Question: Among adults with overweight or obesity without diabetes, what is the effect of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg, on weight loss when each is added to counseling for diet and
physical activity?
Findings: In this randomized clinical trial that included 338 participants, mean body weight change from baseline to 68 weeks was −15.8% with
semaglutide vs −6.4% with liraglutide, a statistically-significant difference.
Meaning: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide, compared with once-daily subcutaneous
liraglutide, added to counseling for diet and physical activity resulted in statistically-significantly greater weight loss at 68 weeks.
Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.
Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous
liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.
Design, Setting, & Participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment:
September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (n =
338).
Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n =
126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical
activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment
and could restart the 4-week titration. Placebo groups were
pooled (n = 85).
Main Outcomes & Measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of
10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label,
with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end
points.
Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD]
body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was −15.8% with
semaglutide vs −6.4% with liraglutide (difference, −9.4 percentage points [95% CI, −12.0 to −6.8]; p < 0.001); weight change with pooled placebo was −1.9%. Participants
had statistically-significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of
participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs
12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all
p < 0.001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal
adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.
Conclusions & Relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with
once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in statistically-significantly greater weight loss at 68
weeks.
Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension,
adult-onset diabetes and elevated cholesterol. However, the treatment of obesity
itself has proven largely resistant to therapy, with anti-obesity
medications(AOMs) often delivering insufficient efficacy and dubious safety.
Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing
obstacles. Recent advances, including increased understanding of the molecular gut-brain communication, are inspiring the pursuit of next-generation AOMs that appear capable
of safely achieving sizeable and sustained body weight loss.
…The pursuit of anti-obesity medications (AOMs) has been tremendously challenging for technical and societal
reasons. Only in the last 2 decades has the definition of the molecular mechanisms that control appetite (Box 1;
Figure 2) advanced to a point where drug discovery can be rationally pursued. Historically, there has been a collection of AOM failures that have occurred after regulatory approval. Most of these pertain to adverse cardiovascular effects (sibutramine, fenfluramine, dexfenfluramine, rainbow pills), increased suicidal risk (rimonabant) or enhanced
likelihood of drug dependence and abuse (methamphetamine)
(Table 1). As such, certain drugs are recommended only for short-term use, due to addictive potential or emergence of tachyphylaxis (phentermine, amfepramone, cathin hydrochloride). Nonetheless, phentermine has not shown adverse cardiovascular
outcomes in real-life studies and remains a commonly prescribed long-term AOM.
…to achieve body weight normalization along with suitable tolerability and safety remained an insurmountable challenge. However, recent clinical trials with
advanced therapeutic candidates including glucagon-like peptide 1 receptor (GLP1R) agonism are promoting the
belief that breakthrough, drug-based management of obesity may be possible. On 4 June 2021, the US Food and Drug Administration (FDA) approvedsemaglutide 2.4 mg for chronic weight
management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure or cholesterol, or T2D), for use in
addition to a reduced-calorie diet and increased physical activity. This now constitutes the second GLP1R agonist
registered for body weight management, as liraglutide 3 mg was approved by the
FDA in 2014 for treatment of adult obesity and in 2020 for obesity in adolescents aged 12–17 years.
With the exception of semaglutide 2.4 mg, the average percentage body weight reduction for currently registered drug treatments varies in the single-digit
range, with only a small fraction of subjects capable of achieving and maintaining >10% loss at tolerable doses (Figure 3). Although such
weight loss is clinically meaningful, and serves to improve the severity of comorbid diseases, it is paltry when viewed against the efficacy of bariatric surgery. An ideal AOM should
sizeably and sustainably correct excess weight whilereducing the risk of CVD and other comorbidities, devoid of
the potential for abuse, tachyphylaxis and other adverse effects that have historically plagued this field. It is a lofty goal and, at times, still
challenged by the question of whether obesity itself constitutes a disease worthy of chronic drug therapy.
Figure 3: Body weight loss by AOMs in humans and rodents. Body weight loss achieved
through lifestyle changes, currently approved anti-obesity medications (AOMs) and bariatric surgery
(part a) and correlation of drug-induced body weight loss in rodents and humans (part b).
Data in panel a refer to liraglutide, orlistat, naltrexone/bupropion, phentermine/topiramate, semaglutide 1 mg, semaglutide 2.4 mg, and tirzepatide (5 and 15 mg). Data in panel b refer to
naltrexone/bupropion, orlistat, lorcaserin, sibutramine, liraglutide, phentermine, semaglutide, and tirzepatide.
…The recent precedent-setting results with semaglutide and tirzepatide, in which each reported mean weight loss well in excess of 10%, employing a
GLP1 mechanism that has separately proven to improve cardiovascular outcomes in T2D studies, inspires confidence for the
future.
Background: Weight regain after weight loss is a major problem in the treatment of persons with obesity.
Methods: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body mass index [the weight in kilograms divided by the square of the height in meters], 32
to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of 4 strategies: a
moderate-to-vigorous—tensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo
plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat
percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed.
Results: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the
active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, −4.1 kg (95% confidence interval, −7.8 to −0.4; p = 0.03); in the liraglutide group, −6.8
kg (95% CI, −10.4 to −3.1; p < 0.001); and in the combination group, −9.5 kg (95% CI, −13.1 to −5.9; p
< 0.001). The combination strategy led to greater weight loss than exercise (difference, −5.4 kg; 95% CI, −9.0 to −1.7;
p = 0.004) but not liraglutide (−2.7 kg; 95% CI, −6.3 to 0.8; p = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage
points, which was approximately twice the decrease in the exercise group (−1.7 percentage points; 95% CI, −3.2 to −0.2; p = 0.02) and the liraglutide group (−1.9 percentage points; 95% CI, −3.3 to −0.5; p = 0.009). Only the combination strategy was associated with
improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart
rate and cholelithiasis were observed more often in the liraglutide
group than in the combination group.
Conclusions: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone.
(Funded by the Novo Nordisk Foundation and others; EudraCT number,
2015–005585–32; ClinicalTrials.gov number, NCT04122716.)
The gut-brain axis plays an essential role in regulating metabolism and leading therapeutics for T2DM and obesity harness this machinery.
Multiple components of the gut-brain axis are involved in an integrated response to sensory information to maintain whole-body homeostasis.
A systems biology approach utilizing advanced technologies is enabling a detailed mechanistic understanding of gut-brain communication.
This understanding is leading to new approaches that may result in the next generation of therapeutics for metabolic diseases.
Background: The gut-brain axis, which mediates bidirectional communication between the gastrointestinal system and central nervous system
(CNS), plays a fundamental role in multiple areas of physiology including regulating appetite, metabolism, and
gastrointestinal function. The biology of the gut-brain axis is central to the efficacy of glucagon-like peptide-1 (GLP-1)-based therapies, which are now leading treatments for type 2 diabetes (T2DM) and obesity. This success and research to
suggest a much broader role of gut-brain circuits in physiology and disease has led to increasing interest in targeting such circuits to discover new therapeutics.
However, our current knowledge of this biology is limited, largely because the scientific tools have not been available to enable a detailed mechanistic
understanding of gut-brain communication.
Scope of Review: In this review, we provide an overview of the current understanding of how sensory information from the gastrointestinal
system is communicated to the central nervous system, with an emphasis on circuits involved in regulating feeding and metabolism. We then describe how recent
technologies are enabling a better understanding of this system at a molecular level and how this information is leading to novel insights into gut-brain
communication. We also discuss current therapeutic approaches that leverage the gut-brain axis to treat diabetes, obesity, and related disorders and describe
potential novel approaches that have been enabled by recent advances in the field.
Major Conclusions: The gut-brain axis is intimately involved in regulating glucose homeostasis and appetite, and this system plays a key role
in mediating the efficacy of therapeutics that have had a major impact on treating T2DM and obesity. Research into the gut-brain axis has historically largely
focused on studying individual components in this system, but new technologies are now enabling a better understanding of how signals from these components are
orchestrated to regulate metabolism. While this work reveals a complexity of signaling even greater than previously appreciated, new insights are already being
leveraged to explore fundamentally new approaches to treating metabolic diseases.
[Keywords: gut-brain axis, diabetes, obesity, gut peptides, vagus]
…First-generation GLP-1 analogs are injectables that are dosed once daily or more frequently and are associated
with relatively modest weight loss. Second-generation GLP-1 analogs, including once-weekly exenatide, semaglutide,
dulaglutide, and oral semaglutide, which have been approved for T2DM have more convenient dosing regimens (1 weekly, oral) and high-dose semaglutide and
dulaglutide have shown the potential for > 10% weight loss in clinical studies. All these analogs are associated with tolerability issues (nausea/vomiting).
Next-generation approaches that are being investigated in the clinic include injectable agents that exploit dual pharmacology and oral small molecule
GLP-1R agonists. Future approaches currently beingexplored include directly targeting gut EEC and vagal circuits with small molecule oral therapeutics.
…An oral formulation of semaglutide has also been approved for T2DM. In head-to-head studies, HbA1c decreases were superior those achieved with the
DPP-4 inhibitor sitagliptin [135]
and non-inferior to liraglutide [136].
Modest weight loss (up to 2.3 kg) was achieved with the oral formulation in a monotherapy study in patients with T2DM [137,
138]. Tolerability remains an
issue, and the dosing regimen is relatively complex. It remains to be determined whether improved formulations can result in greater convenience and efficacy.
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.
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).
Figure A: Body Weight Change from Baseline by Week, Observed In-Trial Data. Figure B: Body Weight Change from Baseline by
Week, Observed On-Treatment Data. Figure C: In-Trial Data at Wk 68 (percent weight loss). Figure D: On-Treatment Data at Wk
68 (percent weight loss)
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 HbA1c, 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.
The U.S. Food and Drug Administration today approved Rybelsus (semaglutide) oral tablets to improve control of blood sugar in adult patients with type 2
diabetes, along with diet and exercise. Rybelsus is the first glucagon-like peptide (GLP-1) receptor protein
treatment approved for use in the United States that does not need to be injected. GLP-1 drugs are non-insulin
treatments for people with type 2 diabetes.
“Patients want effective treatment options for diabetes that are as minimally intrusive on their lives as possible, and the FDA welcomes the advancement of new therapeutic options that can make it easier for patients to control their condition”, said Lisa
Yanoff, M.D, acting director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug
Evaluation and Research. “Before this approval, patients did not have an oral GLP1 option to treat their
type 2 diabetes, and now patients will have a new option for treating type 2 diabetes without injections.”
Type 2 diabetes is the most common form of diabetes, occurring when the pancreas cannot make enough insulin to keep blood sugar at normal levels.
GLP-1, which is a normal body hormone, is often found ininsufficient levels in type 2 diabetes patients. Like
GLP-1, Rybelsus slows digestion, prevents the liver from making too much sugar, and helps the pancreas produce more
insulin when needed.
The efficacy and safety of Rybelsus in reducing blood sugar in patients with type 2 diabetes were studied in several clinical trials, 2 of which were
placebo-controlled and several of which were compared to other GLP-1 injection treatments. Rybelsus was studied as
a stand-alone therapy and in combination with other diabetes treatments, including metformin, sulfonylureas (insulin secretagogues), sodium-glucose co-transporter-2 (SGLT-2) inhibitors, insulins and thiazolidinediones, all in patients with type 2 diabetes.
In the placebo-controlled studies, Rybelsus as a stand-alone therapy resulted in a statistically-significant reduction in blood sugar (hemoglobin A1c) compared
with placebo, as determined through HbA1c tests, which measure average levels of blood sugar over time. After 26 weeks, 69% of those taking 7 mg once daily
and 77% of those taking 14 mg once daily of Rybelsus decreased their HbA1c to lower than 7%, compared with 31% of patients on placebo.
Objective: This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise
alone. 2 estimands addressed 2 efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a
trial product estimand (on trial product without rescue medication use) in all randomized patients.
Research Design & Methods: This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93
sites in 9 countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7
mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26
in body weight.
Results: In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced
HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, −0.6% [3 mg], −0.9% [7 mg], and −1.1% [14 mg]; trial product estimand, −0.7%
[3 mg], −1.2% [7 mg], and −1.4% [14 mg]; p < 0.001 for all) and body weight (treatment policy, −0.1 kg [3 mg], −0.9 kg [7 mg], and −2.3 kg [14 mg,
p < 0.001]; trial product, −0.2 kg [3 mg], −1.0 kg [7 mg, p = 0.01], and −2.6 kg [14 mg, p < 0.001]). Mild-to-moderate transient
gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3–7.4% with oral semaglutide and
2.2% with placebo.
Conclusions: In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c
(all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor
agonists.
Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for
type 2 diabetes, lowering glycated haemoglobin (HbA1c) and weight, but are currently only approved for use as subcutaneous injections. Oral semaglutide, a
novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes.
Methods: In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12
countries. Eligible patients were aged 18 years or older, with HbA1c of 7·0–9·5% (53–80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly
assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral
semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. 2 estimands were defined: treatment
policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in
all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in
HbA1c (oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary
endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who
received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the
European Clinical Trials registry, number EudraCT 2015-005210-30.
Findings: Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral
semaglutide (n = 285), subcutaneous liraglutide (n = 284), or placebo (n = 142). 341 (48%) of 711 participants were female and the mean
age was 56 years (SD 10).
All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and
134 (94%) in the placebo group completed the 52-week trial period.
Mean change from baseline in HbA1c at week 26 was −1·2% (SE 0·1) with oral semaglutide, −1·1% (SE 0·1) with subcutaneous liraglutide, and −0·2% (SE 0·1) with
placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] −0·1%, 95% CI −0·3 to 0·0;p <0·0001) and superior to placebo (ETD −1·1%,
−1·2 to −0·9;p <0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had
statistically-significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD −0·2%, 95% CI −0·3
to −0·1; p= 0·0056) and placebo (ETD −1·2%, −1·4 to −1·0;p <0·0001) at week 26. Oral
semaglutide resulted in superior weight loss (−4·4 kg [SE 0·2]) compared with liraglutide (−3·1 kg [SE 0·2]; ETD −1·2 kg,
95% CI −1·9 to −0·6;p = 0·0003) and placebo (−0·5 kg [SE 0·3]; ETD −3·8 kg, −4·7 to −3·0;p <0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was statistically-significantly greater with
oral semaglutide than with subcutaneous liraglutide (−1·5 kg, 95% CI −2·2 to −0·9; p<0·0001) and placebo (ETD −4·0 kg, −4·8 to −3·2;p <0·0001).
Adverse events were more frequent with oral semaglutide (n = 229 [80%]) and subcutaneous liraglutide (n = 211 [74%]) than with placebo
(n = 95 [67%]).
Interpretation: Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in
decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide.
Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the
diabetes treatment continuum of care.
The discovery of glucagon-like peptide-1(GLP-1), anincretin
hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in
people with type 2 diabetes (T2D). The development of
short-acting and then long-acting GLP-1 receptor agonists (GLP-1RAs)
followed.
Our article charts the discovery and development of the long-acting GLP-1 analogsliraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate
their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs.
Reversible binding to albumin was used for the systemic protraction of
liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency.
GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract,
heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective
improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect
cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Substantial weight loss, through an effect to reduce
energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other
ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease(NASH) and its use in an oral formulation for
the treatment of T2D.
In summary, rational designhas led to the development
of 2 long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D
in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral
formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the
treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.
Importance: Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of
glucose-lowering therapy.
Objective: To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to
metformin with or without sulfonylurea, in patients with type 2 diabetes.
Design, Setting, and Participants: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14
countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin
with or without sulfonylurea were randomized.
Interventions: Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or
sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage
was achieved.
Main Outcomes and Measures: The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body
weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with
respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight.
Results: Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5
[SD, 6.4]; n = 879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for
semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced
HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; p < 0.001 for both) and body weight (differences,
-1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; p < 0.001 for both) from baseline to week 26. Noninferiority of
semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically-significantly greater with semaglutide,
14 mg/d, vs sitagliptin.
Conclusions and Relevance: Among adults with type 2 diabetes uncontrolled with metformin with or without
sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there
was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting.
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 semaglutideco-formulated with 300 mg SNAC was chosen for further clinical development.
The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing.
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
thatco-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 withliraglutide 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.
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 HbA1c level from baseline. Secondary end
points included change in body weight, safety, and tolerability.
Results: Semaglutide dose-dependently reduced the level of HbA1c 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 HbA1c level of <7%. HbA1c
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 HbA1c 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 albuminaffinity and GLP-1 receptor (GLP-1R)
potency and in obtaining aprolonged 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 onceor 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 availableagonists, 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 agonistscompared with exenatide BID, while the effect on postprandialhyperglycemia 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 withexenatide 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.
