Patient Disposition and Baseline Characteristics
Of the 221 patients who gave informed consent, six did not meet the eligibility criteria and were not enrolled into the study. The remaining 215 patients initiated treatment with semaglutide and were included in the FAS. In total, 34 patients attended the EOS visit after 38 weeks. A total of 44 patients did not complete the study and/or discontinued study treatment (Fig. 1). The 171 patients who completed the study on treatment comprised the EAS. The mean baseline HbA1c of patients in the FAS was 74.0 mmol/mol (8.9%), and 20 (9.3%) patients had HbA1c < 7% (Table 1). The majority (90.2%) were white and most (85.4%) had obesity, as defined by a BMI ≥ 30 kg/m2; this was reflected in the mean baseline body weight (107.8 kg), BMI (37.2 kg/m2) and waist circumference (118.6 cm) (Table 1).
Hypertension and dyslipidaemia were the most prevalent cardiovascular comorbidities at baseline, affecting 67.0% and 42.3% of patients, respectively (Table 1). The majority of the 215 patients in the FAS (94.9%) initiated semaglutide treatment at a dose of 0.25 mg (Table 1). Physicians primarily initiated semaglutide to improve glycaemic control; weight reduction was a secondary reason (Table 1). No patients were receiving both a dipeptidyl peptidase-4 inhibitor and a GLP-1RA (other than semaglutide) at baseline.
In the EAS, the estimated mean change in HbA1c from baseline to EOS was − 16.3 mmol/mol [95% CI − 18.22, − 14.37; p < 0.0001] or − 1.5%-points [95% CI − 1.67, − 1.31; p < 0.0001] (Table 2). The change in mean HbA1c over the course of the study in the FAS is shown in Supplementary Fig. S1. Analysis of the FAS produced results for the overall population that were consistent with those for the EAS (Table 2), and the sensitivity analysis carried out on the FAS, including all HbA1c measurements in the on-treatment observation period, supported the conclusions from the primary analysis. The results from the post-hoc sensitivity analysis, which was restricted to patients with visit 6 within the original visit window (week 28 to 38), were in line with the results of the primary analysis (Supplementary Table S1). At EOS, the proportion of patients achieving an HbA1c level of 53 mmol/mol (< 7%) was 46.4% in the EAS (Fig. 2).
Among the 130 patients in the EAS who were GLP-1RA naïve, the estimated mean change in HbA1c from baseline to EOS was comparable with that from the main analysis: − 17.1 mmol/mol (95% CI − 19.26, − 15.01; p < 0.0001) or − 1.6%-points (95% CI − 1.76, − 1.37; p < 0.0001). The estimated mean change in HbA1c from baseline to EOS in the EAS for the 82 patients who did not reach the target of a ≥ 1%-point HbA1c reduction and weight reduction of ≥ 3% at EOS was lower than in the complete EAS: − 10.1 mmol/mol (95% CI − 12.92, − 7.25; p < 0.0001) or − 0.9%-points (95% CI − 1.18, − 0.66; p < 0.0001). There were 63 patients in the EAS who had a BMI of < 35 kg/m2 at baseline. Among these patients, the estimated mean change in HbA1c from baseline to EOS was similar to that from the main analysis: − 17.2 mmol/mol (95% CI − 20.22, − 14.19; p < 0.0001) or − 1.6%-points (95% CI − 1.85, − 1.30; p < 0.0001).
Body Weight and Waist Circumference
In the EAS, the estimated mean change in body weight from baseline to EOS was − 5.8 kg (95% CI − 6.75, − 4.94; p < 0.0001), with similar results seen in the FAS (Table 2) and the EAS restricted to patients with a visit 6 within the original visit window (Supplementary Table S1). At EOS, the proportion of patients in the EAS achieving a weight reduction of ≥ 3% or ≥ 5% was 62.4% and 49.7%, respectively (Fig. 2). For the change in waist circumference, the estimated mean change from baseline to EOS was − 5.8 cm (95% CI − 7.05, − 4.55; p < 0.0001); again, similar results were seen in the FAS (Table 2).
The estimated mean change in body weight from baseline to EOS was − 6.5 kg (95% CI − 7.45, − 5.48; p < 0.0001) for the 130 GLP-1RA-naïve patients, − 2.6 kg (95% CI − 3.73, − 1.55; p < 0.0001) for the 82 patients who did not reach the target of a ≥ 1%-point HbA1c reduction and a weight reduction of ≥ 3% at EOS, and − 4.2 kg (95% CI − 5.33, − 2.98; p < 0.0001) for the 60 patients who had a BMI of < 35 kg/m2 at baseline (and weight reduction data available for analysis).
The proportion of patients achieving the composite endpoint of a ≥ 1%-point HbA1c reduction and a weight reduction of ≥ 3% was 39.7% (Fig. 2).
Use of Semaglutide and Other Antihyperglycaemic Medications (EAS)
The mean weekly dose of semaglutide at EOS was 0.73 ± 0.31 mg. At EOS, one patient (0.6%) was not receiving semaglutide at any dose (likely due to an interruption in treatment at the time of study completion), 29 (17.0%) patients were receiving 0.25 mg OW semaglutide; 47 (27.5%) were receiving 0.5 mg; one (0.6%) was receiving 0.75 mg OW semaglutide; and 93 (54.4%) were receiving 1.0 mg. Use of antihyperglycaemic medication either remained the same or declined from baseline to EOS, except that one additional patient reported the use of premixed insulin at EOS (Table 3).
Patient- and Physician-Reported Outcomes
The estimated mean self-reported treatment adherence score, measured using the MMAS-8, was 6.4 at baseline and 7.1 at EOS, with 29.7% and 48.1% of patients reporting high adherence, respectively (Table 4). Mean DTSQs score was 28.6 at baseline (observed) and 31.8 at EOS (estimated), resulting in an estimated change of 3.3 (95% CI 2.39, 4.11; p < 0.0001) (Supplementary Fig. S2). At EOS, the overall estimated mean DTSQc (change version) score was 14.4, indicating increased treatment satisfaction at EOS, and estimated changes from baseline to EOS in SF-36®v2 PCS and MCS scores were 1.7 (95% CI 0.44, 2.89; p = 0.008) and 0.8 (95% CI − 0.72, 2.33; p = 0.299), respectively (Supplementary Fig. S2). According to their physicians, the majority of the patients (85.4%) achieved clinical success at EOS in relation to the reason to initiate semaglutide treatment.
Overall, 157 AEs were reported in 76 patients in the FAS during the study (Table 5); the majority (137) of these events were considered non-serious. More than half of the 157 events (83) were gastrointestinal (Table 5). A total of 43 AEs in 22 patients (10.2% of the FAS) led to discontinuation of treatment. Twenty serious AEs were reported in 13 (6.0%) patients in the FAS. Twelve events in six (2.8%) patients were judged by the physician to be probably or possibly related to semaglutide treatment (i.e. 12 SADRs) (Table 5): five SADRs resolved by EOS, one SADR resolved with sequelae (a pancreatitis event of moderate severity) and one SADR was not resolved by EOS. The status of the remaining five events was unknown at EOS. Of the eight serious AEs (in eight patients) deemed unlikely to be related to semaglutide treatment, one event with a fatal outcome was reported (sudden death). Documented hypoglycaemia was reported from baseline to EOS in 14 (6.5%) patients in the EAS. There were no severe hypoglycaemic events reported.