semaglutide

How semaglutide drugs such as Ozempic can help with long-term weight loss and heart health

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A needle on an Ozempic pen
Researchers say weight-loss medications such as Ozempic can help with heart health as well as long-term weight loss.
  • Researchers say a new study has found that GLP-1 drugs such Ozempic result in long-term weight loss and slimmer waistlines.
  • They noted that about half of study participants were also able to significantly cut their body mass index scores.
  • They added that semaglutide drugs seemed to promote better overall cardiovascular health as well.

Semaglutide — a glucagon-like peptide-1 (GLP-1) receptor agonist found in medications such as Ozempic, Rybelsus, and Wegovy — has dramatic benefits for people with obesity and other weight management issues, a pair of new studies finds.

One study published in the journal Nature Medicine involved 17,000 adults without diabetes who were classified as overweight or obese.

In the study, researchers found that taking semaglutide-based medication resulted in an average weight loss of 10% of body weight and a reduction in waistline measurements of more than 7 centimeters (2.7 inches) over a four-year period.

“Weight-loss strategies have been transformed by the introduction of GLP-1s… compared to previous approaches to weight loss,” Luke Twelves, the medical director at clinical research firm Lindus Health who was not involved in the study, told Medical News Today. “This study adds further data to our understanding of the potential roles for GLP-1s and strengthens the case for their inclusion earlier in treatment pathways.”

The study, led by Dr. Donna Ryan of the Pennington Biomedical Research Center in New Orleans, also found that more than half of participants moved down at least one body mass index (BMI) category after two years of taking semaglutide (compared to 16% among a placebo group), and 12% reached a healthy BMI (compared to 1% of the placebo group).

“Such sustained weight loss of this magnitude is infrequently observed in clinical trials of other weight-loss interventions,” Michelle Routhenstein, RD, CDN, a preventive cardiology dietitian at EntirelyNourished.com who was not involved in the study, told Medical News Today.

She added that “waist circumference was measured because it specifically targets abdominal weight, which is closely associated with inflammation and the risk of heart disease.”

Antoni Adamrovich, the chief of medicine and co-founder of weight-loss program Tb2.health who was not involved in the research, told Medical News Today that the study indicated that GLP-1 drugs are significantly more effective than other popular weight-loss medications. Other weight loss medications such as phentermine or naltrexone/bupropion are associated with an average weight loss of 3% to 7% percent of body weight.

GLP-1 drugs such as Ozempic and heart health

A companion study from researchers at University College London reported that GLP-1 drugs, which are used to treat type 2 diabetes as well as weight loss, also seemed to benefit the cardiovascular system regardless of how much weight people lost or what their starting weight was.

While this study, which has not been published yet in a peer-reviewed journal, did not involve people with diabetes, “it is likely that semaglutide would produce similar outcomes among individuals with diabetes,” said Routhenstein. “This is because semaglutide primarily functions by mimicking the actions of the body’s natural incretin hormone, GLP-1, to slow down the absorption of food, allowing for more satiety and controlled blood sugar metabolism.”

Positive outcomes were seen among all genders, races, ages, regions, and body sizes when compared to placebo effects, researchers said.

“Our long-term analysis of semaglutide establishes that clinically relevant weight loss can be sustained for up to four years in a geographically and racially diverse population of adults with overweight and obesity but not diabetes,” said Ryan in a press statement. “This degree of weight loss in such a large and diverse population suggests that it may be possible to impact the public health burden of multiple obesity-related illnesses. While our trial focused on cardiovascular events, many other chronic diseases including several types of cancer, osteoarthritis, and anxiety and depression would benefit from effective weight management.”

John Deanfield, a professor of cardiology at University College London who led the companion study, added that the findings suggest that semaglutide “has other actions which lower cardiovascular risk beyond reducing unhealthy body fat.”

“These alternative mechanisms may include positive impacts on blood sugar, blood pressure, or inflammation, as well as direct effects on the heart muscle and blood vessels, or a combination of one or more of these,” he said.

Side effects of semaglutide treatment can include gastrointestinal symptoms such as nausea and diarrhea as well as a higher risk of developing gallbladder stones. However, the researchers said that negative symptoms were actually lower among the semaglutide recipients than in the placebo group.

The findings were presented at the May 2024 European Congress on Obesity.

The data were sourced from the ongoing Semaglutide and Cardiovascular Outcomes (SELECT) research trial, launched in 2018. In 2023, studies based on SELECT trial data on a similar population found that taking semaglutide for more than three years reduced risk of heart attack, stroke, and death from cardiovascular disease by 20%.

Adamrovich said more research to show the impact of GLP-1 treatment beyond four years would be beneficial “to see if the weight loss and cardiovascular benefits were sustained long term.”

“It would also be helpful to conduct some follow-up studies focusing on certain heart-healthy diets and moderate-intensity exercise in conjunction with semaglutide or tirzepatide use,” he said.

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes

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Abstract

BACKGROUND

Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes.

METHODS

We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.

Download a PDF of the Research Summary.

RESULTS

A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was −9.8% with semaglutide and −3.4% with placebo (estimated difference, −6.4 percentage points; 95% CI, −7.6 to −5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P=0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group.

CONCLUSIONS

Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure–related symptoms and physical limitations and greater weight loss than placebo at 1 year.

How semaglutide and similar drugs act on the brain and body to reduce appetite

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Wegovy injection dose
How do semaglutide drugs like Wegovy, and other GLP-1 analogues, help suppress appetite? Image credit: UCG/Getty Images.
  • GLP-1 analogues, such as semaglutide, are prescribed for people with type 2 diabetes, including those with the condition who have obesity, in order to promote weight loss and improve control of blood sugars.
  • Their use as a treatment for obesity, often off-label, has gained a lot of attention in recent years.
  • The number of potential benefits of these drugs for minimising the risk of other conditions, such as cancer and cardiovascular disease, has also become a focus of research.
  • Researchers have now carried out a review of existing medical literature to summarise our understanding about how, exactly, GLP-1 analogues contribute to reduced calorie consumption.

GLP-1 analogues, such as semaglutide (brand names Ozempic, Wegovy) that were initially licensed for treating type 2 diabetes have received a lot of publicity in the past couple of years, in great part due to their ability to help people lose weight.

The understanding so far has been that GLP-1 analogues work by mimicking the action of a similarly shaped molecule called glucagon-like peptide, which is naturally released by the intestines soon after eating food.

This peptide binds to a specific receptor on the surface of beta cells in the pancreas, causing them to release insulin, and for a long time researchers assumed that GLP-1 analogues only affected insulin release, hence why they were prescribed for type 2 diabetes.

The effect these drugs had on weight did not long go unnoticed, however, as losing fat can help people with type 2 diabetes control their blood sugars better, and even make the condition go into remission.

Studies conducted in recent years have discovered that GLP-1 analogues work in a variety of ways that contribute to weight loss, including by slowing gastric emptying, and by increasing a person’s sense of fullness after eating.

Semaglutide, liraglutide, and weight loss

There has been significant research in recent years focused on the other potential benefits of GLP-1 analogues, many of which could be due to the impact they have on body mass index (BMI) and obesity.

People with obesity are more likely to have cancer and cardiovascular disease, and recent research has shown that people who use GLP-1 analogues could have a lower risk of both. It remains unclear however, whether this is due to weight loss or other effects of the drugs.

Dr. Mir Ali, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA, told Medical News Today:

“As these medications increase in use and popularity, we will likely see more effects as people achieve their weight loss goals; there are still concerns with weight gain after stopping these medications, so more research is needed in order to understand the main reasons for the weight gain.”

Research is now focused on trying to figure out more about how these drugs work. A new review published in the International Journal of ObesityTrusted Source looked at the existing literature on this topic, how studies had been carried out, and how data had been collected on GLP-1 analogue use.

To carry out the review authors searched PubMed for the terms “obesity,” “semaglutide,” “liraglutide,” and “GLP-1 analog.”

Like semaglutide, liraglutide (brand name Saxenda) is a GLP-1 analog.

Initial phase of weight loss while on GLP-1 analogues

Researchers found that most of the research done into the effect of GLP-1 analogues on weight loss looked at the initial weight loss phase of action, which tends to last 12–18 months for semaglutide users, rather than the maintenance phase, when weight loss plateaus after this.

So far, researchers have understood that side effects, including gastric upset and nausea, tend to occur at the beginning of treatment, but a review of the available literature suggested that the weight loss in the early stages of using the drug, was not linked to nausea.

While the impact of the drug on reducing eating dropped between 12–18 months, users’ caloric intake was still found to be more restricted than baseline during the so-called maintenance phase after this.

Reviewing studies where people using the drug had been asked about their food cravings and preferences, researchers showed that there was an overall lower desire for dairy and starchy foods, and salty and spicy foods, and also that they wanted a lower number of foods, particularly high-fat, non-sweet foods.

However, macronutrient profiles of what people ate remained the same before and after initiation of the drug. There is still a lack of clarity over whether GLP-1 analogues lead to increased desire for sweeter foods, particularly those containing sucralose.

The authors found that existing research had shown that individuals using exenatide (brand name Byetta) — another GLP-1 analogue — had decreased neuronal responses to pictures of food in parts of the brain regulating appetite and reward. This response was measured through functional magnetic resonance imaging (fMRI).

Research has also shown that semaglutide does not permeate the blood-brain barrier, the layer that “insulates” the brain, protecting it from external agents.

Instead, this drug interrupts signalling that could affect appetite in parts of the central nervous system that are not behind the blood-brain barrier.

Data collection on GLP-1 agonists potentially flawed

Prof. Alex Miras, clinical professor of medicine at Ulster University, United Kingdom, and obesity expert — not involved in this review — told MNT that our understanding of obesity and GLP-1 analogues is limited by the way in which data on diet are collected in these studies.

He noted that studies where the data are self-reported by the participants may have inaccuracies, and argued that the best way to confirm findings is through observational studies, which carry a lower risk of inaccuracies.

”I think I think the overall conclusion from this [paper] is that there is some evidence that pharmacotherapy for obesity changes food preferences in some people,” he said. “But if we want to find [out] for certain, we should stop asking people what they do, and […] actually observe people as to what they do, and then we will get robust answers.”

“I need to be observing people in a research setting or a clinical research setting, which should be as close to normal life as possible. But with that caveat, we should be studying how these people behave, rather than what they’re telling us,” added Prof. Miras.

Dr. Ali, who was also not involved in this review, noted that a problem affecting a lot of research in this area is that it comes out of smaller studies as double-blind controlled studies “require a lot of time and monetary investment.”

“Obesity is a multifactorial condition; genetics, hormones, activity, environment, socio-economic status all play a role in obesity. Therefore, no one intervention can work for all people suffering from obesity, and that makes it difficult to find the most effective treatment,” he cautioned.

“Zepbound,” the newest weightloss drug

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As Zepbound dominates headlines as a new obesity-fighting drug, experts warn that weight loss shouldn’t be the only goal.

A tube with the word Zepbond on it, designed specifically for weight loss.

Zepbound is the newest addition to the weight loss drug arena. In November 2023, it joined the list of obesity-fighting drugs – administered as an injection – to be approved by the U.S. Food and Drug Administration. 

The key to Zepbound’s weight loss potential is its active ingredient, tirzepatide. This is the same active ingredient found in the drug Mounjaro, which is approved to treat Type 2 diabetes. 

The relationship between Zepbound and Mounjaro is similar to two other popular drugs making headlines, Wegovy and Ozempic. Both Wegovy and Ozempic contain the active ingredient semaglutide, with Ozempic approved for the treatment of Type 2 diabetes and Wegovy approved for the treatment of obesity.

Tirzepatide and semaglutide both mimic the digestive hormone GLP-1, which is released by the intestines when we eat to stimulate insulin production and help regulate blood sugar. GLP-1 also suppresses appetite while promoting a sensation of fullness.

Weight loss medications are intended to be used in conjunction with lifestyle changes, such as exercise and a healthy diet. But too often, people view them as a silver bullet for weight loss. And the high price tag and variable insurance coverage for these popular weight loss drugs create a barrier for many people. 

Health risks of obesity

The potential impact of these drugs is staggering, since more than 2 in 5 American adults are obese, according to the National Institutes of Health. 

Obesity is not just an American issue, nor is it going away. The World Obesity Federation estimates that by 2030, 1 in 5 women and 1 in 7 men will be living with obesity worldwide.

Many serious health conditions are associated with obesity, including heart disease, diabetes, high blood pressure, stroke, certain cancers, and osteoarthritis. By treating obesity, a person can reduce or reverse obesity-related disease and improve both their health and quality of life.

However, long-term weight management depends on a number of complex factors. Meal timing and types of foods eaten can affect energy levels, satisfaction and hunger levels. A person’s typical schedule, culture and preferences, activity level and health history must be taken into consideration as well. No single “best strategy” for weight management has been identified, and research indicates that strategies for weight loss and maintenance need to be individualized.

In addition, it is critical to note that research on the long-term effects of these newer weight loss drugs is limited. The available research has focused specifically on weight loss, heart health and metabolism and has found that ongoing use of these new medications is necessary to maintain improvements in weight and related health benefits. 

Common side effects and the emotional toll experienced by those who regain weight once they stop taking the drugs are trade-offs that need to be considered. More research is needed to better understand the long-term impact of both direct and indirect health consequences of taking drugs for weight loss.

It’s not just what you see on the scale

Throughout my years working as a registered dietitian, I have counseled numerous people about their weight loss goals. I often see a hyperfocus on weight loss, with much less attention being placed on the right nutrients to eat.

Societal standards and weight stigma in the health care setting can negatively affect patients’ health and can lead them to obsess about the number on a scale rather than on the health outcome.

Weight loss may be necessary to reduce risks and promote health. But weight loss alone should not be the end goal: Rather, the focus should be on overall health. Tactics to reduce intake and suppress appetite require intention to ensure that the body receives the nutrients it needs to support health.

Additionally, I remind people that long-term results require attention to diet and lifestyle. When a person stops taking a medication, the condition it’s meant to treat can often return. If you stop taking your high blood pressure pills without altering your diet and lifestyle, your blood pressure goes back up. The same effects can happen with medications used to treat cholesterol and obesity.

Nourish your body with nutrients

Despite the prevalence of obesity and the emergence of newer drugs to treat it, 95% of the world’s population doesn’t get enough of at least one nutrient. According to one study, nearly one-third of Americans have been found to be at risk of at least one nutrient deficiency. Additional research indicates that those actively trying to lose weight are more prone to nutrient deficiencies and inadequate intake. 

For instance, a decline in iron intake can lead to iron deficiency anemia, which can cause fatigue as well as an increased risk of many conditions. Adequate intake of calcium and Vitamin D reduce the risk of bone fractures, yet many people get less than the recommended amounts of these nutrients. 

It is true that a healthy body weight is associated with reduced health risks and conditions. But if a person loses weight in a manner that does not provide their body with adequate nourishment, then they may develop new health concerns. For example, when a person follows a diet that severely restricts carbohydrates, such as the ketogenic diet, intake of many vitamins, minerals, phytochemicals – or biologically active compounds found in plants – and fiber are reduced. This can increase risk of nutrient deficiencies and impair the health of bacteria in our gut that are important for nutrient absorption and immune function.

Nutrition recommendations set by the Food and Nutrition Board of the National Academies of Sciences, Engineering, and Medicine and the Dietary Guidelines for Americans provide guidance and resources to help meet nutrient needs to promote health and prevent disease, regardless of the strategy used to lose weight.

Optimizing health

There is no doubt that striving for a healthy body weight can reduce certain health risks and prevent chronic disease. Whether a person strives to maintain a healthy body weight through diet alone or with medications to treat obesity, the following tips can help optimize health while attempting to lose weight.

  1. Adopt an individualized approach to healthy behaviors that promote weight loss while considering personal preferences, environmental challenges, health conditions and nutrient needs.
  2. Focus on nutrient-dense foods to ensure the body is getting required nutrients for disease prevention and optimal function. If medications reduce your appetite, it is crucial to maximize the amount of nutrients in the foods you do consume.
  3. Include exercise in your program. Weight loss as a result of reduced calorie intake can decrease both fat and lean body mass, or muscle. An exercise routine that includes strength training will help improve muscle strength and preserve muscle during weight loss. 
  4. Seek professional help. If you are uncertain about how to adopt an individualized approach while ensuring adequate intake of essential nutrients, talk to a registered dietitian. They can learn about your individual needs based on preferences, health conditions and goals to make dietary recommendations that support health.

The Ozempic Aesthetic: Can Anti-Obesity Medications Cause More Harm Than Good?

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Overweight-young-woman-in-glasses-admires-choice-of-clothes-standing-in-front-of-large-mirror-in-stylish-room-reflection-view.

The American Medical Association officially recognized obesity as a disease in June 2013 after decades-long controversy.1 Although lifestyle interventions are promoted as a first-line obesity treatment, the resultant short-term weight loss often fails to improve long-term outcomes.2 In the search for other solutions, glucagon-like peptide-1 (GLP-1) receptor agonists such as tirzepatide (Mounjaro™) and semaglutide (Wegovy® or Ozempic®) have greatly increased in popularity throughout the past year.

However, the media frenzy surrounding tirzepatide and semaglutide has raised concerns about this latest obesity treatment. Originally developed for diabetes, tirzepatide and semaglutide faced widespread drug shortages as celebrities such as Elon Musk and Chelsea Handler accredited the drugs for their weight loss. Resultant backlash attributed the anti-obesity medication boom to fatphobia.3

Still, the myriad of obesity’s biological and psychosocial obstacles can feel insurmountable after lifelong efforts to lose weight. But are GLP-1 receptor agonists the right solution for patients struggling to climb uphill to a “healthy weight”? Or do these injectables amplify disordered eating, weight stigma, and reliance on expensive pharmaceuticals? 

Perhaps it depends on who you ask.

For an insider’s view on this timely topic, we spoke with board-certified bariatric physician Kevin Huffman, DO and leading psychiatrist Michael Olla, MD, both of whom have decades of experience treating obesity and navigating its social implications.

Can BMI Justify Anti-Obesity Injections?

Although obesity is associated with higher risks for type 2 diabetes, certain cancers, mobility issues, and heart disease,1 some experts feel that anthropometric measures such as body mass index (BMI) fail to reflect true health status.

A veteran in his field, Dr. Huffman has treated more than 10,000 patients with obesity and trained and mentored hundreds of physicians and allied healthcare providers. He is also the CEO and founder of AmBari Nutrition and the founder and president of The American Bariatric Consultants. 

Dr. Huffman admits that BMI does not tell the whole story about whether anti-obesity medication makes sense for an individual patient.

“BMI, a useful initial screening tool, necessitates more nuanced considerations when prescribing injectable weight loss medications,” he explains. “We acknowledge the uniqueness of each patient; body composition, fat distribution, metabolic health, and underlying medical conditions significantly influence our decision-making process.” 

He continues, “For instance, certain patients may present with central obesity despite having a lower BMI — this suggests an escalated risk for obesity-related complications. Diabetes or hypertension, obesity-related health issues, may still qualify individuals for intervention despite a slightly lower BMI than the conventional threshold.”

Providing Quality Care in a “Fatphobic” Environment

Medical professionals are far from immune to stigmatizing patients with obesity. Research findings show that over 50% of healthcare professionals attribute obesity to a lack of willpower.4

In addition, more than half of adults with overweight in Western countries report experiencing weight stigma. As a result of this stigma, patients with obesity and overweight are more likely to avoid healthcare.2

According to Dr. Huffman, “Navigating through this deeply ingrained prejudice is crucial when prescribing injectable anti-obesity medications: potent tools in aiding patients on their weight loss journey. Unfortunately, many barriers arise due to the fear and stigma surrounding obesity — these factors tragically deter numerous individuals from pursuing these potentially life-altering treatments.”

https://e.infogram.com/949722e5-602d-4397-b2b2-5878eb0758dc?src=embed

He urges prescribers to approach these conversations with empathy, understanding, and a non-judgmental attitude to foster support and empower patients to access necessary, deserved care for a better quality of life.

Dr. Olla is the medical director at Valley Spring Recovery Center. He is a leading authority figure in the field of psychiatric medicine who focuses on holistic healing, patient well-being, and evidence-based practices.

“Believe it or not, fatphobia or weight bias is a common issue in plenty of medical professionals,” Dr. Olla explains. “Heavier patients tend to encounter lots of medical professionals with weight stigma. In these cases, doctors tend to focus so much on their weight that they ignore other symptoms these patients primarily come in for. This doesn’t just affect patients but also doctors who mean well.”

To address these biases, Dr. Olla encourages medical professionals to have honest conversations with patients before prescribing anti-obesity medications. He suggests openly discussing fatphobia’s potential influence on the decision-making process and explaining the medication’s benefits and risks without pressuring patients to use medication unless medically justified.

According to Dr. Olla, reviewing other treatment options respects a patient’s autonomy and right to make their own treatment decisions.

“The key is to focus on how the drug can help reverse or at least slow down the effects of obesity on the body,” he explains. “This can help the patient understand that their doctor is concerned about their overall health, rather than their weight.”

Weighing the Costs and Benefits of Anti-Obesity Medications

Prescribing anti-obesity medications in today’s cultural climate is no simple task. Physicians must carefully weigh the pros and cons to lead patients to the most appropriate and beneficial treatment path.

“As a doctor myself, I am 50/50 on prescribing weight loss medications,” Dr. Olla shares. “Obviously, you wouldn’t want your patients to develop metabolic or cardiovascular diseases caused by excess weight. However, at the same time, I don’t want to encourage a medication that can only cause more health problems to the patient. In my opinion, there should be more research on how anti-psychotics and weight loss medications could go hand in hand without putting an individual in further danger.”

A multidisciplinary approach is the key to ensuring that patients receive not just comprehensive care, but also unwavering support throughout their weight loss efforts.

According to research findings published in Endocrine Practice, over 70% of healthcare providers believe that anti-obesity medicine as an adjunct to lifestyle counseling is an appropriate therapy that can kick-start weight loss and give patients a greater sense of control over their weight.5

However, clinicans remain hesitant to prescribe anti-obesity medications, with some seeing anti-obesity medication as a short-term solution and others being concerned about safety, efficacy, and cost of staying on these medications. These barriers lead to low prescribing rates, which perpetuates a cycle of low perceived demand and lack of coverage by insurance carriers.6

Dr. Olla also explains how psychiatric comorbidities can complicate obesity treatment. He notes that anti-psychotics and antidepressants can raise hunger levels and cause unwanted weight gain.

“Some patients press for medications that can counteract the side effects,” he says.

He feels that it is not safe to prescribe anti-obesity medication to those with psychiatric conditions, particularly eating disorders. Doing so may increase body weight focus, promote disordered eating habits, increase anorexia risk, and lead to a psychological dependency on weight loss medication.

Aside from psychiatric comorbidities, clinicians must also consider whether a patient has diabetes or other physical conditions. As a bariatric physician, Dr. Huffman explains the counseling differences between those prescribed injectables for weight loss vs type 2 diabetes.

“In managing type 2 diabetes, the counseling provides specific guidance such as carbohydrate counting instructions, recommendations for blood glucose monitoring methods, advice on medication adherence — emphasizing its critical role in the effective management of this condition — and underlining consistency as key when maintaining stable blood sugar levels.”

Dr. Huffman emphasizes that, before prescribing injectables, clinicians should (1) take a holistic approach, (2) assess a patient’s motivation to implement lifestyle changes, and (3) monitor patient adherence to anti-obesity medication regimens. According to him, motivational interviewing and a tailored approach empowers patients to make lasting change.

Leveraging Collaboration to Ensure the Best Treatment

According to Dr. Olla, clinians should remember that they do not need to navigate the complexities of obesity treatment alone. For instance, psychiatrists may work with endocrinologists before prescribing weight loss medications to patients with mental health conditions.

“The expertise of an endocrinologist is needed because anti-psychotic drugs can cause significant weight gain, and careful health monitoring is required,” Dr. Olla explains.

In Dr. Huffman’s practice, prescribing obesity medication is far from the final step in a comprehensive approach to weight management.

“Prescribing patients with injectable weight loss medications necessitates crucial care elements: ongoing support, referrals, and follow-ups,” Dr. Huffman says. “Primarily, I guarantee comprehensive counseling and educational resources for the patients.” 

Dr. Huffman encourages prescribers to refer to registered dietitians for individualized meal plans and exercise specialists or physical therapists for safe and effective exercise programs. Mental health providers, behavioral therapists, and support groups can also play a pivotal role in a patient’s success.

“A multidisciplinary approach is the key to ensuring that patients receive not just comprehensive care, but also unwavering support throughout their weight loss efforts,” he says.

It remains to be seen whether anti-obesity medications will help or hurt in the fight against obesity and weight stigma. However, clinicians can build an army of specialists to not only optimize patient care but also help share the responsibility of treating this weighty issue.

People taking semaglutide had lower risk of suicidal thoughts

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At a Glance

  • Semaglutide was associated with a lower risk of suicidal thoughts than other anti-obesity and anti-diabetes drugs.
  • The findings do not support reports suggesting that increased suicidal thoughts might be a side effect of semaglutide.

Closeup of hands preparing a semaglutide injection.

Researchers have been investigating concerns about the safety of semaglutide as they arise. myskin / Shutterstock

Semaglutide is a drug sold under the brand names Ozempic and Rybelsus for diabetes and Wegovy for weight loss. It belongs to a class of drugs called glucagon-like peptide 1 receptor (GLP1R) agonists. While these drugs have proven effective, concerns linger about their potential side effects. Recently, cases have been reported of suicidal thoughts associated with semaglutide. This has prompted investigations by regulatory agencies in Europe. 

A team of researchers led by Dr. Rong Xu at Case Western Reserve University and Dr. Nora Volkow, director of the National Institute on Drug Abuse (NIDA), used electronic health records to examine the relationship between semaglutide and suicidal thoughts. They compared semaglutide to other, non-GLP1R agonist drugs for diabetes and weight loss. Their findings appeared in Nature Medicine on January 5, 2024.

The team first analyzed electronic health records for more than 240,000 people with overweight or obesity. Most had no previous history of suicidal thoughts. Among this group, 0.11% of those prescribed semaglutide reported suicidal thoughts within the first six months. For those prescribed non-GLP1R agonists, the risk of suicidal thoughts was almost four times as great—0.43%. Among the almost 8,000 people with a prior history of suicidal thoughts, 6.5% of those prescribed semaglutide reported suicidal thoughts. More than twice as many prescribed non-GLP1R agonists, 14.1%, had such thoughts. These findings weren’t affected by sex, age, or ethnicity.

The researchers next analyzed records for more than 1.5 million people with type 2 diabetes. As in the group with overweight or obesity, people taking semaglutide had a lower risk of suicidal thoughts than those taking non-GLP1R agonist drugs. This was true independent of sex, age, or ethnicity, and in people both with and without a previous history of suicidal thoughts. The reduced risk associated with semaglutide lasted through up to three years of follow-up.

The findings do not support concerns that have been raised about an increased suicide risk associated with semaglutide. Previous reports of such an association may need to be examined in more detail.

“The exploding popularity of this drug makes it imperative to understand all its potential complications,” says co-author Dr. Pamela Davis. “It’s important to know that prior suggestions that the drug might trigger suicidal thoughts [are] not borne out in this very large and diverse population in the U.S.”

“Our study suggests semaglutide can be safe for those with mental health conditions,” Volkow says. “As researchers are also investigating semaglutide as a treatment for substance use disorders—which often co-occur with other mental health disorders—it is vital to ensure the medication is safe and does not place vulnerable groups at even greater risk of harmful health impacts.”

The authors recommend that future studies look at associations between semaglutide and suicidal thoughts over longer periods of time. They also suggest exploring any associations between semaglutide and suicide attempts.

Semaglutide linked to lower suicidal ideation risk than other obesity, diabetes drugs

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Key takeaways:

  • Adults with obesity or type 2 diabetes receiving semaglutide have a lower risk for suicidal ideation than those taking non-GLP-1 medications.
  • More studies are needed to assess possible causal associations.

Adults receiving semaglutide as a type 2 diabetes or obesity medication have a lower risk for suicidal ideation than those who are using a drug that is not a GLP-1 receptor agonist, according to findings published in Nature Medicine.

“Anecdotal reports of suicidal thoughts emerging from patients that use semaglutide signaled the need for particular attention to this potential association,” Nora Volkow, MD, director of the National Institute on Drug Abuse at the NIH, told Healio. “Our study is one answer to this call, and we did not find evidence to substantiate concerns of increased suicidal risk following reports of suicidal ideations from semaglutide use.”

Nora Volkow, MD

Volkow and colleagues collected electronic health record data from the TriNetX analytics platform based on the Research U.S. Collaborative Network. Data were obtained from adults with overweight or obesity who were prescribed semaglutide (Wegovy, Novo Nordisk) or a non-GLP-1 receptor agonist obesity medication from June 2021 to December 2022. Data were also collected for adults with type 2 diabetes who were prescribed semaglutide (Ozempic, Novo Nordisk) or a non-GLP-1 receptor agonist diabetes therapy from December 2017 to May 2021. Researchers analyzed suicidal ideation incidence among adults with no history of suicidal ideation, and recurrence of suicidal ideation for those who had a history of suicidal ideation prior to being prescribed their diabetes or obesity medication. Participants in the semaglutide and non-GLP-1 groups were selected using propensity score matching with covariates that were considered potential risk factors for suicidal ideation.

“Suicide is among the top 10 leading causes of death worldwide,” Rong Xu, PhD, professor and director of the Center for Artificial Intelligence in Drug Discovery at Case Western Reserve University School of Medicine, told Healio. “Semaglutide is dispensed as either an anti-diabetes or an anti-obesity medication, with Wegovy being an immensely popular weight management strategy. Any concerns of potential risk for suicidal ideations associated with semaglutide can be of critical importance.”

Semaglutide lowers suicidal ideation risk

There were 52,783 adults with overweight or obesity and no history of suicidal ideation who received semaglutide matched with 52,783 adults who received a non-GLP-1 receptor agonist for the treatment of obesity. The semaglutide group had a lower risk for incident suicidal ideation than the non-GLP-1 group (HR = 0.27; 95% CI, 0.2-0.36). There were no suicide attempts in the semaglutide group vs. 14 reported suicide attempts for those receiving other obesity medications at 6 months (P < .001). Among 1,730 adults with a history of suicidal ideation, the semaglutide group had lower risk for recurrent suicidal ideation than the placebo group (HR = 0.44; 95% CI, 0.32-0.6).

Among adults with type 2 diabetes without a history of suicidal ideation, 27,726 adults receiving semaglutide were matched with 27,726 adults receiving a non-GLP-1 medication. Adults receiving semaglutide had a lower risk for incident suicidal ideation than those receiving a non-GLP-1 diabetes therapy (HR = 0.36; 95% CI, 0.25-0.53). Among 502 adults with type 2 diabetes and history of suicidal ideation, a lower risk for recurrent suicidal ideation was observed for the semaglutide group compared with those taking a non-GLP-1 medication (HR = 0.51; 95% CI, 0.31-0.83).

“Our findings, while they require replication, do not support concerns that semaglutide might increase suicidal ideations in patients being treated for their obesity or diabetes compared to other medications used for these indications,” Volkow said. “Regardless, they highlight the importance for screening for suicidal ideations in patients with obesity and diabetes so that proper support can be given to those at risk, and to ensure that studies like ours that evaluate long-term effects of semaglutide or other medications can properly evaluate potential suicidal risk.”

Among adults with type 2 diabetes who had longer follow-up data available, those receiving semaglutide had a lower risk for suicidal ideation at 1 year (HR = 0.39; 95% CI, 0.28-0.53), 2 years (HR = 0.53; 95% CI, 0.41-0.67) and 3 years (HR = 0.58; 95% CI, 0.49-0.72).

More studies needed

The researchers noted the findings serve as preliminary evidence that semaglutide may be a safer medication for adults who have suicidal ideation or other mental health conditions. However, Xu said more studies are needed to confirm the findings.

“Although patients prescribed semaglutide had lower risk of suicidal-ideation incidence and recurrence, our data do not yet justify off-label treatment,” Xu said. “Future controlled trials are necessary to assess any causal relationships between semaglutide and other GLP-1 receptor agonist medications with suicidal ideations.”

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss

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Methods

We used a random sample of 16 million patients (2006-2020) from the PharMetrics Plus for Academics database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US through the International Classification of Diseases, Ninth Revision (ICD-9) or ICD-10. In our cohort study, we included new users of semaglutide or liraglutide, 2 main GLP-1 agonists, and the active comparator bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists. Because semaglutide was marketed for weight loss after the study period (2021), we ensured all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the 90 days prior or up to 30 days after cohort entry, excluding those with a diabetes or antidiabetic drug code.

Patients were observed from first prescription of a study drug to first mutually exclusive incidence (defined as first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including gallstone pancreatitis), bowel obstruction, or gastroparesis (defined as use of a code or a promotility agent). They were followed up to the end of the study period (June 2020) or censored during a switch. Hazard ratios (HRs) from a Cox model were adjusted for age, sex, alcohol use, smoking, hyperlipidemia, abdominal surgery in the previous 30 days, and geographic location, which were identified as common cause variables or risk factors.6 Two sensitivity analyses were undertaken, one excluding hyperlipidemia (because more semaglutide users had hyperlipidemia) and another including patients without diabetes regardless of having an obesity code. Due to absence of data on body mass index (BMI), the E-value was used to examine how strong unmeasured confounding would need to be to negate observed results, with E-value HRs of at least 2 indicating BMI is unlikely to change study results. Statistical significance was defined as 2-sided 95% CI that did not cross 1. Analyses were performed using SAS version 9.4. Ethics approval was obtained by the University of British Columbia’s clinical research ethics board with a waiver of informed consent.

Results

Our cohort included 4144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users. Incidence rates for the 4 outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users (Table 1). For example, incidence of biliary disease (per 1000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for bupropion-naltrexone and 4.6, 7.9, and 1.0, respectively, for pancreatitis.

Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (adjusted HR, 9.09 [95% CI, 1.25-66.00]), bowel obstruction (HR, 4.22 [95% CI, 1.02-17.40]), and gastroparesis (HR, 3.67 [95% CI, 1.15-11.90) but not biliary disease (HR, 1.50 [95% CI, 0.89-2.53]). Exclusion of hyperlipidemia from the analysis did not change the results (Table 2). Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results (Table 2). E-value HRs did not suggest potential confounding by BMI.

Discussion

This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but not biliary disease.

Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes. Limitations include that although all GLP-1 agonist users had a record for obesity without diabetes, whether GLP-1 agonists were all used for weight loss is uncertain.

Diabetes and obesity drugs linked to thyroid cancer

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The European Medicines Agency (EMA), the European Union’s (EU) version of the Food and Drug Administration (FDA), issued a drug safety signal this week about the elevated thyroid cancer risk associated with certain classes of pharmaceuticals for Type 2 diabetes and obesity.

Semaglutide, the active ingredient found in the widely used anti-diabetes and anti-obesity drugs Ozempic and Wegovy, respectively, are linked to an increased risk of thyroid cancer in patients who take the drugs in accordance with a doctor’s prescription.

Known as glucagon-like peptide-1 (GLP-1) receptor agonists, the drugs in question are manufactured by Novo Nordisk, AstraZeneca, Eli Lilly and Sanofi Winthrop, all of which must submit supplementary information about them to the EMA by July 26, 2023.

While a safety signal does not necessarily imply a direct causal relationship between a drug and the reported adverse event, the EMA uses it to help better determine whether or not a causal link exists by examining whatever the drug manufacturers send its way as part of the supplementary information requirement.

“Novo Nordisk is aware of the signal and the request by EMA and will deliver a thorough assessment of all relevant data to elucidate this topic,” said Lars Otto Andersen-Lange, the media relations director at Novo Nordisk, in a statement.

Andersen-Lange added that all associated Novo Nordisk products, including semaglutide, have been on the market for more than a decade, and that the safety data gathered from post-marketing surveillance of the drugs has not shown any “conclusive” evidence tying them to thyroid cancer.

(Related: Did you catch our earlier report about how doctors kill more people today than cancer does?)

Big Pharma criticizes researchers for exposing thyroid cancer risk of anti-diabetes, anti-obesity drugs – says their study contains “important limitations”

As usual, Novo Nordisk and the other drug companies responsible for producing the offending drugs continue to deny that their products are in any way unsafe. In fact, they even went so far as to take aim at the new study exposing the link, claiming it contains “important limitations.”

Some of the “important limitations” highlighted by Andersen-Lange includes the absence of validated case identification, inadequate differentiation of recurrent events, potential misclassification of events, and unconfirmed drug exposure, to quote one media source.

The study in question was pioneered by French researchers who looked at data from the French national health care insurance system database. From this, they noticed an increased risk of thyroid cancer among individuals who take the drugs in question, particularly between one and three years of being on them.

Diabetes Care reportedly published two commentaries on the study, one of which suggests that “detection bias” could be making it seem like the drugs cause thyroid cancer when they really do not. The other suggests the study might be invalid because it did not account for obesity as a confounding factor in thyroid cancer.

Interestingly, Novo Nordisk’s prescribing information for Ozempic and Wegovy contains a warning about the risk of developing thyroid C-cell tumors. The manufacturer also notes in the prescribing literature that semaglutide is linked to “dose-dependent and treatment-duration-dependent thyroid C-cell tumors” in rodents, but that human cancers remain “undetected.”

Those with a family history of thyroid cancer are warned against taking Wegovy by the FDA, which seems to be in acknowledgement that something is very wrong with these drugs in terms of their cancer risk.

It turns out that a big factor in Novo Nordisk’s success as a drug company is due to semaglutide. The company is now the second most valuable company in Europe, trailing only behind the French luxury goods group LVMH.

Combination insulin icodec and semaglutide cuts HbA1c and body weight in type 2 diabetes

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Key takeaways:

  • A combination therapy of insulin icodec and semaglutide confers a similar HbA1c reduction as once-daily insulin glargine and insulin aspart.
  • Most adverse events with the combination agent were gastrointestinal.

Once-weekly combination therapy of basal insulin icodec and semaglutide was noninferior to insulin glargine plus insulin aspart for lowering HbA1c among adults with type 2 diabetes, according to topline results from a phase 3a trial.

In the COMBINE 3 trial, 679 adults with type 2 diabetes inadequately controlled with basal insulin were randomly assigned to receive a fixed-ratio combination of basal insulin icodec and semaglutide (IcoSema, Novo Nordisk) or 100 units of once-daily insulin glargine plus insulin aspart injected 2 to 4 times a day at mealtimes for 52 weeks. Adults in the study had a baseline HbA1c of 8.3% and a baseline body weight of 85.8 kg.

Diabetes Words 2019
A combination drug of insulin icodec and semaglutide was deemed noninferior to insulin glargine and insulin aspart for reducing HbA1c among adults with type 2 diabetes. Image: Adobe Stock

At 52 weeks, the combination therapy demonstrated noninferiority. The group receiving combined insulin icodec and semaglutide had an HbA1c reduction of 1.47 percentage points compared with an HbA1c reduction of 1.4 percentage points for those receiving insulin glargine plus insulin aspart.

The combination therapy group lost 3.6 kg of body weight at 52 weeks, whereas those receiving insulin glargine and insulin aspart gained 3.2 kg. There were 0.26 hypoglycemia events per patient-year of exposure for those receiving the combination therapy compared with 2.18 events per patient-year of exposure with insulin glargine plus insulin aspart.

Adverse events were mostly gastrointestinal, which is consistent with other GLP-1 receptor agonist drugs. The majority of adverse events were mild to moderate in nature.

“We are very pleased to share the first phase 3a results for once-weekly IcoSema,” Martin Holst Lange, executive vice president for development at Novo Nordisk, said in a press release. “The results demonstrate the potential of IcoSema to simplify insulin intensification by reducing the injection burden to a single injection per week compared to around 28 injections per week for people with type 2 diabetes inadequately controlled on basal insulin while providing glycemic control as well as weight benefits and lower rates of hypoglycemia.”

The phase 3a COMBINE trial program includes three randomized trials, of which COMBINE 3 was the first to have topline results released. The COMBINE 1 trial, is comparing once-weekly IcoSema with insulin icodec. The COMBINE 2 trial, which compares IcoSema with semaglutide 1.0 mg, was initiated in the second quarter of 2022, and results are expected to be announced later in 2024, according to the press release.