- Journal List
- J Pharm Technol
- v.38(4); 2022 Aug
- PMC9272494
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more: PMC Disclaimer | PMC Copyright Notice
J Pharm Technol. 2022 Aug; 38(4): 239–246.
Published online 2022 May 13. doi:10.1177/87551225221092681
PMCID: PMC9272494
PMID: 35832567
Abby Fornes, PharmD,1 Jamie Huff, PharmD, BCACP, BC-ADM,2 Roger Iain Pritchard, PharmD, BCACP,2 and Miranda Godfrey2
Author information Copyright and License information PMC Disclaimer
Abstract
Objective: To review the efficacy, safety, and role of theglucagon-like peptide-1 (GLP-1) receptor agonist semaglutide for chronic weightmanagement. Data Sources: A literature search of PubMed/MEDLINE andGoogle Scholar was performed using the search terms: semaglutide 2.4, weight,and obesity. Ongoing studies of semaglutide were identified utilizingclinicaltrials.gov. Study Selection and Data Extraction: AllEnglish-language articles evaluating the efficacy and safety of semaglutide 2.4mg for weight management in humans were included. Data Synthesis:Once-weekly injectable semaglutide 2.4 mg is indicated as an adjunct to areduced-calorie diet and increased exercise for chronic weight management inadults with a body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2with at least one weight-related comorbidity, such as hypertension, type 2diabetes mellitus, or dyslipidemia. Semaglutide 2.4 mg has consistentlydemonstrated clinically significant weight loss across all phase 3 STEP(semaglutide treatment effect in people with obesity) trials, and long-termefficacy and safety have been confirmed for up to 2 years. Gastrointestinal sideeffects were the most frequently reported side effects, including nausea,vomiting, constipation, and diarrhea. Safety data for semaglutide 2.4 mg wereconsistent with that reported previously for the GLP-1 receptor agonist class.Conclusions: Semaglutide 2.4 mg is a highly efficacious agentfor weight management, with a safety profile similar to that of other GLP-1receptor agonists. It is a feasible option for chronic weight management, withdata for up to 2 years. It is currently the only once-weekly weight lossmedication, although cost may limit its utilization.
Keywords: glucagon-like peptide 1, antiobesity agents, obesity, overweight, semaglutide, review
Introduction
Obesity is a chronic disease that places a considerable burden on affectedindividuals and is considered a global public health challenge.1 Obesity can cause insulin resistance, which is associated with thedevelopment of cardiovascular and metabolic conditions, such as hypertension,dyslipidemia, type 2 diabetes mellitus, nonalcoholic fatty liver disease, andpolycystic ovary syndrome.2,3Management of obesity through weight loss has shown to reduce the risk of developingtype 2 diabetes, improve lipid profiles, and reduce blood pressure.4 Targeting a minimum weight loss of 5% total body weight is recommended.However, weight loss of 10% or more is often desired because it is associated withincreased benefits for obesity-related risk factors and diseases.4 Recommended first-line options for weight loss include lifestylemodifications that prioritize dietary changes and increased physical activityincluding both aerobic and resistance training exercises.4 Limiting caloric intake between 1200 and 1800 kilocalories (kcal) per day,and reducing kcal to ensure at least a 500 kcal deficit per day are two methods thatcan enhance weight loss.4 Additionally, individuals should target a minimum of 150 minutes or more ofmoderate-intensity exercise spread over 3 to 5 sessions per week. As adjuncts tofirst-line lifestyle modifications, pharmacotherapy is available to aid patients inweight management. Before the approval of semaglutide, five medications have beencommonly used: orlistat, phentermine, phentermine-topiramate, naltrexone-bupropion,and liraglutide.5
Semaglutide, a GLP-1 receptor agonist, was initially approved in December 2017 as anadjunct to diet and exercise for the management of type 2 diabetes at doses up to 1mg weekly. Across the phase 3 trial program for type 2 diabetes (SUSTAIN),semaglutide consistently demonstrated clinically significant weight loss (up to -6.5kg with 1.0 mg semaglutide).6-12 Subsequently, semaglutide hasbeen approved at a higher dose, 2.4 mg, as an adjunct to a reduced-calorie diet andincreased physical activity for chronic weight management in patients who haveobesity, or are overweight with at least one other weight-related comorbid condition.13 This article reviews clinical trials assessing the efficacy and safety ofsemaglutide at a dose of 2.4 mg for chronic weight management.
Data Sources
A literature search of PubMed/MEDLINE and Google Scholar was performed using thesearch terms: semaglutide 2.4, weight, and obesity. All English-language articlesevaluating the efficacy and safety of semaglutide 2.4 mg for weight loss in humanswere included. Ongoing studies of semaglutide were identified utilizingclinicaltrials.gov. Trials evaluating the use of semaglutide at a dose of 1.0 mgwere excluded as this dose is not indicated for weight management purposes.
Pharmacology and Pharmacokinetics/Pharmacodynamics
GLP-1 is an incretin hormone with receptors present in several areas of the body,including pancreatic alpha and beta cells, the stomach, and the central nervoussystem. GLP-1 is a target for weight management as it slows gastric emptying andpromotes satiety, which leads to a reduction in food intake. Additionally, GLP-1crosses the blood-brain barrier where it activates areas of the hypothalamus andprefrontal cortex and regulates feeding behavior.14,15
The bioavailability of semaglutide is 89% when injected subcutaneously. Peakconcentrations occur 3 days after injection, and steady state is achieved by Week 5when injected once weekly. Similar exposure was achieved in three subcutaneousadministration sites: the abdomen, thigh, and upper arm. Semaglutide is greater than99% bound to plasma albumin, which provides protection from degradation and renalclearance. Semaglutide is modified through the substitution of alanine at position 8to protect from natural degradation by dipeptidyl-peptidase 4 (DPP-4). Theelimination half-life of semaglutide is approximately 1 week; therefore, semaglutidewill be present for approximately 5-7 weeks after the last dose. Semaglutide iseliminated via the urine and feces. Dosage adjustments are not required based onhepatic or renal function.13
Dosing and Administration
Semaglutide for weight loss should be initiated at 0.25 mg once weekly and injectedsubcutaneously without regard to meals. Dose escalation should occur after 4 weeksto doses of 0.5 mg, 1 mg, and 1.7 mg, and the maintenance dose of 2.4 mg. Ifpatients do not tolerate a dose during escalation, clinicians should consider a4-week delay in dose escalation. If patients do not tolerate the maintenance dose,the dose may be decreased to 1.7 mg for 4 weeks followed by escalation back tomaintenance dosing. If patients permanently fail to tolerate maintenance dosing,semaglutide should be discontinued.13
Clinical Efficacy
The efficacy of semaglutide 2.4 mg is being assessed across 8 trials in the STEPprogram. Five of these trials have been published.16-21 The results of STEP 5 werepresented at the 2021 Annual Meeting of the Obesity Society but have not beenpublished at the time of manuscript writing.20 Additionally, cardiovascular benefits of semaglutide 2.4 mg are beingevaluated in the SELECT trial, which is currently enrolling patients.22 Details of these trials are shown in Table 1. Across all published trials,semaglutide demonstrated a statistically significant greater percent decrease inweight from baseline and a greater likelihood of patients losing ≥5% of their bodyweight when compared with either placebo or liraglutide. In each trial, all patientsreceived lifestyle intervention(s).16-21,23
Table 1.
Clinical Efficacy Trials of Semaglutide.
| Study | Purpose | Study design | Summary of population enrolled | Summary of baselinecharacteristics | Efficacy outcomes | |
|---|---|---|---|---|---|---|
| Percent weight change from baseline to end oftreatment | Percentage of patients achieving ≥5% body weightloss at the end of treatment | |||||
| STEP 116 | To evaluate the efficacy and safety of semaglutide 2.4 mg ascompared with placebo as an adjunct to lifestyle interventionsfor reducing body weight | n=1961 patients; 68-week phase 3 randomized, double-blind,placebo-controlled trial; multicenter study performed in 16countries | Adults with a BMI of 30 kg/m2 or more, or 27kg/m2 or more with at least 1 weight-relatedcomorbidity; patients with diabetes were excluded | Female: 74.1% White: 75% Mean age: 46years Mean body weight: 105.3 kg Mean BMI: 37.9kg/m2 | -14.9% with semaglutide 2.4 mg vs. -2.4% in the placebo(estimated treatment difference, -12.4%; 95% CI, -13.4 to -11.5;p<0.001) | 86.4% of patients treated with semaglutide 2.4 mg vs. 31.5% inthe placebo group (p<0.001) |
| STEP 217 | To evaluate the efficacy and safety of once-weekly SQsemaglutide 2.4 mg vs. semaglutide 1.0 mg and placebo for weightmanagement in adults with overweight or obesity, and type 2diabetes. | n=1210 patients; 68-week phase 3 randomized, double-blind,double-dummy, placebo-controlled, multicenter superiority studyperformed in 12 countries | Adults with at least 1 unsuccessful dietary effort to loseweight, with a BMI of ≥27 kg/m2 and HbA1cof 7-10% and had been diagnosed with T2DM >180 days beforescreening, managed with diet and exercise alone or treated withstable doses of up to 3 oral glucose-lowering agents (metformin,SU, SGLT-2 inhibitors, or TZDs) for at least 90 days beforescreening | Female: 49.5% White: 62.1% Mean age: 55years Mean body weight: 99.8 kg Mean BMI: 35.7kg/m2 Mean duration of diabetes: 8 years | -9.6% with semaglutide 2.4 mg and -3.4% with placebo (estimatedtreatment difference, -6.2%; 95% CI, -7.3 to -5.2; p<0.0001).-7.0% with semaglutide 1.0 mg (estimated treatment differencefor semaglutide 2.4 mg vs. semaglutide 1.0 mg, -2.7%; 95% CI,-3.7 to -1.6; p <0.0001) | 68.8% of patients treated with semaglutide 2.4 mg vs. 28.5% withplacebo (OR, 4.88; 95% CI, 3.58-6.64; p<0.0001) or 57.1% ofpatients treated with semaglutide 1.0 mg (OR, 1.62; 95% CI,1.21-2.18; p=0.0012) |
| STEP 318 | To evaluate the effects on body weight and cardiometabolic riskfactors of adding SQ semaglutide 2.4 mg to intensive behavioraltherapy. | n=611; 68-week phase 3, randomized, double-blind,placebo-controlled, multicenter study conducted in the UnitedStates. All participants in this trial received a low-caloriediet (1000-1200 kcal/day) for the first 8 weeks, followed by ahypocaloric diet (1200-1800 kcal/day) for the remainder of the68 weeks. All participants were also provided with 30 individualintensive behavioral therapy visits with a registered dietitianover the 68-week trial period. | Adults with 1 or more unsuccessful dietary efforts to loseweight, and had either BMI ≥27 kg/m2 with at least 1weight-related comorbidity, or BMI ≥ 30 kg/m2.Patients with diabetes were excluded. | Female: 81% White: 76.1% Mean age: 46years Mean body weight: 105.8 kg Mean BMI: 38kg/m2 | -16.0% with semaglutide vs. -5.7% with placebo, both combinedwith intensive behavioral therapy and meal replacements(treatment difference, -10.3%; 95% CI, -12.0 to -8.6;P<0.001) | 86.6% of patients treated with semaglutide vs. 47.6% in theplacebo group (OR, 6.1; 95% CI, 4.0 to 9.3; p<0.001) |
| STEP 419 | To compare the effect of continuing once-weekly treatment withSQ semaglutide 2.4 mg vs. switching to placebo, both withlifestyle intervention, on body weight in participants withoverweight/obesity who reached a semaglutide treatment dosage of2.4 mg during an initial 20-week run-in | n=902; 68-week, phase 3 randomized, double-blind,placebo-controlled withdrawal study conducted in 10countries | Adults with at least 1 self-reported unsuccessful dietary effortto lose weight and with a BMI of ≥27 kg/m2 with atleast 1 weight-related comorbidity, or BMI ≥ 30kg/m2. Patients with diabetes were excluded. | Female: 79% White: 83.7% Mean age: 46years Mean body weight: 107.2 kg Mean BMI: 38.4kg/m2 | From Week 20 to Week 69, -7.9% with continued semaglutide vs.+6.9% in those switched to placebo (treatment difference,-14.8%; 95% CI, -16.0 to -13.5; p<0.001). From Week 0 to Week68, -17.4% with continued semaglutide vs. -5.0% with placebo(treatment difference, -12.4%; 95% CI, -13.7 to -11.0). | From Week 0 to Week 68, 88.7% with continued semaglutide vs.47.6% with placebo. |
| STEP 520 | To evaluate the efficacy and safety of semaglutide 2.4 mg ascompared with placebo as an adjunct to lifestyle interventionsfor reducing body weight over a 2-year period | n= 304; 104-week phase 3b randomized, double-blind,placebo-controlled, multicenter clinical trial | Adults with a BMI of 30 kg/m2 or more, or 27kg/m2 or more with at least 1 weight-relatedcomorbidity; patients with diabetes were excluded. | Female: 78% White: 93.1% Mean age: 47years Mean body weight: 106 kg Mean BMI: 38.5kg/m2 | -15.2% with semaglutide vs. -2.6% with placebo (estimatedtreatment difference, -12.6%; 95% CI, -15.3, -9.8;p<0.0001). | 77.1% of patients treated with semaglutide vs. 34.4% of thosetreated with placebo (p<0.0001) |
| Efficacy and safety of semaglutide compared with liraglutide andplacebo for weight loss in patients with obesity: a randomized,double-blind, placebo and active-controlled, dose-ranging, phase2 trial23 | To evaluate the weight-loss efficacy and safety of semaglutidegiven once daily for 52 weeks at different doses (0.05 mg, 0.1mg, 0.2 mg, 0.3 mg, and 0.4 mg daily) in individuals withobesity compared to both an active control (liraglutide 3.0 mg)and an placebo | n=957; randomized, double-blind, placebo and active-controlled,multicentre, parallel group, dose-ranging, phase 2 trial. | Adults without diabetes and a BMI of 30 kg/m2 or morenot of endocrine etiology and have undergone at least 1 previousunsuccessful nonsurgical weight-loss attempt and been free frommajor depressive symptoms | Female: 65% White: 73% Mean age: 47years Mean body weight: 111.5 kg Mean BMI: 39.3kg/m2 | Mean weight reductions with semaglutide ranged from -6% with0.05 mg to -13.8% with 0.4 mg vs. -7.8% for those receivingliraglutide and -2.3% for those receiving placebo. | Among participants still receiving semaglutide at Week 52,60-91% had a weight loss of 5% or more depending on dose vs. 72%receiving liraglutide and 23% receiving placebo. |
| STEP 821 | To compare once-weekly semaglutide 2.4 mg vs once-dailyliraglutide 3.0 mg for weight management in adults withoverweight or obesity to rigorously assess differences inefficacy and safety | n= 338; 68-week phase 3b randomized, open-label trial conductedin the United States | Adults without diabetes with a BMI of 30 kg/m2 ormore, or 27 kg/m2 or more with 1 or moreweight-related comorbidity | Female: 78.4% White: 73.7% Mean age: 49years Mean body weight: 104.5 kg Mean BMI: 37.5kg/m2 | -15.8% with semaglutide vs. -6.4% with liraglutide (difference:-9.4% [95% CI: -12 to -6.8]; p<.001). | 87.2% of patients treated with semaglutide vs. 58.1% treatedwith liraglutide (exploratory endpoint). 70.9% of patientstreated with semaglutide achieved ≥10% body weight loss vs.25.6% with liraglutide (secondary endpoint; p<.001) |
Abbreviations: BMI, body mass index; CI, confidence interval; OR, oddsratio; SGLT-2, Sodium-glucose Co-transporter 2; SQ, subcutaneous; SU,sulfonylurea; T2DM, type 2 diabetes mellitus; and TZD,thiazolidinediones.
STEP 1 evaluated the change in body weight and weight reduction of at least 5%between semaglutide 2.4 mg and placebo in adults who were obese or overweight withat least one weight-related comorbidity and did not have diabetes. Lifestyleinterventions for all patients included counseling, a reduced-calorie diet, andincreased physical activity. For 68 weeks, patients treated with semaglutide onaverage lost 14.9% of their body weight compared to 2.4% with placebo (p<0.001),and 86.4% of semaglutide patients achieved weight loss of 5% or more compared to31.5% of placebo patients (p<0.001).16 STEP 2 compared the same endpoints as STEP 1 for semaglutide 2.4 mg,semaglutide 1.0 mg, and placebo in overweight or obese adults with type 2 diabetes.Lifestyle interventions were consistent with STEP 1. On average, patients treatedwith semaglutide 2.4 mg lost 9.64% of body weight and 68.8% of patients achieved aweight loss of 5% or more at 68 weeks. Both endpoints were found to be statisticallysignificant compared to either semaglutide 1.0mg (6.99%, 57.1%) or placebo (3.42%, 28.5%).17 STEP 3 evaluated semaglutide 2.4 mg and placebo when combined with intensivebehavioral therapy in adults who were obese or overweight with at least oneweight-related comorbidity and did not have diabetes. Intensive behavioral therapyconsisted of a low-calorie diet (1,000-1,200 kcal/day) for 8 weeks followed by ahypocaloric diet (1,200-1,800 kcal/day) for the remainder of the trial; 100 minutesper week of physical activity increased by 25 minutes every 4 weeks to reach 200minutes per week; and 30 individual visits with a registered dietitian. For 68weeks, patients treated with semaglutide 2.4 mg on average lost 16.0% of their bodyweight compared to 5.7% with placebo (p<0.001), and 86.6% of semaglutide patientsachieved weight loss of 5% or more compared to 47.6% of placebo patients (p<0.001).18 STEP 4 evaluated the impact of semaglutide 2.4 mg for maintenance of weightloss after discontinuation of semaglutide. Each patient received semaglutidetitrated over 16 weeks to 2.4 mg followed by 4 weeks of semaglutide 2.4 mg for atotal of 20 weeks of semaglutide therapy. Patients were then randomized to eithercontinue semaglutide therapy or replace therapy with placebo. Lifestyleinterventions as described in STEP 1 were provided to both groups. For 68 weeks,patients who continued semaglutide therapy saw an additional -7.9% mean weight lossfrom weeks 20 to 68 compared to a mean weight gain of 6.9% in patients switched toplacebo (p<0.001).19 In the last placebo-controlled trial with available results, STEP 5 evaluatedthe change in body weight and weight reduction of at least 5% between semaglutide2.4 mg and placebo in adults who were obese or overweight with at least oneweight-related comorbidity and did not have diabetes for a period of 2 years.Described lifestyle interventions appear similar to STEP 1. For 104 weeks, patientstreated with semaglutide on average lost 15.2% of their body weight compared to 2.6%with placebo (p<0.0001), and 77.1% of semaglutide patients achieved weight lossof 5% or more compared to 34.4% of placebo patients (p value not reported).20
Two published trials directly compare semaglutide to liraglutide; another GLP-1receptor agonist indicated for weight loss. In a phase 2 trial, daily doses ofsemaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, or 0.4 mg) were compared toliraglutide 3.0 mg daily or placebo. All participants received nutritional andphysical activity counseling every 4 weeks. For 52 weeks, all doses of semaglutideshowed statistically greater mean weight loss (-6.0%, -8.6%, -11.6%, -11.2%, and-13.8% listed, respectively, to doses above) compared to placebo (-2.3%). However,only doses of 0.2 mg or more showed statistically greater mean weight loss whencompared to liraglutide 3.0 mg (-7.8%).23 In the STEP program, STEP 8 confirmed the results of this phase 2 trial.Adult patients who were obese or overweight with at least one weight-relatedcomorbidity and without diabetes were randomized to either weekly semaglutide 2.4mg, daily liraglutide 3.0 mg, or a matching placebo. For 68 weeks, patients treatedwith semaglutide lost an average of 15.8% body weight compared to 6.4% withliraglutide (p<0.001). Secondary endpoints also showed patients were more likelyto achieve 10%, 15%, or 20% weight loss with semaglutide compared to liraglutide(all p<0.001).21
Adverse Effects, Precautions/Contraindications, and Interactions (Safety)
Consistent with prior trials of semaglutide, results of the STEP program showgastrointestinal disorders are the most frequently reported adverse reactionassociated with semaglutide, with incidence rates of any gastrointestinal reaction(nausea, vomiting, diarrhea, or constipation) ranging from 10.3 to 82.2%.16-21 Most reported reactions weremild-to-moderate in severity, transient in nature, and resolved withoutdiscontinuation of semaglutide (Table 2).5,13,24-35 Rates of semaglutidediscontinuation due to gastrointestinal disorders were low across the STEP trialsevaluated (0.8-4.5%).16-21
Table 2.
Comparison of Efficacy, Side Effects, Contraindications, and Significant DrugInteractions for Common Antiobesity Medications.
| Medication | Weight reduction (% weight loss from baseline; %of patients achieving ≥5% weight loss) | Common side effects | Contraindications | Significant drug interactions | Wholesale acquisition cost (duration oftherapy) | Additional notes |
|---|---|---|---|---|---|---|
| Semaglutide 2.4 mg5,13,16,29 | STEP 1: -14.9%; 86.4% | Nausea, diarrhea, vomiting, constipation, abdominal pain,headache, fatigue, dyspepsia, dizziness, abdominal distension,eructation, hypoglycemia in patients with type 2 diabetes,flatulence, gastroenteritis, and gastroesophageal refluxdisease | Personal or family history of medullary thyroid carcinoma or apersonal history of multiple endocrine neoplasia syndrome type2 | Limited documented interactions, concern with narrow therapeuticindex drugs | $1349.02 (28 days) | Manufacturer coupon available. |
| Liraglutide 3.0mg5,24,30 | -8.0%; 63.2% | Nausea, diarrhea, and vomiting | Personal or family history of medullary thyroid carcinoma or apersonal history of multiple endocrine neoplasia syndrome type2 | Limited documented interactions, concern with narrow therapeuticindex drugs | $1349.02 (30 days) | Manufacturer coupon available. |
| Phentermine HCl/topiramate5,25,31 | 7.5 mg/46 mg: -7.8%; 62% 15 mg/92 mg: -9.8%; 70% | Constipation, xerostomia, dysgeusia, dizziness, insomnia | Glaucoma, hyperthyroidism | MAOIs, substrates of CYP3A4 and 2C19 | $199.50 (30 days) | Schedule IV. Manufacturer coupon available. |
| Bupropion HCl/naltrexone5,26,32 | -6.1%; 48% | Constipation, diarrhea, nausea, xerostomia, dizziness, insomnia,hypertension, increased heart rate | Bulimia or anorexia nervosa, seizure disorder, chronic opiateuse, uncontrolled hypertension | Opioids, bupropion, MAOIs, ritonavir, lopinavir, efavirenz | $303.60 (30 days) | Manufacturer coupon available. |
| Orlistat5,27,33 | -7.9%; 50.5% | Abdominal discomfort, defecation urgency, leakage of oilystools, flatulence | Cholestasis, chronic malabsorption syndrome | May impair absorption of numerous medications, particularcaution with cyclosporine | $685.81 (30 days at max dose of 3 tabs per day) | Patients should be counseled to take a multivitamin, separatedby 2 hours, to ensure appropriate vitamin levels are maintained.No manufacturer coupon available. |
| Phentermine5,28,34,35 | 7.5 mg: -5.5%; 43.3% 15 mg: -6.1%; 46.2% | Xerostomia, insomnia, dizziness, increased blood pressure,increase heart rate | History of cardiovascular disease, glaucoma,hyperthyroidism | MAOIs | Tablets: $6.80 (30 days) Capsules: $13.65 (30 days) | Schedule IV. Manufacturer coupon available. |
Abbreviation: MAOIs, Monoamine oxidase inhibitors.
Semaglutide is contraindicated in patients with a personal or family history ofmedullary thyroid carcinoma (MTC), in patients with multiple endocrine neoplasiasyndrome type 2 (MEN 2) or in those with serious hypersensitivity reactions tosemaglutide or its excipients.13 Thyroid C-cell tumors were reported in rodent studies when treated withsemaglutide in a dose-dependent, duration-dependent manner. In humans, it is unknownwhether semaglutide causes thyroid C-cell tumors, including MTC. In evaluated STEPtrials, no causation was established between the use of semaglutide and malignantneoplasms.13,16-21
Across the STEP trials evaluated, acute pancreatitis events were low, varying from 0%to 0.2%.16-21 However, acute gallbladderdisease was observed at higher rates in semaglutide treated patients (0.2-4.9%) thanin placebo-treated patients (0.7-3.7%).16-21 Acute kidney injury has beenreported, but no significant difference was established in the STEP trials evaluatedbetween patients treated with semaglutide and placebo.16-21 It is believed that acutekidney injury is associated with dehydration due to severe gastrointestinal side effects.13 Consistent with prior semaglutide trials, heart rate increases were reportedin STEP trials one through four with a mean increase of 1-4 beats perminute.13,36
Consistent with other semaglutide trials, patients with type 2 diabetes treated withsemaglutide 2.4 mg experienced higher rates of diabetic retinopathy than thosetreated with placebo (4.0% vs. 2.7% in STEP 2).11,17 Rapid improvements in glucosecontrol as seen with semaglutide have been associated with a temporary worsening ofdiabetic retinopathy.37 Hypoglycemia is not common unless used in conjunction with insulinsecretagogues or insulin.13
In vitro studies have shown a low potential for semaglutide to affect CYP enzymes orinhibit drug transporters. Because semaglutide may influence the rate of gastricemptying, the absorption of concomitantly administered oral medications may be delayed.13 There was no apparent effect on the rate of gastric emptying observed duringthe paracetamol absorption test with semaglutide 2.4 mg.38 Two studies showed no clinically significant pharmacokinetic or dynamicimpacts on warfarin, digoxin, atorvastatin, or metformin when taken withsubcutaneous semaglutide 1.0 mg or oral semaglutide 20 mg.39,40 Further studies should beconsidered to evaluate semaglutide 2.4 mg on narrow therapeutic index drugs.
Relevance to Clinical Practice
Semaglutide 2.4 mg is the first once-weekly injectable medication available forweight management in overweight or obese adults. In published data from the STEPprogram, patients treated with semaglutide 2.4 mg consistently achieved clinicallymeaningful weight loss compared to both placebo and liraglutide.16-21 Despite the lack ofhead-to-head trials, semaglutide 2.4 mg documented safety and efficacy for periodsup to 2 years establishes it as a top option for weight management when combinedwith lifestyle changes. In addition to a strong efficacy and safety profile,once-weekly therapy has the potential to improve adherence over daily therapy. Whilethis was not directly evaluated in the STEP program, trials have demonstratedimproved adherence with once-weekly GLP-1 therapy for diabetes mellitus overonce-daily therapy.41,42
Semaglutide 2.4 mg is not included in current obesity guidelines by the AmericanAssociation of Clinical Endocrinologists (AACE) and the American Heart Association,American College of Cardiology, and The Obesity Society (AHA/ACC/TOS), which werepublished in 2016 and 2013, respectively.4,5 In the AHA/ACC/TOS guidelines,there is limited mention of pharmacotherapy due to a paucity of FDA-approvedmedications at the time of development. AACE guidelines do provide a summary ofliterature for orlistat, lorcaserin, phentermine/topiramate ER, naltrexoneER/bupropion ER, and liraglutide 3 mg and recommendations for their use. AACE doesnot give preference to any individual agent, except in select patient populationsbased upon the side effects, precautions, and contraindications of a medication. Asemphasized by the AACE guidelines, there is a lack of head-to-head comparisons ofapproved medications for chronic weight management. However, when compared toaverage weight loss seen in major clinical trials of other FDA-approved medications,semaglutide 2.4 mg consistently showed greater weight loss and a greater proportionof patients achieving 5% body weight loss in STEP program trials.5,43 Additionally, semaglutide 2.4mg has fewer restrictions on its use than most other FDA-approved medications,excluding orlistat and liraglutide 3 mg. Common side effects, contraindications,drug interactions, and clinical pearls for these medications are shown in Table 2.5,13,24-35 Gastrointestinal side effectsof semaglutide 2.4 mg may limit its usability in some patients. Nausea and vomitingmay be reduced through appropriate patient counseling focused on consuming smallermeals more frequently.
Guidelines also recommend bariatric surgery as an option for adults with a BMI ≥40kg/m2, or for those with a BMI ≥35 kg/m2 and at least oneweight-related comorbidity.4,5To compare with semaglutide, one trial of patients who received Roux-en-Y GastricBypass (RYGB), sleeve gastrectomy (SG), or laparoscopic adjustable gastric banding(LAGB) showed 30.9%, 23.4%, and 13% body weight reduction at 1 year, respectively,with results being less at 5 years.44 While efficacy can be high with bariatric surgery, it is invasive in natureand side effects and complications can be severe with few ways to reverse theprocedure if any. Treatment with antiobesity medications is not permanent and allowsfor dosage adjustments and discontinuation of the medication. However, theavailability of pharmacotherapy should not rule out bariatric surgery.
Based on available literature, semaglutide 2.4 mg is a strong addition topharmacotherapeutic options for chronic weight management. It has shown consistentclinically significant weight loss across the STEP program, with limited major sideeffects or contraindications. Despite this, one barrier to its use that willcontinue is its cost as it is currently among the most expensive of available agents(Table 2).Clinicians who are considering prescribing semaglutide 2.4 mg should make sure toevaluate opportunities from the manufacturer to reduce the cost.
Conclusions
Semaglutide is a GLP-1 receptor agonist recently approved by the FDA for weightmanagement at a dose of 2.4 mg once weekly in patients with a BMI of ≥30kg/m2 or ≥27 kg/m2 with more than one weight-relatedcomorbidity. Semaglutide is highly efficacious, with the majority of patientsexperiencing clinically significant weight loss across STEP trials to date. Itsefficacy and safety have been demonstrated for up to 2 years, making it an idealoption for chronic weight management, although its use may be limited by itscost.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to theresearch, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/orpublication of this article.
ORCID iDs: Roger Iain Pritchard 
https://orcid.org/0000-0003-4037-1618
Jamie Huff https://orcid.org/0000-0002-6828-907X
References
1. World Health Organization. Obesity andoverweight. Accessed August 27, 2021.https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
2. Kahn BB, Flier JS. Obesity and insulin resistance.J Clin Invest.2000;106(4):473-481. [PMC free article] [PubMed] [Google Scholar]
3. Reaven GM. Pathophysiology of insulin resistance in humandisease. Physiol Rev.1995;75(3):473–486.doi: 10.1152/physrev.1995.75.3.473. [PubMed] [CrossRef] [Google Scholar]
4. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guidelinefor the management of overweight and obesity in adults.Circulation.2014;129(25 Suppl2):S102-S138. doi: 10.1161/01.cir.0000437739.71477.ee. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
5. Garvey WT, Mechanick JI, Brett EM, et al. American Association ofClinical Endocrinologists and American College of Endocrinologycomprehensive clinical practice guidelines for medical care of patients withobesity. Endocr Pract.2016;22:1-203.doi: 10.4158/EP161365.GL. [PubMed] [CrossRef] [Google Scholar]
6. Sorli C, Harashima S-I, Tsoukas GM, et al. Efficacy and safety ofonce-weekly semaglutide monotherapy versus placebo in patients with type 2diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled,parallel-group, multinational, multicentre phase 3a trial.Lancet Diabetes Endocrinol.2017;5(4):251-260.doi: 10.1016/S2213-8587(17)30013-X. [PubMed] [CrossRef] [Google Scholar]
7. Ahrén B, Masmiquel L, Kumar H, et al. Efficacy and safety ofonce-weekly semaglutide versus once-daily sitagliptin as an add-on tometformin, thiazolidinediones, or both, in patients with type 2 diabetes(SUSTAIN 2): a 56-week, double-blind, phase 3a, randomisedtrial. Lancet Diabetes Endocrinol.2017;5(5):341-354.doi: 10.1016/S2213-8587(17)30092-X. [PubMed] [CrossRef] [Google Scholar]
8. Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and safety ofonce-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes(SUSTAIN 3): a 56-week, open-label, randomized clinicaltrial. Diabetes Care.2017;41(2):258-266.doi: 10.2337/dc17-0417. [PubMed] [CrossRef] [Google Scholar]
9. Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety ofonce-weekly semaglutide versus once-daily insulin glargine as add-on tometformin (with or without sulfonylureas) in insulin-naive patients withtype 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group,multicentre, multinational, phase 3a trial. LancetDiabetes Endocrinol.2017;5(5):355-366.doi: 10.1016/S2213-8587(17)30085-2. [PubMed] [CrossRef] [Google Scholar]
10. Rodbard HW, Lingvay I, Reed J, et al. Semaglutide added to basalinsulin in type 2 diabetes (SUSTAIN 5): a randomized, controlledtrial. J Clin Endocrinol Metab.2018;103(6):2291-2301.doi: 10.1210/jc.2018-00070. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
11. Marso SP, Bain SC, Consoli A, et al. Semaglutide andcardiovascular outcomes in patients with type 2 diabetes.N Engl J Med.2016;375(19):1834-1844.doi: 10.1056/NEJMoa1607141. [PubMed] [CrossRef] [Google Scholar]
12. Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versusdulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): arandomised, open-label, phase 3b trial. LancetDiabetes Endocrinol.2018;6(4):275-286.doi: 10.1016/S2213-8587(18)30024-X. [PubMed] [CrossRef] [Google Scholar]
13. Wegovy [package insert].Plainsboro, NJ: Novo NordiskInc; 2021. https://www.novo-pi.com/wegovy.pdf. [Google Scholar]
14. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2diabetes. Lancet.2006;368(9548):1696-1705.doi: 10.1016/S0140-6736(06)69705-5. [PubMed] [CrossRef] [Google Scholar]
15. Neff LM, Kushner RF. Emerging role of GLP-1 receptor agonists in thetreatment of obesity. Diabetes Metab Syndr ObesTargets Ther.2010;3:263-273.doi: 10.2147/dmsott.s6816. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
16. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide inadults with overweight or obesity. N Engl JMed.2021;384(11):989-1002.doi: 10.1056/NEJMoa2032183. [PubMed] [CrossRef] [Google Scholar]
17. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2·4 mg once aweek in adults with overweight or obesity, and type 2 diabetes (STEP 2): arandomised, double-blind, double-dummy, placebo-controlled, phase 3trial. Lancet.2021;397(10278):971-984.doi: 10.1016/S0140-6736(21)00213-0. [PubMed] [CrossRef] [Google Scholar]
18. Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneoussemaglutide vs placebo as an adjunct to intensive behavioral therapy on bodyweight in adults with overweight or obesity: the STEP 3 randomized clinicaltrial. JAMA.2021;325(14):1403-1413.doi: 10.1001/jama.2021.1831. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
19. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weeklysubcutaneous semaglutide vs placebo on weight loss maintenance in adultswith overweight or obesity: the STEP 4 randomized clinicaltrial. JAMA.2021;325(14):1414-1425.doi: 10.1001/jama.2021.3224. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Garvey WT, Batterham RL, Bhatta M, et al. Two-year effect ofsemaglutide 2.4 Mg vs placebo in adults with overweight or obesity (STEP5). Paper presented at the 39th Annual Meeting ofThe Obesity Society (TOS) held at ObesityWeek®;November 1-5, 2021. [Google Scholar]
21. Rubino DM, Greenway FL, Khalid U, et al. Effect of weeklysubcutaneous semaglutide vs daily liraglutide on body weight in adults withoverweight or obesity without diabetes: the STEP 8 randomized clinicaltrial. JAMA.2022;327(2):138-150.doi: 10.1001/jama.2021.23619. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. U.S. National Library of Medicine.ClinicalTrials.gov. Semaglutide effects on heart disease andstroke in patients with overweight or obesity (SELECT).Published July 2, 2018. Accessed July 27, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03574597.
23. O’Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety ofsemaglutide compared with liraglutide and placebo for weight loss inpatients with obesity: a randomised, double-blind, placebo and activecontrolled, dose-ranging, phase 2 trial.Lancet.2018;392(10148):637-649.doi: 10.1016/S0140-6736(18)31773-2. [PubMed] [CrossRef] [Google Scholar]
24. Saxenda [package insert]. Plainsboro,NJ: Novo Nordisk Inc;2018. Accessed April 4, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206321s007lbl.pdf. [Google Scholar]
25. Qsymia [package insert]. Campbell,CA: Vivus;2020. Accessed April 4, 2022. https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf. [Google Scholar]
26. Contrave [package insert]. Morristown,NJ: Nalpropion PharmaceuticalsLLC; 2021. Accessed April 4,2022. https://contravehcp.com/wp-content/uploads/Contrave_PI_MedGuide.pdf. [Google Scholar]
27. Xenical [package insert]. South San Francisco,CA: Genentech USA;2012. Accessed April 4, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020766s029lbl.pdf. [Google Scholar]
28. Adipex-P [package insert]. Sellersville,PA: Teva PharmaceuticalsUSA; 2012. Accessed April 4,2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/085128s065lbl.pdf. [Google Scholar]
29. Active Ingredient: Semaglutide. RED BOOKOnline. IBM Micromedex [database online]. Truven HealthAnalytics/IBM Watson Health; 2021. Accessed September 1,2021. https://www.micromedexsolutions.com.
30. Active Ingredient: Liraglutide. RED BOOKOnline. IBM Micromedex [database online]. Truven HealthAnalytics/IBM Watson Health; 2021. Accessed September 1,2021. https://www.micromedexsolutions.com.
31. Active Ingredient: Phentermine HCl/Topiramate.RED BOOK Online. IBM Micromedex [databaseonline]. Truven Health Analytics/IBM Watson Health; 2021.Accessed September 1, 2021. https://www.micromedexsolutions.com.
32. Active Ingredient: Bupropion HCl/Naltrexone. REDBOOK Online. IBM Micromedex [database online]. Truven HealthAnalytics/IBM Watson Health; 2021. Accessed September 1,2021. https://www.micromedexsolutions.com.
33. Active Ingredient: Orlistat. RED BOOKOnline. IBM Micromedex [database online]. Truven HealthAnalytics/IBM Watson Health; 2021. Accessed September 1,2021. https://www.micromedexsolutions.com.
34. Active Ingredient: Phentermine HCl. RED BOOKOnline. IBM Micromedex [database online]. Truven HealthAnalytics/IBM Watson Health; 2021. Accessed September 1,2021. https://www.micromedexsolutions.com.
35. Aronne LJ, Wadden TA, Peterson C, Winslow D, Odeh S, Gadde KM. Evaluation of phentermine and topiramate versusphentermine/topiramate extended-release in obese adults.Obes Silver Spring Md.2013;21(11):2163-2171.doi: 10.1002/oby.20584. [PubMed] [CrossRef] [Google Scholar]
36. Ozempic [package insert]. Plainsboro,NJ: Novo Nordisk Inc;2021. [Google Scholar]
37. The Diabetes Control and Complications Trial Research Group.Early worsening of diabetic retinopathy in the diabetescontrol and complications trial. ArchOphthalmol.1998;116(7):874-886.doi: 10.1001/archopht.116.7.874. [PubMed] [CrossRef] [Google Scholar]
38. Friedrichsen M, Breitschaft A, Tadayon S, Wizert A, Skovgaard D. The effect of semaglutide 2.4 mg once weekly onenergy intake, appetite, control of eating, and gastric emptying in adultswith obesity. Diabetes Obes Metab.2021;23(3):754-762.doi: 10.1111/dom.14280. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
39. Bækdal TA, Borregaard J, Hansen CW, Thomsen M, Anderson TW. Effect of oral semaglutide on thepharmacokinetics of lisinopril, warfarin, digoxin, and metformin in healthysubjects. Clin Pharmacokinet.2019;58(9):1193-1203.doi: 10.1007/s40262-019-00756-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Hausner H, Derving Karsbøl J, Holst AG, et al. Effect of semaglutide on thepharmacokinetics of metformin, warfarin, atorvastatin and digoxin in healthysubjects. Clin Pharmacokinet.2017;56(11):1391-1401.doi: 10.1007/s40262-017-0532-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
41. Weeda ER, Muraoka AK, Brock MD, Cannon JM. Medication adherence to injectable glucagon-likepeptide-1 (GLP-1) receptor agonists dosed once weekly vs once daily inpatients with type 2 diabetes: a meta-analysis. IntJ Clin Pract.2021;75(9):e14060.doi: 10.1111/ijcp.14060. [PubMed] [CrossRef] [Google Scholar]
42. Polonsky WH, Arora R, Faurby M, Fernandes J, Liebl A. Higher rates of persistence and adherence inpatients with type 2 diabetes initiating once-weekly vs daily injectableglucagon-like peptide-1 receptor agonists in US clinical practice (STAYstudy). Diabetes Ther.2022;13(1):175-187.doi: 10.1007/s13300-021-01189-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
43. American Diabetes Association Professional Practice Committee.8. Obesity and weight management for the prevention andtreatment of type 2 diabetes: standards of medical care indiabetes—2022. Diabetes Care.2021;45(Suppl1):S113-S124. doi: 10.2337/dc22-S008. [PubMed] [CrossRef] [Google Scholar]
44. Maciejewski ML, Arterburn DE, Van Scoyoc L, et al. Bariatric surgery andlong-term durability of weight loss. JAMASurg.2016;151(11):1046-1055.doi: 10.1001/jamasurg.2016.2317. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Articles from The Journal of Pharmacy Technology : JPT : Official Publication of the Association of Pharmacy Technicians are provided here courtesy of SAGE Publications
