Dual agonist medications look set for a major role in the management of type 2 diabetes and obesity, with several novel treatments in the pipeline, the 2023 Australasian Diabetes Congress in Adelaide has heard.

Hailing the arrival of “the era of incretin-based multiagonists”, international speaker Dr Juan Pablo Frías predicted an “ever-expanding role” for therapies such as the dual GIP and GLP-1 receptor agonist tirzepatide.

The drug – which was recently approved by the TGA but has been knocked back by the PBAC – had been backed by several clinical trials showing unprecedented glycaemic and weight control across the spectrum of T2D, exceeding that seen with once-weekly semaglutide 1mg and titrated insulin degludec, he told the conference.

A dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, tirzepatide “demonstrated really pan-metabolic effects in persons with overweight and obesity and persons with T2D,” said Dr Frías, the medical director of Velocity Clinical Research (formerly National Research Institute) in Los Angeles.

“I think in general we should intervene early and address what is frequently at the root of the issue in our patients with T2D … that is obesity. So access to these medications is critically important, although they are extremely expensive,” he said

He pointed to data from the SURPASS-2 and 3 trials, where up to 90% of tirzepatide-treated patients achieved an HbA1c  below 7% and approximately 40-50% achieved normoglycemia as indicated by an HbA1c <5.7%.

Additionally, a significant, dose-dependent reduction in body weight was seen with each tirzepatide dose, with up to 60% of patients achieving greater than 10% weight loss.

And in the recently published SURMOUNT-1 study, assessing tirzepatide for weight management in persons with overweight or obesity (without T2D), participants lost an average of 22% body weight at 72 weeks, with 40% achieving ≥25% weight loss, Dr Frías said.

Cardiovascular effects

Trials examining cardiovascular outcomes in patients treated with tirzepatide were also underway, as were data on CV outcomes for oral and once-weekly semaglutide in patients with overweight and obesity without T2D, and assessing the renal and hepatic benefits of the selective GLP-1 RAs and tirzepatide.

Early results from these semaglutide studies study suggested it was demonstrating cardiovascular benefits, he said.

Nevertheless, Dr Frías stressed all the evidence to date with both classes of medications suggested metabolic benefit was temporary, with patients quickly regaining weight after drug discontinuation.

“There has just been such an onslaught of new medications we really need to be educated,” he told the conference.

“We also need to be educating patients about the importance of taking medication but also lifestyle measures that go along with this.”

“The weight loss is great, but we want to minimise loss of lean mass which is critically for our elderly patients but also for our younger patients who are going to be on these medications for a very long time.”

In terms of the future, he said studies were currently assessing higher than currently approved doses of injectable selective GLP-1 RAs, and there were now non-peptide oral GLP-1 RAs in clinical development.

These oral agents could be administered with or without food thus do not have the administration restrictions of oral semaglutide, which may increase adherence and persistence with therapy.

Another significant advance in incretin-based therapies was the development of retatrutide, a tri-agonist of the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors. Early trials had been promising and the drug was now in Phase 3 of clinical development, he said.

“Some key advances that we will likely see in the clinic within the next few years include higher doses of selective GLP-1 RAs, oral non-peptide GLP-1 RAs, unimolecular triple agonists, and combination therapies,” he said.