Tirzepatide SURPASSes semaglutide for HbA1c reductions, weight loss

In patients with type 2 diabetes (T2D), once-weekly doses of the dual glucose-dependent insulinotropic polypeptide–GLP-1* receptor agonist tirzepatide for 40 weeks resulted in superior HbA_1c reductions compared with the GLP-1 receptor agonist semaglutide, according to results from the phase III SURPASS-2** trial presented at ADA 2021.

A total of 1,879 adults (mean age 56.6 years, 53 percent female, mean body weight 93.7 kg) with T2D (mean HbA_1c 8.28 percent, duration 8.6 years) inadequately controlled by metformin (≥1,500 mg/day) were randomized 1:1:1:1 to receive subcutaneous tirzepatide 5, 10, or 15 mg, or semaglutide 1 mg QW for 40 weeks.

At week 40, mean reductions in HbA_1c from baseline were -2.01, -2.24, -2.30, and -1.86 percentage points for tirzepatide 5, 10, and 15 mg, and semaglutide, respectively. Mean HbA_1c was significantly reduced with any of the tirzepatide dosing regimens compared with semaglutide (estimated treatment difference [ETD], -0.15 percentage points; p=0.02 [5 mg], -0.39 percentage points; p<0.001 [10 mg], and -0.45 percentage points; p<0.001 [15 mg]), with tirzepatide demonstrating noninferiority and superiority over semaglutide. [ADA 2021, abstract 84-LB; N Engl J Med 2021;doi:10.1056/NEJMoa2107519]

Tirzepatide also resulted in greater weight loss compared with semaglutide, with mean losses of -7.6, -9.3, -11.2, and -5.7 kg with tirzepatide 5, 10, and 15 mg, and semaglutide, respectively, at 40 weeks (least-squares [LS] mean ETD, -1.9, -3.6, and -5.5 kg for tirzepatide 5, 10, and 15 mg, respectively vs semaglutide; p<0.001 for all).

A greater proportion of tirzepatide than semaglutide recipients achieved HbA_1c <7.0 (82–86 percent vs 79 percent) and <5.7 percent (27–46 percent vs 19 percent), as well as ≥5, ≥10, and ≥15 percent weight loss.

More tirzepatide than semaglutide recipients achieved the composite of HbA_1c ≤6.5 percent and ≥10 percent weight loss without clinically significant (<54 mg/dL) or severe hypoglycaemia (32–60 percent vs 22 percent).

Triglyceride and serum very-low-density lipoprotein (VLDL) levels were lower and high-density lipoprotein cholesterol levels higher among tirzepatide than semaglutide recipients at 40 weeks.

Adverse event (AE) incidence was comparable across the four groups. Serious AEs were more common among tirzepatide than semaglutide recipients (7.0, 5.3, and 5.7 percent [5, 10, and 15 mg, respectively] vs 2.8 percent), the most common being COVID-19–related pneumonia in all groups. AEs led to discontinuation in more tirzepatide than semaglutide recipients (6.0, 8.5, and 8.5 percent vs 4.1 percent).

The most common AEs were gastrointestinal (GI), namely nausea (17–22 percent [tirzepatide] vs 18 percent [semaglutide]), diarrhoea (13–16 percent vs 12 percent), vomiting (6–10 percent vs 8 percent), and decreased appetite (7–9 percent vs 5 percent), with most cases of nausea, diarrhoea, and vomiting mild to moderate in severity, transient, and occurring during initial dose escalation.

There were four deaths in each tirzepatide group (five COVID-19–related) and one in the semaglutide group, none deemed study drug related.

Clinically significant hypoglycaemia occurred in 0.6, 0.2, 1.7, and 0.4 percent of tirzepatide 5, 10, and 15 mg, and semaglutide recipients, respectively, and one patient each in the tirzepatide 5 mg and 15 groups experienced severe hypoglycaemia. Persistent hyperglycaemia necessitating rescue therapy was noted in 1.3–1.5 percent of tirzepatide and 2.8 percent of semaglutide recipients, respectively. Pancreatitis was documented in four tirzepatide and three semaglutide recipients, none serious. Four patients in each tirzepatide and two patients in the semaglutide group reported cholelithiasis. Two tirzepatide 10 mg recipients experienced diabetic retinopathy. There were no serious cases of injection-site reactions or hypersensitivity.

New horizons

“The novel concept of combining a glucose-dependent insulinotropic polypeptide with a GLP-1 receptor agonist takes incretin therapeutic agents to a new level,” remarked Professor Katherine Tuttle from the Providence Medical Research Center, Spokane, and the University of Washington, Seattle, Washington, US, in a commentary. [N Engl J Med 2021;doi:10.1056/NEJMe2109957] “In principle, [this combined treatment] would augment glucose lowering while providing defence against hypoglycaemia.”

“[HbA_1c <5.7 percent] without an increased risk of hypoglycaemia has not been considered attainable with current treatment options. In our trial, this goal was met with a GI-related side-effect profile that was similar to that reported with GLP-1 receptor agonists,” the authors highlighted.

“We speculate that [this] dual agonism … may allow some patients to reach near-normal glycaemia with potential long-term benefits,” they added.