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Adding an investigational glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist to insulin improved glycemic control in patients with type 2 diabetes, according to the phase III SURPASS-5 trial.

Among 475 patients randomized in a 1:1:1:1 fashion, those on one of three doses of injectable tirzepatide -- 5 mg, 10 mg, or 15 mg -- in addition to insulin glargine saw a significantly greater mean change in HbA1c from baseline, reported Ángel Rodríguez, MD, PhD, of Lilly Spain in Madrid, and colleagues in .

All doses resulted in a greater mean change in HbA1c at 40 weeks compared with placebo (-0.86%, 95% CI -1.03 to -0.70; P<0.001 for all):

• 5 mg: -2.11% (95% CI -2.28 to -1.94)
• 10 mg: -2.40% (95% CI -2.56 to -2.23)
• 15 mg: -2.34% (95% CI -2.51 to -2.16)

Likewise, a significantly greater proportion of patients on tirzepatide were able to achieve a target HbA1c under 7% by week 40: 87.3% with 5 mg, 89.6% with 10 mg, and 84.7% with 15 mg versus 34.5% with placebo. This pattern continued, with a significantly greater proportion of those on tirzepatide also achieving an HbA1c under 6.5% and even under 5.7%.

As for mean changes in body weight -- one of the many secondary endpoints -- participants on all doses of tirzepatide saw a significant drop from baseline, whereas the placebo group gained a bit (mean change 1.6 kg, 95% CI 0.5-2.8):

• 5 mg: -5.4 kg (95% CI -6.6 to -4.3)
• 10 mg: -7.5 kg (95% CI -8.6 to -6.3)
• 15 mg: -8.8 kg (95% CI -10.0 to -7.7)

These findings build upon other positive findings from the SURPASS clinical program. For example, the open-label SURPASS-2 trial, the results of which were presented at the virtual American Diabetes Association Scientific Sessions last year, found that tirzepatide was both noninferior -- and superior -- to the GLP-1 receptor agonist semaglutide (Ozempic) at reducing HbA1c levels.

All 475 patients (44% women, mean age 60.6) included in the current study had type 2 diabetes, a baseline HbA1c of 7% to 10.5%, and a BMI of at least 23, and were receiving stable doses of once-daily insulin glargine (over 20 IU/d or over 0.25 IU/kg/d) with or without metformin (≥1,500 mg/d).

At randomization, all patients were not well-controlled with their insulin glargine and required a dose increase, based on a median value of the last three self-monitored fasting blood glucose levels over 100 mg/dL.

During the 40-week treatment period, the first 4 weeks included an insulin stabilization period, which were then followed by a 36-week insulin titration period. All patients continued to administer insulin glargine once daily for the duration of the study. Any patients on metformin at baseline continued on their original dose.

Those on tirzepatide were started on a subcutaneous injection of 2.5 mg, which was subsequently increased by 2.5 mg every 4 weeks until the target dose was achieved.

As to be expected with an agent containing a GLP-1 receptor agonist, the most common treatment-emergent adverse events in the tirzepatide group were gastrointestinal related and included diarrhea (12%-21% vs 10% for placebo) and nausea (13%-18% vs 3% for placebo).

Treatment was discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg group, 18% in the 15-mg group, and 3% in the placebo group.

In an , Stuart R. Chipkin, MD, of the University of Massachusetts in Amherst, pointed out that the study protocol deviated slightly from usual clinical care, in that it didn't allow for dividing glargine doses, or adding short-acting insulin or other prandial therapies.

Based on baseline 7-point self-monitored blood glucose profiles, these participants had a history of steadily increasing glucose levels.

"Clinicians who encounter patients with such a profile may target postprandial control rather than continuing to 'double down' on once-daily glargine," Chipkin wrote. "Conversely, because the inclusion criteria allowed study participants with HbA1c values of 7.5%, many clinicians might look to other treatment options besides insulin glargine to achieve the small improvement needed to reach target levels."

While he praised tirzepatide for resulting in significant drops in HbA1c and weight, he noted that the trial didn't quite answer the question of whether or not these patients could reduce their insulin.

Although the study further confirmed the efficacy of this novel agent and will likely help to solidify the highly anticipated FDA approval, Chipkin said it "may leave clinicians uncertain about when and how to best use tirzepatide to improve clinical outcomes for patients with type 2 diabetes."

Developer that the FDA accepted its new drug application for tirzepatide in mid-December 2021. The company also said it has plans to initiate more tirzepatide trials, which will include phase III studies focusing on obesity-related outcomes and obstructive sleep apnea, plus a phase II mechanism-of-action study in chronic kidney disease.

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