Novel obesity treatments

Shohinee Sarma; Susan Tran; Michael Fralick

doi:10.1503/cmaj.230820

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP1RA) is a weekly subcutaneous injection for adults with obesity

Semaglutide was approved for adults with a body mass index (BMI) of 30 kg/m² or greater, and those with a BMI of 27 kg/m² or greater with 1 or more obesity-related comorbidities (e.g., hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea). The starting dose is 0.25 mg with up-titration, as tolerated, to 2.4 mg.1

As an adjunct to intensive behavioural therapy, semaglutide results in more weight loss and improves measures of cardiometabolic health than behavioural therapy alone

In a randomized controlled trial (RCT) of participants undergoing intensive behavioural therapy — involving decreased caloric intake, increased physical activity and counselling sessions — those who also received semaglutide (2.4 mg) lost an average of 16.0% of their baseline weight, compared with 5.7% among those who received placebo.1 Participants who received semaglutide had improvements in diastolic blood pressure, lipid profiles and glycated hemoglobin levels.1 Weight gain may occur if semaglutide is stopped, but long-term data on safety for indefinite use are not yet available.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP1RA, is a weekly subcutaneous injection approved for adults with obesity

In an RCT, adults who received tirzepatide lost a mean weight of 15.0%, 19.5% and 20.9% at doses of 5 mg, 10 mg or 15 mg, respectively, compared with 3.1% with placebo; waist circumference, blood pressure and lipid levels also decreased over 72 weeks.2

Semaglutide and tirzepatide have a similar profile of adverse effects and contraindications

Both medications are associated with gastrointestinal adverse effects, which are minimized by slow dose titration. Contraindications include personal or family history of medullary thyroid cancer, multiple endocrine neoplasia type 2 or hypersensitivity. Both semaglutide and tirzepatide are safe in people with a glomerular filtration rate greater than 15 mL/min/1.73 m².3 No laboratory monitoring is required.

Potential adverse effects of GLP1RAs continue to be monitored with post-market surveillance

Regulatory bodies are investigating a possible link between GLP1RAs and suicidal ideation. The United States Food and Drug Administration has a medication guide warning of suicidal behaviour for GLP1RAs.4 A recent study found a higher risk of thyroid cancer of all histologic subtypes for patients treated with GLP1RAs compared with matched controls.5 Further investigation is ongoing, and patients should be counselled using current evidence.

Footnotes

Competing interests: Shohinee Sarma reports support from the Clinician Investigator Program and the Clinician Scientist Training Program at the University of Toronto, and has received honoraria for presentations from the American Diabetes Association. Susan Tran reports honoraria from Novo Nordisk for content unrelated to obesity treatments. Michael Fralick was a consultant for ProofDx, a start-up company creating a point-of-care device for COVID-19 using CRISPR. and is an advisor for SIGNAL1, a start-up company that implements machine-learned solutions into clinical practice. No other competing interests were declared.
This article has been peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

References

↵
1. Wadden TA,
2. Bailey TS,
3. Billings LK,
4. et al.
STEP 3 Investigators. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021;325:1403–13.
OpenUrl CrossRef PubMed
↵
1. Jastreboff AM,
2. Aronne LJ,
3. Ahmad NN,
4. et al.
SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205–16.
OpenUrl
↵
1. Tuttle KR,
2. Lakshmanan MC,
3. Rayner B,
4. et al
. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018;6:605–17.
OpenUrl
↵
Highlights of prescribing information: Wegovy. Silver Spring (MD): US Food and Drug Administration; 2017. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215256s007lbl.pdf (accessed 2023 Sept. 1).
↵
1. Bezin J,
2. Gouverneur A,
3. Pénichon M,
4. et al
. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care 2023;46:384–90.
OpenUrl