Impact of baseline characteristics and beta‐cell function on the efficacy and safety of subcutaneous once‐weekly semaglutide: A patient‐level, pooled analysis of the SUSTAIN 1‐5 trials

Abstract

Aim To evaluate the impact of relevant patient‐level characteristics on the efficacy and safety of subcutaneous, once‐weekly semaglutide in subjects with type 2 diabetes. Materials and Methods Exploratory post hoc analyses of pooled SUSTAIN 1‐5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose‐confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%‐8.0%, >8.0%‐8.5%, >8.5%‐9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta‐cell function. Results Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (−0.9%, −1.2%,‐1.5%, −1.7% and −2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and −1.1%, −1.4%, −1.9%, −2.1% and −2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%‐7.3% and 6.1%‐6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (−4.4, −3.9, −3.9, −3.3 and −2.9 kg [P = 0.004], and −6.4, −5.9, −5.2, −4.5 and −4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta‐cell function subgroups. Adverse events with semaglutide were consistent with the glucagon‐like peptide‐1 receptor agonist class, with gastrointestinal events the most common. Conclusions Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.

Effect of dulaglutide 3.0 and 4.5 mg on weight in patients with type 2 diabetes: Exploratory analyses of AWARD‐11

“…Changes in weight across all dulaglutide dose groups, as well as dose‐related treatment differences in weight loss, were larger among patients with lower (<8.5% [69 mmol/mol]) versus higher (≥8.5%) baseline HbA1c. This is consistent with prior studies suggesting an inverse relationship between the magnitude of GLP‐1 RA‐mediated weight loss and baseline HbA1c 21,29,30 . The physiological basis for this phenomenon is not clear, but could be related to greater reductions in energy loss through glucosuria following greater improvements in glycaemic control observed in the higher baseline HbA1c subgroup (and thus poorer baseline glycaemic control) compared with the lower baseline HbA1c subgroup 30–32 .…”

“…This is consistent with prior studies suggesting an inverse relationship between the magnitude of GLP‐1 RA‐mediated weight loss and baseline HbA1c. 21 , 29 , 30 The physiological basis for this phenomenon is not clear, but could be related to greater reductions in energy loss through glucosuria following greater improvements in glycaemic control observed in the higher baseline HbA1c subgroup (and thus poorer baseline glycaemic control) compared with the lower baseline HbA1c subgroup. 30 , 31 , 32 In other words, weight loss may be partially mitigated by greater calorie (energy) retention dictated by the diminished glucosuria occurring in subjects with more pronounced baseline hyperglycaemia.…”

Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A subgroup analysis by baseline variables in the PIONEER 9 and PIONEER 10 trials

“…This result was not consistent with subgroup analyses of the global PIONEER trials, in which there were no apparent patterns between the change in bodyweight and baseline HbA 1c 26 . For once‐weekly s.c. semaglutide, baseline HbA 1c did significantly affect the change from baseline in bodyweight in a global population, with weight loss decreasing as baseline HbA 1c increased 27 . In addition, the subgroup analysis of Japanese patients receiving dulaglutide 0.75 mg also found that lower baseline HbA 1c was significantly associated with greater bodyweight changes from baseline 28 .…”

“…A subgroup analysis of the global PIONEER 1–5, 7, and 8 trials, which used the same HbA 1c cut‐offs as the present analysis, also found that HbA 1c reductions from baseline were greater in patients with higher baseline HbA 1c compared with lower baseline HbA 1c 26 . This pattern was also observed in a subgroup analysis of once‐weekly s.c. semaglutide in a global population, although that analysis had a greater number of HbA 1c subgroups 27 . Furthermore, similar findings were also observed in subgroup analyses of Japanese patients who received other GLP‐1RAs, specifically dulaglutide 0.75 mg 28 and lixisenatide 20 μg 29 .…”

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme

“…Notably, patients with higher baseline HbA1c experienced greater estimated treatment differences in HbA1c with oral semaglutide compared to placebo. A greater glycaemic response at higher baseline HbA1c levels is a known phenomenon as baseline HbA1c is often a predictor of glycaemic response for many glucose‐lowering treatments, 19 including other glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) 20‐23 and once‐weekly subcutaneous semaglutide 24 . Since this phenomenon also applies to other glucose‐lowering treatments, it is not surprising that HbA1c level had less impact on the magnitude of estimated treatment differences in trials with an active comparator.…”