FDA approves tirzepatide, first dual incretin agonist for type 2 diabetes

Daniel S. Hsia, MD

To have another novel agent to add to our armamentarium — the first combination GLP-1/GIP agonist — is really exciting. On top of that, the added benefit of weight loss for patients with type 2 diabetes is equally exciting. From the clinical trial data, GLP-1 and GIP seem to work synergistically. From a CV standpoint, we want to make sure these agents are safe; that trial is currently ongoing. We also hope to see additional benefits, similar to what we see with the SGLT2 inhibitors and GLP-1 receptor agonists with lowering CV risk; SGLT2 inhibitors are approved specifically for heart failure. The weight loss benefits of tirzepatide are promising. Many of our patients do not have type 2 diabetes alone; there are other comorbidities. If we can treat multiple diseases with one drug, our patients are much better off. Hopefully, this will be covered by insurance plans, so our patients have access to it.

Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC

This FDA approval is for the type 2 diabetes indication; however, on the heels of the recent announcement of the topline results released from SURMONT-1, I also anxiously await the FDA approval of tirzepatide for weight loss management. SURMONT-1 enrolled 2,539 adult patients without type 2 diabetes who were overweight or obese with a history of weight-related comorbidities and at least one previous unsuccessful attempt at weight loss through dieting. In that trial, tirzepatide conferred significant weight loss in a dose-responsive fashion, with an astonishing 22.5% weight loss (–24 kg or –52 lb) at the highest tested dose (15 mg). I am still blown away by these results. I will repeat: 52 lbs. This is in the territory of degree of weight loss conferred by bariatric surgery, now delivered with a pharmacologic agent. Indeed, we are definitely in a brand-new territory.

Semaglutide 2.4 mg is already FDA-approved for weight management and in the STEP 1 trial, semaglutide 2.4 mg conferred 12.4% weight loss or an average of 15.3 kg, which already was impressive. We should use caution when comparing STEP 1 and SURMOUNT-1, since they were not compared head-to-head in the same population; however, it does seem that the dual incretin agonists of GIP and GLP-1 together seem to confer much greater weight loss than GLP-1 alone, without an apparent excess of adverse effects.

I am happy to have a new option for type 2 diabetes in the form of tirzepatide. I eagerly await its approval for weight management, which should come soon. A bit further down the line, I also anxiously await the CV outcome trial for tirzepatide (SURPASS-CVOT) which is being conducted in persons with type 2 diabetes. This is going to be an interesting trial because the comparator is dulaglutide (Trulicity, Eli Lilly), so it will be interesting to see if tirzepatide confers additional CV outcome benefits over dulaglutide alone.

George Grunberger, MD, FACP, MACE

This approval was long-awaited. There are two things that are relevant for clinicians and patients. One, it is the first drug in its class. The second is that this drug was compared in head-to-head studies against a leader, semaglutide. Apart from insulin, this is the most effective medication, at least in the research studies, to show reduction in HbA1c in addition to weight loss. It is unprecedented. That is the good news. The “old fashioned” results reported how many people are meeting the American Diabetes Association target of an HbA1c of 7%. With this drug, a large percentage saw their HbA1c fall to under 5.7%, non-diabetic range. Between that and the weight loss, this could potentially set a new paradigm of what constitutes “success.” The reduction in HbA1c may be due to the weight loss. That is exciting. If this turns out to be effective for weight loss, it should be used immediately, perhaps for patients with prediabetes, overweight or obesity to prevent disease.

Keith C. Ferdinand, MD, FACC, FAHA, FASPC, FNLA

The rates of diabetes in the U.S. continue to increase, which is one of the major factors contributing to the national increase in CV mortality. This agent appears to be an effective added means of lowering HbA1c beyond what we have in already well-described studies of antidiabetes medications, including the GLP-1 receptor agonists.

As a cardiologist, I am impressed with the weight loss shown with this agent. In fact, although it is not yet approved for weight loss per se, overall there appears to be more than 12 lbs of weight loss compared with semaglutide, 29 lbs greater weight loss compared with insulin degludec and 27 lbs greater weight loss than insulin glargine. I look forward to the national approval for weight loss to help combat the marked increase in obesity across all populations, especially African American and Hispanic individuals, which is an underlying reason for the increasing rates of diabetes and CVD.

This agent appears to be a potentially effective agent in terms of BP reduction. Though the patients in the trial had systolic BP in the 129 mm Hg to 131 mm Hg range, there was a significant BP reduction with tirzepatide. We know that 80% of persons with type 2 diabetes have comorbid hypertension, and that hypertension is perhaps the most prevalent and potent CV risk factor, along with hyperlipidemia, for coronary disease, MIs and strokes. We would not expect this to be approved for hypertension per se, but it would be a bonus if the planned CV outcomes trial comparing it with dulaglutide, a proven GLP-1 receptor agonist, showed positive benefit in that area.

Unfortunately, as with many breakthrough medications, the clinical trials on which tirzepatide’s approval was based have an underrepresentation of the diverse population that represents the U.S. Only approximately 4% of the patients in the trial were Black, whereas the rates of CVD, MI, strokes, obesity and diabetes are disproportionately high in that population. I would not expect any unusual results in terms of benefits or adverse events with this agent in non-Hispanic Black populations, but with the underrepresentation seen in the randomized clinical trial, this has not been proven.