The pursuit of optimal semaglutide dosing in type 2 diabetes continues
Christina H Sherrill , Andrew Y Hwang
Diabetes remains a pressing global health concern, affecting approximately 540 million people worldwide.1
As prevalence continues to rise, diabetes places substantial burdens on individuals and health-care systems, influencing overall quality of life and health-care expenditures.
Moreover, type 2 diabetes is associated with an increased risk of cardiovascular disease, which remains the primary cause of death among individuals with type 2 diabetes.
Effective treatment of type 2 diabetes assumes paramount importance.
Optimal type 2 diabetes management requires consideration of comorbidities (specifically cardiovascular disease, heart failure, and chronic kidney disease), desired glycaemic efficacy, and weight management goals. GLP-1 agonists with evidence of cardiovascular benefit are preferred along with SGLT2 inhibitors in the setting of cardiovascular disease and secondary to SGLT2 inhibitors in the setting of chronic kidney disease. GLP-1 agonists have high or very high glycaemic efficacy and intermediate to very high weight lowering efficacy.
Semaglutide is a GLP-1 agonist that is available in oral and subcutaneous formulations; subcutaneous semaglutide has proven cardiovascular benefit and very high glycaemic and weight lowering efficacy, and oral semaglutide at a dose of 14 mg was found to be non-inferior to placebo regarding cardiovascular risk.
The full glycaemic and weight lowering potential of higher doses of oral semaglutide is unknown.
In The Lancet, Vanita R Aroda and colleagues report the results from the PIONEER PLUS study, a multicentre, randomised, double-blinded, active-controlled, phase 3b trial evaluating the efficacy and safety of two high-dose formulations of oral semaglutide (25 mg and 50 mg) compared with the standard oral dose (14 mg) among adults with uncontrolled type 2 diabetes. From 177 global sites, 1606 participants (mean [SD] age 58·2 [10·8] years; 42% women, 58% men. 78% identified as White, 17% Asian, 4% Black or African American, and 1% American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or Other ethnicity; mean glycated haemoglobin [HbA1c] 9·0%; mean bodyweight 96·4 kg) were randomly assigned 1:1:1 to receive once-daily maintenance doses of 14 mg, 25 mg, or 50 mg of oral semaglutide. Baseline metformin, sulfonylurea, or SGLT2 inhibitor were allowed to be continued throughout the study, although sulfonylurea dose could be decreased at the discretion of the investigator to reduce hypoglycaemia risk. Oral semaglutide was initiated following a titration schedule: 3 mg once daily, increasing to 7 mg at week 4, and 14 mg at week 8. Dose escalation continued in participants assigned to the intervention groups by increasing to 25 mg at week 12 and, for those assigned to receive the 50 mg maintenance dose, 50 mg at week 16. At week 12, extension of dosing intervals or dose reductions were permitted if participants had moderate-to-severe gastrointestinal adverse effects. The primary outcome was change in HbA1c from baseline to 52 weeks.