glucagon-like peptide-1 (GLP-1) peptide analogs (eg. Ozempic)

see also:

• oral hypoglycaemic agents
• obesity and weight management
• glucagon

• these peptides mimic the action of the incretin glucagon-like peptide-1 (GLP-1) and need to be given by s/c injection
• patients with pre-diabetes or type 2 diabetes mellitus often have defects in the effect of incretin
• these agents lower fasting and postprandial blood glucose in those with type 2 diabetes and can reduce body weight

• mimics the action of the naturally occurring gut hormone GLP-1, a modulator of insulin secretion, glucagon, stomach emptying, and satiety signalling
  • when people eat, GLP-1 increases insulin secretion in response to glucose intake and inhibits glucagon secretion of islet cells, resulting in a decrease in postprandial blood glucose levels
  • appears to enhance growth of pancreatic beta cells
  • inhibits the production of glucagon, the hormone that increases glycogenolysis and gluconeogenesis
  • reduces food intake by lowering appetite and slowing down digestion in the stomach
• additional actions:
  • widespread multi-organ effects which and driven by complex mechanisms¹⁾
    • 20% reduction in risk of major adverse cardiovascular events (MACE – heart attack, stroke, or cardiovascular death) not solely dependent upon degree of weight loss in the SELECT trial (17,600 patients with cardiovascular disease and obesity but without T2D)
    • 24% reduction in the risk of kidney failure events and death from kidney- or cardiovascular-related causes in the FLOW trial (3,500 patients with T2D and chronic kidney disease)
    • reduced apnoea-hypnoea events by 20–24 events per hour more than controls in patients with OSA in the SURMOUNT-OSA trials
    • improved knee OA pain and physical functionality in the STEP 9 trial
    • can lead to the resolution of MASH without worsening of liver fibrosis
    • appears to show a 10% reduced cumulative risk of dementia compared to metformin in type II diabetics and a 12% lower risk of developing Alzheimer's disease, and a 25% lower risk of developing non-vascular dementias ²⁾
  • anti-inflammatory
    • appear to reduce biomarkers such as C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α)
  • metabolic properties

• commonly cause many GIT symptoms such as nausea, vomiting, diarrhea, and constipation
• delayed gastric emptying may affect absorption of other medications and increase risk of aspiration in anaesthesia
• mildly increased (13% and 22% mean increase respectively) serum amylase and lipase levels are common
• less commonly may cause:
  • cholelithiasis (0.4-1.5% of patients)
  • gastroparesis
  • ileus / bowel obstruction
  • pancreatitis
• sarcopenia / generalised muscle wasting risk
• risk of hypoglycaemia is increased if the drug is used in combination with sulfonylureas or insulin
• increases risk of diabetic retinopathy by 50-80% ³⁾
• apparent marginally increased risk of acute kidney injury (AKI) / acute renal failure (ARF) with it seemingly occurring in 1% of patients of whom nearly half need admission and 2-3% die from the AKI ⁴⁾, interstitial nephritis, and acute tubular necrosis - usually in the 1st 50 days but can occur over 1yr after commencing
• risk of antibody production with cross-reaction to native GLP-1 in 0.6% of those taking semaglutide ⁵⁾
• potential risk of medullary thyroid carcinoma
  • hence contraindicated in people with a personal or family history of medullary thyroid carcinoma or with multiple endocrine neoplasia type 2 due to risk of GLP-1-mediated thyroid C-cell hyperplasia
• there may be potential risks to the fetus from exposure during pregnancy ⁶⁾
• in Australia in May 2024, it is alleged that illegal compounding and aggressive marketing of these products by an unregistered online pharmacy “Total Compounding Pharmaceuticals (TCP)” was causing additional side effects such as haematemesis and peripheral neuropathy. “Tests by the TGA also found vials from TCP had 10 times the amount of vitamin B12 than what was advertised on the label.” The pharmacist has since been suspended from practising. “Compounding pharmacies are meant to fill a gap in the market, providing one-off medications for patients with a script when there's no commercial product available. They aren't allowed to manufacture medications in bulk and the drugs they produce aren't checked for safety, quality and efficacy by the regulator, the Therapeutic Goods Administration (TGA).” It seems the pharmacist has now moved operations off-shore and continues to market to other countries. ⁷⁾

• introduced in 2010, marketed as Saxenda
• daily s/c injections for Mx of obesity
• generally results in ~5% weight loss by 8 weeks of Rx
• in Australia it is not covered by PBS, needs a prescription and costs $440/month

• introduced in 2012,approved in US in 2017, marketed as Ozempic and Wegovy
• Novo Nordisk spent nearly $500 million on U.S. advertising for its GLP-1 drugs Wegovy and Ozempic in the first nine months of 2025, more than double what Eli Lilly shelled out for its ‌rival medicines (Zepbound and Mounjaro), up 54% and 44%, respectively from the same period in 2024⁸⁾
• weekly s/c injections as it has a long half life of ~ 1 week due to binding to albumin
  • start at 0.25 mg once weekly. After 4 weeks, increase the dose to 0.5 mg once weekly. If after at least 4 weeks additional glycaemic control is needed, increase to 1 mg once weekly
• in Australia, it is covered by PBS on an authority prescription for some diabetic patients only⁹⁾:
  • 1.34 mg/mL injection and scripts are either for a single 1.5mL or 3mL pen device at a cost of ~$31
  • as of 2024, authority script requires:
    • type 2 diabetes, AND,
    • results of the blood glucose monitoring, which must be no more than 4 months old at the time of initiation of treatment with a gliptin, a glitazone, a glucagon-like peptide-1 or an SGLT2 inhibitor, must be documented in the patient's medical records, AND,
      • for authority 5500:
        • to be used in combination with either metformin or a sulfonylurea, AND,
        • patient is unable to take both metformin and a sulfonylurea, AND,
        • patient must have, or have had, a HbA1c measurement greater than 7% prior to the initiation of a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagon-like peptide-1 or a sodium-glucose co-transporter 2 (SGLT2) inhibitor despite treatment with either metformin or a sulfonylurea, OR,
        • patient must have, or have had, where HbA1c measurement is clinically inappropriate, blood glucose levels greater than 10 mmol per L in more than 20% of tests over a 2 week period prior to initiation with a gliptin, a glitazone, a glucagon-like peptide-1 or an SGLT2 inhibitor despite treatment with either metformin or a sulfonylurea.
      • for authority 5478:
        • must be used in combination with BOTH metformin and a sulfonylurea, AND,
          • patient must have, or have had, a HbA1c measurement greater than 7% prior to the initiation of a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagon-like peptide-1 or a sodium-glucose co-transporter 2 (SGLT2) inhibitor despite treatment with maximally tolerated doses of metformin and a sulfonylurea; OR
          • patient must have, or have had, where HbA1c measurement is clinically inappropriate, blood glucose levels greater than 10 mmol per L in more than 20% of tests over a 2 week period prior to initiation with a gliptin, a glitazone, a glucagon-like peptide-1 or an SGLT2 inhibitor despite treatment with maximally tolerated doses of metformin and a sulfonylurea.
      • for authority 5469:
        • must be used in combination with insulin, AND,
        • must be used in combination with metformin unless contraindicated or not tolerated, AND,
          • patient must have, or have had, a HbA1c measurement greater than 7% prior to the initiation of a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagon-like peptide-1 or a sodium-glucose co-transporter 2 (SGLT2) inhibitor despite treatment with insulin and oral antidiabetic agents, or insulin alone where metformin is contraindicated; OR ,
          • patient must have, or have had, where HbA1c measurement is clinically inappropriate, blood glucose levels greater than 10 mmol per L in more than 20% of tests over a 2 week period prior to initiation with a gliptin, a glitazone, a glucagon-like peptide-1 or an SGLT2 inhibitor despite treatment with insulin and oral antidiabetic agents, or insulin alone where metformin is contraindicated.
• studies seem to show people lost 10-15% of body weight on Ozempic compared to 5-10% on Saxenda
  • SELECT trial published 2024 ¹⁰⁾:
    • over half of patients lost at least 5% of their initial weight by week 20
    • weight loss typically plateaued after about 65 weeks
    • the 10% average weight loss was sustained for up to four years, while people continued to take the medication
    • it also results in a 20% reduced risk of heart attacks and other cardiovascular events in those with pre-existing cardiovascular disease and obesity but without diabetes, irrespective of how much weight people lost suggesting reduced inflammation may play a role
• NB. discontinue in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide
• NB. long half life means that those with overdosage may need extended monitoring
• appears to increase risk of nonarteritic anterior ischemic optic neuropathy (NAION) however the study was based on ophthalmic presentations and was relatively small¹¹⁾
  • Hazard Ratio (HR) 4.3 for type 2 diabetics - the cumulative incidence of NAION over 36 months was 8.9% for those prescribed semaglutide vs 1.8% among those taking non–GLP-1 medications
  • HR 7.6 for obesity - the cumulative incidence of NAION over 36 months was 6.7% for the semaglutide cohort vs 0.8% for those in the other group

• teduglutide
• dulaglutide
  • approved in US and EU in 2014, marketed as Trulicity; once-weekly injection;
• albiglutide
  • approved in US in 2014, marketed as Tanzeum and Eperzan

• tirzepatide (Mounjaro, Zepbound)

• these are exendin-4 analogs
• exenatide (approved in US in 2005)
• lixisenatide (approved in US in 2016)
• tirzepatide
  • marketed as Mounjaro