Key Points:

• Question: In adults with overweight or obesity without diabetes, what effect does once-weekly subcutaneous semaglutide, 2.4 mg, have on body weight when added to intensive behavioral therapy with an initial low-calorie diet?
• Findings: In this randomized clinical trial that included 611 adults with overweight or obesity, 68 weeks’ treatment with once-weekly subcutaneous semaglutide vs placebo, combined with intensive behavioral therapy (and a low-calorie diet for the initial 8 weeks), resulted in reductions in body weight of 16.0% vs 5.7%, respectively; the difference was statistically-significant.
• Meaning: When used as an adjunct to intensive behavioral therapy and initial low-calorie diet, once-weekly subcutaneous semaglutide produced statistically-significantly greater weight loss than placebo during 68 weeks in adults with overweight or obesity.

Importance: Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.

Objective: To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.

Design, Setting, and Participants: Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (n = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).

Interventions: Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.

Main Outcomes and Measures: The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.

Results: Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was −16.0% for semaglutide vs −5.7% for placebo (difference, −10.3 percentage points [95% CI⁠, −12.0 to −8.6]; p < 0.001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; p < 0.001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; p < 0.001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.

Conclusions and Relevance: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in statistically-significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.

Trial Registration: ClinicalTrials.gov Identifier: NCT03611582

Background: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks [1.3 years] of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Results: The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; p < 0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (p < 0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Objective: The obesity epidemic is a public health concern, warranting further research into pharmacological treatments for weight management (WM) as an adjunct to lifestyle interventions. The Semaglutide Treatment Effect in People with obesity (STEP) program aims to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with obesity or overweight.

Methods: Across 5 phase 3 trials (NCT03548935⁠, WM; NCT03552757⁠, WM in type 2 diabetes; NCT03611582⁠, WM with intensive behavioral therapy; NCT03548987⁠, sustained WM; and NCT03693430⁠, long-term WM), ~5,000 participants are being randomly assigned to receive semaglutide 2.4 mg once weekly subcutaneously versus placebo. Results will be available in 2020–2021. For all trials, the primary end point is change from baseline to end of treatment in body weight.

Results: Participants have a mean age of 46.2 to 55.3 years, are mostly female (mean: 74.1%–81.0%), and have a mean BMI of 35.7 to 38.5 kg/​​​m2 and a mean waist circumference of 113.0 to 115.7 cm.

Conclusions: The STEP program evaluates the efficacy and safety of semaglutide 2.4 mg subcutaneously once weekly in a broad population. The trials will provide insights on WM in people with obesity with and without type 2 diabetes and on long-term follow-up.

GLP-1, a peptide hormone secreted from the gut, stimulating insulin and suppressing glucagon secretion was identified as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) and eliminated (mainly by kidneys) too fast (half-life 1–2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist has been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007. Compounds with longer duration of action (once daily, once weekly) and with increasingly better efficacy with respect to glycemic control and body weight reduction have been developed, and in a recent ADA/​​​EASD consensus statement, were recommended as the first injectable diabetes therapy after failure of oral glucose-lowering medications.

Most GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide q.w., all for s.c. injection, and the first oral preparation, oral semaglutide) have been examined in cardiovascular outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease, liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to first major adverse cardiovascular events (non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular and all-cause mortality.

It is the purpose of the present review to describe clinically important differences, regarding pharmacokinetic behaviour, glucose-lowering potency, effectiveness of reducing body weight and controlling other cardiovascular risk factors, and of the influence of GLP-1 receptor agonist treatment on cardiovascular outcomes in patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive heart failure).

…Recently, an oral preparation of semaglutide has been developed, which contains semaglutide (identical to the compound used for s.c. injection) and an absorption enhancer, Sodium N-(8-(2-hydroxybenzoyl) Amino) Caprylat (SNAC), which locally raises pH, prevents degradation of semaglutide, and facilitates absorption, most likely through gastric mucosa (28). Note that the bioavailability is still low, and much more peptide needs to be ingested to achieve similar plasma concentrations and efficacy (up to 14 mg per day as compared to 1 mg per week in the case of semaglutide for s.c. injection, ie. a 98-fold difference). To compensate for low and variable absorption, this oral preparation of semaglutide is recommended to be taken once daily. Predictable absorption and exposure to the drug requires it to be taken after an overnight fast with a small volume of water. A 30-min interval between the ingestion of the drug and the subsequent meal is required, before more fluid, food or other medications can be taken (28). Nevertheless, the development of an oral drug is a remarkable achievement and innovation.

In individuals with type 2 diabetes, glycemic control and cardiovascular risk factor management reduces the likelihood of late-stage diabetic complications. Guidelines recommend treatment goals targeting HbA_1c⁠, body weight, blood pressure, and low-density lipoprotein cholesterol. Development of new treatments for type 2 diabetes requires an understanding of their mechanism and efficacy, as well as their relative effects compared to other treatment choices, plus demonstration of cardiovascular safety.

Subcutaneous semaglutide is a glucagon-like peptide-1 receptor agonist currently approved in several countries for once-weekly treatment of type 2 diabetes. Semaglutide works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion from the pancreatic islets, leading to lower blood glucose levels. Semaglutide also decreases energy intake by reducing appetite and food cravings, and lowering relative preference for fatty, energy-dense foods. Semaglutide was evaluated in the SUSTAIN clinical trial programme in over 8000 patients across the spectrum of type 2 diabetes. This review details the efficacy and safety profile of semaglutide in the SUSTAIN 1–5 and 7 trials, and its cardiovascular safety profile in the SUSTAIN 6 trial. Semaglutide consistently demonstrated superior and sustained glycemic control and weight loss vs. all comparators evaluated. In SUSTAIN 6, involving patients at high risk of cardiovascular disease, semaglutide statistically-significantly decreased the occurrence of cardiovascular events compared with placebo/​​​standard of care (hazard ratio 0.74, p < 0.001 for non-inferiority).

Through a comprehensive phase 3 clinical trial program, we have a detailed understanding of semaglutide’s efficacy, safety, cardiovascular effects and comparative role in the treatment of type 2 diabetes.

[Keywords: cardiovascular, efficacy, glucagon-like peptide-1 receptor agonist, semaglutide, SUSTAIN, type 2 diabetes]

Background: Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP-1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials⁠.

Methods: In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2–20 mg semaglutide co-formulated with 150–600 mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC.

Results: Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when co-formulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20 mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1 week in all groups.

Conclusion: The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300 mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing.

ClinicalTrials.gov identifiers: NCT01037582, NCT01686945.

Key Points:

• Oral semaglutide is a novel tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analogue semaglutide, with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). In a first-in-human, single ascending dose trial in healthy males, and in a 10-week, once-daily, multiple-dose trial in healthy males and males with type 2 diabetes, oral semaglutide was safe and well-tolerated, with a safety profile as expected for the GLP-1 receptor agonist drug class.
• The half-life of oral semaglutide was approximately 1 week, which is similar to semaglutide administered subcutaneously, suggesting that the elimination phase of semaglutide administered orally is comparable with that seen with subcutaneous administration.
• Following administration of oral semaglutide with 150–600 mg SNAC, semaglutide plasma exposure levels suggested that co-formulation with 300 mg SNAC is optimal to enhance the absorption of orally administered semaglutide. Oral semaglutide co-formulated with a fixed amount of SNAC (300 mg) was therefore chosen for further clinical development.

Background: Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss.

Methods: We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/​​​m2 or more. We randomly assigned participants (6:1) to each active treatment group (ie, semaglutide [0·05 mg, 0·1 mg, 0·2 mg, 0·3 mg, or 0·4 mg; initiated at 0·05 mg per day and incrementally escalated every 4 weeks] or liraglutide [3·0 mg; initiated at 0·6 mg per day and escalated by 0·6 mg per week]) or matching placebo group (equal injection volume and escalation schedule to active treatment group) using a block size of 56. All treatment doses were delivered once-daily via subcutaneous injections. Participants and investigators were masked to the assigned study treatment but not the target dose. The primary endpoint was percentage weight loss at week 52. The primary analysis was done using intention-to-treat ANCOVA estimation with missing data derived from the placebo pool. This study is registered with ClinicalTrials.gov, number NCT02453711⁠.

Findings: Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102–103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/​​​m2. Bodyweight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was −2·3% for the placebo group versus −6·0% (0·05 mg), −8·6% (0·1 mg), −11·6% (0·2 mg), −11·2% (0·3 mg), and −13·8% (0·4 mg) for the semaglutide groups. All semaglutide groups versus placebo were statistically-significant (unadjusted p≤0·0010), and remained statistically-significant after adjustment for multiple testing (p≤0·0055). Mean bodyweight reductions for 0·2 mg or more of semaglutide versus liraglutide were all statistically-significant (−13·8% to −11·2% vs −7·8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37–65% receiving 0·1 mg or more of semaglutide (p <0·0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists.

Interpretation: In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses.

Funding: Novo Nordisk A/​​​S.

Aim: The aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide⁠.

Materials and methods: This randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks of treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed.

Results: After a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (−1255 kJ; p < 0.0001) and during the subsequent evening meal (p = 0.0401) and snacks (p = 0.0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (−3036 kJ; p < 0.0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass.

Conclusion: After 12 weeks of treatment, ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide-induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy-dense foods.

Video Abstract: A free Video Abstract to accompany this article is available⁠.

Objective: To investigate the dose-response relationship of semaglutide versus placebo and open-label liraglutide in terms of glycemic control in patients with type 2 diabetes.

Research Design And Methods: This was a 12-week, randomized, double-blind phase 2 trial. Patients (n = 415) were randomized to receive a subcutaneous injection of semaglutide once weekly without dose escalation (0.1–0.8 mg) or with dose escalation (E) (0.4 mg steps to 0.8 or 1.6 mg E over 1–2 weeks), open-label liraglutide once daily (1.2 or 1.8 mg), or placebo. The primary end point was change in HbA_1c level from baseline. Secondary end points included change in body weight, safety, and tolerability.

Results: Semaglutide dose-dependently reduced the level of HbA_1c from baseline (8.1 ± 0.8%) to week 12 by up to −1.7%, and body weight by up to −4.8 kg (1.6 mg E, p < 0.001 vs. placebo). Up to 81% of patients achieved an HbA_1c level of <7%. HbA_1c level and weight reductions with semaglutide 1.6 mg E were greater than those with liraglutide 1.2 and 1.8 mg (based on unadjusted CIs), but adverse events (AEs) and withdrawals occurred more frequently. The incidence of nausea, vomiting, and withdrawal due to gastrointestinal AEs increased with the semaglutide dose; most events were mild to moderate, transient, and ameliorated by dose escalation. There were no major episodes of hypoglycemia and few cases of injection site reactions.

Conclusions: After 12 weeks, semaglutide dose-dependently reduced HbA_1c level and weight in patients with type 2 diabetes. No unexpected safety or tolerability concerns were identified; gastrointestinal AEs typical of glucagon-like peptide 1 receptor agonists were mitigated by dose escalation. On this basis, weekly semaglutide doses of 0.5 and 1.0 mg with a 4-week dose escalation were selected for phase 3.

Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity.

The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue.

Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib⁸, Arg³⁴) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs.

Semaglutide is currently in phase 3 clinical testing.

Incretin-based therapies, such as the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and orally administered dipeptidyl peptidase-4 (DPP-4) inhibitors, have recently been introduced into clinical practice.

At present, the GLP-1 receptor agonists need to be administered once or twice daily. Several once-weekly GLP-1 receptor agonists are in phase 3 development. This review examines the efficacy, safety and perspective for the future of the once-weekly GLP-1 receptor agonists: exenatide once weekly, taspoglutide⁠, albiglutide⁠, LY2189265 and CJC-1134-PC, and compared them to the currently available agonists, exenatide BID and liraglutide QD.

A greater reduction in haemoglobin A1c (HbA1c) and fasting plasma glucose was found with the once-weekly GLP-1 receptor agonists compared with exenatide BID, while the effect on postprandial hyperglycemia was modest with the once-weekly GLP-1 receptor agonist. The reduction in HbA1c was in most studies greater compared to oral antidiabetic drugs and insulin glargine. The reduction in weight did not differ between the short-acting and long-acting agonists.

The gastrointestinal side effects were less with the once-weekly agonists compared with exenatide BID, except for taspoglutide. Antibodies seem to be most frequent with exenatide once weekly, while hypersensitivity has been described in few patients treated with taspoglutide. Injection site reactions differ among the long-acting GLP-1 receptor agonists and are observed more frequently than with exenatide BID and liraglutide. In humans, no signal has been found indicating an association between the once-weekly agonists and C-cell cancer. The cardiovascular safety, durability of glucose control and effect on weight will emerge from several ongoing major long-term trials.

The once-weekly GLP-1 receptor analogues are promising candidates for the treatment of type 2 diabetes, although their efficacy may not be superior to once-daily analogue liraglutide.