GLP-1 agonists have also shown promise in reducing the risk of major adverse cardiovascular events, such as stroke and heart attack. This adds to their potential benefits in managing obesity and its related health complications.

Clinical Trial of Semaglutide and Bimagrumab

One promising avenue of research involves combining existing GLP-1 receptor agonists with experimental drugs designed to preserve muscle mass. A clinical trial, known as the BELIEVE Phase 2b study, is currently underway to test the combination of semaglutide and bimagrumab. Bimagrumab is a first-in-class, fully humanized monoclonal antibody developed by Versanis Bio, a clinical-stage biopharmaceutical company recently acquired by Eli Lilly. It targets activin type II receptors, which play a role in regulating muscle growth and fat storage. This trial aims to assess the efficacy and safety of bimagrumab in preserving or increasing muscle mass while promoting weight loss with semaglutide in non-diabetic patients with overweight or obesity.

To be eligible for the BELIEVE study, participants must have a body mass index (BMI) greater than or equal to 30, or greater than or equal to 27 with one or more obesity-related comorbidities. Key exclusion criteria include a history of hypersensitivity to monoclonal antibody drugs, treatment with any medication for obesity within 30 days before screening, and a diagnosis of diabetes requiring current use of any antidiabetic drug.

Pre-clinical studies have shown that blocking activin type II receptors with bimagrumab leads to increased lean mass and decreased fat mass in mice. In a Phase 2 study, bimagrumab produced a 22% reduction in fat mass and a 4.5% increase in lean mass in patients with type 2 diabetes and obesity. Notably, no weight regain was observed after stopping bimagrumab treatment, unlike the rebound effect often seen with GLP-1 therapies. This suggests that bimagrumab may offer long-term benefits in maintaining weight loss even after treatment cessation.

The ongoing clinical trial will provide valuable insights into the potential of combining semaglutide and bimagrumab to achieve superior fat loss while preserving muscle mass. This combination therapy could offer a more comprehensive weight management approach, addressing fat loss and muscle preservation.

Semaglutide and Bimagrumab: Mechanisms of Action

Semaglutide and bimagrumab work through distinct mechanisms to achieve their therapeutic effects. Semaglutide, a GLP-1 receptor agonist, mimics the action of GLP-1, a natural gut hormone crucial in regulating blood sugar and appetite. GLP-1 agonists work by

• Triggering insulin release from the pancreas
• Blocking glucagon secretion
• Slowing stomach emptying
• Increasing feelings of fullness

Semaglutide helps lower blood sugar levels, reduce appetite, and promote weight loss by mimicking these effects.

Bimagrumab, on the other hand, is a human monoclonal antibody directed against type II activin receptors (ActRII). Upon administration, bimagrumab binds to ActRII, which prevents binding the natural ligands, myostatin and activin, to activin receptors and blocks ActRII-mediated signalling. This increases protein synthesis, decreases protein degradation, stimulates skeletal muscle cell growth, and increases muscle function and strength10. Overstimulation of the ActRII-mediated signalling pathway is associated with muscle loss and weakness.

Other Anti-Obesity Drugs in Development

The success of semaglutide and tirzepatide has fueled a surge in the development of new anti-obesity drugs. These drugs target various biological pathways and aim to improve upon the limitations of existing therapies. Targeting multiple pathways simultaneously could allow for lower doses that achieve the same weight loss with fewer side effects. Some of the key areas of development include:

GLP-1 and GIP Receptor Agonists

Tirzepatide is a dual GLP-1 and GIP receptor agonist that has shown superior weight loss results compared to semaglutide in a large head-to-head trial by Eli Lilly. Participants who took tirzepatide lost an average of 20% of their body weight, outpacing the 14% reduction achieved with semaglutide. Tirzepatide is already available under the brand names Mounjaro and Zepbound.

There are two main strategies for modulating GIP activity: activation and blocking. While both approaches can lead to weight loss, they have different potential benefits and drawbacks. As seen with tirzepatide, GIP activation can further enhance energy metabolism and promote weight loss. However, some concerns blocking GIP signalling could adversely affect bone health, as GIP also plays a role in bone metabolism.

Amylin Analogues

Amylin is a hormone co-secreted with insulin that regulates blood sugar and appetite. CagriSema, a combination therapy developed by Novo Nordisk that pairs a long-acting analogue of amylin (cagrilintide) with semaglutide, has shown promising results in clinical trials. Participants in a 68-week, phase 3 trial lost an average of nearly 23% of their body weight.

Glucagon and GLP-1 Receptor Co-agonists

Glucagon is a hormone that raises blood sugar levels, while GLP-1 lowers them. Combining these two hormones in a single drug could offer a balanced approach to weight loss by increasing energy expenditure while maintaining blood sugar control. Survodutide, a glucagon and GLP-1 receptor co-agonist developed by Boehringer Ingelheim, is currently in clinical trials.

Triple-Hormone Receptor Agonists

Retatrutide, a triple-hormone receptor agonist developed by Eli Lilly that targets GLP-1, GIP, and glucagon receptors, has shown impressive weight loss results in Phase 2 trials. This drug, dubbed “triple G,” delivered an average weight reduction of 24% after 48 weeks, setting a new benchmark for obesity treatments.

Alternative Delivery Methods for Anti-Obesity Drugs

Companies are also exploring alternative delivery methods to once-weekly injections, which can be challenging to incorporate into people’s routines and come with manufacturing challenges. Once-monthly injectables are in the works, but oral formulations of GLP-1 receptor agonists, such as orforglipron produced by Eli Lilly, could arrive first.

Another potential alternative is oral semaglutide. In a phase 3 study called OASIS 1, people taking oral semaglutide 50 mg once daily lost up to 15% of their initial body weight after about 15 months (68 weeks) of use. This is comparable to the weight loss benefits of Wegovy, the injectable version of semaglutide.

Potential Side Effects of Anti-Obesity Drugs

While anti-obesity drugs offer a promising approach to weight management, they can also cause side effects. Some of the common side effects of GLP-1 receptor agonists include nausea, vomiting, diarrhoea, and constipation. More serious side effects, such as pancreatitis and gallbladder problems, are rare but can occur.

Specific side effects associated with semaglutide include nausea, vomiting, diarrhoea, abdominal pain, constipation, heartburn, and burping. In rare cases, semaglutide can cause more serious side effects such as pancreatitis, kidney problems, and changes in vision.

Tirzepatide can cause similar side effects, including nausea, diarrhoea, decreased appetite, vomiting, constipation, and stomach pain. Serious side effects, such as pancreatitis, gallbladder problems, and low blood sugar, can also occur.

Another concern with GLP-1 and GIP drugs is the potential risk of pulmonary aspiration during anaesthesia. These drugs can cause delayed gastric emptying, which may increase the risk of residual gastric contents despite preoperative fasting. This can lead to aspiration, where food or liquid gets into the lungs during surgery.

The increased demand for GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists has led to temporary product shortages. This has resulted in the emergence of compounded formulations of these drugs, which produce entities that bypass regulatory measures. The American Diabetes Association recommends against using non-FDA-approved compounded GLP-1 and dual GIP/GLP-1 receptor agonist products due to concerns regarding their safety, quality, and effectiveness. The FDA has also issued an alert on dosing errors associated with compounded semaglutide injectable products, which have led to adverse events and hospitalisations in some cases.

It is important to note that the potential side effects of anti-obesity drugs vary depending on the specific medication and individual factors. Patients should discuss these medications’ possible risks and benefits with their healthcare provider to determine the most appropriate treatment option.

Alternative Treatments for Obesity: Bariatric Surgery

For some individuals, bariatric surgery may be an alternative treatment option for obesity. Bariatric surgery involves making changes to your digestive system to help you lose weight. It is typically considered for people with a BMI of 40 or higher or those with a BMI of 35 or higher who have obesity-related health problems.

There are several types of bariatric surgery, including

• Roux-en-Y gastric bypass: This procedure involves creating a small pouch at the top of the stomach and connecting it directly to the small intestine, bypassing most of the stomach and the first section of the small intestine
• Sleeve gastrectomy: This procedure involves removing about 80% of the stomach, leaving a long, tube-like pouch
• Biliopancreatic diversion with duodenal switch (BPD/DS): This is a two-part surgery that involves performing a sleeve gastrectomy and then connecting the end of the small intestine to the duodenum, bypassing most of the small intestine

Bariatric surgery can be very effective for long-term weight loss and can also improve or reverse obesity-related conditions such as diabetes, high cholesterol, and sleep apnoea. However, it is a major surgical procedure with potential risks and complications, such as bleeding, infection, and leaks in the gastrointestinal system. Patients should carefully consider the risks and benefits of bariatric surgery with their healthcare provider.

Emerging Applications of GLP-1 and GIP Drugs

While GLP-1 and GIP drugs are primarily known for their role in treating obesity and type 2 diabetes, research is exploring their potential applications in other disease areas. These include:

• Neurodegenerative diseases: Conditions such as Parkinson’s and Alzheimer’s disease involve protein misfolding and chronic inflammation. Studies have found that GLP-1 mimetics can cross the blood-brain barrier and have neuroprotective effects, including reducing oxidative stress and chronic inflammatory responses in the brain.
• Liver disease: GLP-1 and GIP receptor agonists have shown potential in improving liver health, particularly in individuals with nonalcoholic fatty liver disease (NAFLD).

These emerging applications highlight the versatility of GLP-1 and GIP drugs and their potential to address a wide range of health challenges beyond obesity and diabetes.

Conclusion

The field of anti-obesity drug development is rapidly evolving, with new therapies emerging that offer the potential for more effective and personalised weight management. While GLP-1 receptor agonists like semaglutide and tirzepatide have revolutionised the field, ongoing research is exploring new targets and combination therapies to address the limitations of existing medications. These advancements, such as the combination of semaglutide and bimagrumab, the development of triple-hormone receptor agonists like retratrutide, and the exploration of alternative delivery methods, hold promise for improving the lives of millions of people struggling with obesity and its related health complications.

However, it is crucial to acknowledge the potential side effects of these therapies, including gastrointestinal issues, pancreatitis, and the risk of pulmonary aspiration during anaesthesia. Patients should carefully consider the risks and benefits of these medications with their healthcare provider to determine the most appropriate treatment option.

Developing new anti-obesity drugs has significant implications for public health and the future of obesity management. These advancements offer hope for a more comprehensive and personalised approach to weight loss, potentially reducing the burden of obesity and its associated health problems.

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Over a thousand epidemiologic papers were examined, including clinical trials of weight-loss or weight-control therapies. These investigations included observational studies on cancer risk and fat excess. Because of this, the assessments focused on the dangers of being overweight rather than the benefits of preventative measures.

Studies varied in their risk assessments; most focused on adults’ body mass index (BMI), while others looked at childhood or adolescent BMI or body shape, weight or BMI changes over time, or other measures of adiposity, such as waist circumference.

The analysis considered relative-risk estimates where sufficient analyses of observational data were accessible. The absence of extra body fat, it was concluded, reduces the risk of cancer at previously described organ sites. In addition, study results point to the fact that being lean reduces the incidence of eight more cancers: gastric, cardiac, liver, gallbladder, pancreatic, ovarian, thyroid, multiple myeloma, and meningioma. Once again, however, we must understand that correlation does not equal causation. But the indicators are of concern and great interest.

If the newly introduced GLP-1 medication can control obesity, which, in turn, may reduce the incidence of cancer, researchers are now questioning whether these drugs may serve other purposes in healthcare. There is a belief that GLP-1 medication use may extend beyond obesity and weight control. What areas are they currently considering for studies with these medications?

GLP-1 for Addiction?

The World Health Organization (WHO) found that 2.6 million people die each year because of alcohol intake (or 4.7% of all deaths), and 0.6 million people die because of the use of psychotropic drugs. Men accounted for 0.4 million drug-related fatalities and 2 million alcohol-related fatalities. But while alcoholism remains a serious health hazard, there are other addictions to street or prescription drugs that are also of concern to healthcare professionals and patients.

Cocaine use disorder affects an estimated 5 million people. Worldwide, the death toll from cocaine overdoses is rising at a faster rate than that from opiate overdoses.

But there is an intriguing relationship between obesity and addiction. Substantial evidence in the literature linking obesity to substance use disorders supports a link of sorts. Studies have shown that when people are exposed to meals that are very tasty, certain hormones in the brain are triggered, which makes consuming unhealthy choices more likely.

This is analogous to what occurs in the brains of those who suffer from substance abuse disorders. Behaviors comparable to addiction to foods high in fat and sugar have led to studies employing animal models of obesity, discovering typical neurobiological features of addiction in the brain systems. The reward system that is engaged, and that perpetuates a preference for specific types of foods, may also be involved in addiction disorders.

The conclusion, currently, is that there is a viable solution for addiction through the use of the GLP-1 medications. Researchers must further investigate these specific connections and detail their interrelationships.

Since the discovery of GLP-1 medications for obesity, several off-label uses have also been shown to be useful. Researchers are actively exploring the growing number of diseases that these medications might treat, which is extremely promising.

The potential utility of GLP-1 disorders of addiction and others include: food addiction (binge eating), alcoholism, Parkinson’s disease, depression, anxiety, heart disease, hypertension, fatty liver, polycystic ovarian syndrome, chronic kidney disease, inflammation, and opiate and narcotic addictions.

Addiction regulation, inflammation reduction, dopamine pathway modulation, and insulin sensitivity are just a few of the many physiological consequences of these receptor agonists. Because of these processes, they are promising candidates for the treatment of diseases outside of their original indications.

Medical and scientific communities are highly intrigued by the prospect of GLP-1 medicines potentially treating this wide array of illnesses, but research into these uses is still in its early phases.

The future, however, appears promising as new indications come to light, and as research reveals the areas where they may be brought into a treatment regime that is successful. At this juncture, however, it is not always apparent which biological pathways are being affected and that is a remaining question for future research efforts.

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Obesity care goes beyond mere body weight reduction in a number of ways, all of which tie back to an unwavering focus on improving patients’ health:

Comprehensive, individualized treatment

Obesity is a complex, multifactorial, relapsing chronic disease that requires a highly individualized treatment approach. Before starting a patient on an anti-obesity medication, we must develop a comprehensive, personalized education and treatment plan that takes into account all the specific factors contributing to that individual’s weight gain and those preventing weight loss (from physical activity and nutrition, to sleep patterns and stress, to previous weight loss experience, to other health conditions and medications). Treatment may include GLP-1 medications, but there’s no one-size-fits-all solution.

Careful prescribing

We call the medications anti-obesity medications rather than weight-loss drugs for a reason: they’re designed for long-term treatment of the chronic disease of obesity. We can’t just prescribe Wegovy or Zepbound and send patients on their way. These medications are generally well tolerated when prescribed appropriately, but not all patients with obesity are good candidates. We need to support those who are with dietary strategies and personalized titration schedules to minimize side effects, as well as education to identify early warning signs way before more serious adverse events occur.

Addressing comorbidities

Obesity leads to dysregulation in a variety of physiological pathways that can affect virtually every body system. Obesity is associated with more than 200 health conditions, including heart disease, hypertension, type 2 diabetes, osteoarthritis, sleep apnea and certain types of cancer, to name just a few. Treating obesity includes addressing these comorbidities. While it’s true that weight loss itself can lead to improvements in many of these weight-related health conditions, it’s not always a straightforward process. Individuals with obesity often have multiple comorbidities, and many are already taking multiple medications — creating additional variables and potential interactions to manage.

Health-related goals

Patients with obesity may present with specific weight goals they’d like to achieve, but as providers, we emphasize instead the importance of health outcomes, such as measurable improvements in metabolic health markers. The healthy lifestyle habits incorporated into the treatment plan underscore this focus, and a patient’s ability to decrease or discontinue other medications — for hypertension or diabetes, for example — often depends not only on the amount of weight lost, but also on these complementary lifestyle changes.

Support for long-term weight maintenance

Patients need to be aware that the initial weight loss period is only the first stage in a lifelong journey. Obesity is a chronic disease — one that we don’t yet have a cure for — which means that weight management requires long-term commitment. As clinicians, our job isn’t finished when our patients bring their weight down; we need to provide ongoing support to help them sustain the healthy behavior changes they’ve made, avoid medication discontinuation, and make adjustments and get back on track when they encounter the inevitable challenges along the way. Weight maintenance is often more difficult than weight loss, and patients frequently underestimate how much ongoing support they’ll need.

We’re thrilled to have so many new anti-obesity medications in our armamentarium — medications that are extraordinarily effective at helping individuals lose weight. But weight reduction is just part of the obesity treatment story. As clinicians, we need to make sure we’re looking beyond the number on the scale and delivering holistic, empathetic, evidence-based care tooptimize our patients’ overall health and well-being.

** I’m honored to be a member of the International Obesity Collaborative (IOC), a global initiative to address obesity internationally. Comprised of 12 leading obesity organizations, the IOC aims to raise awareness, share best practices, and implement effective interventions to treat obesity around the world.  We recently published the consensus statement: “Obesity Care vs. Weight Loss.” Stay tuned for more publications by the IOC.

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Thanks to viral social media posts and constant press coverage, Ozempic and Wegovy have become almost household names, and many primary care providers face questions — some based on social media misinformation — from patients eager to give these new medications a try. The following are common questions I’m asked, and suggested context to frame a response.

• “Can you write me a prescription for Wegovy?”

Patients should understand that it’s not just a matter of writing a prescription. Obesity is a complex, chronic disease, and many interrelated factors, including genetics, environment, sleep patterns, stress, medications, hormonal imbalances, and other health conditions, need to be considered to determine the best treatment. Wegovy isn’t suitable for everyone who has obesity; there may be other, more appropriate medications. It’s also important to provide education and ongoing support for sustainable dietary, physical activity, and behavior changes. Lifestyle interventions are rarely sufficient on their own, but they’re always essential components of any effective weight management plan. A successful weight loss strategy needs to address all these factors comprehensively and in a personalized way as part of a long-term care plan. There’s no quick fix for obesity.

• “I don’t want to resort to medication. It feels like cheating. Why won’t diet and exercise work for me?”

Most people with obesity cannot lose significant weight and keep it off long-term with lifestyle changes alone. This is because weight loss triggers the body’s physiological “anti-starvation” mechanisms, leading to increased hunger and cravings and a lower metabolic rate. With obesity, the area around the hypothalamus (the energy regulatory center in the brain) becomes inflamed, interfering with feedback signals from the gut and fat cells. Anti-obesity medications address these underlying dysregulated hormonal and metabolic pathways. Semaglutide, for example, mimics the GLP-1 hormone, which helps people feel full sooner after eating and slows the passage of food through the gastrointestinal tract. It targets areas of the brain that control appetite and influence eating decisions. Other anti-obesity medications work differently, but they all help the body overcome its anti-starvation responses to enable weight loss and weight maintenance.

• “Are the horror stories about Ozempic’s side effects — abdominal pain, constipation, diarrhea, and vomiting — typical? I don’t want to feel miserable.”

These are known adverse events associated with semaglutide, and it’s to be expected that as more and more people take these medications, we hear more about the side effects, including the rare ones. Symptoms may be worse when the medication is not used appropriately — if the dose is too high or it’s escalated too quickly, if the medication is prescribed without adequate screening (for example, to identify people who have risk factors for these symptoms), or if patients aren’t given the necessary education and support (dietary and behavioral modifications can minimize symptoms). When best practices are followed, patients generally tolerate semaglutide well.

There’s a risk-benefit calculation when prescribing any medication, of course, but for people with a high BMI, who face elevated risk of many serious weight-related conditions, the benefits may outweigh the risks.

• “What about aesthetic changes? I’ve heard about ‘Ozempic face.’ Will my skin get saggy?”

Loose skin is common with major weight loss, regardless of how it’s achieved, especially if the weight is lost rapidly. But this aftereffect is highly variable, with age, diet, and genetics among the factors that play a role. Some people lose 100 pounds and have no loose skin, and others develop a significant amount of loose skin after losing much less weight.

It’s important to note that weight reduction involves the loss of muscle as well as fat, so I always recommend and regularly encourage  patients to incorporate strength training into their weight management program in order to maintain as much lean body mass as possible.

• “How long will I need to take Wegovy?”

Patients should expect to take the medication for the foreseeable future. Obesity is a chronic disease., We don’t counsel patients with other chronic illnesses about weaning medications once their condition is controlled. When a person with diabetes stops taking an antidiabetic medication, we expect blood sugar to increase. And when someone with high blood pressure stops taking an antihypertensive medication, we expect blood pressure to rise. Obesity is the same. The FDA has approved these medications for long-term use for this reason. Weight gain isn’t just possible after stopping an anti-obesity medication discontinuation, it’s expected.

• “Why doesn’t my insurance cover Wegovy?”

For years, weight loss was considered strictly “cosmetic,” and obesity was attributed to individuals’ poor lifestyle choices. Today, most industry players — including insurers — recognize that obesity is a complex, chronic disease. But the new anti-obesity medications are extremely costly, especially considering the huge number of potential users (more than 42% of U.S. adults have obesity).

Access needs to improve, and it needs to improve dramatically, but simply handing out GLP-1 prescriptions left and right isn’t the answer either.

A comprehensive approach to weight management can improve health outcomes for more than 200 other conditions that obesity causes or worsens, from high blood pressure and type 2 diabetes to sleep apnea and certain types of cancer. It makes more sense — in terms of both patient health and economics — to treat the underlying obesity directly rather than waiting for these preventable obesity-related diseases to develop.

Now that we have a critical mass of patients taking these new, highly effective medications, we will have more comprehensive data demonstrating the mortality benefits of anti-obesity medications. For example, results from Novo Nordisk’s landmark SELECT trial, a five-year cardiovascular outcomes trial of Wegovy compared to placebo in individuals with overweight or obesity, recently found that semaglutide reduced the risk of major adverse cardiovascular events (heart attack, stroke, and cardiovascular deaths) by 20 percent. With this evidence from the SELECT trial, improved insurance coverage should be next.

• “If my insurance doesn’t cover semaglutide, are there alternatives?”

Semaglutide is an important part of our anti-obesity armamentarium, but we don’t automatically prescribe it to everyone who qualifies. Other options include Contrave, Saxenda, and Qsymia, for example. Any anti-obesity medication needs to be selected in the context of a comprehensive individualized evaluation and prescribed as part of a personalized treatment plan. Depending on a patient’s specific situation and risk factors, I prescribe many medications that are considerably less expensive than semaglutide, and individuals on these medications are still able to lose a significant amount of weight. Everyone’s situation is different, and individuals respond to different medications in different ways. Obesity is not a simple disease, and there’s no one medication that’s right for everyone.

• “What about supplements like berberine? Some people are calling it ‘nature’s Ozempic.’ Is it worth trying?”

I caution my patients about dietary supplements for weight management because we don’t have high-quality evidence demonstrating efficacy. Worse, the lack of regulatory oversight in the supplement market makes it challenging to know exactly what’s contained in any given product. The actual amount of berberine could be different from what’s claimed, and other undisclosed ingredients could be included as well. For example, some dietary supplements have been shown to contain amphetamines or anti-obesity medications that have been withdrawn from the market.

• “What about compounded semaglutide? Is it safe?”

When patients present to me on compounded semaglutide, I recommend that they stop. As with dietary supplements, these drugs are not regulated. We have no idea what the products contain, what the actual dose of the active ingredient is, or whether the product has contaminants. The FDA has issued a warning about compounded semaglutide.

• “I’m having surgery next month. Is it true that I need to suspend my Wegovy?”

Because GLP-1 receptor agonists are associated with increased risk of nausea, vomiting, and delayed gastric emptying, the American Society of Anesthesiologists recently issued guidance suggesting that individuals who take these medications daily should stop the medication the day of the surgery, or, if they take them weekly, hold the dose the week before surgery. People who are taking these medications for diabetes in addition to weight management may need to consult with their endocrinologist to identify an alternative diabetes medication to bridge the gap.

Wegovy and the other anti-obesity medications in the pipeline that are even more promising are and will be extremely important agents in our armamentarium, but successful weight management requires more than just one medication in isolation. Media coverage of these new medications sometimes creates the impression that obesity is a simple disease that can be treated with a one-size-fits-all, short-term approach. In reality, however, obesity is, a complex, multifactorial, relapsing chronic disease, and treating it requires a comprehensive evaluation and a customized treatment plan with education and long-term support.

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The discovery that Ozempic (semaglutide) supports weight loss is not new, but the unexpected spotlight on weight loss as a side effect of a diabetes medication serves as a good reminder to healthcare providers (or a wake-up call, for some) that all medications’ potential effects on weight should be taken into account, because the opposite result — drug-induced weight gain — is more common than most practitioners realize.

A typical case

A 33-year-old woman, Jill, recently presented to my obesity medicine practice because she had suddenly started to gain weight — 32 pounds over the previous six months. Through my evaluation, I learned that she had received two Depo-Provera injections during that time. She had previously used oral contraceptive pills, but she often forgot to take her pills and wanted a lower-maintenance form of birth control. Although progestin injections work well for many women, weight gain is a known and fairly common side effect, and the timing of Jill’s weight gain suggested a causal link. As part of her weight-management plan, we discussed birth control alternatives, and she ultimately chose to switch to a nonhormonal IUD.

The OB-GYN who prescribed her Depo-Provera had not mentioned the possibility of weight gain. While it’s understandable that many practitioners don’t want to create unnecessary worry about a side effect that might never materialize, it can be extremely difficult to lose weight once it has been gained, particularly for those who already have overweight or obesity. Since many patients who don’t track their weight can gain significant amounts without realizing it, simply advising patients to monitor their weight and notify their provider if they notice an increase can prevent tremendous frustration.

Jill was on only one weight-gain-promoting medication, but I often identify two, three, or even four such culprits when taking a new patient’s history. In addition to injectable or implantable birth control, some of the most common weight-gain-promoting drugs include diabetes medications, blood pressure medications, and antidepressants. In many cases the effect is modest, but with long-term medication use for chronic conditions, even a small effect can lead to a significant increase in weight over time.

Prevention starts with awareness

What can healthcare practitioners do to help their patients avoid drug-induced weight gain? Essentially, four things:

1. Be aware. First, practitioners need to recognize how common the problem is and educate themselves about the weight profiles of various classes of drugs and different agents within classes. (The Endocrine Society’s practice guidelines for the pharmacological management of obesity include information on drugs that cause weight gain and recommended alternatives; see the original article in the Journal of Clinical Endocrinology and Metabolism, or a summary listing in Table 2 of our more recent best practices article.) As with most contributors to the multifactorial disease of obesity, the interactions are complex, and a medication’s impact on weight may vary based on a variety of physiological, genetic, and lifestyle factors. But despite some unpredictability, many medications do have a well-documented track record of promoting weight gain, and providers should be alert to this potential side effect.
2. Choose alternatives when possible. When prescribing any medication, providers should consider the drug’s weight profile in assessing the benefits and risks, and seek to avoid weight-promoting drugs when possible. Weight-neutral or weight-loss-promoting medications are available for many common conditions that are frequently associated with obesity, including type 2 diabetes, hypertension, and depression. These alternatives should be prioritized when appropriate as first- and second-line treatments — especially for patients with overweight, obesity, or metabolic risk factors. For example, for patients with type 2 diabetes, weight-loss-promoting medications such as metformin and glucagon-like peptide-1 (GLP-1) receptor agonists (semaglutide and liraglutide, for instance), or weight-neutral options such as DPP-4 inhibitors, are preferred over insulin and insulin secretagogues that promote weight gain. For patients with hypertension, weight-neutral angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be chosen over weight-gain-promoting alpha- or beta-adrenergic blockers if possible. Many antidepressants present a risk of weight gain, for example, but only one, bupropion, has been consistently shown to promote weight loss, though it’s not appropriate for all patients. When recommending changes to existing prescriptions, providers should either consult with the original prescribing physician or ensure that the patient does so. The topic of drug-induced weight gain needs to be discussed extremely carefully with patients, though, or they may feel alarmed and stop taking their medications before a plan for replacement is in place.
3. Use the minimum dose. Drugs in the same class often aren’t interchangeable, and if no appropriate alternative to a weight-gain-promoting medication is available, providers should aim to prescribe the lowest effective dose for the shortest possible duration needed to manage the patient’s symptoms. Too often, patients are started on a medication, and then the dose and duration of the drug regimen are never reevaluated.
4. Counteract the effects with anti-obesity medication. When weight-gain-promoting medications must be used, practitioners should consider adding an anti-obesity medication, in conjunction with appropriate lifestyle modifications, to counteract weight-promoting effects in their patients with obesity. Providers who don’t feel comfortable prescribing these medications can refer their patients to an obesity medicine specialist.

The challenge of reversing weight gain

Optimizing medication choices may seem like low-hanging fruit in the effort to help patients manage their weight, and in a certain sense it is: prescribing weight-loss-promoting instead of weight-gain-promoting drugs can be a relatively simple way to prevent unwanted weight gain. This is an important strategy because reversing drug-induced weight gain is not always simple.

Jill was disappointed to find out that weight gained due to medication is sometimes no easier to lose than weight gained due to any of the other myriad contributing factors. Although switching birth control stopped the increase, she didn’t immediately lose the pounds she had gained. This is such a crucial point: many patients aren’t alarmed when realize they’re gaining weight on a medication because they assume the weight will come off easily when the medication is discontinued — however, this is often not the case. Jill and I developed a comprehensive, personalized weight-management plan that is beginning to show results, but it will be a long-term effort.

There’s no silver bullet in the fight against excess weight; obesity is a chronic disease that requires lifelong management. While weight-loss-promoting medications are a valuable addition to our armamentarium, they are not a quick fix, and pharmacotherapy needs to be part of a multidisciplinary approach that also includes diet, physical activity, and behavioral modifications. So it won’t be a surprise if most of the people who recently flocked to Ozempic without proper medical supervision regain the weight as soon as they stop taking the medication.

The ratchet nature of weight gain (easy come, decidedly not easy go) makes it even more critical that healthcare providers be aware of the potential weight-related side effects of medications and adjust their prescription choices accordingly. Obesity has many complex and interrelated causes, and the more of these underlying factors we can eliminate — like weight gain secondary to medications — the more successful we will be in helping our patients move toward a healthier weight.

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The prevalence of obesity has doubled worldwide since 1980, but a range of new treatments is being introduced to help patients lose weight. For years, the FDA did not approve any new drugs for use in the fight against obesity. With drugs being withdrawn, rather than approved, the list of available medications for obesity was rapidly shrinking.

In 2012, for the first time in 13 years the FDA approved a new drug, Belviq. Interestingly, in February of this year, 2020, the drug was withdrawn over cancer concerns (see below). It was one of only eight FDA approved drugs and in Europe, only three drugs have achieved licensing.

The role of Pharma in the fight against obesity

Obesity is a hugely complex issue. There are strong genetic and epigenetic factors, in addition to the influence of gut hormones, gut microbes and viruses, and environmental factors (such as the promotion of sugar and refined carbohydrates). There is also evidence that psychological and mental health conditions are risk factors for obesity, and vice versa. 

Obesity cannot be simply cured with a pill, but requires a multi-faceted approach to treatment that can involve life-style changes, surgery, diet, counselling and a pharmacological element. 

There is no magic pill in the fight against obesity and the use of medications should always be accompanied by a healthy diet and — if your health allows it — an exercise regime.

According to an NIH article, on average, people who take prescription medications as part of a lifestyle program lose between 3 and 9 percent more of their starting body weight than people in a lifestyle program who do not take medication.

Before we list drugs that may assist you to combat obesity, you should be made aware of the fact that drugs often have the reverse effect on your weight, not intentionally, but as a side effect. Drugs that cause weight gain include corticosteroids, atypical antipsychotics, combined oral contraceptives and beta-blockers. Discuss with your doctor, the option of replacing these medications with alternatives, if possible.

FDA Approved Medications

The following drugs have been approved in the U.S. to combat obesity. Each drug is listed with its method of action (how it works) and any associated health warnings.There are no approved medications for children under the age of 12, and only one drug is approved for children aged 12 and over, namely orlistat (Xenical).

Orlistat

Available in lower dosages without prescription(Alli). Itis considered safe for long term use, although weight loss is modest. It is the only product licensed for use by children aged 12 years an over.

Method Of Action: A pancreatic lipase inhibitor that causes around 30% of dietary fat to be excreted unabsorbed in the faeces. Orlistat works in your gut to reduce the amount of fat your body absorbs from the food you eat.

Side effects: Common, including oily stools, cramps and occasional faecal incontinence. Risk improvement includes a reduction in the cumulative incidence of diabetes over four years of 37.3% in obese normoglycaemic subjects, reducing LDL cholesterol by 5–10%, and lowering blood pressure and HbA1c.

Warnings: Rare cases of severe liver injury have been reported. Avoid taking with cyclosporine. Take a multivitamin pill daily to make sure you get enough of certain vitamins that your body may not absorb from the food you eat

Liraglutide (Saxenda)

Available only as an injection and at a lower dosage under the name Victoza

Method of Action: A glucagon-like peptide-1 (GLP-1) receptor agonist, which is given as a daily subcutaneous injection and has been used as a glucose-lowering agent in diabetes. 

The mechanism is not entirely understood, but appears to regulate appetite by inducing a feeling of fullness and reducing hunger pains. The EMA recommends it should only be offered to adults with a BMI of more than 30, or 27 if they have a weight-related condition such as type 2 diabetes. Patients should receive a daily 3mg dose, with treatment stopped if body weight has not been reduced by at least 5% after 12 weeks.

Side Effects: nausea, diarrhea, constipation, abdominal pain, headache, raised pulse.

Warnings:May increase the chance of developing pancreatitis. Has been found to cause a rare type of thyroid tumor in animals.

Lorcaserin (Belviq)

Withdrawn from the market in February of 2020. There is an increased risk of developing cancer if you use this medication. This exert below from the FDA website

The U.S. Food and Drug Administration (FDA) has requested that the manufacturer of Belviq, Belviq XR (lorcaserin) voluntarily withdraw the weight-loss drug from the U.S. market because a safety clinical trial shows an increased occurrence of cancer. The drug manufacturer, Eisai Inc,. has submitted a request to voluntarily withdraw the drug.

US Food and Dug Administration

Phentermine-topiramate (Qsymia)

Method of Action: An Adult medication that combines a mix of two medications: phentermine, which lessens your appetite, and topiramate, which is used to treat seizures or migraine headaches. May make you less hungry or feel full sooner.

Common Side Effects: constipation, dizziness, dry mouth, taste changes, especially with carbonated beverages, tingling of your hands and feet and trouble sleeping.

Warnings: Don’t use if you have glaucoma or hyperthyroidism. Tell your doctor if you have had a heart attack or stroke, abnormal heart rhythm, kidney disease, or mood problems. MAY LEAD TO BIRTH DEFECTS. DO NOT TAKE QSYMIA IF YOU ARE PREGNANT OR PLANNING A PREGNANCY. Do not take if you are breastfeeding.

Naltrexone-bupropion (Contrave)

Method of Action: An adult medication utilizing a mix of two medications: naltrexone, which is used to treat alcohol and drug dependence, and bupropion, which is used to treat depression or help people quit smoking. May make you feel less hungry or full sooner.

Common Side Effects: constipation, diarrhea, dizziness, dry mouth, headache, increased blood pressure, increased heart rate, insomnia, liver damage, nausea and vomiting.

Warnings: Do not use if you have uncontrolled high blood pressure, seizures or a history of anorexia or bulimia nervosa . Do not use if you are dependent on opioid pain medications or withdrawing from drugs or alcohol. Do not use if you are taking bupropion (Wellbutrin, Zyban). MAY INCREASE SUICIDAL THOUGHTS OR ACTIONS.

There are other medications that curb your desire to eat and these include;

• phentermine
• benzphetamine
• diethylpropion
• phendimetrazine

Method of Action: Increase chemicals in your brain to make you feel you are not hungry or that you are full.These drugs are FDA-approved only for short-term use — up to 12 weeks

The following applies to all four the drugs listed above.

Common Side Effects: dry mouth, constipation, difficulty sleeping, dizziness, feeling nervous, feeling restless, headache, raised blood pressure, raised pulse

Warnings: Do not use if you have heart disease, uncontrolled high blood pressure, hyperthyroidism, or glaucoma. Tell your doctor if you have severe anxiety or other mental health problems.

Off-Label Use of Prescription Drugs by Doctors

Sometimes doctors use medications in a way that’s different from what the FDA has approved, known as “off-label” use. By choosing an off-label medication to treat overweight and obesity, your doctor may prescribe

• a drug approved for treating a different medical problem
• two or more drugs at the same time
• a drug for a longer period of time than approved by the FDA

You should feel comfortable asking your doctor if he or she is prescribing a medication that is not approved just for treating overweight and obesity. Before using a medication, learn all you need to know about it.

There are excellent and reliable government resources available online. Simply type in the name of the medication into Google and look for links to the NIH or FDA. Pharmaceutical websites such as Drug.com also offer detailed breakdowns of the drugs they sell.

Lastly, remember that a medication is only effective when used as part of a larger treatment plan that includes steps to address your diet, lifestyle and other factors. If you suffer from depression because of obesity be particularly careful of the medication listed above and always make your doctor aware of how you are feeling.

The post The Role of Drugs in Combating Obesity and How These Drugs Affect Your Health appeared first on Medika Life.