Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial

Abstract

Context: Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin.

Objective: To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D.

Design: Phase 3a, double-blind, placebo-controlled, 30-week trial.

Setting: This study included 90 sites in five countries.

Patients: We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin.

Interventions: Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo.

Main outcome measures: Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30.

Results: At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/mol) with placebo [estimated treatment difference (ETD) vs placebo, -1.35 (14.8 mmol/mol); 95% CI, -1.61 to -1.10 and ETD, -1.75% (19.2 mmol/mol); 95% CI, -2.01 to -1.50; both P < 0.0001]. Severe or blood glucose-confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, -2.31; 95% CI, -3.33 to -1.29 and ETD, -5.06; 95% CI, -6.08 to -4.04 kg; both P < 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders.

Conclusions: Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.

Trial registration: ClinicalTrials.gov NCT02305381.

Figure 1.

Change in (A) mean HbA_1c, (B) fasting plasma glucose, (C) body weight, and (D) time to onset of hypoglycemia over time. Values are estimated means ± standard error from a mixed model for repeated measurements analysis using “on-treatment without rescue medication” data from patients in the full analysis set. The dashed line indicates the overall mean value at baseline. Values in square brackets indicate 95% CIs. ^aSignificant at P < 0.0001. ^bSignificant at P ≤ 0.0002. ETD, estimated treatment difference.

Figure 2.

Patients achieving (A) an HbA_1c target of <7% and (B) a body weight loss target of ≥5% (American Association of Clinical Endocrinologists target) at week 30. Values are observed proportions using “on-treatment without rescue medication” data from patients in the full analysis set. Missing HbA_1c and body weight data are imputed from a mixed model for repeated measurements analysis and subsequently classified. Values in square brackets indicate 95% CIs. ^aSignificant at P < 0.0001. EOR, estimated OR.

Figure 3.

Patients achieving the composite endpoint target of HbA_1c <7.0% without severe or blood glucose–confirmed symptomatic hypoglycemia and with no weight gain. Values are observed proportions using “on-treatment without rescue medication” data from patients in the full analysis set. Missing HbA_1c and body weight data were imputed from a mixed model for repeated measurements analysis and subsequently classified. “Blood glucose-confirmed” defined as blood glucose <3.1 mmol/L (56 mg/dL). Values in square brackets indicate 95% CIs. ^aSignificant at P < 0.0001. EOR, estimated OR.

Figure 4.

Observed mean seven-point self-measured blood glucose profile at baseline and at week 30. Values are observed means based on “on-treatment without rescue medication” data from patients in the full analysis set. Dashed lines represent week 0 data; solid lines represent week 30 data.