Tirzepatide is a novel GLP-1 and GIP receptor agonist, currently being investigated in phase 3 trials.
Juan Pablo Frias, MD, Medical Director and Principal Investigator at the National Research Institute in California discussed the trial results with MD /alert, highlighting the strong efficacy and safety data.
What was the idea behind this research?
Tirzepatide is a unimolecular multifunctional agonist and it basically targets two different receptors, the GLP-1 receptor and the GIP receptor, which are both of the intricate hormones, whereas semaglutide is what’s called a GLP-1 receptor agonist. And this is the currently available GLP-1 receptor agonists like semaglutide and dulaglutide for example. So, tirzepatide is still investigational, and what we were looking at is to compare the GIP GLP-1 dual agonist to really the most potent GLP-1 receptor agonist, which is semaglutide.
How was the study set up?
It's a randomized control trial. It was open label, but it assessed the three doses of tirzepatide that are being assessed throughout the phase 3 program. So this is 5 mg once a week, 10 mg once a week and 15 mg once a week, versus semaglutide, the 1 mg semaglutide once a week.
Again, it was a randomized trial: 4 arms, 3 tirzepatide arms and one semaglutide arm. And then patients were treated over a 40-week period and the primary endpoint was the change in hemoglobin A1C from baseline to week 40. Looking at the three tirzepatide doses versus semaglutide 1 mg dose.
What were your findings?
What we found in this study was that tirzepatide at all three doses, the 5 to 10, and the 15-mg dose was superior to semaglutide at 1 mg with respect to lowering of hemoglobin A1C. The proportion of patients achieving a hemoglobin A1C less than 7 less than or equal to 6.5% and less than 5.7%, or 5.6% I should say. And also superior with respect to weight reduction with very high proportion of participants achieving clinically relevant weight targets which would be greater than or equal to 5, 10, and 15% weight loss over the 40-week period.
And I think a very important finding, I mean clearly, it's important to see what the overall or the absolute reduction in hemoglobin A1C is, but it's the percent of patients achieving hemoglobin A1C targets. And what we found not only in SURPASS 2, which was versus semaglutide, but in the other SURPASS trials that have completed, is very high proportion of patients, you know up to 90% or even more of patients achieving a target A1C of less than 7%. And I think very importantly and very consistent across these trials anywhere from 45 to up to 60+ percent of patients actually normalizing glucose and achieving hemoglobin A1C’s of less than 5.6%.
And similarly with weight targets, I mean a very high proportion of patients achieving really weight reduction that has not been seen in patients with type 2 diabetes previously, with up to 40-45% of patients achieving greater than or equal to 15% on weight reduction with tirzepatide.
I think very importantly if I could add, that’s looking at the efficacy endpoints, but with respect to safety and tolerability, very positive as well. In the earlier trials when we have reached the highest receptive doses very quickly, there was more of an issue with GI tolerability in the phase 2 studies. But with the titration and dose escalation algorithm that have been used in these phase 3 studies much better tolerability.
And in fact, if you look at the tolerability of tirzepatide versus semaglutide for example, so a selective GLP-1 receptor agonist you get basically the same nature or the same type of adverse events, the primary one being gastrointestinal adverse events or nausea, vomiting, diarrhea. But much better tolerated in phase 3 compared to phase 2 with the new escalation algorithms that were used.
How do you determine dosing for tirzepatide?
As with the GLP-1 receptor agonist, you definitely have better tolerability of these drugs when you started with a lower dose and then dose escalate slowly. So, what was done in in all of the phase 3 tirzepatide trials is to initiate therapy with 2.5 mg once weekly. And this is a subcutaneous injection. And the dose was then escalated by 2.5 mg every four weeks. So, patients went from 2.5 mg for four weeks to 5 mg. So to get to the 5 mg dose that was studied, it took four weeks and to get to the 10 milligram dose it took 12 weeks that the patient went from 2.5mg for four weeks, then five, 7.5, and then 10, and then to get to the 15 mg dose it was actually 20 weeks or 2.5 mg increments every four weeks. So, in these studies, you know, was set the patients were randomized either to 5, 10, or 15 mg. And that was, you know, blinded to the investigator what doses the patient ended up on. But all three doses were very effective.
I mean, as an example, in the SURPASS-2 study, which was recently published in the New England Journal versus semaglutide, even though the 5 mg dose, which was the lowest dose that was studied, was superior with respect to hemoglobin A1C reduction as well as weight reduction compared with semaglutide. So I imagine in clinical practice should tirzepatide get approved by FDA and become commercially available, we’ll just need to decide this in the clinic. You know, if a patient’s doing very well with the 5mg dose there may not be a need to escalate to the 10mg dose. And if patients are, you know, get escalated and they're having GI side effects at a higher dose, you know that's a patient that I would potentially deescalate or reduce the dose on. And I think it is important to point out that in, for example, the SURPASS-2 study we were not allowed as investigators to reduce the dose as we would in clinical practice if a patient did have issues with tolerability.
Judging whether a dose is going to really be as successful, it’s going to be individualized, you know. If clearly, I mean, I’m treating diabetes here. So, one of my key endpoints is going to be improving hemoglobin A1C. So, generally, in practice we’ll individualize the target hemoglobin A1C depending on a number of different patient characteristics. But, you know, I think the key one would be is my patient achieving the A1C target that we’d like to get to.
Some patients were more concerned about weight loss, so maybe they've achieved their A1C target, but we feel that we'd like them to lose more weight. So that may be another reason to escalate if I'm on a dose that's lower than the maximal dose. And certainly, tolerability plays a huge role in this as well. The patient might be achieving all these targets, but if they're not tolerating the medication well, I may want to reduce the dose. But primarily, you know, knowing whether to escalate, and whether I've sort of reached the maximum dose, those will primarily be based on hemoglobin A1c. So, glycemic control as well as body weight control.
What role did previous metformin use have on your findings?
So, these patients were all taking metformin. So, it was a study in patients on metformin monotherapy, so metformin therapy for at least three months. In this case they had a mean duration of diabetes of a little over 8 years. There was another study, this one called SURPASS-1. This study was recently published in The Lancet. And that looked at tirzepatide as a monotherapy. So, these were patients and were either drug naive or at some point had been on oral antidiabetic agents but were not on them for at least three months. So, this was looking at tirzepatide on top of diet and exercise therapy. And very consistent looking at that population compared to SURPASS-2.
But most patients, I mean the recommendation today if we look at our guidelines is that you would initiate with metformin therapy or maybe metformin and SGLT 2 inhibitor for example, particularly in patients that have cardiovascular disease or a renal disease. So, this could be looked at tirzepatide as an add-on therapy as we consider GLP-1 receptor agonists today. But certainly, there are going to be situations where patients can’t tolerate metformin or have complications from metformin, for example. Or when we want to initiate combination therapy from the get go where incretin-based therapy like a GLP-1 receptor agonist may be appropriate as, you know, the first step in the therapy, or in combination with metformin from the beginning. So I think this is where tirzepatide could eventually fit in as well, either, you know, as a monotherapy, or as add-on therapy to pre-existing treatment in patients with type 2 diabetes.
Could tirzepatide fill an unmet need in diabetes care?
I think it addresses an unmet need. If we look at GLP-1 receptor agonist therapy today, you know, these agents are very potent, semaglutide, dulaglutide as well. There’s still patients that remain basically without achieving their optimal control. And, in fact, if we look at dulaglutide for example, there was recently a study and a new indication for higher doses. So going from 1.5 to 3 or 4.5 mg once weekly to address that same unmet need that some patients at 1.5mg do not achieve their target. And similarly, with semaglutide, the maximal dose is 1mg. But we recently presented data looking at 2mg, a higher dose of semaglutide for type 2 diabetes, again because of that unmet need that, you know, although in clinical trials up to 80% of patients with the 1mg semaglutide dose achieve an A1C of less than 7%, you’re still left with some people who are not achieving this target.
So, I think this addresses the need. One of the needs for better glycemic control in many patients as well as this combination of really unsurpassed glycemic control with the weight reduction that's seen with this new agent, this dual agonist. And I think, you know, if you, if you look at these studies as well, it’s not only the A1C and body weight, but you're also seeing improvements in blood pressure, improvements in the lipid profile as well.
And I think some very interesting if you look at the New England Journal paper, there's a composite endpoint that was predefined, and I thought it was very impressive and I think clinically relevant. It looked at the proportion of patients with tirzepatide that achieved a hemoglobin A1C of less than or equal to 6.5% and weight loss greater than or equal to 10%, and no significant hypoglycemia. So, sort of this triple composite endpoint. And with the 15 mg dose, this was reached by approximately 60% of the patients. And with semaglutide it was reached by 20%, so 1/5 of the patients, which is still pretty darn good. Because they’re just very sort of extreme targets if you will. So I think it is addressing the need for better control in some of our patients that are already treated, sort of, with the most potent antidiabetic agents.
What can be done to help diabetes care overall going forward? Is it more medications? Better education?
You know, I think I think it's all of the above and I would say you know, despite the fact that we've had significant advances, I think in pharmacotherapy, in diabetes related devices, in our knowledge about the importance of good glycemic control. You know in cardio renal protection, many patients are still not achieving their targets. I mean, we saw that recently in the latest latest data from CDC and you know, and Haynes and in the New England Journal of Medicine looking that despite all of this, you know as a population we're not achieving glycemic targets are not getting better with respect to achievement of glycemic targets. So I think a lot of this also has to do with education, physician education, patient education, and very importantly access to these medications. I mean, you know it's great to have these very powerful medications, but our patients need to have access to them. So I think it's having the more powerful and more efficacious medicines, but it also is education and actually having access to these medications if you're a patient. I mean, that's obviously critical to this as well.
Disclosures: Frias reports research support, advisory board and consulting roles, and speakers bureau roles with Eli Lilly. Frias also reports additional pharmaceutical disclosures unrelated to the study.
Any views expressed above are the author's own and do not necessarily reflect the views of MD /alert. This transcript was digitally generated and edited for clarity.