COMMENTARY

With Tirzepatide, a 'Great Future' for Patients With T2D

Juan P. Frias, MD; Mark Harmel, MPH

Disclosures

July 15, 2021

This transcript has been edited for clarity.

I'm here to talk about tirzepatide, a dual GIP/GLP-1 receptor agonists that's under investigation for the management of type 2 diabetes, obesity, and fatty liver disease.

We're all very used to GLP-1 receptor agonists. They've been around for over a decade. These are medications such as dulaglutide or semaglutide, which is sort of the new frontier in the management of type 2 diabetes. They're what we call unimolecular multiagonists, the drugs that are agonizing not just the GLP-1 receptor but other receptors as well. With tirzepatide, it is GLP-1 as well as the second incretin hormone, GIP.

Tirzepatide has completed five of the pivotal clinical trials in type 2 diabetes. It's my understanding that these will be used for a regulatory filing with the FDA sometime this year, and there have been recent publications and presentations of four of these studies.

These trials span the spectrum of patients with type 2 diabetes: one study in patients treated only with diet and exercise, with a duration of about 4.5 years of diabetes, comparing three doses of tirzepatide with placebo, all the way to a trial in patients already on basal insulin. So, in this case, insulin glargine with a 14-plus-year history of type 2 diabetes. It's also been in one study compared with semaglutide in patients who are on metformin monotherapy. Another one of the studies, in patients who were on metformin with or without an SGLT2 inhibitor, compared tirzepatide with advancing therapy with a basal insulin, in this case, insulin degludec.

Consistent A1c Lowering and Weight Loss

What was found across these trials are very consistent data with respect to A1c lowering, which was the primary endpoint in these studies. The studies were either 40 or 52 weeks in duration, and very consistently, we found extremely robust reductions with the 5, 10, and 50 mg doses of tirzepatide.

A very important metric from a clinical perspective is the proportion of patients achieving the A1c target of < 7% across these four studies, which have been reported in the range of 90%-93%. I think very unique to tirzepatide is the percentage of patients achieving normoglycemia, or A1c of < 5.7%, which was up to 62% of patients.

Unique, also, is having this level of glycemic control and A1c improvement with significant weight loss — achieving clinically significant targets of weight reduction of ≥ 5%, 10%, and even 15%. Some of the studies showed up to 40% of patients on tirzepatide having ≥ 15% weight reduction. These are reaching weight reduction targets you sometimes see with bariatric surgery.

Safety and Tolerability

We also have to look at safety and tolerability. There was really no increased risk for hypoglycemia. In fact, in SURPASS-1, a trial in patients on diet and exercise only vs placebo, patients reached an A1c of 6% or less, on average, with 5, 10, and 15 mg of tirzepatide, with around 50% of patients achieving an A1c of < 5.7%. And in those tirzepatide-treated patients, there was no clinically significant hypoglycemia in the entire trial in any patient.

If we look at the tolerability profile, it's very similar to what we see with GLP-1 receptor agonists, with gastrointestinal side effects being the most common. This would generally be nausea, vomiting, diarrhea, and loss of appetite. Importantly, the vast majority of the GI side effects are mild to moderate in severity. And as with GLP-1 receptor agonists, they tend to occur — if they occur — early in the course of therapy. So, we saw it more as we were uptitrating doses of tirzepatide. I anticipate that we'll be able to manage these GI side effects as we do with the current GLP-1 receptor agonist.

Tirzepatide in the Clinic

Should tirzepatide be approved, we have a range of doses, which I think is important. We will generally start with a low dose and escalate the dose to 5, 10, or 15 mg. We need to individualize care as we do with any patient, with any chronic disease. We may have predetermined A1c goals or weight goals, and as we escalate the dose of tirzepatide, we'll see if patients are achieving these targets. If not, we may decide to escalate further.

We also need to take tolerability into the equation. If, for example, the patient is having GI side effects at a lower dose, we may want to escalate a bit more slowly or we may want to just stop escalating for that reason. If they're not achieving their A1c targets, we may want to see how they do with a higher dose. Having these three doses gives us flexibility, as we have with the GLP-1 receptors dulaglutide and semaglutide.

We're still awaiting the cardiovascular safety data. This is clearly very important. One cardiovascular study has completed, on which we'll report relatively soon, and there's a much longer cardiovascular trial that's currently ongoing. We'll need to weigh the cardiovascular safety and the safety profile we've seen in the other trials with the very robust efficacy we've seen in these trials.

I think there is a great future for patients with type 2 diabetes. In addition to tirzepatide, there are other dual and triple agonists that are being studied. They are earlier in clinical development, and we'll be seeing data in the next several years.

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