Clinical Review of Subcutaneous Semaglutide For Obesity

13652710, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.13574 by Health Research Board, Wiley Online Library on [27/01/2023].
See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Received: 10 September 2021 | Revised: 27 October 2021 | Accepted: 3 November 2021
DOI: 10.1111/jcpt.13574
REVIEW ARTICLE
Clinical review of subcutaneous semaglutide for obesity
Anna Phillips PharmD Candidate1 |

Jennifer N. Clements PharmD, FCCP, FADCES, BCPS, CDCES, BCACP, BC-ADM2
1
Presbyterian College School of Pharmacy,
Clinton, South Carolina, USA Abstract
What is known and objective: The purpose of this review paper is to review the ef-
2
Department of Nursing Administration,
Spartanburg Regional Healthcare System,
Spartanburg, South Carolina, USA
ficacy and safety of subcutaneous semaglutide, marketed as Wegovy, a glucagon-like
peptide-1 receptor agonist for obesity management.
Correspondence
Jennifer N. Clements, PharmD, FCCP,
Methods: A MEDLINE search (1970 to June 2021) was conducted to identify Phase 3
FADCES, BCPS, CDCES, BCACP, BC-ADM, trials of subcutaneous semaglutide for obesity management. Published Phase 3 trials
Clinical Pharmacist -Diabetes Transition,
Department of Nursing Administration,
from The Semaglutide Treatment Effect in People with obesity (STEP) program were
Spartanburg Regional Healthcare System, reviewed and summarized.
101 East Wood Street, Spartanburg, SC
29303, USA.
Results and discussion: Based on four Phase 3 trials, subcutaneous semaglutide as
Email: jclements1027@outlook.com; 2.4 mg once weekly was compared in efficacy and safety among 5000 randomized
jclements@srhs.com
participants who were overweight or had obesity. A change in body weight from base-
Funding information line to end of study was the primary outcome in the STEP program. Participants who
The author(s) received no financial
support for the research, authorship and/
received semaglutide had a dose-dependent reduction in body weight from baseline,
or publication of this article. compared to placebo. Higher percentages of participants had 5%–10% weight reduc-
tion from baseline when receiving subcutaneous semaglutide. The patient population
was mainly middle-aged female participants with Class II obesity. Additional studies
are needed, especially active-comparator trials, to determine the efficacy and safety
of semaglutide in a diverse patient population.
What is new and conclusion: Subcutaneous semaglutide is another available option
as adjunct therapy to lifestyle modifications for people who are overweight or have
obesity based on body weight and body mass index. It resulted in more weight reduc-
tion than placebo with gastrointestinal adverse events being the most common safety
concerns. Clinical utilization of subcutaneous semaglutide will be determined, as in-
surance coverage will be a limitation for this new medication.
KEYWORDS
GLP-1 receptor agonist, glucagon-like peptide-1, obesity, overweight, semaglutide
1 | W H AT I S K N OW N A N D O B J EC TI V E consequences of obesity can include type 2 diabetes (T2D), dys-

lipidaemia, hypertension, cardiovascular disease, osteoarthritis and
According to the Obesity Medicine Association, obesity is chronic obstructive sleep apnea.1
and treatable disease state from multiple factors with a complex In 2015, it was estimated that 603.7 million adults had their
pathophysiology leading to potential health consequences.1 Many weight classified as obesity, with an overall prevalence of 12%
factors affect the prevalence of obesity with the most common worldwide in adults. 2 This study also discovered that approximately
2
factors including age, gender, race and economic status. Health 4 million deaths and increasing rates of disability were associated
184 | © 2021 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jcpt J Clin Pharm Ther. 2022;47:184–193.
|
13652710, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.13574 by Health Research Board, Wiley Online Library on [27/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
PHILLIPS and CLEMENTS 185
with the negative health effects of a higher body mass index (BMI). 2 The first GLP-1 RA approved by the FDA for the treatment of obe-
In 2019, the Centers for Disease Control estimated the national sity was liraglutide, marketed by Novo Nordisk as Saxenda. Based
prevalence of 31.4% for obesity in the United States.3 During 2020, on efficacy and safety outcomes from Phase 3 trials, subcutaneous
it was noted that people with obesity were at an increased risk of semaglutide was approved by the FDA on 4 June 2021, for the indi-
mortality when infected with COVID-19.4 The health and cost bur- cation of long-term weight management. A MEDLINE search (1970
den of obesity on patients, families and health systems does not to June 2021) was conducted to identify Phase 3 trials of subcuta-
appear to be going away. It is projected that 1 in 2 adults will have neous semaglutide for obesity management. Published Phase 3 tri-
obesity and 1 in 4 adults will have severe obesity in the United States als from The Semaglutide Treatment Effect in People with obesity
by 2030.5 Therefore, new, innovative medications to treat both obe- (STEP) program were reviewed and summarized.
sity and its weight-related comorbidities would be ideal for clinical
practice.
The current clinical guidelines are all similar by recommend- 3 | R E S U LT S A N D D I S CU S S I O N
ing a goal to improve the health of the patient by preventing and/
or treating weight-
related complications through weight loss by 3.1 | GLP-1 RA
non-
pharmacologic, pharmacologic, or surgical measures when
necessary. The short-term treatment goal is reduction of weight by Semaglutide has shown improved weight reduction compared to
5%–10% over 3–6 months, with a long-term goal of maintenance of liraglutide in patients with or without type 2 diabetes. Superiority
6–8
weight loss. The aggressiveness of a patient's weight loss is often of semaglutide to liraglutide in weight reduction was initially shown
driven by their BMI and other comorbidities. The guidelines define in a dose-finding trial for treatment of patients with T2D.10 In this
2
overweight as a BMI between 25 and 29.9 kg/m and obesity as a trial, participants were treated with either semaglutide once weekly
BMI of equal to or above 30 kg/m2.8 First-line therapy should be without dose escalation (0.1–0.8 mg), semaglutide once weekly with
non-pharmacologic therapy such as behavioural therapy in conjunc- dose escalation (0.4 mg escalated every 1–2 weeks until reaching 0.8
tion with increased physical activity and significant caloric reduction or 1.6 mg), liraglutide once daily (1.2 or 1.8 mg) or placebo. At the
for 6 months. If non-pharmacologic therapy is not adequate after end of the 12 weeks, participants in both the liraglutide and sema-
6 months, then pharmacotherapy with an anti-obesity agent can glutide experienced ≥5% dose-dependent weight reduction, how-
be initiated as adjunct therapy. The guidelines recommend the im- ever, only participants in the semaglutide group experienced ≥10%
plementation of non-pharmacologic and pharmacologic therapy in dose-dependent weight reduction.10 Results like this, began the in-
2 2
people with BMI ≥30 kg/m or in those with a BMI ≥27 kg/m with vestigation of semaglutide's therapeutic potential for the treatment
one or more cardiovascular risk factors, such as hyperlipidaemia, hy- of obesity.
6–8
pertension or diabetes. The guidelines are limited when it comes In a trial investigating the efficacy of semaglutide compared with li-
to choosing an anti-obesity agent for weight management. However, raglutide and placebo, participants were treated with once daily sema-
the choice would be determined based on risks and benefits.9 With glutide at varying doses (initiated at 0.05 mg per day, and escalated to
lorcaserin removed from the market in 2020, there are now only 0.1, 0.2, 0.3 or 0.5 mg per day by 0.05 mg every 4 weeks), liraglutide
five medications, approved by the Food and Drug Administration (initiated at 0.6 mg per day, and escalated to 3.0 mg by 0.06 mg per
(FDA), for long-term weight management: orlistat, phentermine- week), or placebo.11 At the end of 52 weeks, semaglutide was shown
topiramate, naltrexone-
bupropion, liraglutide and most recently to be superior to liraglutide 3.0 mg per day with a dose of 0.2 mg or
semaglutide. The purpose of this review was to provide an analysis more per day. In this study, the liraglutide group experienced a mean
of subcutaneous semaglutide as a pharmacotherapeutic option for weight reduction of 7.8% at a dose of 3.0 mg per day which was sig-
obesity. nificantly less than the semaglutide group which experienced weight
reduction of 11%–14% at a dose of 0.2 mg per day or more.11 In both
trials, both the liraglutide and semaglutide groups had discontinuation
2 | M E TH O D S due to adverse effects. The most common adverse effects from these
early trials were gastrointestinal-related, mainly nausea, vomiting and
In people with diabetes, glucagon-like peptide-1 receptor agonists diarrhoea.10,11 In the second trial, the semaglutide group experienced
(GLP-1 RA) promote weight reduction. The weight loss benefits of higher dose-related gastrointestinal adverse events than the liraglu-
this class of medications have led to the investigation of certain tide group.11 This could be potentially explained by the fact the sema-
GLP-1 RA, at higher doses, for the treatment of obesity. For people glutide group experienced more dose titration over a longer period of
with obesity, weight loss and glycaemic improvement from GLP-1 time than the liraglutide group. The adverse events of GLP-1 RA are
RA are not the only potential benefits. In clinical trials, long-acting thought to be dose dependent, present during the titration phase and
GLP-1 RA appear to also be cardioprotective through the reduction transient in nature.12 From these trials, it can be concluded that both
9
of blood pressure and cholesterol. Due to the potential health care liraglutide and semaglutide play a role in the treatment of obesity. In
consequences from obesity, people at an increased risk for cardio- the future, the choice of which agent to use will likely be based on the
vascular events may benefit from a GLP-1 RA for cardioprotection. individual weight reduction goals of each patient.
|
186 PHILLIPS and CLEMENTS
An endogenous hormone, GLP-1 is produced in response to 3.2 | Clinical trials

9
the intake of food by the L cells within the intestinal mucosa.
GLP-1 receptors are present throughout the body. However, the The FDA has a guiding document of clinical trials for obesity man-
receptors within the pancreas, gastrointestinal tract, heart and agement.16 To determine effectiveness, the FDA suggested an end-
brain are what potentially play a role in diabetes, weight manage- point of weight loss from baseline; clinical significance would be met
12
ment and the cardioprotective effects of GLP-1 RA. The exact if an active medication results in a 5% or more placebo-subtracted
mechanism behind how GLP-1 RA promote weight reduction is not difference for the primary outcome. The guiding document also
entirely understood. Many potential mechanisms of action have suggests additional endpoints, including percentage of participants
been suggested. In the pancreas, GLP-1 upregulates the secretion achieving 5% or 10% of weight loss from baseline. This endpoint
of insulin from pancreatic beta cells, while increasing insulin sen- aligned with recommended weight loss from clinical practice guide-
sitivity throughout the body. GLP-1 also acts on the alpha cells lines. For this endpoint, clinical significance would be met if either
of the pancreas to simultaneously decrease the release of gluca- the active medication had 35% or more of the participants have a
gon.9,12 GLP-1 also appears to have other effects on metabolism weight loss of 5% or at least double the number of participants with
such as promoting fat oxidation over carbohydrates and decreas- the active medication had a weight loss of 5%, compared to placebo.
ing hepatic gluconeogenesis.9 In the gastrointestinal tract, GLP-1 Most likely these three outcomes would also be statistically signifi-
works to slow down gastrointestinal motility, increase satiety, as cant upon analysis.16
well as potential protective effects of decreased acid production In the Semaglutide Treatment Effect in People with obesity
12
from the parietal cells and increased intestinal mucus secretion. (STEP) program with semaglutide, all participants were adults with
In the heart, GLP-1 receptors are found mainly on the sinoatrial obesity or were overweight regardless of diabetes status.17–20
nodes and myocytes, which may be the cause of the sustained Counselling on lifestyle modifications were provided periodically by
increase in heart rate with GLP-1 RA treatment.12 In the brain, a dietitian or healthcare professional and throughout the trial. In ad-
GLP-1 communicates with the hypothalamus, regulating the ap- dition, participants also received tools for physical activity, such as
petite by increasing satiety signalling.9,12 Semaglutide is thought kettlebells and jump ropes. Lifestyle modification did vary though
to affect the brain with a unique mechanism apart from other among the five clinical trials. In STEP 1, 2, 4 and 5, participants were
GLP-1 receptor agonists. Treatment with semaglutide has been advised on a daily 500 calorie reduction and 150 min of physical
associated with the food/reward system, increasing an individ- activity, whereas participants in STEP 3 were encouraged to follow
ual's ability to control food intake and altering food preferences intensive behavioural therapy with a low-calorie diet. Overall, there
(ie, a lower liking for high-f at foods).12 Taking all of these potential were more than 5000 participants in the STEP program to evaluate
mechanisms of action into consideration, there does not appear semaglutide versus placebo. In all clinical trials, semaglutide was ti-
to be just one main mechanism behind how GLP-1 RA promote trated to a maximum dose of 2.4 mg subcutaneously per week. Refer
weight reduction. It is most likely that each mechanism plays a to Table 1 for baseline characteristics of participants within STEP
role in a combined effect which ultimately leads to improved 1–4 trials.17–20
weight control.
Both liraglutide and semaglutide are modified to reversibly
bind to serum albumin in the body, increasing the half-life of these 3.3 | Efficacy
agents through protecting the peptide from dipeptidyl pepti-
dase-I V degradation and renal filtration.12 Semaglutide's structure STEP 1 was a randomized, double-b lind, multi-centred, placebo-
is 94% homologous to the endogenous hormone GLP-1. Three controlled trial. In this trial, adults with a BMI of ≥30 or a BMI of
modifications to semaglutide's structure improve it is half-life to ≥27 kg/m2 with one or more treated or untreated weight-related
13
165 hours which is approximately 1 week. These modifications co-
existing conditions, such as hypertension, cardiovascular
include, the substitution of alanine to alpha-aminoisobutyric acid disease or obstructive sleep apnoea, who reported at least one
at position eight, lysine to arginine at position thirty-four, and fi- unsuccessful dietary effort to lose weight were included in this
nally, acylation of the lysine in position twenty-six that includes a trial.17 Individuals who had diagnosed diabetes, a haemoglobin
spacer consisting of two 8-amino-3 ,6-dioxaoctanoic acid moieties, A1C of ≥6.5%, a history of chronic pancreatitis, acute pancrea-
a C-18 fatty di-a cid side chain and a glutamic acid moiety.12,13 titis within 180 days before enrolment, previous surgical obesity
Metabolism of semaglutide occurs slowly through proteolysis of treatment, or the use of anti-obesity medication within 90 days
the peptide backbone, as well as beta oxidation of the di-f atty acid were all excluded from enrolment in this trial. Randomized in a 2:1
side chain.13 The degradation products are then excreted through ratio, 1961 participants either received semaglutide at a dose of
the urine and faeces, with a very limited amount of unchanged 2.4 mg administered subcutaneously once a week for 68 weeks
13
semaglutide excreted in the urine approximately three per cent. or a matching placebo combined with lifestyle interventions.
Due to no single organ being implicated in semaglutide's metabo- Lifestyle interventions include counselling sessions every 4 weeks
lism, dose adjustment may not be necessary for patients with he- to help participants adhere to a reduced calorie diet and increased
patic or renal impairment.14,15 physical activity of 150 min per week. The coprimary endpoints
|
TA B L E 1 Baseline characteristics of
Step 1 Step 2 Step 3 Step 4
participants in STEP program17–20
N = 1961 N = 1210 N = 611 N = 902
Female, n (%) 1453 (74.1) 616 (50.9) 495 (81.0) 717 (79.5)
Age, y 46.5 ± 12.7 55.3 ± 10.6 46.2 ± 12.7 46.4 ± 11.9
Race, n (%)
White 1472 (77.2) 751 (62.1) 465 (76.1) 751 (83.3)
African American 111 (5.8) 100 (8.3) 116 (19.0) 123 (13.6)
Asian 261 (13.7) 317 (26.2) 11 (1.8) 19 (2.1)
Hispanic 236 (12.0) 155 (12.8) 121 (19.8) 70 (7.8)
Other 62 (3.2) 42 (3.5) 19 (3.2) 9 (1.0)
2
BMI, kg/m 37.9 ± 6.7 35.7 ± 6.3 38.0 ± 6.7 38.3 ± 7.0
Waist Circumference, cm 114.7 ± 14.7 114.6 ± 14.1 113.0 ± 15.5 115.1 ±
15.6
Blood pressure, mmHg)
Systolic 126.5 ± 14.3 130.0 ± 13.5 124.4 ± 14.8 126.4 ±
14.3
Diastolic 80.3 ± 9.6 79.8 ± 9.0 80.5 ± 9.7 80.9 ± 9.9
Cholesterol, mg/dl
Total 4.9 ± 20.0 4.4 ± 23.3 4.8 ± 19.7 5.0 ± 19.5
HDL 1.3 ± 25.5 1.1 ± 24.5 1.3 ± 23.6 1.29 ± 24.6
LDL 2.9 ± 28.7 2.3 ± 35.6 2.8 ± 28.5 3.0 ± 27.3
VLDL 0.6 ± 51.1 0.8 ± 51.6 0.6 ± 48.1 0.6 ± 53.6
Triglycerides 1.4 ± 70.0 1.8 ± 64.2 1.2 ± 49.8 1.4 ± 54.9
Overall eGFR, ml/ 96.6 ± 17.2 93.7 ± 19.5 96.8 ± 19.5 97.6 ± 17.8
min/1.73 m2
were the percentage change in body weight and a weight reduc- with lifestyle interventions. Lifestyle interventions were the same
tion of at least 5%. At week 68, in the semaglutide group, the as those listed above in the STEP 1 trial. Patients were counselled
mean change in body weight was −14.9% compared to −2.4% in every 4 weeks, by a qualified health professional and were encour-
the placebo group (p < 0.001). In the semaglutide group, 86.4% of aged to keep a food and activity diary. The coprimary endpoints
participants achieved weight reductions of ≥5%, and 69.1% of par- were the percentage change in body weight and a weight reduction
ticipants achieved weight reductions of ≥10%, compared to 31.5% of at least 5%. At week 68, in the 2.4 mg semaglutide group, the
and 12.0% of participants within the placebo group (p < 0.001, mean change in body weight was −9.64% compared to −6.99% in
NNT = 2).17 Limitations to consider are the relative short duration the 1.0 mg semaglutide group, and −3.42% in the placebo group
of the trial, the limited representation of minorities, and the higher (p < 0.001). The percentages of participants who achieved weight
percentage of women in participation of this study than men. In reduction of ≥5% were 68.8%, in the 2.4 mg semaglutide group,
STEP 1, 2.4 mg of semaglutide once weekly was associated with 57.1% in the 1.0 mg semaglutide group, and 28.5% in the placebo
clinically relevant reductions in body weight. group (p < 0.001). The percentages of participants who achieved
STEP 2 was a randomized, double-blind, multi-centred, placebo- weight reduction of ≥5% were 68.8%, in the 2.4 mg semaglutide
18
controlled, superiority trial. Adults who were eligible for this trial group, 57.1% in the 1.0 mg semaglutide group, and 28.5% in the pla-
must have reported at least one unsuccessful dietary effort to lose cebo group (p < 0.001, NNT = 4). The percentages of participants
weight, a BMI of at least 27 kg/m2, a haemoglobin A1C of 7%–10% who achieved weight reduction of ≥10% were 45.6%, in the 2.4 mg
and had been diagnosed with T2D within 180 days before screening semaglutide group, 28.7% in the 1.0 mg semaglutide group and 8.2%
and were managed with diet and exercise alone or with up to three in the placebo group (p < 0.001).18 A limitation from the STEP 2 trial
different oral glucose-lowering agents for at least 90 days before could be the exclusion of patients who are on insulin, as this patient
screening.18 Adults who reported body weight changes of more population could benefit from the weight loss associated with the
than 5 kg within 90 days before screening or who had previous or add on of semaglutide with insulin; this information is difficult to
planned obesity treatment with surgery, or a weight loss device were extrapolate to individuals on insulin therapy. In STEP 2, 2.4 mg of
excluded from this study. Randomized in a 1:1:1 ratio, 1210 partic- semaglutide once weekly achieved superior and clinically relevant
ipants, received once weekly either 2.4 mg of semaglutide, 1.0 mg reductions in body weight compared with placebo in participants
of semaglutide or placebo subcutaneously for 68 weeks combined who were overweight or obese, with T2D.
|
STEP 3 was a randomized, double-blind, placebo-controlled,
(n = 268)
Placebo
multi-centred trial.19 In this trial, adults with a BMI of ≥30 kg/m2 or
−1.5
N/A
N/A
N/A
3.3
4.4
a BMI of ≥27 kg/m2 with one or more treated or untreated weight-
related co-existing conditions, who reported at least one unsuccess-
ful dietary effort to lose weight were included in this trial. Adults
Semaglutide
who had diagnosed diabetes, a haemoglobin A1C of ≥6.5%, who
(n = 535)
reported body weight changes of more than 5 kg within 90 days be-
STEP 4
−6.4
N/A
N/A
N/A
fore screening or who had previous or planned obesity treatment
0.5
1.0
with surgery, or a weight loss device were excluded from this study.
In the trial, 611 participants were randomized 2:1 to receive either
once weekly 2.4 mg of semaglutide subcutaneously or placebo, com-
(n = 204)
Placebo
bined with a low-calorie diet for the first 8 weeks and behavioural
−6.3
13.2
−1.6
27.0
N/A
1.6
therapy during the 68 weeks. For the first 8 weeks, participants
received low-calorie (1000–1200 kcal/d) meal replacements pro-
vided by Nutrisystem. After 8 weeks, participants transitioned to a
Abbreviations: IWQOL-Lite, Impact of Weight on Quality of Life –Lite; SBP, systolic blood pressure; SF-36, Short Form 36; WC, waist circumference.
Semaglutide
hypo-caloric diet (1200–1800 kcal/d) of conventional food for the

(n = 407)
STEP 3
remaining 68 weeks. Participants were also prescribed 100 min of

−14.6
55.8
75.3
−5.6
N/A
physical activity per week which was increased weekly by 25 min

2.4
until participants reached 200 min/wk. Participants also received 30

individual therapy visits with a registered dietician who counselled
(n = 402)
on diet, physical activity and behavioural strategies. The coprimary

Placebo
endpoints were the percentage change in body weight and a weight

8.2
3.2
−4.5
−0.5
5.3
1.0
reduction of at least 5%. At week 68, the mean weight reduction in

the semaglutide group was −16.0% compared to the placebo group
which was −5.7% (p < 0.001). The percentage of those who achieved
≥5% weight reduction in the semaglutide group was 86.6% and
Semaglutide
47.6% in the placebo group (p < 0.001, NNT = 3). The percentage of
(n = 402)
1.0 mg
those who achieved ≥10% weight reduction in the semaglutide group

2.4
8.7
28.7
13.7
−6.7
−2.9
was 75.3% and 27.0% in the placebo group (p < 0.001).18 Limitations
of this trial include the short duration of the trial and the inability
to identify the separate contributions to weight loss of the lifestyle
Semaglutide 2.4 mg
modifications. Overall, semaglutide in combination with both a low-

calorie diet and behavioural therapy resulted in significantly greater
(n = 403)
weight loss than placebo based on results from the STEP 3 trial.
STEP 2
The STEP 4 was a randomized, double-b lind, placebo-

2.5
25.8
45.6
−9.4
−3.9
10.1
centred withdrawal study. 20 Included in this

controlled, multi-
trial was adults with a BMI of ≥30 kg/m2 or a BMI of ≥27 kg/m2
with one or more treated or untreated weight-related co-existing
(n = 655)
Placebo
conditions, who reported at least one unsuccessful dietary effort

5.25
−1.06
0.41
−4.13
TA B L E 2 Confirmatory secondary endpoints17–20
12.0
4.9
to lose weight. Excluded were those who reported body weight

changes of more than 5 kg within 90 days before screening or
a haemoglobin A1C of ≥6.5%. For 20 weeks, all 803 individuals
Semaglutide
participated in a run-in period. During this period, participants re-

(n = 1306)
ceived semaglutide starting at 0.25 mg and titrated up to 2.4 mg

STEP 1
−13.54
2.21
14.67
−6.16
Changes from baseline to week 68
50.5
69.1
by week 16 and continued to week 20. At week 20, participants

were randomized 2:1 to either continue the semaglutide 2.4 mg
or to receive placebo for the remaining 48 weeks. All participants
received behavioural therapy, a reduced calorie diet and increased
Weight reduction of
Weight reduction of
physical activity during the 68 weeks. The primary endpoint of

SBP (mmHg)
IWQOL-Lite
≥10% (%)
≥15% (%)
this study was the per cent change in body weight from week 20
WC (cm)
to week 68. At week 68, the mean per cent body weight change in
SF-36
the semaglutide 2.4 mg group was −7.9% compared to 6.9% in the

placebo group (p < 0.001). 20 Limitations to consider in the STEP4
|
trial are the potential selection bias due to the run-in period and 3.6 | Investigational trials
withdrawal design, and the lack of assessment of adherence to
lifestyle modifications. In STEP 4, continued treatment with sema- Additional trials will complete the STEP program for semaglutide
glutide showed sustained clinically relevant weight loss as com- in obesity management. Maintenance or long-
term benefit of
pared to switching to placebo. semaglutide over a 2-year period will be determined in the STEP
5 trial (NCT03693430). 21 The efficacy and safety of semaglutide,
compared to placebo among East Asian participants who are over-
3.4 | Other outcomes weight or have obesity; this trial as STEP 6 has been completed
and published results will be forthcoming on the change in body
In the STEP trials, confirmatory secondary endpoints were weight from baseline to Week 68 and proportion of participants
achievement of a reduction in body weight of ≥10% and ≥15% by with at least 5% reduction in body weight (NCT03811574). 22 In
week 68 and the change from baseline to week 68 in waist cir- STEP 7, Chinese participants are being recruited to determine the
cumference, systolic blood pressure and physical function score efficacy and safety of semaglutide versus placebo among the same
on the Short Form Health Survey (SF-36) version 2 and on the outcomes for the STEP 6 trial. 23 The STEP 7 trial will evaluate in-
Quality of Life-L ite Clinical Trials Version questionnaire (IWQOL- tervention over a 44-week period (NCT04251156). 23 Semaglutide
17–2 0
LiteCT). Table 2 summarizes the confirmatory secondary end- will be investigated in an active-comparator trial in the STEP 8
points from the STEP program. trial. 24 The dose of 2.4 mg semaglutide will be compared in ef-
Supplementary secondary endpoints in all trials were changes ficacy and safety to liraglutide 3.0 mg, which is the recommended
from baseline to week 68 in BMI, body weight, A1C, fasting plasma dose of liraglutide for obesity management. STEP 8 trial will have a
glucose, diastolic blood pressure and a fasting lipid panel.17–20 Other primary outcome of change in body weight from baseline to Week
supplementary secondary endpoints not included in every trial was 68 (NCT04074161). 24 A cardiovascular trial will conclude in 2023
a body weight reduction ≥20% in STEP 1 and 3, body composition to determine the effect of semaglutide in participants with car-
changes in STEP 1 and changes in baseline C-reactive protein in diovascular disease. The Semaglutide Effects on cardiovascular
STEP trials 1, 2 and 3.17–19 Outcomes in People with Overweight or Obesity (SELECT) will
In STEP 1, other exploratory endpoints favoured the use of determine semaglutide's effect on the time to first occurrence of
semaglutide. In the prediabetes subpopulation, 84.1% of partici- cardiovascular death, non-f atal myocardial infarction or non-f atal
pants had normoglycemia at week 68 compared to 47.8% in the pla- stroke over 31 to 59 months (NCT03574597). 25
cebo group.17 The comparison of A1C levels from baseline to week
68 showed a reduction of 0.52 percentage points in the semaglutide
group compared to a reduction of 0.17 percentage points in the pla- 4 | W H AT I S N E W A N D CO N C LU S I O N
cebo group.17 In STEP 2, the exploratory endpoint focused around
the potential reduction of other glucose-lowering medications with Semaglutide, marked as Wegovy™ (Novo Nordisk), is available in a
semaglutide use.18 In STEP 2, the 2.4 mg semaglutide group expe- prefilled, single-d ose pen with an integrated needle. 26 Following
rienced a 28.6% reduction in concomitant use of glucose-lowering administration, the prefilled pen can be disposed of in the trash.
medication as compared to 25.1% in the 1.0 mg semaglutide group Five strengths are available in the pen (0.25, 0.5, 1.0, 1.7 and
and 7.1% in the placebo group.18 Table 3 highlights secondary end- 2.4 mg) and each box would be packaged with 4 pens for a 1-
points from the STEP 1–4 trials. month supply. The 2.4 mg dose of semaglutide is approved for
obesity management, and the monthly titration is recommended
to improve tolerance and minimize gastrointestinal adverse
3.5 | Safety events. The benefit with a prolonged titration with semaglutide
is unknown but may be acceptable in clinical practice for those
In STEP 1–4, the most frequently reported adverse effects who experience intolerable gastrointestinal adverse events. The
were gastrointestinal such as nausea, vomiting, diarrhoea and manufacturer provides specific instructions for missed doses of
constipation.17–20 These adverse effects were reported more often semaglutide and time frame to the next dose (eg, less than or
in the semaglutide group than the placebo group. Mild-to-moderate more than 2 days). Semaglutide may be resumed at the individu-
in severity, the gastrointestinal adverse effects usually resolved al's normal administration schedule or restarted at 0.25 mg once
without discontinuation of semaglutide.17–20 In the STEP 3 trial, the weekly to minimize gastrointestinal adverse events if more than
median time of nausea was 5 days in both groups, 2 days of vomiting two consecutive doses have been missed. Semaglutide can be ad-
in both groups, 3 days of diarrhoea in both groups, and 27 days of ministered under the skin of the abdomen, upper arm or thigh on
constipation in the semaglutide group compared to 16 days in the a weekly basis. As a GLP-1 RA, there may be some effect on the
placebo group.19 The deaths which were reported, were not thought absorption of oral medications due to gastric emptying from the
to be associated with the study treatment.17,18 Refer to Table 4 for general mechanism of the therapeutic class. For those with T2D
summary of adverse events in STEP 1–4 trials. and obesity, caution should be considered if semaglutide is added
| 190
TA B L E 3 Supplementary secondary endpoints17–20
STEP 1 STEP 2 STEP 3 STEP 4
Semaglutide Semaglutide
Semaglutide Placebo 2.4 mg 1.0 mg Placebo Semaglutide Placebo Semaglutide Placebo
(n = 1306) (n = 655) (n = 403) (n = 402) (n = 402) (n = 407) (n = 204) (n = 535) (n = 268)
Changes from baseline to week 68

BMI −5.54 −0.92 −3.5 −2.5 −1.3 −6.0 −2.2 −2.6 2.2
Body weight (kg) −15.3 −2.6 −9.7 −6.9 −3.5 −16.8 −6.2 −7.1 6.1
Change in A1C (percentage points) −0.45 −0.15 −1.6 −1.5 −0.4 −0.51 −0.27 −0.1 0.1
Fasting plasma glucose (mg/dl) −8.35 −0.48 −2.1 −1.8 −0.1 −6.73 −0.65 −0.8 6.7
DBP (mmHg) −2.83 −0.42 −1.6 −0.6 −0.9 −3.0 −0.8 0.3 0.9
Cholesterol parameters (mg/dl)
Total cholesterol 0.97 1.00 0.99 0.98 0.99 −3.8 2.1 5 11
HDL 1.05 1.01 1.07 1.05 1.04 6.5 5.0 18 18
LDL 0.97 1.01 1.00 0.99 1.00 −4.7 2.6 1 8
VLDL 0.78 0.93 0.79 0.83 0.90 −22.5 −6.6 −6 15
Free fatty acids 0.83 0.93 0.84 0.86 0.99 −11.9 4.0 −18 −14
Triglycerides 0.78 0.93 0.78 0.83 0.91 −22.5 −6.5 −6 15
CRP (mg/L) 0.47 0.85 0.51 0.58 0.83 −59.6 −22.9 N/A N/A
Weight reduction of ≥20% (%) 32.0 1.7 N/A N/A N/A 35.7 3.7 N/A N/A
Abbreviations: BMI, body mass index; CRP, C-reactive protein; DBP, diastolic blood pressure.
PHILLIPS and CLEMENTS
PHILLIPS and CLEMENTS
TA B L E 4 Adverse events and tolerability profile.
STEP 1 STEP 2 STEP 3 STEP 4
Semaglutide
Semaglutide Placebo Semaglutide 2.4 mg 1.0 mg Placebo Semaglutide Placebo Semaglutide Placebo
(n = 1306) (n = 55) (n = 403) (n = 402) (n = 402) (n = 407) (n = 204) (n = 535) (n = 268)
Any adverse event 1171 566 (86.4) 353 329 309 390 196 435 201
(89.7) (87.6) (81.8) (76.9) (95.8) (96.1) (81.3) (75.0)
Serious adverse events 128 42 40 31 37 37 6 41 15
(9.8) (6.4) (9.9) (7.7) (9.2) (9.1) (2.9) (7.7) (5.6)
Adverse events leading to 92 20 25 20 14 24 6 13 6
discontinuation (7.0) (3.1) (6.2) (5.0) (3.5) (5.9) (2.9) (2.4) (2.2)
GI events 59 5 17 14 4 14 0 N/A N/A
(4.5) (0.8) (4.2) (3.5) (1.0) (3.4)
Fatal events 1 1 1 1 1 0 0 1 1
(0.1) (0.2) (0.2) (0.2) (0.2) (0.2) (0.4)
Acute pancreatitis 3 0 1 0 1 0 0 0 0
(0.2) (0.2) (0.2)
Malignant neoplasms 14 7 5 7 8 3 1 6 1
(1.1) (1.1) (1.2) (1.7) (2.0) (0.7) (0.5) (1.1) (0.4)
Abbreviation: GI, gastrointestinal.

All information reported as n (%).
| 191
|
to a regimen of insulin or sulfonylurea therapy due to the risk of C O N FL I C T S O F I N T E R E S T

hypoglycaemia. If hypoglycaemia occurs, the insulin or sulfonylu- The author(s) declared no potential conflicts of interest with respect
rea therapy should be reduced or discontinued. 26 to the research, authorship and/or publication of this article.
For the general management of obesity, lifestyle modifications
are the cornerstone of a successful weight loss program. If an in- ORCID
dividual does not achieve 5% weight loss over 6 months with life- Jennifer N. Clements https://orcid.org/0000-0003-2431-6651
style modifications, then an anti-obesity agent may be indicated.
Anti-
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investigating how well semaglutide works in people suffering from

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Clinical review of subcutaneous semaglutide for obesity

Anna Phillips PharmD Candidate1 |

1 | W H AT I S K N OW N A N D O B J EC TI V E consequences of obesity can include type 2 diabetes (T2D), dys-

An endogenous hormone, GLP-­1 is produced in response to 3.2 | Clinical trials

STEP 3 was a randomized, double-­blind, placebo-­controlled,

hypo-­caloric diet (1200–­1800 kcal/d) of conventional food for the

remaining 68 weeks. Participants were also prescribed 100 min of

physical activity per week which was increased weekly by 25 min

until participants reached 200 min/wk. Participants also received 30

on diet, physical activity and behavioural strategies. The coprimary

endpoints were the percentage change in body weight and a weight

reduction of at least 5%. At week 68, the mean weight reduction in

those who achieved ≥10% weight reduction in the semaglutide group

modifications. Overall, semaglutide in combination with both a low-­

The STEP 4 was a randomized, double-­b lind, placebo-­

centred withdrawal study. 20 Included in this

conditions, who reported at least one unsuccessful dietary effort

to lose weight. Excluded were those who reported body weight

participated in a run-­in period. During this period, participants re-

ceived semaglutide starting at 0.25 mg and titrated up to 2.4 mg

by week 16 and continued to week 20. At week 20, participants

physical activity during the 68 weeks. The primary endpoint of

the semaglutide 2.4 mg group was −7.9% compared to 6.9% in the

TA B L E 3 Supplementary secondary endpoints17–­20

STEP 1 STEP 2 STEP 3 STEP 4

Changes from baseline to week 68

TA B L E 4 Adverse events and tolerability profile.

STEP 1 STEP 2 STEP 3 STEP 4

Abbreviation: GI, gastrointestinal.

to a regimen of insulin or sulfonylurea therapy due to the risk of C O N FL I C T S O F I N T E R E S T

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An endogenous hormone, GLP-1 is produced in response to 3.2 | Clinical trials

STEP 3 was a randomized, double-blind, placebo-controlled,

hypo-caloric diet (1200–1800 kcal/d) of conventional food for the

modifications. Overall, semaglutide in combination with both a low-

The STEP 4 was a randomized, double-b lind, placebo-

participated in a run-in period. During this period, participants re-

TA B L E 3 Supplementary secondary endpoints17–20