• 30 Oct 2018
  • 15 min
  • 30 Oct 2018
  • 15 min

Dhineli Perera interviews Dr Carolyn Petersons about the second- and third-line drugs for type 2 diabetes. After metformin, what comes next? Read the full article in Australian Prescriber.


Welcome to the Australian Prescriber podcast. Australian Prescriber, independent, peer reviewed, and free.

I'm Dhineli Perera, your host for this episode and it's a pleasure to be speaking to Dr Carolyn Petersons. Dr Carolyn Petersons is an endocrinologist at Canberra Hospital and Health Services. Carolyn writes about the importance of understanding the ever-growing list of second- and third-line medication options for managing type 2 diabetes. Dr Petersons, welcome to the program.

Thanks very much.

Carolyn, can you start by taking us back to basics. What are the key considerations for setting treatment targets for a patient with type 2 diabetes?

Look I think this is actually probably the main important thing in managing diabetes is to really individualise targets depending on the age of the patient, the comorbidities of the patient, and there are other factors to consider, you know, such as occupation, such as are there risks for example with their day-to-day activities. So, in the younger patient often we're more aggressive in managing type 2 diabetes and set closer, sort of tighter targets with their HbA1c and their overall glycaemic profile, whereas with the older patient we set much higher targets where safety is really paramount. So, the most important thing I think is to make sure that we try and avoid significant hypoglycaemia as well as avoiding symptomatic hyperglycaemia from the short-term point of view, and then really the main aims beyond that is look at minimising the risk of development of long-term complications of diabetes. It's really important to make sure you work with the patient, optimise their compliance, and this involves an understanding of the adverse effects of the drugs and how that will impact on the patient. And for the patient that you have a good understanding of the drug effects as well. The other important thing to consider is the mode of drug delivery, whether the patient will be able to manage injecting either insulin or other injectable therapies, whether they will be able to and happy to, whether there are physical things that get in the way of that as well, and that often also helps us individualise our targets.

Okay so metformin is a well-accepted first-line therapy for type 2 diabetes. Are there reasons why it should not be used first line?

There's really only one major contraindication to the use of metformin and that's renal disease, so in a lot of cases you will need a dose reduction of metformin in renal disease and if the creatinine clearance is less than 15 mL/min then metformin is contraindicated. The other reason why it wouldn't be used first line is in patients who have significant gastrointestinal adverse effects from metformin. Now this is something that tends to occur either at the higher doses or if the metformin was initiated at the higher doses to start with rather than started at a low dose and built up. And you'll find often that most people can tolerate some dose of metformin and even, you know, at a dose of say 500 mg a day you can still get some improvements in insulin sensitivity

So, in patients that do experience those gastrointestinal side effects, you would suggest down-titrating the dose first before ceasing it all together.


So, sulfonylureas have similarly been around for a long time. In the past they've been used as the second-line drug treatment after metformin. Is this still the case?

That's a really difficult question and I guess that's where I found writing this article quite difficult. Sulfonylureas aren't an expensive drug because they've been around for a long time, but they are effective or at least when the pancreas can still produce good amounts of insulin, and they do play a role in the management of type 2 diabetes. For us here in Australia there are a number of PBS prescribing rules that make them part of that regular algorithm for managing type 2 diabetes. The thing to remember though about sulfonylureas is that they have adverse effects and significant ones of hypoglycaemia and weight gain so yes sulfonylureas do remain in the algorithm but they're not necessarily the best second step these days.

Sure, so I guess on to the new stuff. Let's start with the incretin mimetics. How do these medicines work, and what are some examples?

So, incretins are essentially a neuroendocrine hormone which are produced in the gut in response to food. So, they're involved in stimulating the secretion of insulin and the suppression of glucagon secretion, so they'll bring down glucose levels. They also play a

really good role in patients with diabetes because they suppress appetite and inhibit gastric emptying, giving you a sort of gastroparesis kind of symptom. The major incretin hormones are glucagon-like peptide and glucose-dependent insulinotropic polypeptide, so GLP and GIP as they’re known, and these hormones are metabolised by something called dipeptidyl peptidase-4, or DPP-4, which again is something that most people will have heard of by its initials. The drugs that currently are there on the market are in two different groups, so one is the DPP-4 inhibitors which are oral drugs, so these inhibit that breakdown of those hormones thereby promoting a lengthening I suppose of the stimulation of insulin secretion and suppression of glucagon secretion. As I said they're an oral drug and they are effective because they only work in response to food. The injectable forms are the GLP-1 analogues.

There are now two different drugs available on the market for that in Australia. There's exenatide which comes in two different formulations and there's also dulaglutide. These are available depending on which drug and which formulation and either a twice daily or a weekly injection, so the injectables have a significant effect on supressing appetite and inhibiting gastric emptying and in so doing they have an extra benefit in reducing blood glucose levels on top of the effect that they actually have on insulin secretion and glucagon secretion.

Okay. So, you've mentioned that there are two families of drugs within this class – the gliptins and the GLP-1 analogues. How do we know when to use each one? Is there sort of benefits or limitations that help guide you to decide which way to go?

I think the first decision that needs to be made obviously is whether a patient is amenable to an injectable therapy because the GLP-1s don't come in an oral formulation, so if a patient doesn't want injections then obviously they're not going to be an option because the patient has to be agreeable to this. Often however once a patient trials an injection be it insulin or be it an incretin mimetic they’ll often realise that it wasn't actually as big a deal as they thought it was going to be, but it's important to have that discussion and to make sure that they're happy to try it. So, if patients are however only interested in oral agents then that makes that decision for you, that the DPP-4 inhibitors are the path to go down. The DPP-4 inhibitors however don't give you as much of a benefit in glycaemic control as the injectable forms and, as I said earlier in the answer to the previous question, that predominantly I think relates to the effects that the injectables have on appetite suppression and on gastric emptying because often it's those lifestyle modifications that the GLP-1 analogues enforce on the patients that make them such effective drugs. Similarly, weight loss again comes much more so with the GLP-1 analogues than the DPP-4 inhibitors. They’re more of a weight-neutral drug.

Okay, excellent, very interesting. So, the sodium-glucose co-transporter 2 inhibitors also known as the flozins are the other new kids on the block. Where is their place in management?

Look these drugs are really emerging now as much higher up in that algorithm than I think they were when they first came out because we've got a lot more usage out there, people are more comfortable with them, and there's also new evidence that’s come out that they're beneficial in patients with cardiac disease in preventing further cardiac disease. So, because of those trials that have shown they have cardiovascular benefits these are a drug that are obviously quite ideal in that respect. They do however have some significant adverse effects and in particular genitourinary tract infections are very common with SGLT2 inhibitors or the flozins. So, a lot of patients will experience thrush. In some patients that’s self-limiting once the glucose levels are better controlled, the thrush tends to resolve. In other patients, however that's something that does tend to continue and can be problematic in the longer term. And if the thrush or other genitourinary infections are intolerable then obviously that limits the utility of these drugs. They also have a significant risk that it's important to know about, which is that of euglycaemic ketoacidosis and in particular this is a risk in the perioperative state or the fasting state, so patients shouldn't take these drugs if they're fasting for any procedure or any reason and generally for about three days pre- and post-surgery. However, they have really good effects on glucose lowering. They also bring down blood pressure a little bit and do have some weight loss involved with them so they're very effective drugs in glycaemic control. I might need to pause there and just get a baby who's grizzling. That’s very bad background noise. Hang on for just two ticks.

No worries … How's your bub going?

Having a feed and has stopped screaming so I'm happy to keep going if you are?

If you're happy to.


Okay. All right, so does acarbose or the glitazones get a look-in these days?

Look they really are largely redundant. Acarbose does have some improvement in glycaemic control but I find very poorly tolerated because of the gastrointestinal symptoms so it's not a drug that I routinely prescribe to my patients. The glitazones again unfortunately, while they're very effective at glucose lowering, have lost their place in the routine management of type 2 diabetes just because of the adverse-effect profile.

So, is there any evidence to show if these drugs are more effective in terms of targets or tolerability – so when I say ‘these drugs’ I'm talking about the newer ones – and have any of them shown any effect on clinical outcomes?

So, look I think all of them have their pros and their cons. Really the overall HbA1c reduction in all of them is fairly similar. It's something in the range of 0.5 to 1% is what you'll get from drug effect alone in reduction in HbA1c. In looking at targets it depends on if you're specifically targeting for example postprandial hyperglycaemia in which case the incretin mimetics are very effective or whether its overall glycaemic control in which case the SGL2 inhibitors or the gliflozins are possibly more effective. Tolerability – they all have adverse effects that some patients won't tolerate so the GI side effects are there from metformin obviously, the GI side effects are also there from the injectable incretin mimetics so they can cause a lot of nausea and vomiting when they're first initiated which is why we tend to start at a half dose and then up-titrate to a full dose. The DPP-4 inhibitors tend to be fairly well tolerated without much in the way of significant day-to-day adverse effects, and the SGLT2 inhibitors as I’ve already mentioned those genitourinary infections sometimes mean that they're not well tolerated at all. From a clinical outcome point of view, obviously by means of their glycaemic control they all improve clinical outcomes and, as I've mentioned, there's other benefits as well with cardio protection from the gliflozins or SGL2 inhibitors

Has the introduction of these newer agents resulted in delaying the need to start insulin? Would it be better to start insulin than to take three or more of the other drugs?

Look absolutely, these have definitely delayed the initiation of insulin in a lot of patients because we now have much more in the way of options up our sleeve that if one patient doesn't tolerate one we can trial them on something else before you end up stepping to insulin. And in an ideal world insulin, unless it's really needed for acute symptomatic hyperglycaemia, is best delayed if possible because its adverse effects are significant in the form of weight gain and hypoglycaemia, so in particular that weight gain of up to four and five kilos could actually make patients more insulin resistant and actually, you know, potentially worsen the problem in the scheme of things. However, insulin is necessary sometimes for acute hyperglycaemia and sometimes because all other drugs have failed. It's also worth realising, I suppose, as well that insulin sometimes is needed for acute hyperglycaemia but can be stopped. So, it used to be thought, and in fact a lot of patients still do think that once they're on insulin they will be on insulin forever, and that's not the case. Would it be better to take insulin than to take three or more of these other drugs? Not necessarily. I think depending on the tolerability of the other drugs, as I said, if you can avoid the weight gain, if you can improve some of those other side effects, if you can minimise the risk of hypoglycaemia and, for a lot of patients, if you can take an oral agent rather than need an injectable, then obviously that's a better option.

So, are there things to consider with regards to continuing or stopping other drugs when your patient needs to start insulin. I guess it leads on from my previous question – that transition –how best would you guide prescribers to do that?

So that one thing I tell all of my patients is definitely they need to sell metformin when they start insulin because it does reduce the amount of insulin that you need and in so doing, you know, minimises those effects of weight gain. So metformin should always continue unless there's a problem with tolerability or renal function. It depends then on what insulin you're starting a patient on, so if you're starting a patient just on basal insulin, so a long-acting once-a-day insulin just to bring down their overall blood glucose levels, then some of the medications that improve prandial or postprandial glucose levels such as a sulfonylurea or the incretin mimetics should still be continued because they can bring down the post-meal sugars while the insulin then just brings down the background glucose level. If however someone starts on prandial insulins, be that a pre-mixed insulin or on some bolus insulin with their meals, so one of the rapid-acting insulin analogues, then it's probably not really worth continuing a sulfonylurea because all you're doing is making that push up more insulin as well and you're really covering that with your injectable insulin. I generally find that you're not likely to get very much extra beneficial effect from one of the gliptins by the time you’re on either basal bolus or premixed insulin, although in saying that some patients you do see a benefit and they're happy to keep taking it. There's definitely a benefit, an additive benefit from being on the incretin mimetics or the injectable one, sorry, so the GLP-1 analogues so your exenatide or dulaglutide with insulin because again that will definitely minimise your insulin dose required. The difficulty unfortunately at the moment that we have is we've got once-a-week versions of the GLP-1 analogues, however they're not PBS approved for use with insulin, so the patients have to be on the twice-daily exenatide if they're going to take insulin with it, so that's something to remember that, while there are beneficial effects, if they're going to be PBS prescribed, you can't use the long-acting weakly GLP-1 analogues in association with insulin at this current point in time, and I don't know if that will change in the future but it's important to realise that the PBS rules do change and so what I say today may not be true down the track. The SGLT2 inhibitors or the gliflozins are also beneficial with insulin. They really do reduce the amount of insulin you need, and so I've in fact had a lot of patients who have been on long-term insulin where I've started one of those in addition and in fact you get a dose reduction of insulin quite effectively and so with that you get some weight benefits as well.

Okay, excellent. So, the combinations all do serve their own benefit. I guess it comes back to that very first question of individualising treatment for your patient.

Absolutely, and that’s what made it a really difficult article to write, and I suppose probably a difficult one to interpret, because there is no nice clear algorithm that you start with A, you then progress to B and then C. It really does need to be individualised according to the patient.

So, speaking of algorithms, Carolyn's article does mention the Australian Diabetes Society website that has an algorithm and some good cases involved on that website. Do you have anything to add on that Carolyn?

No, except to say that the cases are actually quite useful at looking at how you would then consider individualising for the different patients as well as just looking at the way the algorithm itself flows.

Excellent, okay. Well unfortunately that's all we've got time for. Thank you so much for joining us today Carolyn.

My pleasure. Thanks very much for asking me on.


The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I’m Dhineli Perera and thanks for joining us on the Australian Prescriber Podcast.