medwireNews: Tirzepatide, a dual agonist of the receptors for glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), is a promising treatment option for Japanese people with type 2 diabetes when used as monotherapy or added to antihyperglycemic agents, show the SURPASS J-mono and SURPASS J-combo trials.
The results of both phase 3 studies are published in The Lancet Diabetes & Endocrinology. SURPASS J-mono included 636 participants who were treatment-naïve or had discontinued glucose-lowering agents, whereas SURPASS J-combo involved 443 individuals with inadequately controlled type 2 diabetes despite receipt of a single oral antidiabetes drug for at least 3 months.
SURPASS J-mono
The SURPASS J-mono investigators, led by Masakazu Takeuchi (Eli Lilly Japan, Kobe), demonstrated significantly greater improvements in glycemic control among participants treated with one of three once-weekly doses of tirzepatide compared with dulaglutide.
Specifically, the least squares mean reduction in glycated hemoglobin (HbA1c) levels from baseline to the 1-year follow-up was 2.4% for participants randomly assigned to receive tirzepatide 5 mg, 2.6% for those given the 10 mg dose, and 2.8% for those given 15 mg, compared with 1.3% for people given dulaglutide 0.75 mg/week.
The SURPASS J-mono participants were predominantly men (76%), with an average age of 56.6 years, an average BMI of 28.1 kg/m2, and an average baseline HbA1c of 8.2% (66 mmol/mol). All participants were given subcutaneous tirzepatide at a starting dose of 2.5 mg/week for 4 weeks, followed by 2.5 mg increases every 4 weeks until they reached their assigned dose.
The researchers also found that a significantly higher proportion of individuals treated with the GLP-1/GIP receptor agonist at any dose versus dulaglutide reached HbA1c targets of 7.0% (53 mmol/mol; 97 vs 67%), 6.5% (48 mmol/mol; 95 vs 40%), or 5.7% (39 mmol/mol; 63 vs 3%).
“Importantly, HbA1c targets were reached without an increased risk of clinically significant hypoglycaemia,” say Takeuchi and team.
They also observed dose-dependent reductions in bodyweight with tirzepatide compared with dulaglutide.
The researchers report that the safety profile of tirzepatide “was consistent with the GLP-1 receptor agonist class and the global SURPASS trials,” with the most frequent treatment-emergent adverse events (TEAEs) being nausea, constipation, and nasopharyngitis.
SURPASS J-combo
SURPASS J-combo was designed as a safety study to evaluate tirzepatide as an add-on treatment option and did not include a comparator arm. Participants (mean age 57 years, 76% men) with inadequate glycemic control on sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, glinides, or sodium-glucose cotransporter 2 inhibitors were randomly assigned to receive once-weekly tirzepatide 5, 10, or 15 mg.
Rina Chin (Eli Lilly Japan, Tokyo) and co-investigators report that add-on tirzepatide was well tolerated, and no new safety signals were identified. A total of 77% of participants experienced TEAEs, with higher rates in the tirzepatide 15 mg group than in the 5 mg and 10 mg groups (84 vs 74 and 74%, respectively). Severe AEs were also more common in the 15 mg group (4 vs 3 and 1%, respectively). The most frequently occurring TEAEs in the overall population were nasopharyngitis (17%), nausea (17%), constipation (12%), and diarrhea (12%).
“Although the type and incidence of treatment-emergent adverse events were similar across various background oral antihyperglycaemic medication, a higher incidence of severe events occurred in patients receiving background biguanide and α-glucosidase inhibitor, which is in accordance with the known tolerability of these compounds in the Japanese population,” write Chin et al.
In accordance with the SURPASS J-mono results, the SURPASS J-combo investigators observed dose-dependent reductions in HbA1c and bodyweight during 1 year of tirzepatide treatment, irrespective of background medication use.
This “is particularly notable as sulfonylureas and thiazolidinediones are generally associated with weight gain,” remark Chin et al.
Writing in an accompanying comment, Michael Horowitz and colleagues from Adelaide Medical School in South Australia say that the two SURPASS J trials “attest to the efficacy of tirzepatide in Japanese patients with type 2 diabetes.”
However, they point out that “[w]hich individuals with type 2 diabetes would benefit the most from tirzepatide is a fundamental issue that needs to be addressed.”
The commentators say that future studies need to elucidate the impact of tirzepatide on gastric emptying, whether its efficacy is sustained in the long term, and whether people adhere to the agent in real-world practice.
“Finally, results from the ongoing SURPASS CVOT trial (NCT04255433; anticipated in 2025) will be pivotal to the positioning of tirzepatide in the therapeutic algorithm,” they conclude.
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