Guiding Obesity Management by Understanding Weight Loss Drugs

July 06, 2023 - As the popularity of weight management drugs, including Ozempic, continues to rise, clinicians and healthcare professionals need a guide to the obesity drug landscape. The nuanced field of weight management continues to become more and more complicated as new drug approvals, off-label use, and drug shortages add additional layers of complexity.

Obesity

Obesity has become a growing problem across the United States, affecting many adults and children. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a subset of the National Institutes of Health (NIH), overweight individuals are classified by a body mass index (BMI) of 25–30. In contrast, obese individuals have a BMI of 30 or more.

Despite BMI as the standard indicator for obesity, it is essential to know that BMI does not account for muscle mass and other fitness factors that may impact weight and patient health.

In the US, obesity has become a common chronic condition, impacting 40% of adults. Additionally, 10% of people in the US are classified as severely obese. In a 2022 report published by the Trust for America’s Health, researchers noted that, between 1999 and 2000, the obesity rate among adults in the US was 37% lower than between 2017 and 2022 (41.9%).

Additional insights from the report revealed that, between 2017 and 2022, the rate of obesity among children was roughly 19.7%.

For centuries, the impact of weight, weight gain, and obesity have been researched by medical professionals, with many chronic and debilitating conditions linked to excess weight gain. The effects of obesity have expanded so much that healthcare professionals and government organizations refer to the ongoing obesity epidemic as a public health crisis.

According to the Framingham Heart Study, adult obesity is correlated with a 6–7 year decline in life expectancy. Additionally, obesity has been linked to type 2 diabetes (T2D), stroke, asthma, and other respiratory diseases.

According to an article published by Nature, Andres Acosta, an obesity specialist at Mayo Clinic in Rochester, Minnesota, states that there are four obesity subtypes:

• Hungry brain, individuals who need to eat more feel to feel full
• Hungry gut, those who are satiated by average-sized meals but feel hunger again quickly
• Emotional hunger, individuals who cope with emotions by eating
• Slow burn, those with a slow metabolism

It is important to note that not all obesity subtypes can be treated using the same weight loss medications. Obesity management and treatment require a personalized and comprehensive approach, typically facilitated by lifestyle changes.

Weight Loss Drugs

Because obesity is a chronic disease with a widespread impact, medical and pharmaceutical research has continued to focus on ways to manage the condition, reduce body weight, and facilitate overall weight loss. Weight loss medications come in many forms, each targeting a reduction in body weight through different pathways. Regardless of the type of weight management drugs, nearly every healthcare professional recommends lifestyle changes, like healthy eating and physical activity, alongside medication for safe, effective, and sustainable weight loss.

Patients taking weight loss drugs and making diet and lifestyle changes lose an average of 3–12% of their starting body weight within one year. Beyond that, most people lose 10% of their starting weight, with variations between patients based on their medication, lifestyle, and other healthcare factors.

A 5–10% body mass reduction in patients who are overweight or obese can reduce blood pressure, lipid levels, and glucose. In addition, it can significantly reduce the risk of heart disease.

According to an article published by Cedars–Sinai Medical Center, roughly 1% of people who qualify for weight loss drugs use them.

Amanda Velazquez, MD, Director of Obesity Medicine at Cedars–Sinai, notes that her organization prioritizes weight management drugs for patients with medically complex conditions, including those who need to lose weight after cancer treatment or before qualifying for an organ transplant.

“I suspect that a very small minority of individuals are using these drugs for cosmetic purposes, and it’s become sensationalized. The attention on the small instances of misuse is taking focus away from the importance of these medications as a tool for populations who are very much in need,” Velazquez told Cedars–Sinai in an interview.

“These are effective, safe drugs that help individuals with obesity improve their medical state and potentially live longer healthier lives. “

Despite the benefits of weight loss drugs for managing weight and weight-related conditions, some potentially dangerous and fatal side effects are associated with these medications.

When starting a new weight-loss medication, patients and providers consider multiple factors, including potential benefits, side effects, other over-the-counter or prescription drugs, medical history, and cost.

Use

Most weight loss medications approved by the US Food and Drug Administration are intended for continual use. As many providers continue to emphasize, obesity is a chronic condition. When patients stop taking the prescribed medication for any chronic disease, their symptoms can return. In the case of obesity, weight gain often occurs after going off the drug.

“When I prescribe these drugs, I explain that they act to calm the biological pressures trying to force your body to be at a higher weight. If you take away that tool, even though you’ve implemented a wonderful diet and exercise program, your body will go back to its previous weight. There are individuals who can get off these medications and stay healthy, but they’re the rare exception,” Velazquez said in her interview.

Even with the outcomes linked to weight management medications, those with severe obesity, characterized as a BMI over 39.9, or those who have a BMI over 34.9 and a weight-related medical condition, such as diabetes, high blood pressure, or obstructive sleep apnea, are often referred for bariatric surgery to reduce morbidity and mortality.

There are six FDA-approved weight loss drugs for long-term use: semaglutide, phentermine–topiramate, naltrexone–bupropion, liraglutide, orlistat, and setmelanotide.

Some medications approved for short-term weight loss include phentermine, benzphetamine, diethylpropion, and phendimetrazine.

GLP-1 Receptor Agonists

One of the most notable FDA-approved weight loss drugs is Wegovy, manufactured by Novo Nordisk. This drug is the only FDA-approved version of semaglutide for weight loss. The prescription injection, given weekly, is part of a new class of weight loss drugs: glucagon-like-peptide-1 (GLP-1) receptor agonists.

These drugs mimic GLP-1 and act on receptors instead of the naturally occurring hormones usually produced by an individual’s gastrointestinal tract. Researchers and medical professionals hypothesize that GLP-1 agonists promote insulin production, which can also help regulate blood sugar. These drugs are also thought to promote fullness.

Semaglutide

The FDA originally approved semaglutide to manage T2D in patients who are overweight or obese. However, in 2021, the organization supported the drug for weight management in patients with a BMI higher than 29. Patients with a BMI over 26 and a concurrent weight-related medical condition are also eligible for the medication.

Novo Nordisk also has other forms of semaglutide on the market, including injectable Ozempic and oral  Rybelsus. Although many physicians use these drugs off-label for weight loss, the FDA has only approved them for glycemic control in patients with T2D.

Even with the social media craze surrounding Ozempic and its off-label use, healthcare professionals warn against the risk associated with semaglutide, emphasizing that this drug is not meant for all patients who want to lose weight. For example, the safety label on Wegovy notes that patients with a family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2) should not take the medication.

Additionally, Wegovy has been known to cause inflammation in the pancreas (pancreatitis), gallbladder problems, hypoglycemia, kidney problems — including kidney failure, allergic reactions, visual changes, increased heart rate, depression, or suicidal thoughts. Some common and less serious side effects include nausea, diarrhea, vomiting, constipation, abdominal pain, headache, dizziness, bloating, gas, heartburn, and more.

Liraglutide

Liraglutide, commercially known as Saxenda or Victoza, is the other type of GLP-1 receptor agonist approved for weight loss in the US. Like Wegovy, the medications are intended for patients 12 years and older. As GLP-1 receptor agonists, liraglutide drugs function similarly to semaglutide to reduce appetite and promote feelings of fullness.

The two drugs have similar safety profiles and contraindications.

Combination Drugs

Another group of FDA-approved weight loss drugs is combination drugs. These medications use two existing treatments and repurpose the drugs to manage appetite and promote fullness.

Naltrexone–Bupropion

Naltrexone–bupropion is a combination drug treatment approved to manage weight in obese or overweight adults. Naltrexone was initially approved as a medication for addiction treatment to curb cravings for drugs and alcohol. Bupropion is also known to have some anti-addictive properties but is mainly used as an antidepressant medication.

Contrave, the brand name for naltrexone–bupropion, also promotes fullness. While the neurochemical mechanism for this drug combination is not fully understood, researchers in the Journal for Managed Care and Hospital Formulary Management indicate that the drug may work with the hypothalamus and dopamine circuit to promote fullness and reduce hunger.

This drug can cause constipation, diarrhea, dizziness, dry mouth, headache, high blood pressure, elevated heart rate, insomnia, liver damage, nausea, and vomiting. Patients with a history of high blood pressure, seizures, and eating disorders should avoid this drug.

Phentermine–Topiramate

Phentermine–topiramate, known by the brand name Qsymia, is an FDA-approved weight loss drug for adults. The medication reduces appetite and hunger while increasing the feeling of satiety.

Topiramate is an anti-seizure drug repurposed for weight management by minimizing binge eating habits. Meanwhile, phentermine is an anorectic known to decrease appetite. 

Common side effects include constipation, dizziness, dry mouth, difficulty sleeping, taste changes, and trouble sleeping. The medication has many contraindications, including glaucoma, hyperthyroidism, and pregnancy.

Orlistat

Orlistat, also known as Xenical, is approved for weight and is a prescription obesity medication for adults and children 12 and older. The drug works by reducing fat absorption in the gut. The remedy is also available over the counter at a lower dose known as Alli.

Setmelanotide

Anyone 6 or older with one of the following rare genetic conditions may also qualify for setmelanotide under the brand name Imcivree. This medication is intended to treat proopiomelanocortin (POMC) deficiency, proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency.

The drug manages weight by reducing appetite, promoting satiety, and increasing resting metabolism. It is known to cause injection site reactions, sexual dysfunction, depression, skin darkening, and adverse neonatal outcomes.

Misuse and Media Implications

The rising popularity of new weight loss drugs has stirred up extensive controversy regarding their benefits and potential for misuse.

Judith Korner, MD, PhD, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and director of the Metabolic and Weight Control Center at Columbia, noted that the media attention surrounding weight loss drugs had had a heterogenous impact on patients and obesity landscape. At the same time, the media coverage of the medications has improved patient familiarity with the treatments and facilitated additional insight.

Although increased attention and access to these medications can benefit many patients needing the medicines, the rhetoric surrounding these discussions can perpetuate weight stigma and body dysmorphia.

The amount of publicity focused on these weight loss drugs has sponsored some drug manufacturers, specifically Novo Nordisk, to pause marketing their medications. In a statement to Fierce Pharma, the company stated that it would delay all TV advertising “to avoid stimulating further demand for this medicine, we’re pausing some key Wegovy promotional efforts.”

Costs and Coverage

The growing popularity of weight loss drugs and the new class of GLP-1 agonists presents concerns beyond biology, bleeding into the payer space.

While the drugs in the weight loss community have proven helpful for weight loss in addition to glycemic control and diabetes management, Medicare will not cover the medications when intended for weight loss use.

Medicare will only cover obesity screenings, behavioral counseling, and bariatric surgery for weight loss. Medicare Part D prescription drugs explicitly deny coverage for weight loss drugs.

Despite current laws and guidelines, drug manufacturers and other stakeholders in the weight loss drug industry are pushing for coverage of these drugs, citing clinical trial data highlighting the additional health benefits of these medications.

The hefty price tags associated with these medications are expected to become a significant burden for Medicare if regulations change and require coverage. KFF estimates that, if only 10% of obese Medicare Beneficiaries use Wegovy, Medicare could have a minimum $13.6 billion increase in annual healthcare costs, with costs reaching up to %26.8 billion.

This estimate is based on the average annual net price for Wegovy, $13,600; 2021 Medicare obesity rate, 19%; and obesity rate from surveys of older adults, 41.5%.

This estimate of drug uptake is relatively conservative and could be significantly higher if more patients use the medications.

Although the estimate seems alarming, it is critical to note that these numbers do not factor in potential savings associated with weight reduction.

According to KFF data, 25% of Black Medicare beneficiaries are obese. Comparatively, the overall obesity prevalence for Medicare beneficiaries is 19%, and the rate among Black individuals is 5% greater than the next highest ethnic group.

Without Medicare coverage of these medications, there is a chance that Black patients will have inequitable access to these drugs due to income and assets.

Suppose Medicare coverage on drugs is expanded. In that case, the medications will be subject to drug price negotiations under the Inflation Reduction Act (IRA), with talks for semaglutide and tirzepatide starting as soon as 2027 and 2031, respectively.

Shortages, Off-Label Use, and Drug Compounding

Beyond the approved uses for these drugs, many providers also consider off-label use of existing drugs for weight management. Off-label use may involve prescribing a drug approved for a different medical problem, multiple drugs at one time, or a medication for a more extended period than approved by the FDA.

With ongoing shortages of multiple medications, many physicians turn to drug compounding — combining, mixing, or altering ingredients to create a drug for each patient’s needs — to manage patient care. The FDA does not monitor or regulate these drugs for safety and effectiveness.

Although compounding is only approved under the Federal Food, Drug, and Cosmetics Act for certain drugs, ongoing shortages of Ozempic and Wegovy have qualified these medications for compounding.

As the healthcare industry’s understanding of these drugs evolves, patients and clinicians should practice vigilance regarding weight loss medications. Thorough evaluations of patient risk and existing health problems should guide medication management. Providers and the public should avoid buying into the social media frenzy surrounding these medications, valuing evidence-based scientific data over celebrity anecdotes.