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

This 30-week, randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter, four-armed trial (NCT02305381↗; Supplemental Fig. 1) recruited patients from 90 sites in Germany, Japan, Serbia, Slovakia, and the United States. The trial was conducted in compliance with the International Conference on Harmonization Good Clinical Practice guidelines (19) and the Declaration of Helsinki (20). The protocol, which is available online, was approved by the relevant institutional review boards.

Eligible patients were ≥18 years of age (or ≥20 years of age in Japan) and diagnosed with T2D. All patients were receiving stable basal insulin therapy (minimum of 0.25 IU/kg/d and/or 20 IU/d of insulin glargine, insulin detemir, insulin degludec, and/or neutral protamine Hagedorn insulin) alone or in combination with metformin for 90 days prior to screening, with an HbA_1c level of 7.0% to 10.0% (53.0 to 85.8 mmol/mol). Key exclusion criteria included treatment with any glucose-lowering agent other than those listed herein in the 90 days prior to screening (excepting short-term bolus insulin therapy of ≤7 days); history of pancreatitis (acute or chronic); family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2; severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m² according to the Modification of Diet in Renal Disease formula); more than three episodes of severe hypoglycemia within the 6 months prior to screening; known proliferative retinopathy or maculopathy requiring acute treatment; or being pregnant, breastfeeding, or intending to become pregnant. Full inclusion and exclusion criteria are listed in Supplemental Table 1. Written informed consent was obtained from all patients before trial-related activities commenced.

Patients were randomized using an interactive voice/web-response system in a 2:2:1:1 ratio to receive once-weekly semaglutide (0.5 or 1.0 mg subcutaneously) or placebo administered subcutaneously as an add-on to pretrial background medication. Semaglutide and placebo treatments were, as far as possible, visually identical and packaged in a way so that study patients and investigators would not be able to distinguish between trial products. Furthermore, semaglutide and placebo were volume-matched during treatment to ensure blinding within dose level. The randomization was stratified according to HbA_1c level at screening (≤8.0% or >8.0%) and use of metformin (yes or no).

Patients with HbA_1c ≤8.0% (63.9 mmol/mol) at screening had their background basal insulin dose reduced by 20% at the start-of-trial medication to limit the potential risk of hypoglycemia. For these patients the insulin dose could be uptitrated from week 10 to week 16 (for further details, please see the titration protocol in the Supplemental Material). Increasing basal insulin dose before week 10 or after week 16 was avoided unless required to control acute hyperglycemia or prevent acute diabetic complications.

For all patients, insulin titrations were based on the lowest of three consecutive fasting self-measured blood glucose (SMBG) values according to a prespecified titration protocol (Supplemental Table 2). As far as possible, doses of basal insulin and metformin were to remain stable throughout the trial, with the exception of (1) dose reduction due to hypoglycemia or (2) confirmatory fasting plasma glucose (FPG) exceeding predefined limits per protocol, where the patient was offered intensification of therapy (rescue medication). Basal insulin dose increase was the first choice of rescue medication (Supplemental Material), which was initiated at the discretion of the investigator and in accordance with the American Diabetes Association (ADA)/European Association for the Study of Diabetes recommendations (21).

Patients received semaglutide (0.5 or 1.0 mg subcutaneously) or volume-matched placebo once weekly for 30 weeks followed by a 5-week follow-up period. Study medication was administered following a fixed dose-escalation regimen. For 0.5 mg, the maintenance dose was reached after 4 weeks of 0.25 mg semaglutide or matching placebo once weekly. For 1.0 mg, the maintenance dose was reached after 4 weeks of 0.25 mg, followed by 4 weeks of 0.5 mg semaglutide or matching placebo once weekly. Trial products were manufactured and supplied by Novo Nordisk A/S (Bagsvaerd, Denmark).

The primary outcome was the change in HbA_1c from baseline to week 30. The confirmatory secondary endpoint was the change in body weight from baseline to week 30. Secondary efficacy endpoints included the proportion of patients who achieved HbA_1c <7.0% (53 mmol/mol) (22) or ≤6.5% (48 mmol/mol) (23) by end of treatment; HbA_1c <7.0% without severe or blood glucose–confirmed symptomatic hypoglycemic episodes [plasma glucose level <3.1 mmol/L (56 mg/dL)] and no weight gain at week 30; change from baseline to week 30 in FPG; SMBG seven-point profiles and postprandial increments (mean over all meals); insulin dose; body mass index; waist circumference; proportion of patients who achieved weight loss of ≥5% and ≥10% at week 30; and change from baseline to week 30 of systolic and diastolic blood pressure, fasting lipids, and patient-reported outcomes [36-Item Short Form (SF-36v2) Health Survey and Diabetes Treatment Satisfaction Questionnaire].

Safety outcomes after 30 weeks of therapy included the number of treatment-emergent adverse events (AEs), severe or blood glucose–confirmed symptomatic hypoglycemic episodes (according to the ADA classification or blood glucose–confirmed by a plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycemia), and pulse rate. Hypoglycemia was assessed as a secondary safety endpoint. When a hypoglycemic episode was suspected, the blood glucose level at the time of the event was recorded as well as additional information relating to the circumstances of the patient. A hypoglycemic episode form was completed for each hypoglycemic episode; if the episode fulfilled the criteria for a serious AE, then an AE form and a safety information form were also completed. Hypoglycemic episodes were classified according to the Novo Nordisk A/S classification and ADA classification guidelines.

An external Event Adjudication Committee (EAC) validated predefined events of special interest [including those associated with GLP-1RA therapy: acute pancreatitis, neoplasm (excluding thyroid), and thyroid disease (including neoplasms)] in an independent, blinded manner (). Supplemental Material

The trial was designed to establish superiority jointly for both doses of semaglutide vs pooled placebo (hereafter referred to as “placebo”) for the change in HbA_1c and body weight at week 30 with a one-sided α of 2.5%, assuming treatment differences vs placebo of 0.45% and 2.25 kg for each semaglutide dose level, and SDs of 1.1% and 4.0 kg. The type I error probability was controlled at 2.5% (one-sided) across the four confirmatory superior hypotheses in a hierarchical testing strategy. For HbA_1c, the superiority of semaglutide vs placebo was tested first, starting with the highest semaglutide dose level, followed by body weight superiority vs placebo in the same dose order. Based on these assumptions and on a target sample size of 390 patients in total, the overall power to simultaneously demonstrate superiority on change in HbA_1c and body weight for the two dose levels of semaglutide vs placebo was 82% (full details are in Supplemental Material).

HbA_1c, body weight, and other continuous endpoints assessed over time were analyzed using a mixed model for repeated measurements, with treatment, country, and stratification variables [HbA_1c level at screening (≤8.0% or >8.0%) crossed with use of metformin (yes or no)] as fixed factors and baseline value as covariate, all nested within visit (full details are in Supplemental Material). Efficacy evaluations were based on the full analysis set, comprising all randomized patients exposed to at least one dose of trial product. The primary analyses used data collected before initiation of any rescue medication or before premature treatment discontinuation. The robustness of the analyses of HbA_1c and body weight was assessed by handling missing data in various ways, including a placebo-based multiple imputation model, in which missing data points were imputed as if the patient was receiving placebo. Details of the sensitivity analyses are included in Supplemental Material.

In total, 397 patients were randomized to receive semaglutide or placebo from 1 December 2014 through 21 November 2015; 396 patients were exposed to treatment, and 380 patients completed the trial (Supplemental Fig. 2). A total of 23 patients required rescue medication: three in the semaglutide 0.5 mg group, one in the semaglutide 1.0 mg group, and 19 in the placebo group. Baseline characteristics were similar between treatment groups (Table 1). The mean duration of diabetes prior to trial entry was 13.3 years (range, 0.4 to 39.6 years). The majority of patients were receiving insulin glargine therapy at baseline (Table 1).

Mean HbA_1c [baseline 8.4%; SD, 0.83 (67.9 mmol/mol; SD, 9.04)] levels decreased over time (Fig. 1A; Supplemental Fig. 3A). At week 30, mean HbA_1c values with semaglutide 0.5 and 1.0 mg were 6.9% and 6.5%, vs 8.3% with placebo, corresponding to reductions of 1.4% and 1.8% vs 0.1% with placebo [estimated treatment difference (ETD) vs placebo, –1.35%; 95% CI, –1.61 to –1.10 and ETD, –1.75%; 95% CI, –2.01 to –1.50; both P < 0.0001]. The changes from baseline in HbA_1c in patients with HbA_1c ≤8% at screening were –0.88% (SD, 0.94), –1.32% (SD, 0.71), and –0.04% (SD, 0.98) with semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo, respectively, whereas in patients with HbA_1c >8% the changes were –1.83% (SD, 1.00), –2.19% (SD, 0.86), and –0.28% (SD, 1.12), respectively.

Significantly more patients achieved an HbA_1c target of <7.0% with semaglutide 0.5 mg and 1.0 mg than with placebo (61%, 79%, and 11%) (Fig. 2A) and an HbA_1c target ≤6.5% with semaglutide 0.5 and 1.0 mg vs placebo (41%, 61%, and 5%) (Supplemental Fig. 4A). Significantly more patients achieved a composite endpoint of <7.0% without severe or blood glucose–confirmed symptomatic hypoglycemia and with no weight gain with semaglutide 0.5 and 1.0 mg compared with placebo (54%, 67%, and 7%) (Fig. 3).

At week 30, mean FPG values with semaglutide 0.5 and 1.0 mg were 7.0 and 6.3 mmol/L, vs 8.2 mmol/L with placebo, corresponding to decreases of 1.6 and 2.4 mmol/L, compared with 0.5 mmol/L with placebo (ETD, –1.14; 95% CI, –17.5 to –0.54 and ETD, –1.88; 95% CI, –2.48 to –1.28; both P < 0.001) (Fig. 1B; Supplemental Table 3). Both incremental and mean seven-point SMBG decreased significantly with semaglutide 0.5 mg (by 0.8 and 2.5 mmol/L; both P < 0.004) and 1.0 mg (by 1.2 and 3.0 mmol/L; P < 0.0001 for both) vs placebo (reductions of 0.2 and 0.8 mmol/L) (Fig. 4; Supplemental Table 3).

Severe or blood glucose–confirmed hypoglycemic episodes were reported in 11 (8.3%) patients (17 events) in the semaglutide 0.5 mg group, in 14 (10.7%) patients (25 events) in the semaglutide 1.0 mg group, and in 7 (5.3%) patients (13 events) in the placebo group. The estimated rate ratio for events of severe or blood glucose–confirmed hypoglycemia was 2.08 (95% CI, 0.67 to 6.51; P = 0.2071) for semaglutide 0.5 mg vs placebo and 2.41 (95% CI, 0.84 to 6.96; P = 0.1030) for semaglutide 1.0 mg vs placebo. Among patients with HbA_1c ≤8.0% at screening, the proportion of patients reporting these events was higher in both semaglutide groups vs the placebo group and highest in the higher-dose semaglutide group (15.7, 46.5, and 9.9 events per 100 patient-years of exposure for semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo, respectively). In subjects with HbA_1c >8%, the rates of “severe or BG-confirmed symptomatic” hypoglycemic episodes were comparable among the three groups (22.9, 21.2, and 18.6 events per 100 patient-years of exposure for semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo, respectively) (Fig. 1D; Supplemental Table 5; Supplemental Fig. 8).

Insulin dose decreased from baseline to week 30 with semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo (geometric means from 39.3 to 35.4, from 37.4 to 31.5, and from 36.6 to 35.2 IU). The end-of-treatment to baseline ratio for insulin dose with semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo was 0.90, 0.85, and 0.96 (estimated treatment ratio for semaglutide 0.5 mg and 1.0 mg vs placebo, 0.94; 95% CI, 0.90 to 0.98 and estimated treatment ratio, 0.88; 95% CI, 0.84 to 0.92; P = 0.0046 and P < 0.0001). The largest overall decrease in insulin dose was in patients with baseline HbA_1c <8.0%. These patients reduced their insulin dose by 20% at randomization, in accordance with protocol (Supplemental Fig. 5).

At week 30, mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo by 3.7, 6.4, and 1.4 kg (ETD for semaglutide 0.5 mg and 1.0 mg vs placebo, –2.31; 95% CI, –3.33 to –1.29 and ETD, –5.06; 95% CI, –6.08 to –4.04; both P < 0.0001) (Fig. 1C; Supplemental Fig. 3B). Body weight reductions of ≥5% were achieved in the semaglutide 0.5 mg, semaglutide 1.0 mg, and placebo groups by 42%, 66%, and 11% of patients and reductions of ≥10% by 9%, 26%, and 3% (Fig. 2B; Supplemental Fig. 4B).

Improvements in other efficacy endpoints, including lipid profile and systolic blood pressure, were observed with semaglutide vs placebo (Supplemental Tables 3 and 4). At week 30, mean systolic blood pressure values were 130.5 and 127.5 mm Hg for semaglutide 0.5 mg and 1.0 mg vs 133.8 mm Hg for placebo (ETD, –3.31; 95% CI, –6.92 to 0.31 and ETD, –6.29; 95% CI, –9.91 to –2.66; P = 0.0728 and P = 0.0007). Overall treatment satisfaction (measured by the Diabetes Treatment Satisfaction Questionnaire, status version) significantly improved with both semaglutide doses vs placebo (0.5 mg: ETD, 1.48; 95% CI, 0.14 to 2.82 and 1.0 mg: ETD, 2.22; 95% CI, 0.87 to 3.56) (Supplemental Fig. 6). No significant changes were evident from the SF-36v2 Health Survey questionnaire with either semaglutide dose compared with placebo.

The proportions of patients with AEs and serious AEs for semaglutide 0.5 and 1.0 mg vs placebo were 68.9%, 64.1%, and 57.9% and 6.1%, 9.2%, and 6.8% (Table 2). Rates of premature treatment discontinuation due to AEs were generally low but were higher with semaglutide 0.5 and 1.0 mg vs placebo (4.5% and 6.1% compared with 0.8% in the placebo group) and were primarily due to gastrointestinal (GI) AEs (Table 2).

No fatalities were reported during the trial. One patient receiving semaglutide 0.5 mg became pregnant during the trial and discontinued treatment after 106 days (fetal exposure was ∼9 weeks). A healthy baby was born with no known congenital abnormalities.

The most frequent AEs with semaglutide were GI AEs (Table 2). Nausea was reported in 11.4% of patients treated with semaglutide 0.5 mg and in 16.8% treated with semaglutide 1.0 mg compared with 4.5% receiving placebo. In general, the prevalence of nausea events over time with semaglutide treatment was ∼3% to 5% throughout the study (Supplemental Fig. 7A). The proportions of patients reporting vomiting were 6.1%, 11.5%, and 3.0% (the prevalence of vomiting events over time is shown in Supplemental Fig. 7B), and the proportions reporting diarrhea were 4.5%, 6.9%, and 1.5%. All GI AEs were mild to moderate in severity. Pulse rate increased from baseline by 1 beat per minute (bpm) with semaglutide 0.5 mg and by 4 bpm with semaglutide 1.0 mg, vs a decrease of 1 bpm with placebo (for semaglutide 1.0 mg vs placebo, P < 0.0001; Supplemental Table 3). The proportion of patients with diabetic retinopathy (DR) events was 3.0% with semaglutide 0.5 mg and 0.8% with semaglutide 1.0 mg; there were no patients with DR events on placebo.

Gallbladder-related AEs were reported in four semaglutide-treated patients. With semaglutide 0.5 mg, cholelithiasis, gallbladder disorder, and blood alkaline phosphatase were reported in three patients; with semaglutide 1.0 mg, acute cholecystitis was reported in one patient (Table 2). Mean lipase and amylase activity increased significantly from baseline to end of treatment with both semaglutide doses compared with placebo (P < 0.0001 for all) (Supplemental Table 6; Supplemental Fig. 9), although no pancreatitis events were confirmed by the EAC. Two investigator-reported events were sent for adjudication: one patient (female, age 47 years) receiving semaglutide 0.5 mg reported acute pancreatitis, which led to premature treatment discontinuation (reported on study day 152, concurrent mild vomiting); the second patient (male, age 55 years) receiving semaglutide 1.0 mg reported elevated lipase but had an elevated level prior to administration of trial product (reported on study day 1, concurrent mild vomiting).

Neoplasms were confirmed by the EAC in four patients treated with semaglutide 0.5 mg and in one patient receiving placebo (Table 2). One malignant neoplasm (basal cell carcinoma) was reported in a patient treated with semaglutide 1.0 mg. Additionally, one patient treated with semaglutide 1.0 mg had confirmed metastatic pancreatic cancer with an onset date of 65 days after the end of treatment. There were no confirmed thyroid malignancies.