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Once-Weekly Semaglutide for Weight Management: A Clinical Review (2022)
Abby Fornes, PharmD, Jamie Huff, PharmD, BCACP, BC-ADM, Roger Iain Pritchard, PharmD, BCACP, and Miranda Godfrey
Abstract
Objective: To review the efficacy, safety, and role of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide for chronic weight management.
Data Sources: A literature search of PubMed/MEDLINE and Google Scholar was performed using the search terms: semaglutide 2.4, weight, and obesity. Ongoing studies of semaglutide were identified utilizing clinicaltrials.gov.
Study Selection and Data Extraction: All English-language articles evaluating the efficacy and safety of semaglutide 2.4 mg for weight management in humans were included.
Data Synthesis: Once-weekly injectable semaglutide 2.4 mg is indicated as an adjunct to a reduced-calorie diet and increased exercise for chronic weight management in adults with a body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with at least one weight-related comorbidity, such as hypertension, type 2 diabetes mellitus, or dyslipidemia. Semaglutide 2.4 mg has consistently demonstrated clinically significant weight loss across all phase 3 STEP (semaglutide treatment effect in people with obesity) trials, and long-term efficacy and safety have been confirmed for up to 2 years. Gastrointestinal side effects were the most frequently reported side effects, including nausea, vomiting, constipation, and diarrhea. Safety data for semaglutide 2.4 mg were consistent with that reported previously for the GLP-1 receptor agonist class.
Conclusions: Semaglutide 2.4 mg is a highly efficacious agent for weight management, with a safety profile similar to that of other GLP-1 receptor agonists. It is a feasible option for chronic weight management, with data for up to 2 years. It is currently the only once-weekly weight loss medication, although the cost may limit its utilization.
Introduction
Obesity is a chronic disease that places a considerable burden on affected individuals and is considered a global public health challenge.1 Obesity can cause insulin resistance, which is associated with the development of cardiovascular and metabolic conditions, such as hypertension, dyslipidemia, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and polycystic ovary syndrome.2,3 Management of obesity through weight loss has been shown to reduce the risk of developing type 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 with increased benefits for obesity-related risk factors and diseases.4 Recommended first-line options for weight loss include lifestyle modifications that prioritize dietary changes and increased physical activity including 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 that can enhance weight loss.4 Additionally, individuals should target a minimum of 150 minutes or more of moderate-intensity exercise spread over 3 to 5 sessions per week. As adjuncts to first-line lifestyle modifications, pharmacotherapy is available to aid patients in weight management. Before the approval of semaglutide, five medications have been commonly used: orlistat, phentermine, phentermine-topiramate, naltrexone-bupropion, and liraglutide.5
Semaglutide, a GLP-1 receptor agonist, was initially approved in December 2017 as an adjunct to diet and exercise for the management of type 2 diabetes at doses up to 1 mg weekly. Across the phase 3 trial program for type 2 diabetes (SUSTAIN), semaglutide consistently demonstrated clinically significant weight loss (up to -6.5 kg with 1.0 mg semaglutide).6-12 Subsequently, semaglutide has been approved at a higher dose, 2.4 mg, as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in patients who have obesity, or are overweight with at least one other weight-related comorbid condition.13 This article reviews clinical trials assessing the efficacy and safety of semaglutide at a dose of 2.4 mg for chronic weight management.
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 nervous system. GLP-1 is a target for weight management as it slows gastric emptying and promotes satiety, which leads to a reduction in food intake. Additionally, GLP-1 crosses the blood-brain barrier where it activates areas of the hypothalamus and prefrontal cortex and regulates feeding behavior.14,15
The bioavailability of semaglutide is 89% when injected subcutaneously. Peak concentrations occur 3 days after injection, and a steady state is achieved by Week 5 when injected once weekly. Similar exposure was achieved in three subcutaneous administration sites: the abdomen, thigh, and upper arm. Semaglutide is greater than 99% bound to plasma albumin, which provides protection from degradation and renal clearance. Semaglutide is modified through the substitution of alanine at position 8 to protect from natural degradation by dipeptidyl-peptidase 4 (DPP4). The elimination half-life of semaglutide is approximately 1 week; therefore, semaglutide will be present for approximately 5-7 weeks after the last dose. Semaglutide is eliminated via the urine and feces. Dosage adjustments are not required based on hepatic or renal function.13
*Dosing and Administration
*Clinical Efficacy
*Adverse Effects, Precautions/ Contraindications, and Interactions (Safety)
*Relevance to Clinical Practice
Conclusions
Semaglutide is a GLP-1 receptor agonist recently approved by the FDA for weight management at a dose of 2.4 mg once weekly in patients with a BMI of ≥30 kg/m2 or ≥27 kg/m2 with more than one weight-related comorbidity. Semaglutide is highly efficacious, with the majority of patients experiencing clinically significant weight loss across STEP trials to date. Its efficacy and safety have been demonstrated for up to 2 years, making it an ideal option for chronic weight management, although its use may be limited by its cost.
Abby Fornes, PharmD, Jamie Huff, PharmD, BCACP, BC-ADM, Roger Iain Pritchard, PharmD, BCACP, and Miranda Godfrey
Abstract
Objective: To review the efficacy, safety, and role of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide for chronic weight management.
Data Sources: A literature search of PubMed/MEDLINE and Google Scholar was performed using the search terms: semaglutide 2.4, weight, and obesity. Ongoing studies of semaglutide were identified utilizing clinicaltrials.gov.
Study Selection and Data Extraction: All English-language articles evaluating the efficacy and safety of semaglutide 2.4 mg for weight management in humans were included.
Data Synthesis: Once-weekly injectable semaglutide 2.4 mg is indicated as an adjunct to a reduced-calorie diet and increased exercise for chronic weight management in adults with a body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with at least one weight-related comorbidity, such as hypertension, type 2 diabetes mellitus, or dyslipidemia. Semaglutide 2.4 mg has consistently demonstrated clinically significant weight loss across all phase 3 STEP (semaglutide treatment effect in people with obesity) trials, and long-term efficacy and safety have been confirmed for up to 2 years. Gastrointestinal side effects were the most frequently reported side effects, including nausea, vomiting, constipation, and diarrhea. Safety data for semaglutide 2.4 mg were consistent with that reported previously for the GLP-1 receptor agonist class.
Conclusions: Semaglutide 2.4 mg is a highly efficacious agent for weight management, with a safety profile similar to that of other GLP-1 receptor agonists. It is a feasible option for chronic weight management, with data for up to 2 years. It is currently the only once-weekly weight loss medication, although the cost may limit its utilization.
Introduction
Obesity is a chronic disease that places a considerable burden on affected individuals and is considered a global public health challenge.1 Obesity can cause insulin resistance, which is associated with the development of cardiovascular and metabolic conditions, such as hypertension, dyslipidemia, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and polycystic ovary syndrome.2,3 Management of obesity through weight loss has been shown to reduce the risk of developing type 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 with increased benefits for obesity-related risk factors and diseases.4 Recommended first-line options for weight loss include lifestyle modifications that prioritize dietary changes and increased physical activity including 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 that can enhance weight loss.4 Additionally, individuals should target a minimum of 150 minutes or more of moderate-intensity exercise spread over 3 to 5 sessions per week. As adjuncts to first-line lifestyle modifications, pharmacotherapy is available to aid patients in weight management. Before the approval of semaglutide, five medications have been commonly used: orlistat, phentermine, phentermine-topiramate, naltrexone-bupropion, and liraglutide.5
Semaglutide, a GLP-1 receptor agonist, was initially approved in December 2017 as an adjunct to diet and exercise for the management of type 2 diabetes at doses up to 1 mg weekly. Across the phase 3 trial program for type 2 diabetes (SUSTAIN), semaglutide consistently demonstrated clinically significant weight loss (up to -6.5 kg with 1.0 mg semaglutide).6-12 Subsequently, semaglutide has been approved at a higher dose, 2.4 mg, as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in patients who have obesity, or are overweight with at least one other weight-related comorbid condition.13 This article reviews clinical trials assessing the efficacy and safety of semaglutide at a dose of 2.4 mg for chronic weight management.
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 nervous system. GLP-1 is a target for weight management as it slows gastric emptying and promotes satiety, which leads to a reduction in food intake. Additionally, GLP-1 crosses the blood-brain barrier where it activates areas of the hypothalamus and prefrontal cortex and regulates feeding behavior.14,15
The bioavailability of semaglutide is 89% when injected subcutaneously. Peak concentrations occur 3 days after injection, and a steady state is achieved by Week 5 when injected once weekly. Similar exposure was achieved in three subcutaneous administration sites: the abdomen, thigh, and upper arm. Semaglutide is greater than 99% bound to plasma albumin, which provides protection from degradation and renal clearance. Semaglutide is modified through the substitution of alanine at position 8 to protect from natural degradation by dipeptidyl-peptidase 4 (DPP4). The elimination half-life of semaglutide is approximately 1 week; therefore, semaglutide will be present for approximately 5-7 weeks after the last dose. Semaglutide is eliminated via the urine and feces. Dosage adjustments are not required based on hepatic or renal function.13
*Dosing and Administration
*Clinical Efficacy
*Adverse Effects, Precautions/ Contraindications, and Interactions (Safety)
*Relevance to Clinical Practice
Conclusions
Semaglutide is a GLP-1 receptor agonist recently approved by the FDA for weight management at a dose of 2.4 mg once weekly in patients with a BMI of ≥30 kg/m2 or ≥27 kg/m2 with more than one weight-related comorbidity. Semaglutide is highly efficacious, with the majority of patients experiencing clinically significant weight loss across STEP trials to date. Its efficacy and safety have been demonstrated for up to 2 years, making it an ideal option for chronic weight management, although its use may be limited by its cost.
