Obesity is a growing global health concern, affecting millions of adults and leading to numerous health complications. The Centers for Disease Control and Prevention report that a significant percentage of adults have obesity, defined as a body mass index (BMI) of 30 or higher. For decades, the advice has been to eat less and move more. However, a new wave of medications is targeting the biology of obesity, offering a promising alternative. This article explores the effectiveness of semaglutide and other weight loss medications, their mechanisms of action, potential side effects, and the broader context of weight management.
The Science Behind Weight Loss Medications
Weight management medications like Wegovy and Ozempic have shown incredible promise, targeting obesity's biology. When we eat, our stomach stretches, signaling to our brain that we’re getting full. Simultaneously, our gut releases peptide hormones that induce satiety and inform the brain that we’re no longer hungry. One of these satiation hormones is called glucagon-like peptide-1 (GLP-1).
Anti-obesity medications contain synthetic GLP-1 receptor agonists that mimic natural GLP-1 and are resistant to enzymes, allowing them to last longer. Semaglutide drugs such as Wegovy and Ozempic are modified, longer-lasting GLP-1 receptor agonists that can be injected just once a week. A similar Type 2 diabetes drug called tirzepatide, sold under the brand names Mounjaro and Zepbound, combines semaglutide with a GIP (glucose-dependent insulinotropic polypeptide) receptor that stimulates insulin secretion, further promoting weight loss and lowering blood sugar. These medications work by regulating appetite centers in the brain, thereby altering the relationship with food. In essence, weight-loss drugs reset the communication between the brain and gut.
GLP-1 receptor agonists also slow down the emptying of our stomach and the movement of food throughout the GI system.
Clinical Evidence of Semaglutide's Effectiveness
The drugs have proven highly effective. The longest clinical trial yet of Wegovy followed people on the drug for four years and found they experienced an average weight loss of just over 10%. Another study saw an average weight loss of 15% for people on semaglutide after 68 weeks.
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A systematic review and meta-analysis of randomized controlled trials (RCTs) examined the efficacy and safety of semaglutide in overweight or obese adults with or without Type 2 diabetes mellitus. The meta-analysis, which included fifteen publications totaling 6984 patients, revealed that the semaglutide group experienced significantly greater reductions in body weight (MD = −7.49, 95% CI [−9.92, −5.07], P < 0.001), body mass index (MD = −3.35, 95% CI [−4.79, −1.92], P < 0.001), and waist circumference (MD = −7.26, 95% CI [−9.94, −4.58], P < 0.001) compared to the control group.
Moreover, the semaglutide group also showed improvements in glycosylated hemoglobin (RR = −0.66, 95% CI [−1.07, −0.25], P = 0.002), fasting blood glucose values (RR = −4.81, 95% CI [−7.03, −2.60], P < 0.001), and systolic blood pressure (RR = −3.37, 95% CI [−5.32, −1.42], P < 0.001). The proportion of patients who lost > 5%, 10%, 15%, and 20% of their overall body weight was also significantly higher in the semaglutide group.
Semaglutide's Impact on Specific Populations
Subgroup analysis indicated that semaglutide led to more weight loss in overweight or obese patients regardless of diabetes status. Specifically, significant weight loss was observed in patients without diabetes (MD = −11.41, 95% CI [−13.14, −9.68], P < 0.001), patients with diabetes (MD = −3.29, 95% CI [−4.78, −1.80], P < 0.001), and patients with or without diabetes (MD = −9.60, 95% CI [−11.44, −7.76], P < 0.001).
Effects on Blood Pressure and Lipid Metabolism
Semaglutide has shown promising results in improving blood pressure and blood glucose, as well as other lipid metabolism. The systolic blood pressure reductions in the semaglutide group (RR = −3.37, 95% CI [−5.32, −1.42], P < 0.001) were higher than those in the control group, with a statistically significant difference. Additionally, the values of glycated hemoglobin reduction (RR = −0.66, 95% CI [−1.07, −0.25], P = 0.002) and fasting glucose reduction (RR = −4.81, 95% CI [−7.03, −2.60], P < 0.001) were higher than those of the control group, which were statistically different.
Adverse Effects and Considerations
Weight-loss medications slow down gastric emptying and the movement of food through our digestive system, so the food we consume sits in our stomach and intestines longer. As a result, these drugs can lead to gastrointestinal side effects such as nausea, constipation or, rarely, diarrhea. Especially when they start taking weight-loss drugs, individuals need to eat smaller meals; avoid fatty, greasy and spicy foods; and drink plenty of water. With time, most people on weight-loss drugs learn to avoid the foods that trigger GI symptoms, or their body gradually adjusts. There’s also a chance of getting gallstones, which can happen when people lose a lot of weight quickly.
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Cost and Accessibility
Without insurance coverage, weight-loss drugs come at a hefty price-around $1,000 to $1,300 every month. The drugs are so expensive, Cummings notes, that a patient could pay for a gastric bypass operation to promote major weight loss permanently for about the same amount it would cost for less than two years’ worth of weight-loss meds. The main reason patients stop taking weight-loss medication is their high cost, Cummings notes. In the face of that challenge, some individuals turn to online compounded medications. A small number of these online meds are counterfeits. One problem with this route is that even if they get good meds, patients don’t get the medical support they need. Their weight loss could mean they need smaller dosages of other drugs they’re taking. If name-brand drugs such as Ozempic and Wegovy aren’t available or simply cost too much for patients, physicians can look for alternative, less expensive medications. People on average might lose only about 2% to 10% of their weight on these alternative drugs-not as much as the 15% average on semaglutide. But those are only averages.
Long-Term Use and Weight Regain
The most common question I get from individuals considering these medicines is, ‘How long am I going to have to take it?’ Most feel they don’t want to be on something that’s a life sentence,” Cummings says. Weight-loss drugs are not a magic pill. You don’t simply take them to hit a certain number on the scale and then never have to take them again. American adults generally gain about half a pound to a pound of weight per year from ages 20 to 65, Cummings says. At some point while taking the meds, individuals tend to plateau and don’t lose any more weight. But if they stop taking the drugs, they likely will regain the weight-and lose the benefits of weight loss. Consider the medications that people take for high blood pressure or high cholesterol. People don’t stop taking those meds once their blood pressure or cholesterol levels are under control-it’s the meds that are keeping them healthy. “We don’t have lifelong studies for these medications, but we do have lifelong studies of obesity,” Tchang says. We know both the risks of uncontrolled obesity and the benefits of weight-loss drugs. “When they think about it in those terms, most of my patients choose to remain on the medication,” Tchang says. patients prescribed Ozempic or Wegovy for weight loss still took the meds two years later, according to a 2024 study that did not look into the reasons why people quit. But allied health professionals can make a difference in people’s experience with weight-loss meds-and can help patients stay on them.
Addressing Obesity Stigma
Learn what obesity is-and what it isn’t. Obesity is a disease a person has, not a choice they’ve made. “Patients with obesity meet a lot of weight stigma in the medical community,” Tchang says. “So, the first step is to educate yourself. Understand that obesity is a disease, and communicate that.” “It’s really important for allied professionals to understand that obesity is a disease and not a moral failing,” Jay says. “We often blame the patient when most causes of obesity are not the patient’s fault. Take a nonjudgmental stance toward people with obesity-and to the way they want to lose weight. Jay has had some patients tell her they prefer to, or have been told they should, “lose weight the natural way or the right way”-as if there’s shame attached to taking medicine for a medical condition. Inform patients about what they might experience on the meds. Communicate the potential GI side effects and how patients can manage their diets to mitigate symptoms. Also, for now, most of these drugs are self-injected once a week. Health professionals can assure patients that the needles are very short and thin.
The Role of Supplements and Alternative Products
The wide world of weight loss products ranges from legitimate medications, to compounded drugs offered by telehealth companies, to the gray market of online peptides, and supplements. “The marketing seems to suggest that you could get with these natural products, these natural ingredients, the same effect that you can get with GLP-1 agonists, which is simply not the case. And in that way, they are being misleading to people,” said C. “Some of them don’t even tell you what ingredients are in it at all. GLP-1 is a hormone the body produces naturally that, among other roles, helps communicate satiety to the brain. Two of the major prescription weight loss medications, semaglutide sold by Novo Nordisk as Wegovy and tirzepatide sold by Eli Lilly as Zepbound, are typically injected once a week. That leaves a hole in the consumer market. Many people know about these drugs and how they affect weight loss, appetite control and “food noise.” But many can’t afford them, don’t like the idea of injecting drugs, or can’t tolerate the side effects, said Bryn Austin, professor of social and behavioral sciences at the Harvard T.H.
The Supplement Industry
Austin said that “from Day One,” supplement companies have tried to capitalize on the GLP-1 craze, putting the phrase in their product names. The supplements, however, do not perform nearly as well as GLP-1 agonists, White said. One ingredient often used in supplements is berberine, which researchers have found can aid in weight loss. But a meta-analysis by the European Society for Clinical Nutrition and Metabolism found that patients taking berberine lose a little over 4 pounds on average. Nonetheless, those who promote the alternative products online often refer to them in the same context as the injectable medications, sometimes calling them “‘Zempic patches” or “natural” versions of the GLP-1 agonists.
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Regulatory Issues
In 1994, Congress passed the Dietary Supplement Health and Education Act, which defined dietary supplements and created a regulatory framework that largely bypasses the FDA. “The FDA cannot require rigorous pre-screening for safety and certainly not for effectiveness because by law, these supplements cannot claim to be treating or curing or preventing disease. Compared to other supplements, experts say products marketed for weight loss have a long history of being adulterated, sometimes including extreme levels of stimulants. Companies do have to tell the FDA that they have evidence, said Jensen Jose, regulatory counsel for the Center for Science in the Public Interest.
The Role of Influencers
The way the influencer economy works is they need to follow certain kinds of rules that will get the algorithm to pick them up, to get more amplified, to get more engagement, and to attract the attention and approval of these companies. And for many of them, it’s just about trying to get by. So the brands recognize that, and they can manipulate people who don’t really know how it works yet,” Ogle said.
Semaglutide for MASH Treatment
Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that has been approved to treat both type 2 diabetes (Ozempic and Rybelsus, Novo Nordisk) and obesity (Wegovy, Novo Nordisk). Semaglutide has been a success story in treating both type 2 diabetes and obesity with very effective weight loss, approximately 17% total body weight loss with around 1 year of treatment.
Studies of lifestyle interventions have shown that losing around 10% of total body weight can induce both MASH resolution and fibrosis regression. We have learned that semaglutide can induce 10% weight loss in approximately 75% of patients, so there was speculation that this agent would be an effective treatment strategy to induce both MASH resolution and fibrosis improvement by 1 stage, which are the 2 primary endpoints that are approved by the US Food and Drug Administration (FDA).
ESSENCE Trial Results
The ESSENCE trial is a phase 3 trial that has 2 parts. Patients were randomized in a 2:1 fashion to either placebo or semaglutide with dose escalation to the high dose of 2.4 mg weekly. All patients underwent biopsy at baseline, were treated for 72 weeks, and then underwent a second liver biopsy.
Semaglutide 2.4 mg weekly achieved both of the primary endpoints. MASH resolution was achieved in approximately 63% in the semaglutide arm and 34% in the placebo arm, with an approximately 29% delta from placebo or what is known as absolute risk reduction or estimated difference in responder proportions (EDP). The number needed to treat to achieve MASH resolution in 1 patient was around 3 patients. The second primary endpoint, fibrosis improvement by 1 stage, was achieved in 37% of patients receiving semaglutide compared with 22.5% receiving placebo, with a 14.5% delta or EDP. This means that the number needed to treat was around 7 patients to achieve fibrosis improvement by 1 stage in 1 patient.
Adverse Events in the ESSENCE Trial
The adverse events in the ESSENCE trial were similar to what has been seen in patients with type 2 diabetes and obesity. The main adverse events were typically gastrointestinal: nausea, constipation, diarrhea, and vomiting in some patients.
Future Directions and Combination Therapy
It should be kept in mind that the delta on fibrosis improvement was only 14.5%. It is important to understand that although these data are very encouraging, many of the patients will probably need to be on combination therapy. Researchers should look into designing a trial combining semaglutide and resmetirom to see if that improves the delta on both MASH resolution and fibrosis improvement.
Addressing Weight Gain in African-American Women
If you really want to understand weight gain and loss among African-American women, a good place to start is the Black Women’s Health Study (BWHS). For the past 20 years, Boston University’s Slone Epidemiology Center has collected detailed health questionnaires from 59,000 Black women across all socioeconomic groups and all regions of the country.
The BWHS found that overweight Black women gain the majority of their weight a decade earlier. “When we look at the prevalence of obesity, the steepest increase is before age 35,” notes Palmer. She says researchers haven’t identified the reasons for the earlier gain, but one possibility is that between 60 and 70 percent of Black women have their first child before age 25.
Atlanta health researcher Fleda Mask Jackson, Ph.D., suggests another factor may be at play. She says before their mid-twenties many African-American women are “cocooned in their communities,” where they received support and validation. Then they transition into the workforce only to face discrimination and the stressors of both racism and sexism.
The Impact of Racism
Participants in the BWHS were asked to rate their experience of racism with questions such as “How often do you feel people are afraid of you?” and “How often do you feel people think you are less intelligent than you are?” The data was then compared with respondents’ weight gain over an eight-year period. “We found a higher weight gain in women who had perceived the most racism,” says Palmer. “What we’re seeing is that the body’s response to the chronic stress of racism can lead to weight gain and obesity.”
The Superwoman Fatigue
Black women are often the primary breadwinners in their families as well as caretakers of children, grandchildren and elderly relatives. All this responsibility can lead to unhealthy patterns, says Bailey. “Black women feel obligated to take care of the family, and we often put ourselves at the bottom of the list. We sometimes cope through emotional eating-often dining after everyone else, so we’re eating in isolation or late at night because we’re trying to get everything done. Sometimes we don’t eat at all, and we know that skipping meals leads to accelerated rates of weight gain.”
Sleep Deficit
Several recent studies have shown that getting fewer than six hours of sleep a night puts you at greater risk for obesity. A 2013 study from UC Berkeley found that lack of sleep causes an increase in appetite and cravings for sugary and high-fat food. “If I had to pick one thing to help with weight loss, it would be to get more sleep,” says fitness and nutrition expert JJ Virgin, author of The Virgin Diet: Drop 7 Foods, Lose 7 Pounds, Just 7 Days (Harlequin). “Just one night of poor sleep creates total hormonal chaos in your body. Your cortisol is higher, which makes you more insulin-resistant, meaning you’re better at storing fat, worse at burning it off.
The Thrifty Gene Hypothesis
Christianson explains that one theory, the thrifty gene hypothesis, holds that certain genes, which may be more prevalent in African-Americans, “respond to an abundance of calorie-rich food by storing weight.” The thrifty gene may have been beneficial when we lived in a time of feast or famine, but in a country with 24-hour access to supersize meals, not so much.
Holly Lofton, M.D., director of the Medical Weight Management Program at NYU’s Langone Medical Center, says genetics can also determine whether you store fat around your middle or on your hips and thighs (think apple-shaped versus pear-shaped). “This is significant,” says Lofton, “because there is a high correlation between having abdominal fat and having fat around the heart and within the coronary vessels. That’s what leads to heart disease.”
The Impact of Childhood Trauma
Nadine Burke Harris, M.D., CEO of the Center for Youth Wellness in San Francisco and an expert on the effects of childhood trauma, says, “Significant data demonstrates that being exposed to trauma increases your risk for a number of poor health outcomes, including obesity.”
The Adverse Childhood Experiences study looks at the health outcomes of adults who, as children, experienced physical, emotional or sexual abuse, physical or emotional neglect; had a parent who was mentally ill, substance dependent or incarcerated; or were exposed to domestic violence, parental separation or divorce. “If you’ve had four or more of these childhood experiences, your risk of being overweight or obese more than doubles,” says Harris. The weight gain is caused by multiple factors connected to the release of cortisol in response to chronic stress.
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