Efpeglenatide for type 2 diabetes

Ally P.H. Prebtani, James Douketis

Dr Ally P.H. Prebtani, professor of medicine in the Division of Endocrinology and Metabolism at McMaster University, joins Dr James Douketis to discuss the role of efpeglenatide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist, in the treatment of type 2 diabetes in patients at risk of adverse cardiovascular and renal outcomes.

Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. N Engl J Med. 2021 Sep 2;385(10):896-907. doi: 10.1056/NEJMoa2108269. Epub 2021 Jun 28. PMID: 34215025.

For a Publications of the Week article discussing the use of efpeglenatide in type 2 diabetes, click here.

James Douketis, MD: Hello everyone, my name is Jim Douketis and it’s my pleasure to welcome you to another iteration of the Paper of the Week, the McMaster Perspective. And I’m pleased to be joined today by Dr Ally Prebtani, a professor of medicine and endocrinology at McMaster University. Welcome, Ally.

Ally P.H. Prebtani, MD: Thank you, Jim, for inviting me to speak today.

James Douketis: We’re going to be talking about the study looking at cardiovascular/renal outcomes with efpeglenatide in type 2 diabetes. Just to set the stage a little bit, Ally, can you perhaps give us a bit of a 30,000-foot view of the typical patient with type 2 diabetes who may be started on metformin, is still hyperglycemic... What are the next general steps in terms of medications that will help to achieve better glycemic control?

Ally P.H. Prebtani: Thanks, Jim. There has never been such a glamorous time in the management of type 2 diabetes mellitus over the last few years. We were so focused on just one [aspect], glycemic control, many years ago, but now we’ve gone beyond that and we have an armamentarium of agents to choose from, based on personalized medicine, which is a key concept that we always aim for in terms of improving our patients’ care regardless what chronic disease we’re dealing with.

In particular, with type 2 diabetes mellitus, we have to think of several things before we choose the next agent, typically after metformin. We look at glycated hemoglobin (HbA1c) [levels], which is important. What is their [patients’] target and how far are they from the target? So, that’s one consideration. But that’s not the only thing. We also want to look at what their risk profile is. In particular, [regarding] the newer agents that we’ll talk about briefly, we want to think about their cardiac profile, their renal profile, and their heart failure profile. Based on this information we will be able to choose the next agent.

That’s some of the information we use, but even more than that you also want to look at the risk of hypoglycemia, weight considerations. Are they [patients] pregnant? Obviously that will change management. Drug affordability is a big thing—you know, coverage. We’re fortunate to have coverage in Ontario, but at the end of the day, it does come out of someone’s pocket, it’s not totally free as we always think. Drug interactions and the safety profile, which is really, really important.

These are some of the things we look at. And [then] their [patients’] actual symptoms... Are they decompensating? If they’re decompensating, we often rely on insulin, at least temporarily. And probably the most important thing, which we often forget, is what the patient wants. That is paramount to all of this, right? It’s often about what we want, but we [should] always think about what’s best for the patient and what the patient wants, and they have to be engaged in the decision making.

James Douketis: Great. Thank you for that. Let’s focus a little bit more on this study and, in general, the place of the glucagon-like peptide-1 (GLP)-1 receptor agonists within that framework. First of all, where would you use this sort of class of agents? What would be the typical patient who you think would benefit the most? And maybe you could talk a little bit about this trial and how it was a bit of a different agent but within that class of drugs?

Ally P.H. Prebtani: Sure. First, let’s start off with broadly [sketching] the role of GLP-1 [receptor] agonists in the management of type 2 diabetes mellitus. We’ve already covered some of the issues in the previous question that you’ve had, but, once again, it is approved only for type 2 diabetes mellitus. In particular GLP-1 analogues [are approved] for the management of type 2 diabetes mellitus, but we also have an indication for obesity, with a different dosing, but we’ll focus today more on [their use] in type 2 diabetes mellitus. Again, we look at HbA1c [levels]. These agents are moderately effective in reducing HbA1c levels. Once again, we have to also look at their [patients’] cardiac profile. In high-risk cardiac patients or those with established coronary artery disease or [at] high risk of coronary artery disease or atherosclerotic disease, these medications have an additional benefit beyond glucose lowering. They have a protective effect on certain major adverse cardiovascular event (MACE) outcomes, and even certain agents in terms of nonfatal stroke, depending on the agent that you choose.

Another fringe benefit that I’ve already mentioned is [that] they can cause significant weight loss, which might be an additional benefit. In fact some patients can lose up to 5 to 10 kilos, and people get worried that there is something else going on, but often this is actually one of the favorable side effects for many with respect to GLP-1 analogues. And we can go down to a pretty low glomerular filtration rate (GFR), so someone who has a low GFR but still needs agents for glycemic control and perhaps cardiovascular protection—this is another role that GLP-1 analogues can have. Fortunately, one of the GLP-1 analogues is actually covered by our drug formulary, so that’s one of the other advantages that we have [with] this new class of agents.

James Douketis: One of the points made by the authors of this trial was that there were patients who were included who were also taking the sodium-glucose cotransporter 2 (SGLT-2) inhibitors. Why is that important? Are there situations where the combination may be a choice, a preferred choice?

Ally P.H. Prebtani: That’s a really important question because SGLT-2 inhibitors [are], again, fantastic agents in the right patient, for our patients with type 2 diabetes mellitus. The question here was “Was the additional use of SGLT-2 inhibitors an effect of addition or was it just independent of the SGLT-2 inhibitors, in fact, related to GLP-1 analogue use?” This study actually showed that the beneficial effect in terms of glycemia and cardiovascular outcome reduction was independent of SGLT-2 [inhibitors], so this really answered that question. We can say now that GLP-1 analogues with or without SGLT-2 [inhibitors] have a beneficial effect on glycemic control and cardiovascular outcomes. There was no conflict here with that issue.

James Douketis: And just the fact that this is a once a week subcutaneously administered medication—how does that play in in terms of day-to-day management of patients?

Ally P.H. Prebtani: We already have 2 agents that are existing right now—GLP-1 analogues that are already once weekly: we have semaglutide, which has been proven in clinical trials to have beneficial cardiovascular outcomes, mainly in a noninferiority study, and we also have dulaglutide, which is also [administered] once weekly, mainly in the primary prevention population. This [efpeglenatide] is just the third additional agent, not available in Canada yet, which is basically consistent with what we’ve already had [with] the previous once-weekly GLP-1 analogues. So, just another tool we have in the armamentarium of management of type 2 diabetes mellitus [and] the study showing that.

James Douketis: And I’m just going to finish with just a very broad question: If you had a patient coming into your clinic who maybe has type 2 diabetes, has a little bit of renal insufficiency, maybe their creatinine clearance is only [within a] 40 to 50 mL/min range, [who] does not have any overt cardiovascular disease, what would be your typical management of a patient like this? Just in very broad terms, acknowledging all of the points you made about individualizing management and cost issues, and patient preferences.

Ally P.H. Prebtani: If they’re stable in terms of they’re not decompensating, I think we have a lot to choose from. And I think most of us would still use metformin as long as there are no contraindications [from] the renal point of view or any other contraindications. But we can even argue right now that maybe we should be using these agents [GLP-1 receptor agonists] first line. But that being said, the key question is how far they [patients] are away from their HbA1c [target levels] after metformin use. If they’re significantly away, the GLP-1 analogues will probably have more of a benefit than the SGLT-2 inhibitors.

Another question we have to ask ourselves [is] what is their cardiac risk, what’s their renal risk and their heart failure risk. If they all have the same HbA1c [levels] and mainly it’s a renal risk, eg, their GFR is, arbitrarily, let’s say, 40, but they have significant microalbuminuria in their urine or proteinuria, then the preference there probably would be [for] an SGLT-2 inhibitor. [Whereas] if the renal risk is not that high, but it’s mainly a cardiac risk, and the HbA1c [levels] are similar, then definitely GLP-1 analogues—because of their effect on cardiovascular outcome [in] trials—would be the next choice if they [patients] meet the high-risk cardiac criteria.

This is actually revolutionary. Now we won’t just ask about glucose levels; we are really addressing—besides other points that I’ve mentioned—[whether] there is a cardiac risk, the atherosclerotic cardiac risk, and also the heart failure risk, and the renal risk. At the end of the day, if you want to see heart outcome reductions, these agents, both of them, depending on the risk profile, have been shown to significantly reduce [adverse] heart outcomes in terms of protecting our patients.

James Douketis: I just want to point out to our audience that this is the 100th anniversary of the discovery of insulin in Canada here, and 100 years later I think we’re on the cusp of a new era—as you pointed out, Ally—with so many choices to help [with] this increasingly common problem. Any final thoughts or pearls of advice that you might want to offer?

Ally P.H. Prebtani: I think the key thing is that we need to go beyond glucose control and really look at what our outcomes are. This is truly the concept of personalized, individualized medicine for that patient in front of us. We can look at all the trials, we have to look at them carefully and decide what’s best for a patient in front of us, based on the criteria that we discussed earlier on, beyond glucose control.

James Douketis: I’d like to thank Dr Ally Prebtani, professor of medicine and endocrinology, for the McMaster perspective on this Paper of the Week [on] cardiovascular/renal outcomes with efpeglenatide in type 2 diabetes. Thank you very much, Ally, for your valuable advice and insights.

Ally P.H. Prebtani: Thank you for having me, Jim.

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