1926 Diabetes Care Volume 41, September 2018 Ildiko Lingvay,1 Cyrus V. Desouza,2 A 26-Week Randomized Katarina S. Lalic,3 Ludger Rose,4 Thomas Hansen,5 Jeppe Zacho,5 and Controlled Trial of Semaglutide Thomas R. Pieber6 EMERGING THERAPIES: DRUGS AND REGIMENS Once Daily Versus Liraglutide and Placebo in Patients With Type 2 Diabetes Suboptimally Controlled on Diet and Exercise With or Without Metformin Diabetes Care 2018;41:1926–1937 | https://doi.org/10.2337/dc17-2381 OBJECTIVE To investigate the efficacy and safety of once-daily semaglutide in comparison with once-daily liraglutide and placebo in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, multicenter, double-blind trial involved patients diagnosed with 1University of Texas Southwestern Medical Cen- type 2 diabetes with HbA1c 7.0–10.0% (53–86 mmol/mol) and treated with diet ter at Dallas, Dallas, TX and exercise with or without metformin. Patients were randomized 2:2:1 to once- 2University of Nebraska Medical Center, Omaha, daily semaglutide, liraglutide, or placebo in one of four volume-matched doses NE 3Faculty of Medicine, University of Belgrade, and (semaglutide 0.05, 0.1, 0.2, or 0.3 mg and liraglutide 0.3, 0.6, 1.2, or 1.8 mg, with Clinic for Endocrinology, Diabetes and Metabolic both compared within each volume-matched dose group). Primary end point was Diseases, Clinical Center of Serbia, Belgrade, Serbia change in HbA1c from baseline to week 26. 4Institute for Diabetes Research in Munster,¨ RESULTS Munster,¨ Germany 5Novo Nordisk A/S, Søborg, Denmark In total, 705 randomized patients were exposed to trial products. At week 26, a 6Medical University of Graz, Graz, Austria 2 dose-dependent change in HbA1c was observed with semaglutide from 1.1% Corresponding author: Thomas R. Pieber, thomas (0.05 mg) to 21.9% (0.3 mg) and with liraglutide from 20.5% (0.3 mg) to 21.3% [email protected]. (1.8 mg) (all P < 0.001 in favor of volume-matched semaglutide dose). Change with Received 13 November 2017 and accepted 18 pooled placebo was 20.02% (P < 0.0001 vs. semaglutide). Gastrointestinal (GI) dis- June 2018. orders were the most common adverse events (AEs) with semaglutide and liraglu- Clinical trial reg. no. NCT02461589, clinicaltrials tide, occurring in 32.8–54.0% and 21.9–41.5% of patients, respectively. .gov. This article contains Supplementary Data online CONCLUSIONS at http://care.diabetesjournals.org/lookup/suppl/ Once-daily semaglutide at doses up to 0.3 mg/day resulted in greater reductions doi:10.2337/dc17-2381/-/DC1. in HbA compared with liraglutide or placebo but with a higher frequency of GI This article is featured in a podcast available at 1c http://www.diabetesjournals.org/content/diabetes- AEs. core-update-podcasts. © 2018 by the American Diabetes Association. Glucagon-like peptide 1 (GLP-1) is a gut-derived peptide and a potent blood glucose Readers may use this article as long as the work (BG)-lowering hormone (1). It functions in a glucose-dependent manner and is is properly cited, the use is educational and not for profit, and the work is not altered. More infor- therefore associated with a low risk of hypoglycemia (2). GLP-1 inhibits gastric mation is available at http://www.diabetesjournals emptying and reduces body weight by lowering energy intake and inducing feelings .org/content/license. care.diabetesjournals.org Lingvay and Associates 1927 of satiety, a mechanism thought to involve Patients were randomized in a 2:2:1 0.05, 0.1, 0.2, and 0.3 mg, respectively, GLP-1 receptors expressed in the hypothal- ratio to semaglutide:liraglutide:placebo and liraglutide 0.3, 0.6, 1.2, and 1.8 mg, amus, the region of the brain that regulates in one of four volume-matched doses respectively. The last treatment arm satiety and appetite (3–5). For these rea- (described below and in Supplementary represents the semaglutide exploratory sons, alongside evidence that some GLP-1 Fig. 1). The trial included an additional flexible escalation arm based on tolera- receptor agonists can improve cardiovas- open-label treatment arm to explore bility to GI AEs (Supplementary Fig. 1). cular outcomes (6,7), these therapies have whether a more flexible semaglutide The randomization session was per- become integral in the treatment of type 2 titration scheme could improve tolera- formed in the interactive voice/web- diabetes and are recommended early in bility. response system, which would allocate the treatment guidelines (8,9). The trial was conducted in compliance the dispensing unit number of trial prod- Semaglutide is a new human GLP-1 an- with the International Conference on uct to be dispensed to the patient. Pa- alog for the treatment of patients with Harmonization Good Clinical Practice tients were assigned to the lowest type 2 diabetes. It has 94% amino acid se- guidelines (17) and the Declaration of available number allocated to the trial quence homology to native GLP-1; amino Helsinki (18). Written informed consent site. The patient number was a six-digit acid substitutions in the semaglutide mol- was obtained from all patients before number. Randomization was performed ecule confer increased albumin affinity any trial-related activities commenced, by the study sponsor. while also making it resistant to degra- in line with institutional review board– A portion of the trial was double dation by dipeptidyl peptidase 4 (DPP-4). approved detailed informed consent blinded to the study sponsor, investiga- Consequently, semaglutide has a half-life procedures: subjects were provided ver- tors, and patients. Semaglutide, liraglu- of ;1 week (10). bal and written information about the tide, and placebo were visually identical In the Semaglutide Unabated Sustain- trial and the procedures involved in a to fulfill the requirements for double- ability in Treatment of Type 2 Diabetes form that they could read and under- blind procedures, and equal volumes (SUSTAIN) phase 3a global clinical trial stand. Subjects were fully informed of of semaglutide, liraglutide, and placebo program in patients with type 2 diabetes, their rights and responsibilities while were administered during treatment, once-weekly subcutaneous semaglutide participating in the trial, as well as the ensuring blinding within dose level. 0.5 mg and 1.0 mg showed superior and risks and benefits of being exposed to The treatment code for a particular pa- clinically meaningful reductions in HbA1c the trial products (19). tient could be broken in a medical emer- and body weight versus a range of com- gency; however, the treatment code parators (sitagliptin, exenatide extended Trial Patients was not broken for any patient during Patients of either sex were eligible for release, insulin glargine, and placebo) this trial. inclusion if they were at least 18 years (11–15). The most common adverse events of age at the time of informed consent, (AEs) with semaglutide were gastrointes- diagnosed with type 2 diabetes at least Trial Drug Administration tinal (GI) in nature (11–15). The effect of After a 2-week screening period, patients 90 days prior to screening, and on stable semaglutide on gastric emptying was in- received trial medication for 26 weeks, diabetes treatment consisting of diet vestigated in a separate trial and showed followed by a 7-week follow-up period and exercise 6 metformin ($1,500 mg that although overall gastric emptying was (Supplementary Fig. 1). For the 12 blinded daily or maximum tolerated dose docu- similar to that of placebo, the observed treatment arms, patients were initiated mented in the patient medical record) for first-hour delay with semaglutide may con- on treatment with 0.05 mg semaglu- at least 90 days prior to screening, with tribute to a slower entry of glucose into tide, 0.3 mg liraglutide, or 50 mL placebo, aHbA 7.0–10.0% (53–86 mmol/mol) the circulation (16). 1c all administered subcutaneously once and a BMI 25.0–40.0 kg/m2. This trial aimed to investigate the daily, titrated every 4 weeks up to their Key exclusion criteria were a history efficacy and safety of a wider dose range final randomized dose. This similar titra- of chronic or idiopathic acute pancre- of semaglutide administered once daily tion algorithm was used in all patients to atitis and moderate-to-severe renal im- in comparison with liraglutide and pla- ensure blinding across the products, and pairment (estimated glomerular filtration cebo in patients with type 2 diabetes. thus liraglutide was initiated at a lower rate ,60 mL/min/1.73 m2). Full details of dose and escalated at a slower pace inclusion and exclusion criteria can be RESEARCH DESIGN AND METHODS than recommended in the label (20). found in Supplementary Table 1. Trial Design The fixeddoseescalationingroups1–13 This was a 26-week, multicenter, random- Randomization and Masking is described as follows: 1) semaglutide ized, double-blind (within dose level), Eligible patients enrolled by the study 0.05 mg/day, 2) liraglutide 0.3 mg/day, dose-finding trial comparing semaglu- investigators were randomly assigned 3) placebo 50 mL/day, 4) semaglutide tide with liraglutide and placebo, all ad- into 1 of 12 treatment arms in a 2:2:1 0.05/0.1 mg/day, 5) liraglutide 0.3/0.6 ministered subcutaneously once daily, in ratio (semaglutide:liraglutide:placebo) mg/day, 6) placebo 50/100 mL/day, 7) patients diagnosed with type 2 diabetes within each of the four dosing levels semaglutide 0.05/0.1/0.2 mg/day, 8) lira- and treated with diet and exercise with (50, 100, 200, and 300 mL) or to an glutide 0.3/0.6/1.2 mg/day, 9) placebo or without metformin. There were 138 additional 13th semaglutide treatment 50/100/200 mL/day, 10) semaglutide participating sites in 10 countries (Aus- arm with the same number of patients 0.05/0.1/0.2/0.3 mg/day, 11) liraglutide tria,Canada, Czech Republic, Germany, as the active treatment arms (Sup- 0.3/0.6/1.2/1.8 mg/day, 12) placebo 50/ Malaysia, Russia, Serbia, South Africa, plementary Fig.