Diabetes is a worldwide epidemic. By 2050, it is projected that the number of people living with diabetes will more than double, reaching 1.3 billion globally.1 Type 2 Diabetes Mellitus (T2DM) is a complex metabolic disorder that significantly reduces quality of life and leads to serious health complications.2 Due to the increasing prevalence and associated complications of the disease, the need for effective treatment strategies is critical.
One recent therapeutic addition in the management of T2DM is Ozempic, an antidiabetic medicine containing semaglutide, approved by the Therapeutic Goods Administration (TGA)
for lowering blood sugar in adults with insufficiently controlled T2DM, as an adjunct to diet and exercise.3 While its primary purpose is to support blood glucose regulation, a side effect
of Ozempic is weight loss. In fact, not yet available in Australia, Wegovy is a new brand of semaglutide indicated specifically for the management of obesity, due to the significant impact this active ingredient can have on weight loss.4
The demand for weight loss products is high, with the prescription weight-loss drug market now a $2.3 billion industry.5 Viral videos on TikTok and across other media that showcased the rapid weight loss achieved with Ozempic, led to a rapid increase in demand due to ‘off-label’ prescribing.4 This has resulted in global shortages, posing challenges for individuals who rely on this medication for management of T2DM.4
MECHANISM OF ACTION OF SEMAGLUTIDE
As a glucagon-like-peptide-1 (GLP-1) agonist,6 semaglutide improves the efficiency of incretin function.7 Incretin acts to suppress gluconeogenesis, inhibit glucagon secretion, and increase insulin sensitivity.7 It also delays gastric emptying, therefore reducing appetite and decreasing caloric intake, which can lead to drastic weight reduction.8
Semaglutide is available in both oral tablets and subcutaneous injection pens. As a once-daily oral tablet (Rybelsus), it is available in 3 mg, 7 mg, and 14 mg doses.10 As a pre-filled syringe pen (Ozempic and Wegovy), various dose options are available which are injected subcutaneously once weekly.5 It is recommended to start with a lower dose and gradually increase to the target dose.5
CONDITIONS
Type 2 Diabetes Mellitus
Semaglutide supports the management of T2DM by reducing HbA1c levels,11,12 in addition to decreasing fasting and post- prandial glucose secretion.13 Studies have also shown that usage can lead to positive influences on hepatic beta cell function.13
If blood sugar levels remain unregulated, insulin therapy is typically used to further support the treatment of T2DM. The most common side effect for treatment with insulin is hypoglycaemia, with a global study reporting the occurrence of severe hypoglycaemia at 2.5 events per patient with T2DM each year.16 As semaglutide primarily lowers blood glucose by stimulating glucose-dependent insulin secretion, the risk of hypoglycaemia is low.6 A study comparing the use of insulin glargine with semaglutide as an add-on to metformin in patients with T2DM found that semaglutide resulted in fewer hypoglycaemic episodes and greater reductions in HbA1c and weight.17
Cardiovascular effects
A lack of glycaemic control increases adverse cardiovascular event risk in those with T2DM. Insulin resistance can cause alterations in signalling pathways, specifically in myocardial cells, which increases risk of heart failure, stroke, and myocardial infarction.18
Studies have demonstrated that semaglutide can reduce the risk of adverse cardiovascular events in patients both with and without diabetes.18 Semaglutide has also been shown to reduce atherosclerosis by impacting inflammatory pathways and reducing apoptosis in cardiac cells.7
Side effects and cautions
The main symptoms of semaglutide toxicity or misuse include gastrointestinal symptoms of nausea, vomiting, diarrhoea, and stomach pain.20 When administered in high doses, semaglutide can cause acute kidney injury, detected through decreased or bloody urine, muscle twitching, and seizures.21 Whilst semaglutide can be used alongside insulin and metformin treatment, dosages of these medications should be reduced to decrease risk of hypoglycaemia.22 Acute pancreatitis has been observed with the use of GLP-1 agonists, so caution should be exercised in patients with a history of pancreatitis and symptoms monitored carefully.23 Patients with a history of diabetic retinopathy should be monitored carefully when treated with semaglutide and insulin, as an increased risk of developing complications has been observed.23 Semaglutide should not be used during pregnancy or lactation.23
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REFERENCES
1. Ong KL, Stafford LK, McLaughlin SA, Boyko EJ, Stein Emil Vollset, Smith AE, et al. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet. 2023 Jun 1;402(10397).
2. Garg P, Duggal N. Type 2 diabetes mellitus, its impact on quality of life and how the disease can be managed-a review. Obesity Medicine. 2022 Oct;35:100459.
3.Therapeutic Goods Administration (TGA). OZEMPIC (Novo Nordisk Pharmaceuticals Pty Ltd). 2022. Available from: https://www.tga.gov.au/resources/prescription-medicines-registrations/oz...
4. Therapeutic Goods Administration (TGA). About the Ozempic (semaglutide) shortage 2022 and 2023. 2022. Available from: https://tga.gov.au/safety/shortages/information-about-major-medicine-sho...
5. Magda Sara Wojtara, Mazumder A, Syeda Y, Nikodem Mozgała. Glucagon-Like Peptide-1 Receptor Agonists for Chronic Weight Management. Advances in medicine. 2023 Sep 20;2023:1–7.
6. Smits MM, Van Raalte DH. Safety of Semaglutide. Frontiers in Endocrinology [Internet]. 2021 Jul 7;12. Available from: https://www.frontiersin.org/articles/10.3389/fendo.2021.645563/full
7. Mahapatra MK, Karuppasamy M, Sahoo BM. Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes. Reviews in Endocrine and Metabolic Disorders [Internet]. 2022 Jan 7;23(3). Available from: https://www.ncbi.nlm.nih. gov/pmc/articles/PMC8736331/
8. Surgery warning on use of popular weight loss drugs [Internet]. 2023 [cited 2024 Feb 12]. Available from: https://anzca.edu.au/resources/media-releases/2023-media-releases/gastri...
9. Sidney Barritt, Marshman E, Mazen Noureddin. Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes—what hepatologists need to know. 2022 Mar 9;55(8):944–59.
10. Therapeutic Goods Administration (TGA). Rybelsus. 2022. Available from: https://tga.gov.au/resources/auspmd/rybelsus
11. Berra C, Maria Chiara Rossi, Mirani M, Daniela Ceccarelli Ceccarelli, Romano C, Sassi L, et al. Real world effectiveness of subcutaneous semaglutide in type 2 diabetes: A retrospective, cohort study (Sema-MiDiab01). Frontiers in Endocrinology. 2023 Jan 18;13.
12. Aroda VR, Capehorn M, Chaykin LB, Frias JP, Lausvig NL, Macura S, et al. Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials. 2019 Nov 14;22(3):303–14.
13. Kapitza C, Dahl K, Jacobsen JB, Axelsen MB, Flint A. Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2017 May 19;60(8):1390–9.
14. Better Health Channel. Diabetes type 2 [Internet]. Vic.gov.au. 2022. Available from: https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/diabe...
15 Forouhi NG, Misra A, Mohan V, Taylor R, Yancy W. Dietary and nutritional approaches for prevention and management of type 2 diabetes. BMJ [Internet]. 2018 Jun 13;361(4):1–9. Available from: https://www.bmj.com/content/361/bmj.k2234
16. Khunti K, Alsifri S, Aronson R, Cigrovski Berković M, Enters-Weijnen C, Forsén T, et al. Rates and predictors of hypoglycaemia in 27 585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study. Diabetes, Obesity and Metabolism. 2016 Jun 20;18(9):907–15.
17. Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. The Lancet Diabetes & Endocrinology. 2017 May;5(5):355–66.
18. A. Michael Lincoff, Kirstine Brown-Frandsen, Colhoun HM, Deanfield J, Emerson SS, Sille Esbjerg, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. 2023 Nov 11;
19. Hauge C, Breitschaft A, Hartoft-Nielsen ML, Jensen S, Bækdal TA. Effect of oral semaglutide on the pharmacokinetics of thyroxine after dosing of levothyroxine and the influence of co-administered tablets on the pharmacokinetics of oral semaglutide in healthy subjects: an open-label, one-sequence crossover, single-center, multiple-dose, two-part trial. Expert Opinion on Drug Metabolism & Toxicology. 2021 Aug 31;17(9):1139–48.
20. Shu Y, He X, Wu P, Liu Y, Ding Y, Zhang Q. Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system. Frontiers in Public Health. 2022 Oct 20;10.
21. Leehey DJ, Rahman MA, Borys E, Picken MM, Clise CE. Acute Kidney Injury Associated With Semaglutide. Kidney Medicine.2021Mar;3(2):282–5. 22.ChamberlinS,DabbsW.Semaglutide(Ozempic)forType2DiabetesMellitus.AmericanFamilyPhysicianwwwaafporg/afp[Internet].2019[cited2024Feb12];100(2).Availablefrom:https://www.aafp.org/pubs/afp/issues/2019/0715/ p116.16.pdf
23. Therapeutic Goods Adminstration. Ozempic® (semaglutide) solution for injection [Internet]. Therapeutic Goods Adminstration. Therapeutic Goods Adminstration; 2020. Available from: https://www.tga.gov.au/sites/default/files/auspar-semaglutide-201030- pi.pdf
24. Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. Weight Regain and Cardiometabolic Effects after Withdrawal of semaglutide: The STEP 1 Trial Extension. Diabetes, Obesity and Metabolism [Internet]. 2022 May 19;24(8). Available from: https://pubmed.ncbi.nlm.nih.gov/35441470/
25. Kanai R, Kinoshita S, Izumi Kanbe, Sameda M, Yamaoka S, Horikawa O, et al. Once-weekly semaglutide administered after laparoscopic sleeve gastrectomy: Effects on body weight, glycemic control, and measured nutritional metrics in Japanese patients having both obesity and type 2 diabetes. Obesity pillars [Internet]. 2024 Mar 1 [cited 2024 Mar 4];9:100098–8. Available from: https://www.ncbi.nlm.gov/pmc/articles/PMC10789635/
26. Alabduljabbar K, Al-Najim W, le Roux CW. The Impact Once-Weekly Semaglutide 2.4 mg Will Have on Clinical Practice: A Focus on the STEP Trials. Nutrients. 2022 May 26;14(11):2217.
27. Gorgojo-Martínez JJ, Mezquita-Raya P, Carretero-Gómez J, Castro A, Cebrián-Cuenca A, de Torres-Sánchez A, et al. Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus. Journal of Clinical Medicine [Internet]. 2023 Jan 1;12(1):145. Available from: https://www.mdpi.com/2077-0383/12/1/145