Journal of Pharmaceutical Research

INTRODUCTION

Obesity is defined as an abnormal or excessive accumulation of body fat that impairs health, with a body mass index (BMI) ≥30 kg/m² widely accepted as the diagnostic threshold[1]. The severity of obesity is categorized as Class I (BMI 30–34.9 kg/m²), Class II (35–39.9 kg/m²), and Class III (≥40 kg/m²), with higher classes conferring progressively greater morbidity risk[2]. The global prevalence of obesity has risen sharply, with recent pooled analyses showing widespread increases across 200+ countries over the past three decades[3]. In India, the ICMR–INDIAB 2023 study reported a combined overweight-and-obesity prevalence of 28.6%, highlighting the growing burden in both urban and rural populations[3]. Urban tertiary hospital studies indicate even higher rates, frequently ranging from 31% to 45%, reflecting lifestyle transitions, socioeconomic factors and reduced physical activity in metropolitan areas.³ Obesity contributes to a spectrum of complications including type 2 diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, osteoarthritis, obstructive sleep apnea and non-alcoholic fatty liver disease, thereby increasing all-cause mortality and posing significant public health challenges[4]. Metabolic syndrome, a closely related condition characterized by central obesity, insulin resistance, dyslipidemia and hypertension, further amplifies cardiometabolic risk[5].

The limited sustainability of lifestyle interventions alone and the chronic, relapsing nature of obesity have intensified the need for effective pharmacotherapies[6]. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), represents a major advancement in medical obesity management due to its substantial and durable weight-loss efficacy demonstrated across diverse populations[6]. The drug acts on key central and peripheral pathways regulating appetite, satiety and glucose homeostasis, offering meaningful improvements in metabolic parameters and obesity-related comorbidities[6]. With a rapidly expanding evidence base and regulatory approval for chronic weight management, semaglutide has become a cornerstone of modern pharmacological treatment strategies for obesity[6].

SEMAGLUTIDE STRUCTURE

Semaglutide is a structurally modified analogue of human GLP-1, incorporating specific amino acid substitutions and acylation with a C18 fatty-diacid side chain to enhance albumin binding and resist degradation by dipeptidyl peptidase-4 (DPP-4)[7]. These modifications prolong its half-life, enabling once-weekly dosing and sustained activation of GLP-1 receptors, thereby improving therapeutic adherence and metabolic efficacy[7].

MECHANISM OF ACTION 

Semaglutide exerts its effects by binding to GLP-1 receptors in the hypothalamus, promoting satiety, reducing appetite and lowering caloric intake[8]. It delays gastric emptying, enhances glucose-dependent insulin secretion, suppresses glucagon release and improves pancreatic β-cell responsiveness[8]. Additionally, its central effects extend to reward pathways, reducing cravings and hedonic eating, which contributes significantly to weight loss in individuals with obesity[8].

PHARMACOKINETICS 

Semaglutide exhibits high bioavailability with subcutaneous administration, achieving slow and sustained absorption due to strong albumin binding, which prolongs its half-life to approximately one week[9]. Its pharmacokinetics remain consistent across age groups and in mild-to-moderate renal or hepatic impairment, allowing predictable drug exposure without major dose adjustments[9]. Oral semaglutide utilizes absorption enhancer Salcaprozate sodium (SNAC) to facilitate gastric mucosal uptake, although with lower bioavailability than injectable preparations[9].

Following systemic absorption, semaglutide undergoes proteolytic degradation and β-oxidation rather than cytochrome P450 metabolism, minimizing the risk of drug–drug interactions[9]. Excretion occurs primarily through the urine and feces as inactive metabolites, and steady-state concentrations are achieved after four to five weeks of weekly dosing, consistent with its extended half-life[10].

ADVERSE DRUG REACTIONS 

Gastrointestinal adverse effects such as nausea, vomiting, diarrhea and constipation are the most common and arise from delayed gastric emptying and increased central satiety signaling[12]. Alopecia has been reported infrequently and is thought to result from rapid weight loss–induced telogen effluvium rather than a direct drug effect[12]. Ocular adverse effects, including transient blurred vision, may occur due to rapid glycemic improvements altering lens hydration dynamics[12]. Pancreatitis is a rare but serious concern, potentially linked to GLP-1–related effects on pancreatic exocrine cells and gallstone formation from weight loss[12]. Thyroid-related risks, including C-cell hyperplasia observed in rodents, underline theoretical concerns, although human evidence remains limited[12].

Following clinical trials have been conducted:

CONTRAINDICATIONS

Semaglutide is contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 due to preclinical findings of C-cell tumors in rodents[13]. It should be avoided in patients with severe gastrointestinal disorders such as gastroparesis, as delayed gastric emptying may worsen symptoms[13]. Hypersensitivity to the formulation constitutes another contraindication[13]. Use during pregnancy is discouraged because intentional weight loss is contraindicated and human fetal safety data remain insufficient[13].

DOSE

For obesity management, semaglutide is initiated at 0.25 mg weekly and titrated gradually to the target dose of 2.4 mg weekly to minimize gastrointestinal intolerance[14]. Oral semaglutide follows a stepwise increase to 14 mg daily for glycemic control, while higher-dose oral formulations for obesity are under active evaluation[14].

COST 

Cost-effectiveness analyses indicate that semaglutide 2.4 mg is economically viable in high-income countries due to reductions in diabetes progression, cardiovascular events and healthcare utilization[15]. However, its high retail cost remains a barrier in resource-limited settings, highlighting the need for pricing negotiations and broader insurance coverage to improve accessibility[15].

FUTURE FORMULATIONS

Future directions include expanded indications for obesity with comorbidities like metabolic liver disease, heart failure and addiction disorders[16]. Oral semaglutide (Rybelsus) formulations currently available include 3 mg, 7 mg and 14 mg tablets, with higher-dose tablets 25 mg and 50 mg are under investigation in OASIS trials for improved weight-loss efficacy[16]. Pen-injector (Ozempic) semaglutide is available as 0.25 mg, 0.5 mg, 1 mg and 2.4 mg pre-filled pens designed for once-weekly dosing[16]. Ongoing innovations aim to improve delivery systems, enhance potency and develop combination therapies to further optimize outcomes[16]. Possible fixed drug combinations are under investigation:

• Semaglutide + Amylin analog (enhanced appetite suppression)

• Semaglutide + GIP/GLP-1 dual agonist (complementary metabolic effects)

• Semaglutide + SGLT2 inhibitor (cardiometabolic additive effect)