Can Medications Help Treat Obesity?

A Review of Medications Used (On- and Off-Label) to Manage Obesity

Obesity is a multi-factorial chronic disease that occurs when a person has an excessive amount of body fat, which can increase the individual’s risk of health complications, such as type 2 diabetes, heart disease, sleep apnea, liver issues, arthritis, and certain cancers.

Until recently, treatment for obesity was primarily limited to diet and exercise, with a smaller number of individuals undergoing bariatric surgery or taking medication. However, these are not always adequate. In the past few years, GLP-1 analogs – also known as glucagon-like peptide-1 receptor agonists (GLP-1-RA) or incretin mimetics – have become popular for treating obesity. Countless individuals have shared stories about finally being able to lose weight using these medications after struggling with obesity for decades. Many celebrities are sharing their experiences and opinions about these drugs, which has raised concerns about misinformation. In this article, we will explain how these medications work, which ones are currently available in Canada, whether they have regulatory approval (are indicated for treating obesity), what the research shows about their efficacy, and which side effects can occur.

Medications that Physicians Prescribe for Weight Management

While a person might experience weight loss as a medication’s side effect, it is not, technically, a weight management drug unless it is approved for that purpose. Some of the medications in this chart are only indicated to treat type 2 diabetes mellitus. However, with both healthcare practitioners and numerous studies noticing incidental weight loss in those who use these medications, physicians in Canada and many other countries prescribe them off-label to treat obesity in those who do not have diabetes.

Note: As a patient group, we regularly hear from individuals whose healthcare providers prescribe products for many, varied, off-label uses, so it is in the context of real-world behaviours that we are providing this information.

GLP-1 Receptor Agonist

Semaglutide (Ozempic®, Rybelsus®, Wegovy®)

The only semaglutide medication approved for weight management (Wegovy®) is not available in Canada. However, many physicians have been prescribing Ozempic® off-label as they have seen success in treating their patients with this medication.

Liraglutide (Saxenda®, Victoza®)

Although Victoza® is indicated for Type 2 diabetes and Saxenda® is indicated for obesity, some patients report having received prescriptions for Victoza® as a weight management tool.

Dulaglutide (Trulicity®)

Dual GLP-1 and GIP Analogues

Tirzepatide (Mounjaro®, Zepbound™)

Fat Digestion Blocker

Orlistat (Xenical®)

Combination Drugs

Bupropion/naltrexone (Contrave®)

How do These Medications Work?

GLP-1 Receptor Agonist

Semaglutide (Ozempic®, Rybelsus®, Wegovy®)
Liraglutide (Saxenda®, Victoza®)
Dulaglutide (Trulicity®)

GLP-1 receptor agonists mimic human GLP-1 (glucagon-like peptide-1), a hormone that reduces blood sugar by stimulating the pancreas to release insulin when glucose is present. GLP-1 receptors are also present in the brain, where they regulate appetite and control food intake. GLP-1 receptor agonists manage weight by activating these receptors, which can make you feel full sooner and eat less.

Dual GLP-1 and GIP Analogues

Tirzepatide (Mounjaro®, Zepbound™)

Dual GLP-1 and GIP analogues mimic the hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). GLP-1 and GIP both reduce blood sugar by stimulating the pancreas to release insulin when glucose is present. In the brain, GIP is thought to enhance the appetite suppressing effects of GLP-1 proteins, which allow you to feel full sooner and eat less. The dual GLP-1 and GIP analogues appear to have a stronger effect on blood sugar and weight loss compared to GLP-1 analogues alone.

Fat Digestion Blocker

Orlistat (Xenical®)

Fat digestion blockers work by blocking an enzyme called lipase, which is released by the pancreas to digest dietary fats into fatty acids for the body to absorb. Taking orlistat can help with weight loss by increasing the proportion of fats that pass undigested through the gastrointestinal system.

Combination Drugs

Bupropion/naltrexone (Contrave®)

This combination medication contains bupropion, which is an antidepressant that increases levels of norepinephrine and dopamine. Increasing these neurotransmitters is thought to increase energy expenditure and reduce cravings. The other ingredient, naltrexone, blocks opioid receptors in the brain which are responsible for euphoria and pleasure. This can reduce addictive pathways in the brain which lead to overeating and binge eating. Together, bupropion and naltrexone can work synergistically to reduce cravings, suppress appetite, and block reward pathways that can lead to addictive behaviours.

How Effective are These Medications?

In this section, we will review some research that looks at the efficacy of weight management medications in persons living with obesity. Much of our weight management data comes from studies in persons who weren’t even trying to lose weight. Rather, the goal of these studies was to look for its effect on lowering blood sugar in people with type 2 diabetes. However, there are ongoing studies on weight management medications in patients with obesity who do not have diabetes. While the results have been promising, there is controversy around what happens when you stop the medications. Early studies and patient reports suggest the weight management effects might not continue after stopping the medication. It’s still unclear whether someone will return to their baseline weight.

GLP-1 Analogues

Liraglutide (Saxenda®, Victoza®)

• In a 1.1-year study, patients lost an average of 8% of their initial bodyweight.

In the SCALE trial,² liraglutide was studied specifically for its weight loss effect. Here, 3,731 patients without diabetes and an average weight of 106.3 kg were given a daily injection of liraglutide 3 mg or placebo over 56 weeks. Liraglutide reduced weight by 8.0% compared to 2.6% with placebo. This dose of liraglutide is only available in Saxenda® brand pens which are indicated specifically for weight loss.

Semaglutide (Ozempic®, Rybelsus®, Wegovy®)

• In a 1.3-year study, patients lost an average of 14.9% of their initial bodyweight.
• In a head-to-head clinical study of 14 mg oral semaglutide with 1.8 mg injectable liraglutide, demonstrated the non-inferiority of the oral drug to the subcutaneous drug.³

In the STEP 1 trial,⁴ which looked at semaglutide’s weight loss effect, 1,961 patients without diabetes with an average weight of 105.3 kg were given a weekly injection of semaglutide 2.4 mg or placebo over 68 weeks. Semaglutide resulted in a weight loss of 14.9% compared with a reduction of 2.4% with placebo. This dose of semaglutide is only available in Wegovy® brand pens, which are not currently available in Canada.

Dual GLP-1 and GIP Analogues

Tirzepatide (Mounjaro®, Zepbound™)

• In a 1.4-year study, patients lost an average of 15-21% of their initial body weight, depending on dose.

Tirzepatide was studied for its weight loss effect most prominently in the SURMOUNT-1 trial.⁵ Here, 2,539 patients without diabetes with an average weight of 104.8 kg were given a weekly injection of either tirzepatide 5, 10, or 15 mg or placebo for 72 weeks. Patients experienced an average/mean percentage reduction in weight of 15% with the 5 mg injection, 19.5% with 10 mg, and 20.9% with 15 mg compared to a weight loss of 3.1% with placebo.

Fat Digestion Blocker

Orlistat (Xenical®)

• In a review of clinical trials, patients lost an average of 2.9 kg more than the control group over 1 year.

Some of the best evidence comes from a systematic review of clinical trials where orlistat was added to behaviour changes for up to 12 months.⁶ Patients taking orlistat lost an additional 2.9 kg compared to those using placebo or behavioural changes alone.

Combination Drugs

Bupropion/naltrexone (Contrave®)

• In a 1.1-year study, patients lost an average of 5-6% of their initial body weight, depending on dose.

Bupropion and naltrexone are used individually for other conditions, such as depression, nicotine addiction, and alcohol abuse. Throughout their use, weight loss was listed as a potential side effect. In the COR-I trial,⁷ these two drugs were combined and studied specifically for their weight loss effects. Here, 1,742 patients living with overweight or obesity were given placebo or daily bupropion S.R. 360 mg with either naltrexone S.R. 16 mg or 32 mg for 56 weeks. Patients had a weight reduction of 5.0% with bupropion plus 16 mg of naltrexone and 5.4% with bupropion and 32 mg of naltrexone. In comparison, patients taking placebo only reduced their weight by 1.3%.

Are They Safe?

Even though medications go through extensive safety, efficacy, and quality studies before marketing, some adverse effects remain unknown until post-market analysis. Thousands of participants were studied in clinical trials, but millions of real-world people will use these medications, often in ways that do not perfectly align with the original study parameters. It is only then that we find the extremely rare or severe side effects. Close medical supervision is important when you are trying a medication, especially one that is relatively new.

Dual GLP-1 and GIP Analogues & GLP-1 Analogues

Tirzepatide (Mounjaro®, Zepbound™)
Semaglutide (Ozempic®, Rybelsus®, Wegovy®)
Liraglutide (Saxenda®, Victoza®)
Dulaglutide (Trulicity®)

The most common side effects for these medications are nausea, diarrhea, vomiting, constipation, abdominal pain, headache, and fatigue. Most cases are mild and will typically wear off after a few weeks. However, some individuals might have to decrease the dose or no longer take the medication to stop experiencing these side effects. The product monograph recommends that if patients do not tolerate the therapeutic/maintenance 2.4 mg dose, then the dose can be temporarily decreased to 1.7 mg weekly, for a maximum of 4 weeks. This medication is injected and can also cause temporary injection site reactions such as redness, itchiness, and stinging.

In rare cases, these medications can cause gastrointestinal complications such as pancreatitis, gallstones, or gastroparesis. Make sure you review your full medical history with your doctor before starting one of these and let them know if you experience any gastrointestinal symptoms. To reduce these potential side effects, your prescriber will likely increase your dose slowly over time. Make sure that you adhere to the prescribed dosing since rapidly increasing the dose can result in severe complications that might not occur if you stay at the lower amount.

Some people may be allergic to these medications and may develop swelling, hives, or difficulty breathing. If this is the case, stop the medication immediately and seek medical attention.

Fat Digestion Blocker

Orlistat (Xenical®)

Because this medication blocks digestion of fats, its most common side effect is gastrointestinal discomfort. Having a high concentration of undigested fats in the gastrointestinal system can lead to fecal incontinence, oily spotting, and leakage. This can be extremely uncomfortable and is the main reason why orlistat is not commonly prescribed. Most people who use this medication manage this side effect by avoiding high-fat foods and limiting the proportion of their calories that come from fats.

If taken long-term, orlistat can also cause deficiencies in fat-soluble vitamins such as Vitamin A, D, E, and K. People who are allergic to this medication may develop swelling, hives, or difficulty breathing. If this is the case, stop taking it immediately and seek medical attention.

Combination Drugs

Bupropion/naltrexone (Contrave®)

The most common side effects for medications in this class include nausea, diarrhea, vomiting, constipation, abdominal pain, headache, and fatigue. If these effects are severe, users may have to stop treatment or decrease the dose. Over time, this effect usually wears off.

While most people tolerate this medication, be aware of other common side effects such as insomnia, increased blood pressure, dizziness, or mood changes. It is best taken in the morning and early evening to minimize the risk of insomnia. To reduce side effects and complications, your prescriber will likely increase your dose slowly. Make sure that you adhere to the prescribed dosing since rapid dose changes can result in severe side effects.

People who are allergic to this medication may develop swelling, hives, or difficulty breathing. If this is the case, stop taking it immediately and seek medical attention.

The Future of Weight-Loss Medications

While the previous sections have focused on medications that are already available, there are many more in development. The following promising medications are currently being studied.

Retatrutide is a GIP, GLP-1, and glucagon (GCG) receptor agonist administered via subcutaneous injection once per week. The GCG receptor agonist increases energy expenditure. It has shown great promise in its Phase II trial.⁸ In 48 weeks, participants taking the highest dose lost an average of 24% of their initial bodyweight, which is higher than all the previous medications.

Survodutide is a GLP-1 and GCG receptor agonist administered via subcutaneous injection once per week. A Phase II trial shows promising results.⁹ At the end of the 46-week study, approximately 40% of participants who were taking the highest two doses had lost at least 20% of their starting weight, compared to 0% of those taking placebo. In addition, their weight loss had not yet plateaued, which could mean that they might continue to lose weight.

Mazdutide is another GLP-1 and GCG receptor agonist administered via subcutaneous injection once per week. In its Phase II trial,¹⁰ after 24 weeks, participants had lost 15% of their initial bodyweight. This study is still in progress.

Orforglipron is a GLP-1 receptor agonist that is a once-daily oral medication. The individuals taking the highest dose of this medication in its Phase II trial¹¹ had lost 15% of their initial bodyweight after 36 weeks.

Oral semaglutide (Rybelsus®) is currently available in 3, 7, and 14 mg tablets. A recent Phase III trial used oral semaglutide at a dose of 50 mg per day and found that after 68 weeks patients lost an average of 17% of their body weight (15.5 kg compared to 2.5 kg with placebo).¹²

Cagrilintide mimics amylin, a natural pancreatic hormone that suppresses appetite. In a Phase II trial, cagrilintide was compared to liraglutide. Over 26 weeks, cagrilintide resulted in an average weight loss of 11.5 kg compared to liraglutide which resulted in 9.6 kg of weight loss.¹³

These medications are currently undergoing the further research necessary before they can be available for the public.

Other Methods

Weight Loss Supplements

Be cautious when considering online or over-the-counter weight loss supplements without medical supervision. These supplements might not be approved by Health Canada and could contain unlisted prescription drugs or harmful ingredients, such as banned substances, especially if purchased online. They might also interact with prescription medications and other therapies.

Other weight loss supplements might not be dangerous but may be ineffective. For example, several supplements contain laxatives or diuretics as their primary ingredient, which may cause short-term weight loss due to dehydration but do not lead to long-term weight loss.

It is important to speak to a healthcare provider before starting any weight loss supplement and to avoid using supplements without medical supervision. Seeking professional medical advice can help you avoid the risks of harmful side effects and achieve safe and effective weight loss.

Diet and Exercise

While medications can help with weight loss, they need to be used in addition to a balanced diet and exercise routine. This should involve cardiovascular exercises such as walking, running, cycling, or swimming, as well as strength training to build muscle. A higher muscle mass can increase your basal metabolic rate, which increases how many calories your body burns in a day.

A varied diet consisting of fruits, vegetables, whole grains, lean protein, and healthy fats is also essential for weight loss. Avoid fad diets that restrict certain food groups or severely limit calorie intake unless recommended by a healthcare professional. Often, these diets are unsustainable and can lead to nutrient deficiencies as well as a weight rebound when they are stopped.

Working with a professional to develop a weight loss plan can maximize results and ensure long-term success. Incorporating lifestyle changes such as diet and exercise along with medication and/or surgery can help you achieve your weight loss goals and improve your overall health and wellness.

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First published in the Inside Tract® newsletter issue 228 – 2023

Garrett Tang, PharmD, RPh (pharmacist)
Gail Attara, Chief Executive Officer, Gastrointestinal Society

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