Oral semaglutide finally here – what you need to know

12th November 2026, A/Prof Chee L Khoo

oral semaglutide

We are finally here. Oral semaglutide (or “oral wegovy”) is now TGA approved. As we highlighted oral semaglutide (oralSema) a little over 12 months ago here, oralSema have demonstrated glycaemia and body weight reduction efficacy way back in 2019 in the PIONEER trial. It has also demonstrated cardiovascular benefits. It was approved back in 2019 by the US FDA on the back of the PIONEER trial. It was approved in Australia in 2022 for glycaemic control and now weight control. There have also been some name and dose changes as well (also see below). There is a lot to unpack here prior to the commercial availability in Australia.

As we know, all the incretin analogues are peptides (seems to be a dirty name these days!). For protein-based drugs, proteolytic degradation in the gastrointestinal tract poses a significant challenge for developing oral formulations. Hence, the need for subcutaneous incretin analogues. OralSema get around the degration by being co-formulated with the absorption enhancer sodium N-[8 (2-hydroxylbenzoyl) amino] caprylate (SNAC). OralSema are absorbed in the stomach, where SNAC causes a localised increase in pH, leading to higher solubility and protection against proteolytic degradation. Semaglutide is believed to be absorbed via the transcellular route.

From complicated pharmacokinetic studies, bioavailability was 0.8% when taken using the recommended dosing conditions (30 min post-dose fasting time, administered with ≤ 120 mL of water), increasing with a longer post-dose fasting time and decreasing with higher water volume. As you can see, only a tiny bit of oralSema gets absorbed. Thus, it had to be given at a much higher dose (30-50X) than the subcutaneous route. There was no significant difference in oral bioavailability of semaglutide in healthy subjects and subjects with type 2 diabetes (T2D).

Glycaemic control

There have many Phase 3 Clinical trials comparing oralSema with many comparators in the PIONEER series:

There were more PIONEER trials looking at different populations of patients – PIONEER 8 (insulin), PIONEER 9 (Japanese on monotherapy), PIONEER 11 & 12 (Chinese). Essentially, the PIONEER series which utilise a maximal dose of OralSema of 14mg demonstrated further HbA1c reduction when added to other glucose lowering agents. The magnitude of weight loss was either non-significant or very modest. It is safe in patients with moderately severe CKD or established CVD.

The PIONEER Series
TrialPopulationComparatorDoseHbA1c reductionWeight lossRef
1T2D on diet/exercisePlacebo14mg1.40%2.6 kg2
2T2D on metforminEmpagliflozin14mg1.3% vs  0.9%NS3
3T2D  on metforminSitagliptin14mg1.3% vs 0.8%2.5kg4
4T2D on metformin +/- SGLT2iLiraglutide or placebo14mg1.2% vs 1.1% vs 0.2%-4.4kg vs – 3.1kg vs -1.2kg5
5T2D with eGR 30-59Placebo14mg1.0% vs 0.2%3.4kg vs 1.1kg6
6T2D with est CVD or risk ofPlacebo14mgCV safeNS9

Weight reduction – The OASIS series

Of course, the PIONEER trial series were primarily looking at glucose lowering efficacy using a maximal dose of OralSema of 14mg. Weight reduction was very modest with 14mg oralSema. We need a much bigger dose than 14mg to lose meaningful body weight. This is where the OASIS trials were looking at.

The OASIS 1 and 2 trials compared the therapeutic efficacy and clinical safety profile of once-daily oral semaglutide 50 mg versus placebo on overweight and obese participants without T2DM and both with and without T2D respectively. The OASIS 3 trial assessed the therapeutic efficacy and clinical safety profile of once-daily oral semaglutide 50 mg versus placebo in 200 Chinese adults who were obese and overweight with one or more weight-related comorbidities, including T2D. The OASIS 4 trial evaluated the safety and effectiveness of once-daily semaglutide 25 mg in obese and overweight patients without T2D.

In the OASIS 1 trial, the “trial product estimand” (taken exactly as intended), the estimated average difference in body weight at week 68 was -17.4% with oral semaglutide 50 mg, compared to -1.8% with placebo. Notably, over two-thirds of the participants in the semaglutide group achieved a minimum of 10% weight loss, greater than half lost no less than 15%.

In the OASIS 2 trial, the participants experienced a mean standard error of mean reduction in weight of -14.3% with oral semaglutide compared to -1.3% in placebo, resulting in an estimated treatment difference (ETD) of -13.07 percentage points (95% CI, -15.61 to -10.52; P<0.001) using the treatment policy estimand. 

In the OASIS 4 trial, 25mg oral semaglutide produced a significantly greater mean weight reduction at 64 weeks than placebo (-13.6% versus -2.2%).

OASIS 3 is yet to report.

Comparison with sci semaglutide

We know how efficaeous injectable semaglutide is but is oralSema as good as the injectable version? The STEP 1 placebo‐controlled randomized controlled trial (RCT) showed that in participants with overweight or obesity, once‐weekly s.c. semaglutide 2.4 mg plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight [7]. Relative to placebo, once‐weekly s.c. semaglutide 2.4 mg was associated with a −14.4% (95% confidence intervals [CI]: −15.3, −13.6; p < 0.0001) change in body weight. In the OASIS 4 trial, relative to placebo, 25mg of oral semaglutide was associated with a −13.9%‐point (95% CI: −16.5, −11.2; p < 0.001) difference in body weight reduction.

Plotkin, M et al conducted an indirect treatment comparison using data from both the STEP 1 and OASIS 4 trials to compare percentage change in body weight, the proportion of participants achieving ≥ 5%, ≥ 10%, ≥ 15%, ≥ 20% weight loss, changes in cardiometabolic parameters, and quality of life. They found that oralSema and s.c. semaglutide delivered comparable efficacy across all outcomes assessed.

CV Outcomes
What about CV outcomes? We know that Wegovy 2.4mg have demonstrated cardiovascular benefits in the SELECT trial (8). Can those benefits be transferrable to oralSema?

In the PIONEER 6 trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo (9). The Semaglutide Cardiovascular Outcomes Trial (SOUL) took the next step to demonstrate CV benefits. It was designed to assess the cardiovascular efficacy of oral semaglutide in persons with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both.

Patients with T2D with an HbA1c of 6.5 – 10.0%, and at least one of the following conditions: coronary artery disease, cerebrovascular disease, symptomatic peripheral artery disease, or chronic kidney disease eGFR of <60 ml per minute per 1.73 m2) were randomised to receive once-daily oral semaglutide (titrated up to 14mg) or matching placebo, in addition to standard care. Over an average of 47.5 months, oralSema was associated with a significantly lower risk of major adverse cardiovascular events than placebo, with a hazard ratio of 0.86.

Adverse events

In the OASIS 4 trial utilising 50mg of oralSema, the number of participants reporting adverse events was 307 (92%) of 334 with oral semaglutide 50 mg and 285 (86%) of 333 with placebo but the number of events leading to discontinuation was 6% in the oralSema group vs 4% in the placebo. Not surprisingly, most of the adverse events with gastrointestinal. Serious adverse events were reported by 10% participants with oral semaglutide 50 mg and 9% with placebo. When the adverse events rate leading to discontinuation in the OASIS 4 were compared with those in the STEP 1 trials, the were similar (6.9% vs 7%) (6).

Drug Interactions

Because of the use of SNAC by oralSema, the absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. In a two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin, oralSema or SNAC alone did not appear to affect the exposure. However, levothyroxine pharmacokinetics were influenced by co-administration with oralSema. Monitoring of thyroid parameters should be considered when treating patients with both oral semaglutide and levothyroxine (

Availability and cost

Strengths approved: 1.5 mg, 4 mg, 9 mg and 25 mg

Form: a once-daily tablet. Oral semaglutide is designed to be taken on an empty stomach with a small sip of water (<120ml); No food or beverages is to be consumed less than 30 mins after dosing.

Who it is approved for: adults with obesity, or adults who need to reduce cardiovascular risk — broadly the same group as the injectable version.

The naming of oralSema can be confusing (see below). We will be getting oral Wegovy (up to 25mg).

As this article went to air, we have not heard from NovoNordisk on the pricing yet but in the US, oral Wegovy cost between US$150-300 depending on the dose. The price in Australia is probably not likely to very much less than the injectable Wegovy.

Thus, it is likely that the company will pitch oralSema to be a tiny little cheaper than the injectable Wegovy and positioned it to be used as a stepdown therapy after patients reached their target weight goals and wants to take a lower dose of semaglutide for maintenance. Perhaps, oralSema might be useful for overseas travelling for those who don’t want the hassles of storage of an injectable pen. There might yet be a few who are truly needle phobic from the outset.

References:

  1. Overgaard RV, Navarria A, Ingwersen SH, Bækdal TA, Kildemoes RJ. Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials. Clin Pharmacokinet. 2021 Oct;60(10):1335-1348.
  2. Aroda VR, Rosenstock J, Terauchi Y, et al; PIONEER 1 Investigators. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1724-1732.
  3. Rodbard HW, Rosenstock J, Canani LH, et al; PIONEER 2 Investigators. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019 Dec;42(12):2272-2281.
  4. Rosenstock J, Allison D, Birkenfeld AL, et al; PIONEER 3 Investigators. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA. 2019 Apr 16;321(15):1466-1480.
  5. Pratley R, Amod A, Hoff ST, et al; PIONEER 4 investigators. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019 Jul 6;394(10192):39-50.
  6. Mosenzon O, Blicher TM, Rosenlund S, et al; PIONEER 5 Investigators. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jul;7(7):515-527
  7. Plotkin M, Ivkovic M, Smith I, et al. Semaglutide 25 mg Oral Versus Semaglutide 2.4 mg Injectable: An Indirect Treatment Comparison of Weight Loss Outcomes. Diabetes Obes Metab. 2026 Aug;28(8):7237-7246.
  8. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Dec 14;389(24):2221-2232.
  9. Husain M, Birkenfeld AL, Donsmark M, et al; PIONEER 6 Investigators. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851.
  10. Bækdal TA, Borregaard J, Hansen CW, Thomsen M, Anderson TW. Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects. Clin Pharmacokinet. 2019 Sep;58(9):1193-1203.
  11. 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 Opin Drug Metab Toxicol. 2021 Sep;17(9):1139-1148