Baseline Characteristics
Pre-semaglutide therapy, 87 (46.0%) of the participants were male, with a mean age (± SD) of 61.1 (± 11.2) years, HbA1c of 77.8 (± 17.9) mmol/mol (9.3 [± 1.8%]), body weight of 101.8 (± 19.5) kg, BMI of 35.6 (± 6.6) kg/m2 and serum creatinine of 83.8 (± 35.0) μmol/L. Prior to commencing semaglutide, 142 (75.1%) patients were prescribed metformin, 66 (34.1%) a sulphonyurea, nine (4.8%) pioglitazone, 43 (22.2%) a dipeptidyl peptidase-4 (DPP-4) inhibitor, 89 (47.1%) a sodium-glucose co-transporter-2 (SGLT-2) inhibitor and 83 (43.9%) insulin. Interestingly, 82 (43.4%) patients were previously prescribed a different GLP-1RA (60 liraglutide, 17 dulaglutide, 4 exenatide once-weekly, 1 lixisenatide). Pharmacological therapies for T2D prescribed to patients prior to semaglutide initiation is presented in Fig. 1. As a result of initiating semaglutide, pre-existing GLP-1RA therapy and DPP-4 inhibitor therapies were discontinued in 82 (43.4%) and 43 (22.2%) participants, respectively. Reasons for initiating or switching to semaglutide included: fewer injections (11.6%), the need for weight loss (17.5%), inadequate glycaemic control (38.1%) or both the need for weight loss and inadequate glycaemic control (32.8%).
Changes in Metabolic Risk Factors
At 6 months following semaglutide initiation, there were significant improvements in mean HbA1c of 13.3 mmol/mol (1.2%) and a mean weight loss of 3.0 kg (both p < 0.001). There were statistically significant reductions in the mean SBP (1.8 mmHg) and serum triglycerides (0.4 mmol/L) (both p = 0.04). There were no significant changes in the DBP, total cholesterol, HDL, ALT or serum creatinine at the 6-month follow-up visit. These data are shown in Table 1.
Table 1 Changes in metabolic risk factors at 6 months Following 12 months of therapy with semaglutide, there were only limited data available to evaluate changes in SBP, DBP and body weight. Exploratory analysis of the available biochemical follow-up data revealed significant reductions in HbA1c (16.4 mmol/mol [1.5%], p < 0.001), total cholesterol (0.5 mmol/L, p < 0.001) and ALT (4.8 IU/L, p = 0.02). These data are presented in Table 2.
Table 2 Changes in metabolic risk factors over 12 months of follow-up Subgroup Analyses
GLP-1RA Groups
There were no statistically significant differences in baseline characteristics (age, BMI, weight, blood pressure, HbA1c and lipid profile) between the two GLP-1RA groups. Patients naïve to GLP-1RA at baseline had a mean HbA1c reduction of 15.3 mmol/mol (12.1–18.4 mmol/mol [1.4%]) at 6 months compared with a reduction of 10.6 mmol/mol (7.2–14.0 mmol/mol [1.0%]) in those switched from a different GLP-1RA. The ANOVA showed an interaction (p < 0.04), indicating significantly greater response in patients with no previous exposure to GLP-1RA. At 6 months, there was a mean reduction in the BMI of 1.7 (0.8–2.7) kg/m2 in those with previous GLP-1RA use compared with a reduction of 1.1 (0.7–1.5) kg/m2 in those naïve to GLP-1RA therapy (interaction not significant, p = 0.14). These data are shown in Fig. 2.
Glycaemic Control Groups
We chose a priori to divide participants into glycaemic control groups based on a HbA1c cutoff of 75 mmol/mol (9.0%), with the aim to compare changes in clinical measurements, as this cutoff is the HbA1c threshold recommended by NICE to consider insulin initiation [9] and previous studies have observed greater HbA1c reductions in those with a greater baseline HbA1c [14]. Patients with a pre-treatment HbA1c ≥ 75 mmol/mol (9.0%) demonstrated significant reductions in HbA1c of 17.7 (13.9–21.5) mmol/mol (1.6%) at 6 months, compared with a mean reduction of 8.4 (6.4–10.4) mmol/mol (0.8%) in those with a baseline HbA1c < 75 mmol/mol (9.0%) (interaction p < 0.001). At 6 months, there was a mean weight loss of 3.3 (1.7–5.0) kg in those with HbA1c ≥ 75 mmol/mol (9.0%) and 3.4 (2.1–4.7) kg in those with HbA1c < 75 mmol/mol (9.0%) (interaction not significant, p = 0.93). At 6 months, there was also a mean BMI reduction of 1.4 (0.6–2.1) kg/m2 in those with baseline HbA1c ≥ 75 mmol/mol (9.0%) and 1.3 (0.8–1.8) kg/m2 in those with baseline HbA1c < 75 mmol/mol (9.0%) (interaction not significant, p = 0.91). These data are shown in Fig. 2.
BMI Groups
We examined changes in clinical measurements grouped by pre-treatment BMI in 144 subjects with available baseline BMI and follow-up data. Participants were divided into two groups defined by baseline BMI of 35.0 kg/m2. This BMI cutoff was selected as people with diabetes and a BMI ≥ 35.0 kg/m2 are generally recommended to commence GLP-1RA therapy [9] and the median baseline BMI of this cohort was 34.9 kg/m2. At baseline, patients with BMI < 35.0 kg/m2 were older than those with BMI ≥ 35.0 kg/m2 (63.0 ± 10.6 vs. 58.5 ± 11.5 years, p = 0.02), but there were no significant differences in blood pressure, HbA1c and lipid profiles. At 6 months, patients with a baseline BMI ≥ 35.0 kg/m2 had a mean reduction in HbA1c of 15.4 (11.5–19.3) mmol/mol (1.4%), compared with a mean reduction of 11.8 (9.1–14.6) mmol/mol (1.1%) in those with a baseline BMI < 35.0 kg/m2 (interaction not significant, p = 0.14). Patients with BMI < 35.0 kg/m2 had a mean weight loss of 3.2 (1.9–4.5) kg at 6 months, compared with 3.6 (1.9–5.2) kg in those with a baseline BMI ≥ 35.0 kg/m2 (interaction not significant, p = 0.77). Those with a baseline BMI < 35.0 kg/m2 had a mean BMI reduction of 1.0 (0.5–1.4) kg/m2 compared with a mean reduction of 1.8 (1.0–2.6) kg/m2 in those with baseline BMI ≥ 35.0 kg/m2 (interaction not significant, p = 0.06). These data are presented in Fig. 2.
Safety and Acceptability
Of the 189 patients with at least one follow-up visit, semaglutide was discontinued in 18 patients (9.5%) because of nausea and vomiting (n = 12), diarrhoea (n = 4), abdominal cramps (n = 1) or tiredness (n = 1). Dose increases were limited in 11 patients (5.8%) by nausea and vomiting (n = 5), dyspepsia (n = 4), abdominal cramps (n = 1) and diarrhoea (n = 1). The remaining 160 patients (84.7%) continued to use semaglutide without significant side-effects.
In participants who switched from an alternative GLP-1RA, semaglutide was started at a dose of 0.25 mg weekly in 21 (25.6%) people, 0.5 mg weekly in 52 (63.4%) people and 1.0 mg weekly in nine (11.0%) people. In those who switched from an alternative GLP-1RA, semaglutide was discontinued in five (6.1%) people compared with 13 (12.1%) of those previously naïve to GLP-1RA. Dose increases were limited by side-effects in three (3.7%) people switching GLP-1RA and in eight (4.4%) people naïve to GLP-1RA treatment.