Combo GIP/GLP-1 Drug Superior for HbA1c Reduction in T2D

A novel antidiabetic agent beat out a tried-and-true favorite when it came to slashing HbA1c, according to the phase III SURPASS-2 trial.

In an open-label trial of adults with type 2 diabetes, tirzepatide was both non-inferior — and superior — in lowering glycated hemoglobin levels over 40 weeks when compared to the injectable glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (Ozempic), reported Juan P. Frías, MD, of the National Research Institute in Los Angeles, and colleagues.

The findings were presented at the virtual American Diabetes Association (ADA) Scientific Sessions and simultaneously published in the New England Journal of Medicine.

Those randomized to any of the three doses of tirzepatide — a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist — saw the greatest estimated mean changes in HbA1c levels from baseline:

• Tirzepatide 5 mg: -2.01%
• Tirzepatide 10 mg: -2.24%
• Tirzepatide 15 mg: -2.30%
• Semaglutide 1 mg: -1.86%

Compared with the 1 mg dose of semaglutide, those on any dose of tirzepatide also saw significantly greater estimated reductions in HbA1c:

• 5 mg: -0.15% (95% CI -0.28 to -0.03, P=0.02)
• 10 mg: -0.39% (95% CI -0.51 to -0.26, P<0.001)
• 15 mg: -0.45% (95% CI -0.57 to -0.32, P<0.001)

Of note, more than 86% of participants on the highest dose of tirzepatide were able to achieve an A1c below 7% (vs 79% of those on semaglutide) — the recommended target set by the ADA — and 46% on the 15 mg dose were able to achieve an A1c below 5.7% (vs 19% of those on semaglutide).

Paired with this HbA1c benefit, the 5 mg, 10 mg, and 15 mg doses of tirzepatide also yielded greater body weight reductions versus semaglutide — with the least-squares mean estimated treatment differences of -1.9 kg (-4.2 lb), -3.6 kg (-7.9 lb), and -5.5 kg (-12.1 lb), respectively (P<0.001 for all).

However, accompanying editorial author Katherine R. Tuttle, MD, of the University of Washington in Seattle, pointed out that although this weight benefit seen with tirzepatide was “impressive,” as weight loss didn’t even plateau yet by 40 weeks, it’s not directly comparable to 1 mg semaglutide since a higher dose (2.4 mg weekly) of semaglutide is currently indicated for chronic weight management.

But following suit after Novo Nordisk’s recent approval of the higher dose of semaglutide for obesity or overweight (Wegovy), Eli Lilly is testing tirzepatide in a phase III trial for the same indication.

In addition to the weight loss trial, Eli Lilly is also currently testing this agent in a phase III cardiovascular outcomes trial, SURPASS- CVOT, with an expected completion date of October 2024.

Semaglutide (Ozempic for injectable, Rybelsus for oral) is one of the several currently FDA approved GLP-1 receptor agonists, others of which include exenatide (Byetta), extended release exenatide (Bydureon), liraglutide (Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and lixisenatide (Adlyxin).

“Head-to-head studies are the gold standard for clinicians assessing the efficacy of investigational treatments, and these results show that all three doses of tirzepatide delivered superior A1C and weight reductions compared to the highest approved dose of semaglutide to treat type 2 diabetes,” Frías explained in a press statement. “Newer treatment options may help people with type 2 diabetes achieve their A1C and weight loss goals.”

“In SURPASS-2, tirzepatide delivered clinically meaningful efficacy, beyond what has been seen with an existing medicine in the established GLP-1 receptor agonist class,” he emphasized.

As expected with any agent including a GLP-1 receptor agonist component, the most common side effects seen with tirzepatide were mild to moderate gastrointestinal symptoms. Nausea was the most common event reported, occurring in 17-22% of those on tirzepatide versus 18% of those on semaglutide. Diarrhea occurred in 13-16% of tirzepatide patients and 12% of the semaglutide group, while vomiting affected 6-10% of the tirzepatide group and 8% of the semaglutide group.

As for hypoglycemia, few participants on either agent experienced an episode of a blood glucose level falling below 54 mg/dL, but was most common in the 15 mg tirzepatide group (1.7%).

A total of 5-7% of the tirzepatide-treated patients experienced a serious adverse event versus 3% of the semaglutide group.

The 40-week trial included 1,879 adults with type 2 diabetes, who were randomized in a 1:1:1:1 fashion. Representing eight countries, the average age of participants at baseline was 57. Mean baseline HbA1c level was 8.28%, the average weight was 93.7 kg (206.6 lb), and the average duration of diabetes was 8.6 years.

Tuttle pointed out one limitation to the trial — the underrepresentation of Black individuals, who made up 4% of the participant population. Instead, the participant pool was 70% Hispanic, owing to the large enrollment in Latin America.

All participants on tirzepatide began on a once-weekly dose of 2.5 mg, which was subsequently titrated up in 4-week intervals until the final maintenance dose was achieved. Those on semaglutide were started on a once-weekly dose of 0.25 mg for the first 4 weeks, and was subsequently titrated to a final 1 mg dose.