Obesity, a chronic relapsing condition defined as excessive fat accumulation, has become a global health concern. It is caused by an imbalance between energy intake and expenditure and is associated with serious clinical complications such as diabetes mellitus, cardiovascular disease, musculoskeletal disorders, and malignancy. The prevalence of obesity has tripled worldwide since 1975, highlighting the urgent need for effective and safe treatments.
Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has emerged as a promising option for weight management. While its weight loss benefits in patients with diabetes are well-documented, its clinical utility in treating obesity among patients without diabetes is less described. This article provides a comprehensive review of semaglutide for weight loss, including its efficacy, safety, and potential benefits for individuals with obesity.
Understanding Semaglutide
Semaglutide belongs to a class of medications known as glucagon-like peptide-1 receptor agonists, or GLP-1 RAs. GLP-1 RAs were developed for the treatment of diabetes since the incretin GLP-1 was shown to decrease blood glucose by stimulating insulin secretion and decreasing glucagon release. It mimics the GLP-1 hormone, released in the gut in response to eating. One role of GLP-1 is to prompt the body to produce more insulin, which reduces blood sugar (glucose). For that reason, health care providers have used semaglutide for more than 15 years to treat Type 2 diabetes.
But GLP-1 in higher amounts also interacts with the parts of the brain that suppress your appetite and signal you to feel full. It also promotes weight loss by inducing satiety, leading to decreased caloric intake by delaying gastric emptying. In the brain, it decreases appetite through the stimulation of satiety centers indirectly through neural afferents and directly by crossing the blood brain barrier. It is currently approved for the treatment of diabetes but not for obesity.
GLP-1 RAs available in the market have different duration of action, frequency of administration and dosing. Dosing frequency affects adherence to therapy and studies show that a once weekly dosing was associated with significantly better adherence. GLP-1 RAs available for once weekly dosing are exenatide, and the larger molecular weight dulaglutide and albiglutide. The bioavailability of semaglutide is 89% when injected subcutaneously and when injected once weekly. Administration sites include the abdomen, thigh, and upper arm. Semaglutide has a long half-life of approximately 1 week due to albumin binding and is protected from natural degradation by dipeptidyl-peptidase 4 (DPP-4). After subcutaneous administration, semaglutide will be present for approximately 5-7 weeks after the last dose. It is eliminated via the urine and feces and should be injected subcutaneously without regard to meals.
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Efficacy of Semaglutide for Weight Loss
Several studies have investigated the efficacy of semaglutide for weight loss in individuals with obesity. A meta-analysis of 4 randomized controlled trials (RCTs) involving 3,613 individuals with obesity without diabetes showed that subcutaneous semaglutide is effective for weight loss, with an 11.85% reduction from baseline compared to placebo. The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. This supports the use of semaglutide for weight management in obesity.
These trials measured the percent change in body weight after treatment with semaglutide versus placebo and reported the most common adverse effects associated with treatment. All were adults ≥18 years old with a BMI of ≥30 kg/m2 or ≥27 kg/m2 with at least 1 treated or untreated weight-related comorbidity without diabetes. The most common comorbidities were hypertension and dyslipidemia.
SELECT Trial: Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity
The SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) studied patients with established CVD and overweight or obesity but without diabetes. In SELECT, semaglutide was associated with a 20% reduction in major adverse CV events (hazard ratio 0.80, 95% confidence interval (CI) 0.72 to 0.90; P < 0.001).
Data derived from the SELECT trial offer the opportunity to evaluate the weight loss efficacy, in a geographically and racially diverse population, of semaglutide compared with placebo over 208 weeks when both are given in addition to standard-of-care recommendations for secondary CVD prevention (but without a focus on targeting weight loss). Furthermore, the data allow examination of changes in anthropometric measures such as BMI, waist circumference (WC) and waist-to-height ratio (WHtR) as surrogates for body fat amount and location.
The SELECT study enrolled 17,604 patients (72.3% male) from 41 countries between October 2018 and March 2021, with a mean (s.d.) age of 61.6 (8.9) years and BMI of 33.3 (5.0) kg m−2 (ref. 21). For those in the semaglutide group, the weight-loss trajectory continued to week 65 and then was sustained for the study period through week 208 (−10.2% for the semaglutide group, −1.5% for the placebo group; treatment difference −8.7%; 95% CI −9.42 to −7.88; P < 0.0001). At week 208, average reduction in WC was −7.7 cm with semaglutide versus −1.3 cm with placebo, with a treatment difference of −6.4 cm (95% CI −7.18 to −5.61; P < 0.0001)21. At week 208, in the group randomized to semaglutide, there was a relative reduction of 6.9% in WHtR compared with 1.0% in placebo (treatment difference −5.87% points; 95% CI −6.56 to −5.17; P < 0.0001). At week 104, 52.4% of patients treated with semaglutide achieved improvement in BMI category compared with 15.7% of those receiving placebo.
Read also: Comprehensive guide: Tirzepatide and Semaglutide for weight management
STEP Trials: Evaluating Semaglutide Dosage and Lifestyle Interventions
Across 4 trials, 3,613 individuals were included in the study (2,350 in the semaglutide group and 1,263 in the placebo group). Baseline characteristics were similar between both groups in the 4 individual trials. The mean weight, BMI, age and sex of the participants included in the trials are shown in Table 2.
The study of Wilding et al., used once weekly semaglutide injected subcutaneously starting at a dose of 0.25 mg and escalated every 4 weeks until the target dose of 2.4 mg was reached. However, unlike the other 2 studies where participants were randomized to receive semaglutide or placebo at the start of study, Rubino’s study randomized participants after the target dose was reached to continue with semaglutide or switch to matching placebo. O’Neil et al., used a smaller dose of semaglutide that was given once daily at 0.05 mg to 0.4 mg. The course of treatment was 68 weeks for Wilding, Rubino and Wadden et al., but only 52 weeks for O’Neil et al.’s study.
Investigation for the use of semaglutide for obesity has been underway because trials in diabetic patients have shown that it is associated with weight loss. Guidelines have recommended weight loss of 5 to 10% to improve metabolic function and health outcomes. A 5% weight loss improves multi-organ insulin sensitivity whereas, a 5 to 10% weight loss was associated with 0.6 to 1% reduction in HbA1c. Combining the results of the trials showed that semaglutide is indeed associated with weight loss with a mean difference of 11.85% compared with placebo. The subjects of the trials all had at least one unsuccessful non-surgical attempt to lose weight, and based on this meta-analysis, a 5 to 10% weight reduction could be achieved with semaglutide.
We observed that aside from the administration of semaglutide, reduced calorie diet and increased physical activity were also part of the intervention. Hence, semaglutide alone probably will not be able to achieve an 11.85% weight loss.
Safety and Tolerability
While semaglutide is generally well-tolerated, it is associated with some adverse events. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003).
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Consolidating the trials showed nausea, vomiting, constipation and diarrhea to be the most common adverse events. The trials have reported that these were of mild to moderate severity and short duration that resolved without treatment. Moreover, adverse events leading to discontinuation and serious adverse events were uncommon. Serious adverse events were defined by the study of Rubino, Wadden and O’Neil et al., as life threatening, results in death, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect, important medical event (may jeopardize subject or may require medical/surgical intervention to prevent outcomes listed previously but may not be immediately life-threatening or result in death or hospitalization), as preventing daily activities by Wilding et al. These were reported to be uncommon.
Considerations for Specific Populations
The effect of semaglutide (versus placebo) on mean percentage body weight loss as well as reduction in WC was found to be heterogeneous across several population subgroups. Women had a greater difference in mean weight loss with semaglutide versus placebo (−11.1% (95% CI −11.56 to −10.66) versus −7.5% in men (95% CI −7.78 to −7.23); P < 0.0001). There was a linear relationship between age category and degree of mean weight loss, with younger age being associated with progressively greater mean weight loss, but the actual mean difference by age group is small. Similarly, BMI category had small, although statistically significant, associations. Those with WHtR less than the median experienced slightly lower mean body weight change than those above the median, with estimated treatment differences −8.04% (95% CI −8.37 to −7.70) and −8.99% (95% CI −9.33 to −8.65), respectively (P < 0.0001). Patients from Asia and of Asian race experienced slightly lower mean weight loss (estimated treatment difference with semaglutide for Asian race −7.27% (95% CI −8.09 to −6.46; P = 0.0147) and for Asia −7.30 (95% CI −7.97 to −6.62; P = 0.0016)). There was no difference in weight loss with semaglutide associated with ethnicity (estimated treatment difference for Hispanic −8.53% (95% CI −9.28 to −7.76) or non-Hispanic −8.52% (95% CI −8.77 to 8.26); P = 0.9769), glycemic status (estimated treatment difference for prediabetes −8.53% (95% CI −8.83 to −8.24) or normoglycemia −8.48% (95% CI −8.88 to −8.07; P = 0.8188) or renal function (estimated treatment difference for estimated glomerular filtration rate (eGFR) <60 or ≥60 ml min−1 1.73 m−2 being −8.50% (95% CI −9.23 to −7.76) and −8.52% (95% CI −8.77 to −8.26), respectively (P = 0.9519)).
Regulatory Considerations and Compounding Concerns
The Food and Drug Administration (FDA) has approved semaglutide for chronic weight management in overweight or obese adults, with lifestyle changes. Semaglutide is only approved for weight loss under the brand name Wegovy. The typical dose for weight loss is 2.4 milligrams, administered weekly as subcutaneous (under the skin) self-injections.
However, the FDA is aware that some patients and health care professionals may look to unapproved versions of GLP-1 (glucagon-like peptide-1 (GLP-1) receptor agonists) drugs, including semaglutide and tirzepatide, as an option for weight loss. This can be risky for patients, as unapproved versions do not undergo FDA’s review for safety, effectiveness and quality before they are marketed.
FDA Recommendations for Health Care Professionals and Patients
Compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug. Patients should obtain a prescription from their doctor and fill the prescription at a state-licensed pharmacy. Visit FDA’s BeSafeRx campaign for resources to safely buy prescription medicines online and talk to your doctor if you have questions about your medicines.
Concerns with Compounded Versions of These Drugs
A compounded drug might be appropriate if a patient’s medical need cannot be met by an FDA-approved drug, or the FDA-approved drug is not commercially available. However, compounded drugs are not FDA approved. This means the agency does not review compounded drugs for safety, effectiveness or quality before they are marketed. The agency has identified some areas of concern for compounded GLP-1 drugs. FDA is working with its state regulatory partners and will continue to communicate with compounders regarding these concerns.
Improper storage during shipping may lead to quality issues. Injectable GLP-1 drugs require refrigeration as indicated in their package inserts. FDA has received complaints that certain compounded GLP-1 drugs have arrived warm or with inadequate ice packs to keep the drug at recommended storage temperatures.
Dosing Concerns with Compounded Semaglutide and Tirzepatide
FDA received multiple reports of adverse events, some requiring hospitalization, that may be related to dosing errors associated with compounded injectable semaglutide products. These dosing errors resulted from patients measuring and self-administering incorrect doses of the drug, and in some cases, health care professionals miscalculating doses of the drug. Additionally, the agency has received adverse event reports that may be related to patients prescribed compounded semaglutide or tirzepatide products in doses beyond what is in the FDA-approved drug label. This could mean using more product in a single dose, taking doses more frequently or increasing the amount more quickly (titration schedule). Some of the adverse events are serious and some patients reported seeking medical attention for their symptoms, including nausea, vomiting, diarrhea, abdominal pain and constipation.
Salt Forms Should Not Be Used to Compound Semaglutide
The agency is aware that some semaglutide products sold by compounders may be the salt forms. These salt forms, including semaglutide sodium and semaglutide acetate, are different active ingredients than are used in the approved drugs. The agency does not have information on whether these salts have the same chemical and pharmacologic properties as the active ingredient in the approved drug, and we are not aware of any lawful basis for their use in compounding.
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