Obesity is a global, chronic, and relapsing disease that considerably influences the health status of individuals, communities, and healthcare systems. The predominance of obesity worldwide has increased dramatically in both children and adults, with the World Health Organization (WHO) revealing that the incidence of obesity has triplicated since 1975. WHO defines obesity as irregular or disproportionate fat accumulation in the human body with a high body mass index (BMI), a degree of the weight relative to the height greater than 30. Fat accumulation beyond healthy limits eventually leads to several cardiovascular complications, including hypertension, heart failure, ischemic heart disease, and stroke. Specifically, the metabolic profile is hugely affected by obesity, including hyperinsulinemia, dyslipidemia, impaired fasting glucose, or hypercholesterolemia. The severity of obesity increases with continuous weight gain and tends to have higher all-cause mortality and mortality due to a wide range of other serious health complications. The negative impact of obesity also increases in the presence of other diseases, for example, diabetes. Oppositely, weight loss results in an improvement in many body functions.
Weight management is crucial for a healthy lifestyle and for reducing obesity-related complications. Dietary changes and behavior modification with regular exercise may help maintain ideal body weight. Specifically, a reduction in caloric intake and a rise in the physical movement are the cornerstones of a bodyweight management program. On the other hand, in some cases, several pharmacological classes of drugs and medical surgery, such as bariatric surgery, along with the change in dietary lifestyle, have been developed over the last decade to counteract obesity and obtain ideal body weight. The prescribed medications include liraglutide, naltrexone-bupropion, orlistat, phentermine, and phentermine-topiramate. The limited available therapeutic options have encouraged researchers, drug manufacturers, and medical teams to think about the available drugs that may help curb the increase in obesity.
Recently, Semaglutide received Food and Drug Administration (FDA) approval to treat obesity in 2021. It demonstrated a beneficial outcome in terms of anti-obesity activity. As this paper focuses on investigating the function of Semaglutide in obesity management. Articles relating to the clinical uses of semaglutide, mechanism of action, pharmacokinetics, and pharmacodynamic side effects of the drug were identified.
Semaglutide: A GLP-1 Receptor Agonist
Semaglutide is a type of glucagon-like peptide-1 (GLP-1) with 94% sequence homology to human GLP. It serves as a receptor agonist that specifically binds and initiates to the GLP-1 receptor. GLP-1 is known to be a physiological hormone with several functions on glucose, acted and regulated by GLP-1 receptors. The concept of extension consequential in the long half-life of semaglutide is the binding of albumin that eventually leads to lowering renal clearance and defense from metabolic deprivation. Semaglutide, unlike other GLP-1 agonists, resists degradation caused by the dipeptidyl peptidase-IV enzyme. It cuts fasting and postprandial blood glucose levels via a mechanism that arouses insulin and drops glucagon secretions in a glucose-dependent mode. Thus, insulin release is stimulated under hyperglycemic conditions while inhibiting glucagon secretion. The process of lowering the blood glucose also includes a trivial interruption in gastric draining in the initial postprandial stage.
Subcutaneous Semaglutide injection contains human GLP-1 receptor agonist semaglutide. The peptide mainstay is formed by the fermentation of yeast. The central machinery of Semaglutide is binding to albumin, a process simplified by altering the position-26 lysine with hydrophilic spacer and a C-18 fatty di-acid. Semaglutide is the first FDA-approved GLP-1 receptor agonist for chronically obese adults who have at slightest one weight-related illness like type 2 diabetes, hypertension, and abnormal changes in lipid profile for use in concurrence with condensed calorie intake and improved physical activity.
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The Anti-Obesity Activity of Semaglutide
The anti-obesity activity of semaglutide, a GLP-1 agonist, occurs because of deferred gastric clearing and intensified gastric volume. Among obese adults, subcutaneous Semaglutide (2.4 mg) given once weekly promotes weight loss via appetite and hunger suppression, decreases energy intake, controls eating, and depresses the relative fondness for fatty, energy-dense foods. This drug has been recently used in several double-blind, randomized placebo-controlled clinical trials, leading to improved weight drop in obese children and adults. The route of drug administration is a vital factor for the duration of action since its subcutaneous delivery allows continuous delivery at a low dose rate. It’s the only GLP-1 receptor agonist currently accessible in subcutaneous and oral formulations.
A recent study in 2021 found that Semaglutide yielded surprising results for continued, clinically pertinent declines in body weight. A 2.4 mg dose was administered to 1306 patients and caused continued, clinically relevant reductions in body weight. The average transformation in body weight from the reference line to week 68 was 14.9% for samples using Semaglutide compared to 2.4% among those taking a placebo. The study revealed that in overweight or obese adults, once a week, subcutaneous injections of Semaglutide in aggregation with lifestyle intervention were related to a substantially constant, clinically substantial mean weight reduction of 14.9%, with 86% of partakers getting at least 5% drop of weight.
Another clinical investigation revealed a similar outcome; in overweight or obese partakers, 2.4 mg of Semaglutide per week together with régime interposition was linked with a persistent, clinically noteworthy drop in body weight. Furthermore, subcutaneous injections of 2.4 mg of Semaglutide in 72 obese adults randomized to once weekly injections or placebo for 20 weeks showed suppression in appetite with a concurrent lessening in food ingestion, energy intake, and body weight versus the placebo group. Another recent study involving 1051 participants over 68 weeks, randomized, double-blind, placebo-controlled withdrawal investigation analyzed data from 73 sites in 10 countries and demonstrated a significant mean bodyweight reduction by 10.6% plus a decrease in waist circumference, body mass index, blood pressure, hemoglobin A1c, fasting plasma glucose and progress in lipid profiles after 20 weeks of treatment.
Semaglutide's Impact on Cardiovascular Risk Factors
Trials investigating the reduction of weight outcomes associated with Semaglutide usage have increased after FDA approval was obtained. Much of the current literature on Semaglutide pays particular attention to other comorbidities, such as cardiovascular risk factors associated with obesity. A comparative study concluded that Semaglutide led to a reduced risk of adverse cardiovascular results likened to placebo when the Semaglutide was added to the standard-of-care regimen. The connection between obesity and Semaglutide has been widely studied, and most studies reveal the efficacy of Semaglutide on weight loss.
Pharmacokinetics of Semaglutide
Overall, the pharmacokinetics of Semaglutide shows a reduction in glycosylated hemoglobin A1c (HbA1c) and total body weight. Across studies and populations, Semaglutide pharmacokinetics were reported with a lengthy eradication half-life and a once-weekly subcutaneous injection of 2.4 mg for its anti-obesity activity. It has shown to be slowly absorbed following subcutaneous injection with a tmax of approximately 1-3 days post-subcutaneous dose. Absolute bioavailability was estimated to be 89%. According to the manufacturer, parallel exposure was attained via subcutaneous dispensation of Semaglutide in the abdomen, thigh, or upper arm and was not affected by other factors except bodyweight. However, Semaglutide exposure was shown to increase in a dose-dependent mode for once-A-week doses of 0.5 mg and 1 mg in diabetic patients treated with Semaglutide. At a dose of 0.5 or 1 mg, Semaglutide has a half-life of 7 days; hence, it would bring off steady-state and present in the circulation for about 4 to 5 weeks.
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Semaglutide forms a high-affinity non-covalent bond with plasma albumin (> 99%), enhancing drug stability. Semaglutide distribution does not include crossing the blood-brain barrier. The main elimination routes of semaglutide are thru the urine and feces. Roughly 3% of the dose is emitted in an integral form in the urine.
Semaglutide and Metabolic Profile Alterations
A strong connection between weight loss and reducing obesity complications has been reported in the literature. To date, the most robust finding concerning semaglutide has been the relationship between the GLP-1 and decreased body weight effects with other alteration at the metabolic profile. Given Semaglutide’s wide therapeutic window, this relationship’s clinical significance is worth investigating. The findings from the review suggest that Semaglutide appears to be beneficial, most notably in its contribution to weight management. This means that Semaglutide provides more patients with a degree of weight reduction that patients feel worthwhile.
Semaglutide: A Comprehensive Approach to Weight Loss
Semaglutide, also known by brand names Ozempic and Wegovy, is a groundbreaking treatment option for weight loss with the science and results to back it. Approved by the FDA, Semaglutide offers a novel approach to weight management. It belongs to a class of medications called glucagon-like peptide-1 (GLP-1) receptor agonists, which were initially developed to treat type 2 diabetes. However, its profound impact on weight loss has been a game-changer.
Semaglutide targets the intricate interplay of hormones, neurotransmitters, and neural circuits that regulate appetite and metabolism. It enhances satiety and appetite control by activating GLP-1 receptors in the brain, leading to increased feelings of fullness and reduced hunger. This means you're more likely to make mindful food choices and consume fewer calories, a fundamental aspect of successful weight loss. Semaglutide goes beyond appetite suppression by slowing down the rate at which your stomach empties. This results in a prolonged feeling of satiety after meals, curbing your cravings and helping you resist the urge to overeat. Semaglutide’s influence extends to the brain's reward centers, which are responsible for the pleasurable sensations associated with food. By targeting these neural circuits, Semaglutide helps dampen the allure of high-calorie, indulgent foods, making it easier to stick to your nutritional plan.
Semaglutide also orchestrates changes in how your body expends energy and utilizes fat stores. It has been shown to increase your basal metabolic rate - the number of calories your body burns at rest. This metabolic boost contributes to a more efficient calorie burn throughout the day, aiding in weight loss even when you're not active. Another remarkable aspect of Semaglutide’s mechanism is its ability to promote the breakdown of stored fat. By enhancing lipolysis, the process by which your body releases fat from fat cells, Semaglutide helps mobilize these energy reserves for utilization, further contributing to weight loss.
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Semaglutide and the GLP-1 Hormone
Semaglutide mimics the natural hormone GLP-1, which is produced in the gut and plays a key role in regulating appetite and food intake. GLP-1 receptors are found in the brain, particularly in the hypothalamus and brainstem, which are involved in controlling hunger and satiety. Semaglutide slows down the rate at which food leaves the stomach and enters the small intestine, a process known as delayed gastric emptying. Semaglutide enhances the secretion of insulin in a glucose-dependent manner, meaning it increases insulin release only when blood glucose levels are elevated. Glucagon is a hormone that is produced by the pancreas and plays a key role in regulating blood sugar levels by stimulating the liver to release glucose into the bloodstream. When semaglutide is administered, it works by binding to GLP-1 receptors in the pancreas, which leads to the suppression of the release of glucagon. By suppressing the release of glucagon, semaglutide helps to lower blood sugar levels in individuals with diabetes. Semaglutide has been shown to increase energy expenditure and promote fat burning, leading to reductions in body weight and improvements in body composition. All of these above mechanisms make semaglutide a highly effective weight-loss medication when used as part of a comprehensive weight management program that includes a healthy diet and exercise.
Dosing and Administration
The injection formulations should be administered subcutaneously into the abdomen, thigh, or upper arm. Patients should be advised to rotate injection sites within the same body region (eg, upper arm) to avoid injecting in the same spot each week. Although insulin and semaglutide injections may be administered in the same body region, patients should be cautioned against using the same injection site. The 0.5-mg weekly dosage can be escalated to 1 mg weekly if glycemic control is inadequate after 4 weeks on the 0.5 mg/week dosage. If a dose of weekly subcutaneous semaglutide is missed, it should be administered promptly within 5 days, and then the regular schedule should be resumed.
For individuals who are semaglutide-naive, the recommended starting dose is 3 mg daily for 30 days, followed by an increase to 7 mg daily. After 30 days on the 7 mg dose, patients may consider escalating to 14 mg daily to achieve their glycemic goals. When transitioning from semaglutide injection Ozempic® 0.5 mg weekly, one may consider switching to either 7 mg or 14 mg taken PO daily for up to 7 days after the last injection. If a dose of oral semaglutide is missed, the individual should skip the missed dose and resume with the next scheduled dose.
To ensure optimal absorption of oral semaglutide, it should be administered at least 30 minutes before the first consumption of food, beverages, or other medications of the day. The medication should be ingested with no more than 4 ounces (120 mL) of water. If patients experience difficulty with a dosage increase, healthcare providers should consider postponing the increase for an additional 4 weeks.
If the 2.4 mg weekly dosage is not well tolerated, healthcare providers may consider reducing the dose to 1.7 mg weekly for a maximum of 4 weeks. After this period, the dosage should be increased to 2.4 mg weekly. If the patient continues to experience intolerance, discontinuing semaglutide (Wegovy®) should be considered.
If a dose is missed and the next scheduled dose is more than 2 days away (48 hours), it should be administered as soon as possible. However, if a dose is missed and the next scheduled dose is less than 2 days away (48 hours), it should not be administered. In such cases, the patient should resume dosing on the regularly scheduled day of the week.
If 2 or more consecutive doses are missed, the patient should resume dosing as scheduled. No dosage adjustment is necessary for subcutaneous or oral semaglutide in mild-to-severe impairment. Caution should be exercised when initiating or escalating doses.
The manufacturer advises against adjusting the dosage of subcutaneous and oral Semaglutide for patients undergoing three or more weekly hemodialysis sessions. However, due to limited clinical evidence, caution is advised. Furthermore, the manufacturer recommends against adjusting the subcutaneous and oral semaglutide dosage for patients undergoing peritoneal dialysis.
Considerations for Pregnancy and Breastfeeding
Current clinical trial data and pharmacovigilance reports on semaglutide use in pregnant women are insufficient to ascertain its association with significant congenital defects, miscarriage, or adverse outcomes for both the mother and the fetus. However, findings from animal reproduction studies indicate potential risks to the fetus with semaglutide exposure during pregnancy. In addition, the weight loss effects of semaglutide are not deemed beneficial for pregnant individuals and may pose a risk of harm to the fetus. As a result, the manufacturer recommends against the use of semaglutide during pregnancy due to the potential fetal risks.
For the management of diabetes mellitus or weight loss, discontinuation of semaglutide is advised for a minimum of 2 months before attempting to conceive. Insufficient data exist regarding semaglutide or its metabolites in human milk and the potential effects on breastfed infants and milk production. Semaglutide was identified in milk at levels 3 to 12 times lower than in maternal plasma in lactating rats. The decision to use injectable semaglutide while breastfeeding should carefully consider the potential risk of infant exposure versus the benefits of breastfeeding.
Regarding the oral formulation containing SNAC, it is unclear whether SNAC is excreted in breast milk. The safety and efficacy of subcutaneous semaglutide (Ozempic®) and oral semaglutide (Rybelsus®) have not been established in individuals aged 18 or younger. However, Wegovy®, specifically indicated for weight loss, is approved for use in pediatric patients aged 12 and older with a BMI corresponding to ≥95th percentile standardized for age and sex.
Side Effects and Precautions
GLP-1 agonists lower blood glucose and may cause hypoglycemia. The adverse effects most frequently reported and most associated with discontinuation of semaglutide include nausea, vomiting, abdominal pain, constipation, and diarrhea. Nearly one-fifth of all patients in clinical trials with Ozempic® and Rybelsus® experienced nausea, which is the most prevalent adverse effect.
These drugs also aren’t recommended if you have a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia. Animal studies have linked these drugs with thyroid tumors. But until more long-term studies are done, the risk to humans isn't known.
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