Semaglutide for cardiovascular risk reduction in people who are overweight or have obesity without diabetes (new indication)

Background:
Potential indications for glucagon-like peptide-1 (GLP‑1) agonists such as semaglutide have expanded rapidly since the Therapeutic Goods Administration (TGA) first approved semaglutide Ozempic (Novo Nordisk) in 2019 for type 2 diabetes mellitus.

In 2022, semaglutide Wegovy (Novo Nordisk) was approved by the TGA, as a higher dose and a different dosage delivery system compared with Ozempic (2.4 mg weekly versus 1 mg weekly) for weight loss and weight maintenance in adults and adolescents aged 12 years and above.

In December 2024, Wegovy was approved for secondary prevention of cardiovascular events in people who are overweight or have obesity (BMI greater than or equal to 27 kg/m²) without diabetes, in addition to standard care of established cardiovascular disease.¹

Mechanism of action:
Semaglutide is a GLP‑1 agonist, closely homologous to human GLP-1 and activating the same receptors. GLP-1s have a key role in glucose and appetite regulation, mediated via receptors in the pancreas (increasing insulin production and reducing glucagon secretion), and in the brain (controlling appetite and causing feelings of fullness, less hunger and less craving for food).²

How semaglutide reduces cardiovascular risk is not specifically known² but may be due to physiological benefits of reducing excess weight including improved glucose and lipid metabolism, and reduction in inflammation and the prothrombotic state associated with obesity.³

Clinical trials:
TGA approval for cardiovascular event reduction was based on results from the SELECT study. SELECT was a 68‑week double-blind, randomised, placebo-controlled study conducted in 41 countries including Australia, involving over 1700 patients with established cardiovascular disease, BMI greater than or equal to 27 kg/m², and no history of diabetes.³ This study demonstrated the primary endpoint of fewer major adverse cardiovascular events in the semaglutide group (6.5%) compared with placebo (8.0%) as well as positive changes in multiple biomarkers of cardiovascular risk.

Adverse effects:
Common adverse effects with semaglutide are nausea (43% compared with 16.1% in the placebo group), vomiting (24.5% compared with 6.3%) and diarrhoea (29.7% compared with 15.9%), which are widely reported in treatment compared with control groups.¹ The SELECT study reported a slightly higher rate of gallbladder disorders in the semaglutide group (2.8% compared with 2.3%).³ Previous studies of semaglutide have reported worsening of diabetic retinopathy in patients with type 2 diabetes and acute pancreatitis.²

The GLP-1 class of drugs is widely and increasingly used and indicated for long-term use which requires careful monitoring for rare but serious and long-term adverse effects.⁴

Dosage and administration:
Wegovy is started at a low dose to minimise adverse effects; 0.25 mg by subcutaneous injection once weekly, and up-titrated every 4 weeks as tolerated (0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg). The recommended maintenance dose for both weight management and secondary prevention of cardiovascular disease is 2.4 mg once weekly.

Wegovy can be administered at any time of day, with or without food. A missed dose should be taken as soon as possible up to 5 days after the scheduled date. After 5 days, the dose should be skipped and the usual schedule resumed. Maintaining administration on the same day of the week is recommended.²

No dose adjustment is required based on age, gender, race, ethnicity or renal impairment, although there is limited experience with people with creatinine clearance less than 30 mL/min.²

Precautions:
There are no data for people younger than 12 years, or people with stage 5 kidney disease or type 1 diabetes; semaglutide (Wegovy) is not recommended in these groups.² Semaglutide should not be used in people with unstable or advanced diabetic retinopathy.²

Semaglutide should not be used in combination with other GLP-1 agonists or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 coagonists.²

Use in pregnancy and breastfeeding:
Semaglutide is a category D medication and should not be used in pregnancy. Animal studies have shown a range of harmful effects associated with exposure during organogenesis including increased early pregnancy loss, impaired growth and fetal abnormalities. Contraception is advised for women who could become pregnant while on semaglutide. Semaglutide should be stopped at least 2 months before a planned pregnancy or immediately if pregnancy occurs.²

The recommendation is to avoid semaglutide during breastfeeding.²

Place in therapy:
Semaglutide appears to favourably impact a range of physiological and metabolic processes that contribute to weight management and to reducing risk of serious cardiovascular events, in addition to standard care of adults with established cardiovascular disease,⁵ in patients with and without type 2 diabetes.

One of the clinical dilemmas associated with semaglutide is that the weight management benefits remain only while on the drug, and weight gain as well as reversal of improved cardiovascular risk factors, such as blood pressure, total cholesterol and low-density lipoprotein, are seen when the drug is stopped.¹

At the time of writing, Wegovy is not listed on the PBS and cost may be prohibitive for many.

This new drug comment was finalised on 13 May 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report for Wegovy was available from the Therapeutic Goods Administration but not updated to include the new indication of reducing risk of serious cardiovascular events. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Therapeutic Goods Administration. Australian Public Assessment Report for Wegovy. Department of Health and Aged Care; 2024. [cited 2025 May 15]
2. Therapeutic Goods Administration. Australian Product Information - Wegovy FlexTouch 1 mg semaglutide 1.34 mg/mL solution for injection pre-filled pen. Department of Health and Aged Care; 2024. [cited 2025 May 15]
3. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023;389:2221-32.
4. Ruder K. As Semaglutide's Popularity Soars, Rare but Serious Adverse Effects Are Emerging. JAMA 2023;330:2140-2.
5. Cardiac Society of Australia and New Zealand. Australian clinical guideline for diagnosing and managing acute coronary syndromes 2025. National Heart Foundation; 2025. [cited 2025 May 15]

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

Report all suspected adverse reactions to new drugs to enable continued monitoring of their benefit–harm balance.