Don’t risk these drugs in type 1 diabetes patients

Although GLP-1 receptor agonists and SGLT2 inhibitors can improve quality of life, it's dangerous territory for GPs.

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Use of GLP-1 receptor agonists and SGLT2 inhibitors in type 1 diabetes is becoming more common, despite the combination being “fraught with danger” outside a specialist setting, experts say. 

The TGA has regularly reminded prescribers of the risk with the second drug class, citing “continued local and international post-marketing reports of off-label use of SGLT2 inhibitors”.

A research letter in JAMA Network Open last month adds to these reports, using US electronic health records to plot the upward prescribing trends, especially for GLP-1RAs.

Using data for almost a million type 1 patients, researchers showed that the percentage prescribed either GLP-1RAs or SGLT2 inhibitors increased from 0.7% to 8.3% between 2010 and 2023, with semaglutide alone going from 0.2% to 4.4%.

Those who were newly prescribed SGLT2 inhibitors had higher rates of cardiovascular disease and kidney conditions while those prescribed GLP-1RAs had a higher rate of obesity. As add-on treatments to insulin, GLP-1RAs help type 1 diabetes patients with weight loss and glycaemic stability and SGLT2is with cardiovascular and renal health.

But SGLT2 inhibitors promote ketosis, leading – sometimes in type 2 diabetes but more often in type 1 – to ketoacidosis. SGLT2is had their approval revoked for use in type 1 diabetes in Europe for this reason, while the US and Australia have never approved them for these patients.

Associate Professor Neale Cohen, Head of the Diabetes Clinical Research laboratory at the Baker Heart and Diabetes Institute, said off-label prescribing of SGLT2 inhibitors and GLP-1 receptor agonists had “become quite commonplace”.

He said obesity and insulin resistance were common in type 1 diabetes.

“Like all populations, there’s many people with type 1 who also have obesity and insulin resistance, because that’s what the normal population has,” he told TMR.

“It’s also quite tricky to lose weight with type 1 because you’re always dosing insulin, and you often have hypos and need to top up with extra snacks. It’s also the fact that we give insulin peripherally, which causes some degree of insulin resistance.”

Dr Jennifer Snaith, an endocrinologist at St Vincents Hospital, Sydney, said even though these drug classes were popular among type 1 diabetes patients, she was “quite shocked” at the extent of prescribing revealed by the JAMA Network Open study.

Dr Snaith is a postdoc researcher at the Garvan Institute, looking into add-on therapies to insulin for type 1 diabetes, and is currently recruiting for a semaglutide study called RESET1, which will monitor for side effects such as heart disease risk, ketosis, hypoglycaemia, and GI effects in people taking both medications.  

“Anecdotally, we are seeing GLP-1 receptor agonists and SGLT2 inhibitors being particularly popular, especially the weekly injections of semaglutide,” she told The Medical Republic.

“It’s driven by doctors, but also a lot by our patients: a lot of the time, they’re coming to us.”

Patients liked the drugs because they helped them lose weight (especially the GLP-1s), kept their blood sugar stable and increased their general wellbeing. A once-a-week injection, though onerous for other patient groups, doesn’t add much to the burden of managing type 1 diabetes. 

Tirzepatide in particular, though still quite new, has already been life-changing for patients.  

One patient taking tirzepatide, who allowed their words to be quoted anonymously, said: “Almost immediately, my insulin sensitivity increased and I started taking less long-acting and short-acting insulin. The level of ‘food noise’ in my mind has decreased and I’m finding it easy to fast during the day and eat a low-carb high-protein meal at night.

“My sugar levels are the most stable they have been since my diagnosis five years ago. I’ve been able to engage in more exercise and strenuous activities as my sugars are more stable and predictable and easy to manage. I’ve been losing about 1kg of weight per week.

“My mental health has improved dramatically … I would often wake up in the morning anxious, as the day ahead would  revolve around constant attention to my disease and its management … With the reduction of the food noise and the amount of time I spend actively thinking about or making decisions based around my sugars and their management, I have more bandwidth to focus on other parts of my life.

“I’d like to thank you for introducing me to this medicine, which has made a drastic improvement to my quality of life.”

However, Dr Snaith said, GPs needed to be mindful of the risks if patients asked them to prescribe these drugs.

“We’re very early in the evidence, so with the risks, I think it’s probably non-GP specialist domain. But then again, patients will be coming to GPs asking about it, and it’s talked about a lot on forums in the community. I wouldn’t say that it’s a no.

“The SGLT2 inhibitors definitely do increase risk of diabetic ketoacidosis: when that medication is taken, it increases urinary glucose loss and the metabolism shifts towards a greater likelihood of ketone development – that’s been demonstrated in type 1 diabetes research trials.

“With the GLP-1 receptor agonists we don’t really know because we don’t have the trial evidence, we only have real-world data.”

Professor Cohen said there were important differences between the two drug classes in efficacy and risk profile.

He said type 1 diabetic patients liked SGLT2 inhibitors because they improved glycaemic control and helped them lose weight, but the risk of diabetic ketoacidosis was serious.

“So much so that I think most of us are not doing that any more, because we’re very concerned about the risk of DKA in our type 1s on SGLT2 inhibitors. So that’s a bit controversial. My personal view is that they probably shouldn’t be used any more, because the benefits are not huge and the risks are probably high.

“But the GLP-1s are another story. GLP-1s, as far as I have seen in the literature, don’t really produce a significant change in DKA rates in type 1 at all. So I think they’re safe.

“I think that they work exceptionally well.”

Nevertheless, he advised that GPs avoid prescribing either drug class to type 1 diabetes patients, and said the TGA warning on SGLT2 inhibitors was “absolutely legitimate”.

“Talking to GPs I would say: please don’t do this. It is fraught with danger. And there’s certainly many countries, European countries, that have similar warnings about these agents.”

GLP-1s were similarly dangerous territory for GPs without a special interest in type 1 diabetes, he said, requiring close monitoring and dose adjustment.

A retrospective cohort study published in Diabetologia last year found that of around 1000 and 2000 type 1 patients prescribed SGLT2is and GLP-1RAs respectively, the former had more than twice the risk of diabetic ketoacidosis. The risk increased over the five-year followup in the SGLT2i cohort while remaining stable in the GLP-1RA group.

SGLT2i use brought increased risk of UTI/pyelonephritis, but also better renal function and reduced risk of heart failure, CKD and hospitalisation.

Neither drug class significantly altered the risk of severe hypoglycaemia.

(Oddly, the GLP-1RA group’s weight loss peaked at three years and rebounded by five years. Only a quarter were on semaglutide, the rest taking older GLP-1RAs.)

Dr Snaith said continuous ketone monitoring would one day accompany continuous glucose monitoring, and this would make it much easier to manage the risk of diabetic ketoacidosis.

But until then, “we do worry about it whenever people need to reduce their insulin. And we find that with these medications – at least anecdotally – insulin dose really drops by quite a lot. It can even halve. So we do worry that with insulin dose dropping that much, we don’t know quite where the balance tips towards ketones. And this is why we tend to do it just in a specialist setting.

“It’s right for there to be warnings, because we really do need the awareness. They’re not medications that can be prescribed lightly.”