reduce stress since menopausal women don't manage cortisol as well.
New weight loss drugs are filling an important need for some people. And even in those instances, it's important that lifestyle changes, including diet and exercise, be addressed with the medication. If not, people may lose weight and be thin, but still be unhealthy. For the rest of us, the risk/benefit of using GLP-1 drugs for weight loss is more complicated. I recommend that you give lifestyle options an honest chance. If you decide to try GLP-1 drugs knowing about possible side effects, cost, and that it's a lifelong decision, remember that as a menopausal woman, you need to take extra steps to protect your muscle mass so committing to a regular, high intensity, heavy weight workout regimen is critical.