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Clinical Professor of Medicine
University of Washington
Rockwood Center for Diabetes and Endocrinology
Rockwood Clinic/MultiCare Health System
Carol Hatch Wysham, MD, has disclosed that she has received funds for research support from Abbott, Allergan, Lilly, and Novo Nordisk; consulting fees from Abbott, Janssen, Novo Nordisk, and Sanofi; and fees for non-CME/CE services from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and Sanofi.
There are many treatment options for managing patients with type 2 diabetes (T2D), ranging from new classes of antihyperglycemic agents to traditional therapies, such as insulin and sulfonylureas. Despite these medications, increasing numbers of patients with diabetes continue to experience complications associated with diabetes. Indeed, recent data suggest that levels of glycemic control in patients with T2D have deteriorated. Thus, there are still practice gaps that healthcare professionals need to address, and to do so, we need more effective medications with longer durability and more favorable tolerability—medications that have even greater impact on the major risk factors for diabetic complications, such as cardiovascular disease, stroke, and chronic kidney disease. Ideally, these medications need to be easy to initiate and should allow us to advise patients on how to adjust dosing based on treatment response.
So there are many features we would like to see in newer antihyperglycemic agents. Although there are many ongoing investigations of novel candidates for T2D at various stages of development, there is one agent in late‑stage development that merits discussion on its potential role in the treatment of T2D: tirzepatide.
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Although healthcare professionals are familiar with GLP-1 receptor agonists, GIP is the other major incretin hormone that stimulates insulin secretion and, therefore, also serves as a potential therapeutic target. Early phase II data indicated that tirzepatide was associated with reductions in A1C and weight in patients with T2D. Additional phase II trials evaluated tirzepatide (5 mg, 10 mg, 15 mg weekly) against dulaglutide 1.5 mg and placebo, showing substantially greater weight loss and A1C reduction with tirzepatide compared with dulaglutide in patients with T2D. Whereas early studies did show gastrointestinal (GI) tolerability issues with tirzepatide, subsequent lower dosing (2.5 mg) followed by uptitration (increase of 2.5 mg monthly) to maximum dose (15 mg) indicated that GI tolerability with tirzepatide was similar to that seen with GLP-1 receptor agonists. The results of these studies led to a series of phase III trials known as the SURPASS studies, 2 of which I’ve highlighted for the effect on glucose and weight of tirzepatide in patients with T2D.
The SURPASS‑2 study was a 40-week study comparing tirzepatide 5 mg, 10 mg, and 15 mg weekly to semaglutide 1 mg weekly in patients T2D. All 3 doses of tirzepatide had significantly greater A1C reduction vs semaglutide 1 mg (-2.46% vs -1.86% at maximum doses, respectively; P = .02). Reductions in body weight were also significantly greater with tirzepatide than with semaglutide (-13.1% vs -6.7% at maximum doses, respectively; P <.001). The observed reduction in body weight is clinically important. As we know from the Look AHEAD study, a 10% body weight loss is associated with an approximately 20% reduction in adverse cardiovascular outcomes. From that perspective, we are looking at an agent that may result in more than one half of our patients achieving a body weight reduction substantial enough to potentially affect their cardiovascular risk. The most common adverse events with tirzepatide and semaglutide were GI in nature, were primarily mild to moderate in severity, and diminished over time.
The SURPASS-4 study evaluated tirzepatide vs insulin glargine in patients with T2D and increased cardiovascular risk. Although all 3 doses of tirzepatide led to superior A1C and body weight reductions over 52 weeks, the maximum dose of tirzepatide reduced A1C by 2.58% and body weight by 13.0% compared with 1.44% and 2.2%, respectively, with insulin glargine. These data support results of previous studies with tirzepatide.
Use in Clinical Practice
The New Drug Application for tirzepatide is likely to be submitted to the FDA by the end of 2021 for regulatory review, so the question for healthcare professionals might be: “How does this medication fit into my treatment regimen?” Current American Diabetes Association guidelines recommend sodium-glucose transport protein 2 inhibitors for patients who have chronic kidney disease or heart failure, and I tend to use the GLP‑1 receptor agonists more often for patients with isolated atherosclerotic vascular disease. Where GLP‑1 receptor agonists are used to avoid hypoglycemia and promote weight reduction, I believe tirzepatide has the potential to replace GLP‑1 receptor agonists in that regard. The ongoing clinical trial of tirzepatide vs dulaglutide (SURPASS-6) will determine its benefits for cardiovascular risk reduction, but I do see the potential for tirzepatide to replace GLP‑1 receptor agonists as my first‑line therapy for patients with T2D who have atherosclerotic vascular disease.
At this time, tirzepatide looks to be highly effective and similarly tolerated as GLP‑1 receptor agonists in patients with T2D. A potential question for healthcare professionals is how best to titrate upwards when using tirzepatide. It will be important to maintain communication with patients to make sure they are titrating as directed, asking how they are tolerating the medication, and whether they have any questions or concerns.
In summary, I’m enthusiastic about the potential benefits of tirzepatide for our patients with T2D and obesity, as well as for cardiovascular disease, if the SURPASS-CVOT study suggests so. Tirzepatide has been compared favorably with semaglutide, insulin glargine, and insulin degludec in patients with T2D, with greater reductions in A1C and body weight, as well as greater improvement in cardiovascular risk factors (blood pressure, triglycerides, and high-density lipoprotein cholesterol) with comparable tolerability to GLP-1 receptor agonists. I look forward to its continued development.
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