Trial results position orforglipron as a potential game-changer for type 2 diabetes care in Australia, offering injectable-level efficacy in a once-daily oral tablet.
An investigational oral non-peptide GLP-1 therapy – known as orforglipron – has achieved major success in two global phase 3 trials, paving the way for its submission to Australia’s Therapeutic Goods Administration (TGA) by the end of this year.
Eli Lilly has released trial results for the once-daily pill, designed to improve blood sugar control and support weight loss in adults with type 2 diabetes.
In the ACHIEVE-2 study, orforglipron reduced A1C levels by up to 1.7% compared with 0.8% for dapagliflozin, a widely used SGLT-2 inhibitor, in adults whose diabetes was inadequately controlled with metformin.
The ACHIEVE-5 trial showed an additional 2.1% A1C reduction when orforglipron was used alongside titrated insulin glargine, compared with placebo.
Both studies met their primary and key secondary endpoints, with consistent improvements in blood glucose, body weight and cardiovascular risk markers.
Safety and tolerability outcomes were consistent with previous studies of GLP-1 receptor agonists. The most common adverse events were gastrointestinal and typically mild to moderate in severity, with no hepatic safety concerns identified.
Detailed results from both trials will be presented at an upcoming medical conference and published in a peer-reviewed journal, Eli Lilly said in a statement.
Results from the final global registration study, ACHIEVE-4, are expected in early 2026.
Pending TGA approval, orforglipron could become the first oral, non-peptide GLP-1 receptor agonist available in Australia, offering a new, convenient treatment option for people with type 2 diabetes.
Orforglipron is a once-daily, small-molecule GLP-1 receptor agonist that can be taken without regard to food or water intake.
Discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018, it is also being investigated for obesity and obesity-related conditions such as obstructive sleep apnoea, hypertension and osteoarthritis pain.
The global ACHIEVE program, launched in 2023, has enrolled more than 6000 participants worldwide and continues to build momentum toward broad regulatory submissions.
Specialist endocrinologist Dr Ted Wu, director of the Royal Prince Alfred Hospital Diabetes Centre, told Gut Republic the release of the trials’ findings was big news.
“It will be even bigger when it’s released,” he said.
He said the trials were important because they comped orforglipron with the other most commonly used treatment options.
“We all know that we start with metformin and it’s been like that for decades,” he said.
“But diabetes progresses. You can have good control initially and then the control is not so great later. One of the big options to add on to metformin these days is a SGLT-2 like dapagliflozin because the PBS says we should do that, the RACGP guidelines [and] the ADS [Australian Diabetes Society] guidelines all point to SGL2s as the next step.
“What this is [the ACHIEVE-2 study] is comparing orforglipron, which is a tablet form of a GLP-1 receptor agonist, to a pretty much standard of care second line therapy, dapagliflozin.
“What it showed is that even at its lowest dose of 3mg, orforglipron outperformed the SGLT-2 dapagliflozin by about 0.5% of HbA1c, which is clinically significant.
“And at the higher doses of both 12 and 36mg, you are getting almost 1% of extra HbA1c lowering, and dapagliflozin wasn’t bad, 0.8% lowering is pretty good on top of metformin.”
He noted that the bulk of the benefit was seen at 12mg of orforglipron, meaning most patients did not have to go to the highest dose.
Side effects were similar to those seen with the injectable GLP-1 RAs like semaglutide, including nausea, vomiting and gastrointestinal issues.
“There were no extra additional side effects that we can see from orforglipron,” said Dr Wu.
“And instead of an injection it’s a tablet, which will hopefully have really positive impacts on availability and certainly of convenience [a daily tablet].”
Dr Wu said he hoped this would mean lower cost to patients and greater accessibility. Current injectable GLP-1s require cold storage, adding to cost and limiting accessibility.
“Cost is out of our hands, we don’t know about this it’s all a commercial decision, but potentially it’s less costly,” he said.
Dr Wu said the ACHIEVE-5 trial looked at the more severe stage of type 2 diabetes and had outstanding results in HbA1c improvement.
“This trial confirms once again that it works in the earlier stages of type 2 diabetes, and it works at the very end stages of type 2 diabetes as well,” he told GR.
“It does have an effect on weight as well, just like the injectable GLP-1s,” he said.
He said orforglipron trials had also shown weight loss ranging from at least 5% at the lower end, up to about 15% at the higher end.
“It is about what we expect from GLP-1 receptor agonists,” he said.
“It’s everything we love about GLP-1s but in oral form, not injectable. The other difference is that it’s a non-peptide oral, not a peptide oral.”
Dr Wu said if the application to the TGA was made by the end of the year, it was likely “we won’t see it until the end of next year or something like that for the approval, it takes a long time in Australia”.
“The evidence and the guidelines do suggest that the combination of SGLT-2 plus GLP-1 is absolutely fantastic and it is, you get synergistic effects of weight lowering as well as glucose lowering and all the cardio renal benefits that we see with GLP-1 and SGL-2,” he said.
“I hope for the day that we can use GLP-1s and SGLT-2s in combination on the PBS for diabetes, because undoubtedly there’s lots of benefits.”
Dr Wu conceded the frustration of not having these drugs available and approved but not on the PBS and available to everyone but said he understood.
“Let’s face it, it’s because of the scale of the issue,” he said.
“If the PBS allowed GLP-1s for overweight and obesity, upwards of 60% of the population would qualify and the health system just cannot afford that at the current cost of GLP-1s.
“So you can kind of understand it, but it is still frustrating.”
Dr Wu said the arrival of an oral GLP-1 had the potential to change practice.
“Hopefully, and this is conjecture, with better access and no shortages, people will be able to prescribe this much more freely, and all people will be able to benefit from the combination of SGLT-2s and GLP-1s in the future.
“The real hope is that the PBS indications will widen once we have oral, non-peptide options available.”
In a statement, Eli Lilly confirmed it planned to submit an application to the TGA for approval to use orforglipron for the treatment of type 2 diabetes as well as for the treatment of obesity.
Dr Jeff Emmick, senior vice president of product development at Lilly Cardiometabolic Health said the trials supported the role orforglipron had to play in the diabetes space.
“In ACHIEVE-2, orforglipron outperformed dapagliflozin, a commonly used SGLT-2 therapy, and in ACHIEVE-3, showed greater efficacy than oral semaglutide,” he said.
“The findings from ACHIEVE-5 add to this momentum, showing significant A1C reduction and weight loss when used in combination with titrated basal insulin. Together, these results reinforce orforglipron’s potential to become a new standard of care for people living with type 2 diabetes.”
Gut Republic approached Eli Lilly with questions around the potential cost benefits of orforglipron given its oral form. The company said it was too early to discuss cost but offered this statement.
“Metabolic conditions, including type 2 diabetes and obesity are among the biggest challenges facing Australia’s health system, with prevalence rates increasing significantly over recent decades. Innovative and scalable solutions are needed to address this challenge,” the company said.
“Although it is premature to comment on our future distribution plans for orforglipron, our goal, as always, is to make our medicines available and accessible to people who need them.
“A submission for orforglipron for the treatment of type 2 diabetes and for the management of obesity and overweight will be made to the Therapeutic Goods Administration by the end of 2025.
“We are committed to working closely with the federal government to ensure that Australians can access the most effective medicines to manage these chronic conditions.
“Lilly also notes the urgent need for reform of Health Technology Assessment in Australia to support more timely and equitable access to innovative medicines through the Pharmaceutical Benefits Scheme.”
