GLP-1s for T2D – the earlier the better?

Dr Sarah Tedjasukmana

writer

Dr Sarah Tedjasukmana

General Practitioner; Co-Director, Sydney Perinatal Doctors

Experts say GLP-1 RAs should be prescribed more often and earlier, citing compelling benefits for type 2 diabetes—but the PBAC has other ideas.

At its latest meeting in March, the Pharmaceutical Benefits Advisory Committee(PBAC) recommended changes that would require GPs to gain prior approval either electronically or over the phone from Services Australia or the Department of Veterans’ Affairs before initiating glucagon-like peptide-1 receptor agonists (GLP-1 RAs). They also recommended the drugs “should be restricted to patients who are contraindicated, intolerant or inadequately responsive to SGLT-2 inhibitors.”

In making its case, the PBAC noted both high use and high cost of GLP-1 RAs versus comparator treatments, as well as “the administrative burden on prescribers associated with telephone/electronic authorities”.

The RACGP has pushed back on the proposed changes to authority required, and say the changes to prescribing critieria may cause confusion.

Associate Professor Ralph Audehm of the University of Melbourne, a GP with a special interest in chronic diseases, especially type 2 diabetes, has worded his criticism even more strongly, calling it “ludicrous” and “short-sighted” and saying it would interfere with person-centred care.

“They’re a potent, powerful drug that have fantastic impacts on A1c,” Associate Professor Audehm says. He describes the GLP-1 RAs as “great drugs, not used enough, and not used early enough.”

He will be facilitating an upcoming panel discussion on GLP-1 RAs with two experts, Professor Richard MacIsaac, director of endocrinology and diabetes at St Vincent’s Hospital in Melbourne, and Professor Richard O’Brien, senior endocrinologist and dean of medicine at the University of Melbourne.

They both largely agree with Associate Professor Audehm on the above points— but Professor O’Brien caveats that GLP-1s are very widely used in specialist practice, though perhaps not so much in general practice.

How effective are they?

Associate Professor Audehm is excited by the degree of effect these drugs have on glycated haemoglobin (HbA1c), and how long this effect seems to last. “I must admit I am a bit enamoured by the GLP-1 receptor agonists because of the impact on the A1c and the durability of this impact. Going out two to three years, the A1c seems to stay down,” he says.

“If their A1c is really high, the benefits you get from GLP-1s are just phenomenal, you know, you can get drops of 1.5%. No other drug apart from insulin does that.”

When to initiate (and in whom)

Currently, GLP-1 RAs are TGA-approved as monotherapy in Australia, but PBS-listed only as second or third line treatments, and not in combination with an SGLT-2 inhibitor (sodium glucose co-transporter inhibitor).

“I use it second line if I can, unless there’s a compelling reason not to,” Associate Professor Audehm says. “So if someone’s got heart failure, I will use an SGLT-2 inhibitor. If they’ve had a previous infarct, depending on what their HbA1c is, I’ll probably go SGLT-2 inhibitor.”

He occasionally does choose GLP-1 RAs as first line monotherapy in a patient who is willing and able to pay for a private script. “If you start it early, I’ve had people go from [an HbA1c in the] low 7s down to almost in remission,” he says.

“Metformin still works,” he clarifies. “The original trial back in the UK showing mortality benefit was only on something like 350 patients so it’s not exactly a very robust trial, but nobody’s going to do a randomised controlled trial on metformin. But it seems to work, it seems to have positive impacts, and observational studies show that it really does seem to have an impact around heart failure and heart disease.”

Additional benefits of GLP-1s

“There are a whole lot of other benefits that go along with GLP-1s – there’s some evidence around renal disease and cardiovascular disease,” says Associate Professor Audehm.

Professor MacIsaac agrees. “This class of medication is beneficial for many of the metabolic abnormalities associated with Type 2 Diabetes, and offers cardiovascular protection and possibly renal protection.”

Professor O’Brien adds that “GLP-1 RAs can be very useful in early Type 2 Diabetes, but can still be very effective later in the disease process, even when people require insulin treatment.”

What are the risks?

Associate Professor Audehm sees very few downsides to using GLP-1 RAs in Type 2 Diabetes. “We do know that about 10% of people will stop it because of nausea. They’re just too sensitive to it. And there’s probably another 5% that for some reason it just doesn’t work on them,” he says.

Professors MacIsaac and O’Brien note that nausea usually subsides within a few weeks of treatment. “Starting with a low dose and gradually increasing can reduce gastrointestinal side effects,” Professor O’Brien adds.

Although regular ophthalmic review is a standard component of diabetic management, Associate Professor Audehm says retinopathy must be treated before commencing GLP-1 RAs.

“The main issue that we’ve got to be cognisant of is that if you lower someone’s A1c very quickly, you can get a flare of their retinopathy,” he explains.

Nutrition can also be a concern. “Now that you’ve got really effective GLP-1s, we’re seeing people’s appetites reduced by over half, and we’re seeing them lose a lot of weight,” he notes. He is concerned about meeting micronutrient requirements, especially iron and calcium, and suggests considering dietitian review before starting the medication.

“Long term impacts, you know there aren’t that many. Exenatide and Liraglutide have been around for about 10 years and we haven’t seen any long term sequelae from that. There was a worry about pancreatitis but they’ve worked out that people with Type 2 Diabetes are at high risk anyway and there doesn’t seem to be much of a risk over the background risk.”

Which one to choose

Associate Professor Audehm describes the evolution of GLP-1 RAs over the last decade as increasing in potency, thus in general he tends to prefer the newer options over the older ones. He does note that although semaglutide is the most potent form currently available in Australia (pending the expected introduction of tirzepatide), the dulaglutide pen “is really easy to use”, especially for older or needle-phobic patients. “The counter to that is that the dulaglutide pen is one pen and then you throw it out, so environmentally it may not be so good, whereas with the semaglutide you get multiple doses in one pen,” he says.

Whichever GLP-1 RA you choose, his enthusiasm remains clear. “It needs to have a bigger presence, because only about 20% of diabetics are on it, and I think that’s shameful,” he says.

Associate Professor Audehm will facilitate a panel discussion with Professor O’Brien and Professor MacIsaac on the evidence behind GLP-1s during the 13 June webcast. Register here. Note: This panel is supported by an independent educational grant from Novo Nordisk.

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Dr Sarah Tedjasukmana

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Dr Sarah Tedjasukmana

General Practitioner; Co-Director, Sydney Perinatal Doctors

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