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An investigational antidiabetic agent proved both non-inferior and superior to insulin for type 2 diabetes management, according to findings of the phase III SURPASS-3 trial.

Over the course of the 52-week trial, all three doses of tirzepatide -- a combination glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist -- led to significantly greater reductions in HbA1c versus insulin degludec, reported Ángel Rodríguez, MD, PhD, of Lilly Spain in Madrid, and colleagues.

Published in , the highest dose of once-weekly subcutaneous injection with tirzepatide yielded the biggest drops in HbA1c from an average baseline of 8.17%:

• Tirzepatide 5 mg: -1.93%
• Tirzepatide 10 mg: -2.20%
• Tirzepatide 15 mg: -2.37%
• Insulin degludec: -1.34%

These drops in baseline HbA1c seen with tirzepatide treatment met the non-inferiority margin of 0.3% when compared with insulin degludec -- meeting the trial's primary endpoint. And overall, the estimated treatment difference compared with insulin degludec ranged from -0.59% to -1.04% for HbA1c reduction when looking at all three tirzepatide doses (P<0.0001 for all).

On top of this, between 82% to 93% of patients on any dose of tirzepatide were able to achieve an HbA1c under 7% -- the set by the American Diabetes Association (ADA) -- by week 52 versus only 61% of those on insulin degludec.

Benefits of tirzepatide weren't just isolated to blood sugar control, but also extended to body weight reduction. By the end of the trial, all three doses of tirzepatide yielded significant body weight reductions from an average baseline of 94.3 kg (207.9 lb):

• Tirzepatide 5 mg: -7.5 kg (-16.5 lb)
• Tirzepatide 10 mg: -10.7 kg (-23.6 lb)
• Tirzepatide 15 mg: -12.9 kg (-28.4 lb)
• Insulin degludec: increase of 2.3 kg (5.1 lb)

Other benefits reaped by participants on tirzepatide included reduction in BMI, waist circumference, mean systolic and diastolic blood pressures, as well as decreases in average alanine aminotransferase and aspartate aminotransferase concentrations. Those on 15 mg of treatment also saw a significant reduction in urine albumin-to-creatinine ratio, triglycerides, and very-low-density lipoprotein (VLDL) cholesterol.

These findings build upon the prior findings from Eli Lilly's SURPASS clinical program. The second installment in this program, presented at this year's virtual ADA Scientific Sessions, found tirzepatide was likewise superior to GLP-1 receptor agonist semaglutide (Ozempic) for reducing HbA1c levels over 40 weeks.

Tirzepatide, a 39-amino acid synthetic peptide, is a novel compound acting as a dual GIP/GLP-1 receptor agonist. Current clinical practice guidelines recommend basal insulin or GLP-1 receptor agonists as the first-line injectable therapy in patients with type 2 diabetes. FDA approved GLP-1 receptor agonists on the market today include semaglutide (Ozempic for injectable, Rybelsus for oral), exenatide (Byetta), extended release exenatide (Bydureon), liraglutide (Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and lixisenatide (Adlyxin).

This open-label trial was conducted across 122 sites in 13 countries. All participants were at least 18 years old with type 2 diabetes, a baseline HbA1c ranging from 7% to 10.5%, and a BMI of at least 25. All participants were insulin-naive.

At the time of randomization, 68% of all participants were on metformin alone and the rest were on metformin plus an SGLT-2 inhibitor. Of note, there were no differences in HbA1c reduction between those participants that were on metformin alone at baseline or metformin plus an SGLT-2 inhibitor.

The intention-to-treat population included 1,437 participants total: 358 on tirzepatide 5 mg, 360 on tirzepatide 10 mg, 359 on tirzepatide 15 mg, and 360 on insulin degludec.

Administered once weekly via subcutaneous injection with a single-dose pen, tirzepatide was titrated up from an initial dose of 2.5 mg for 4 weeks, subsequently titrated up 2.5 mg every 4 weeks thereafter until the target dose was achieved.

Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 90 mg/dL. By week 52, the average insulin degludec dose was about 48.8 U per day.

As expected with any GLP-1 receptor agonist, the most common adverse events were gastrointestinal related, including diarrhea (15-17%), decreased appetite (6-12%), and nausea (12-24%) or vomiting (6-10%). Most occurred during dose-escalation, according to the authors, and discontinuation for toxicity was more common with tirzepatide.

Severe hypoglycemia -- defined as a blood glucose under 54 mg/dL -- was rare, only occurring in 1-2% of all tirzepatide group and 7% of the insulin group.

Five deaths occurred during the study, but none were deemed to be treatment related.

Developer Eli Lilly is also currently testing tirzepatide in a phase III trial for a . And in addition to the weight loss trial, the company is also currently testing this agent in a phase III cardiovascular outcomes trial, , with an expected completion date of October 2024.

These findings will ultimately tell us more about how tirzepatide will better fit into the type 2 diabetes treatment strategies, wrote authors Christopher Rayner, MBBS, PhD, and Michael Horowitz, MBBS, both of the University of Adelaide in Australia, who wrote "the positioning of tirzepatide in the therapeutic algorithm will be influenced by emerging information on cardiovascular outcomes, fatty liver disease, renal protection, and durability of effects, which is awaited with interest."

Nonetheless, Rayner and Horowitz said SURPASS-3 demonstrated "clinically meaningful outcomes" and "suggests that tirzepatide might be more potent than available GLP-1 receptor agonists" due to its combination with the GIP receptor agonist counterpart. However, they underscored that this GIP component is still poorly understood, particularly regarding its effects on adipose tissue, intestinal blood flow, glucagon secretion, and bone resorption.

As far as limitations to the trial, the commentators pointed out that there were relatively few Asian and Black participants included -- 5% and 3%, respectively -- and that the open-label design may have influenced patient reporting of gastrointestinal adverse events due to the "nocebo phenomena."

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