medwireNews: The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 receptor agonist tirzepatide has “potent glucose-lowering effects towards near-normal ranges,” and also induces significant weight loss in people with type 2 diabetes, say the SURPASS-1 investigators.
The phase 3 findings were reported at the virtual ADA 81st Scientific Sessions and simultaneously published in The Lancet.
In a commentary accompanying the publication, Tricia Tan (Imperial College London, UK) and Bernard Khoo (University College London) compare the findings with published GLP-1 receptor agonist efficacy data and conclude that the dual agonist – or “twincretin” – “appears to represent an advancement over current GLP-1 analogues, providing enhanced glycaemic and weight benefits without an added penalty in terms of gastrointestinal adverse effects.”
But they add: “The mechanism by which it achieves this effect remains unclear.”
SURPASS-1 tested tirzepatide against placebo in 478 people (average age 54 years, 48% women) with uncontrolled type 2 diabetes, who had never used injectable diabetes medications and had not used oral ones within the 3 months prior to baseline.
Julio Rosenstock (Dallas Diabetes Research Center at Medical City, Texas, USA) and co-investigators randomly assigned these study participants to receive tirzepatide at a weekly dose of 5, 10, or 15 mg, or to receive placebo injections.
To help minimize the known gastrointestinal side effects of GLP-1 receptor agonists, participants received tirzepatide at a starting dose of 2.5 mg/week, which was escalated by 2.5 mg every 4 weeks to the target dose, which was continued to week 40. Participants taking 5, 10, and 15 mg therefore took tirzepatide at the target dose for 36, 28, and 20 weeks, respectively.
The study participants had an average baseline glycated hemoglobin (HbA1c) level of 7.94% (63 mmol/mol), and by week 40 the average reductions achieved versus placebo were 1.91%, 1.93%, and 2.11% (20.80, 21.10, and 23.10 mmol/mol) for people taking 5, 10, and 15 mg tirzepatide, respectively.
Compared against people taking placebo, the proportions of people achieving HbA1c below 7.0% (53 mmol/mol) were 49.0%, 80.4%, and 52.9% with tirzepatide 5, 10, and 15 mg, respectively. The corresponding proportions for the more stringent target of 5.7% (39 mmol/mol) were 40.3%, 34.1%, and 85.1%.
Tirzepatide treatment also resulted in significant weight loss, with average bodyweight reductions versus placebo of 6.3, 7.1, and 8.8 kg for the 5, 10, and 15 mg groups, respectively. Moreover, 67–78% of people treated with tirzepatide lost at least 5% of their starting bodyweight, while 31–47% lost at least 10% and 13–27% at least 15%.
As expected, and despite the slow dose titration, gastrointestinal events were the most common treatment-emergent adverse events, with nausea reported in 12–18% of people taking tirzepatide versus 6% of the placebo group, and diarrhea in a corresponding 12–14% versus 8%.
Although the largest number of study discontinuations occurred in the tirzepatide 15 mg group (26 vs 11–17 of the other groups), the researchers note that most of these discontinuations “were for reasons other than adverse events.” None of the tirzepatide-treated participants experienced clinically significant hypoglycemia (blood glucose <54 mg/dL; 3.0 mmol/L), but this occurred in 6% of the placebo group.
In their commentary, Tan and Khoo highlight the favorable changes in lipid profiles, including around a 20% reduction in triglyceride levels, which they describe as “encouraging,” given the uncertain effects of GIP on adipose tissue and atherogenesis.
But they say that the results of SURPASS-CVOT, due in 2024, “will be pivotal in reassuring clinicians that twincretins indeed represent the next step in type 2 diabetes treatment.”
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