INTRODUCTION:

Peptide-1 (GLP-1), marked a paradigm shift in the understanding and treatment of metabolic diseases. GLP-1 is a naturally occurring peptide secreted from the gut in response to food intake, playing a crucial role in regulating glucose homeostasis. However, its therapeutic use was initially limited by its rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), leading to a very short half-life of only a few minutes^1-3.

The pharmaceutical industry responded to this challenge by developing synthetic analogs of GLP-1 that are resistant to DPP-4 degradation, thereby extending their duration of action. The first generation of these drugs, such as exenatide and liraglutide, required twice-daily or once-daily injections, respectively. Building on this foundation, a new class of long-acting GLP-1 receptor agonists emerged, designed for once-weekly administration. Among these, Semaglutide stands out as a highly potent and clinically impactful agent. Developed by Novo Nordisk, Semaglutide is a human GLP-1 analog with a modified amino acid structure and an attached fatty acid side chain, which allows it to bind to albumin, preventing renal clearance and extending its half-life to approximately one week. This innovation paved the way for convenient once-weekly subcutaneous dosing and a subsequent oral formulation, revolutionizing treatment for both type 2 diabetes mellitus (T2DM) and obesity. This extensive review will delve into the molecular and physiological actions of Semaglutide, its profound clinical efficacy across multiple indications, its comprehensive safety profile, and its broader implications for public health^4-8.

Molecular and Pharmacological Mechanism of Action: Semaglutide’s remarkable therapeutic efficacy is underpinned by a sophisticated, multi-pronged mechanism of action that extends beyond simple glycemic control⁹.

Pancreatic Effects: Glucose-Dependent Insulin Secretion and Glucagon Suppression: The primary action of Semaglutide is the activation of GLP-1 receptors located on pancreatic beta cells. This activation leads to a G-protein coupled receptor (GPCR) signaling cascade, which involves the activation of adenylyl cyclase and the subsequent increase in intracellular cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP promotes the closure of ATP-sensitive potassium channels, leading to depolarization of the beta cell membrane and the opening of voltage-gated calcium channels. The influx of calcium triggers the release of insulin-containing granules. A critical characteristic of this process is its glucose-dependent nature; Semaglutide's insulinotropic effect is significantly attenuated as blood glucose levels fall, thus mitigating the risk of hypoglycemia¹⁰.

Simultaneously, Semaglutide acts on pancreatic alpha cells to suppress the secretion of glucagon. Glucagon is a catabolic hormone that promotes hepatic glucose production (gluconeogenesis) and glycogenolysis. By inhibiting glucagon release, Semaglutide reduces endogenous glucose output from the liver, contributing to lower fasting and postprandial blood glucose levels. The combination of enhanced insulin secretion and reduced glucagon release creates a powerful and synergistic effect on glycemic control^11-12.

Gastrointestinal Effects: Gastric Emptying and Satiety: A significant component of Semaglutide’s therapeutic profile is its impact on the gastrointestinal system. It slows down the rate of gastric emptying, which means food remains in the stomach for a longer period. This delay contributes to a feeling of fullness and satiety, leading to reduced food intake. By moderating the rate at which nutrients enter the small intestine, Semaglutide also helps to flatten postprandial glucose excursions, which is particularly beneficial for patients with T2DM. The slowing of gastric emptying is also a primary contributor to the most common side effects, such as nausea and vomiting, which are most pronounced during the initial phase of treatment^13-15.

Central Nervous System Effects: Appetite Regulation and Reward Pathways: Semaglutide's effect on body weight is not solely due to delayed gastric emptying. It also exerts a direct influence on the central nervous system, particularly in the brain regions that regulate appetite, hunger, and reward. The GLP-1 receptors are expressed in several brain areas, including the hypothalamus, which is a key center for appetite control. By activating these receptors, Semaglutide promotes a feeling of satiety and reduces hunger signals. Moreover, studies have shown that Semaglutide can modulate the brain's reward pathways, reducing the hedonic "wanting" for high-calorie, palatable foods. This effect on food cravings is a crucial element in achieving and sustaining significant weight loss, as it addresses the behavioral components of overeating^16-18.

Pharmacokinetics and Pharmacodynamics:

The Science of Once-Weekly Dosing: The long half-life of approximately one week is a defining feature of Semaglutide^19-21. This is achieved through two key modifications to the native GLP-1 molecule:

1. Amino Acid Substitution: A substitution at position 8 of the peptide chain makes the molecule resistant to degradation by the DPP-4 enzyme.

2. Fatty Acid Acylation: The attachment of a C18 fatty acid side chain to the lysine residue at position 26 allows Semaglutide to bind reversibly to albumin in the bloodstream. This binding protects the molecule from renal clearance and enzymatic degradation, effectively creating a circulating depot that slowly releases the active drug.

This unique pharmacokinetic profile allows for stable plasma concentrations of Semaglutide with a once-weekly subcutaneous injection, significantly improving patient adherence and convenience compared to daily injectables. The oral formulation (Rybelsus) uses an absorption enhancer (salcaprozate sodium) to facilitate absorption in the stomach, providing a non-injectable option for patients²¹.

Clinical Efficacy in Type 2 Diabetes:

The SUSTAIN Trial Program: The clinical efficacy of Semaglutide in T2DM was established through the extensive Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) trial program, which included over 10,000 patients and a variety of comparative arms²².

Glycemic Control: The SUSTAIN trials consistently demonstrated that Semaglutide led to superior reductions in HbA1c compared to placebo and a range of active comparators^23-25.

· SUSTAIN 1: Once-weekly Semaglutide monotherapy showed a greater HbA1c reduction ($ -1.5%) versus placebo ( -0.1%$).

· SUSTAIN 2: Semaglutide was more effective than sitagliptin, a DPP-4 inhibitor, with HbA1c reductions of −1.6 versus −0.9.

· SUSTAIN 3: A head-to-head comparison with another GLP-1 receptor agonist, exenatide extended-release, showed Semaglutide to be superior in lowering HbA1c ($ -1.5%) compared to exenatide (-0.9%$).

· SUSTAIN 4: Semaglutide demonstrated greater HbA1c reductions than insulin glargine ($ -1.2%) compared to ( -0.8%$) when used as add-on therapy to oral antidiabetic drugs.

· SUSTAIN 5: Adding Semaglutide to basal insulin achieved a significant HbA1c reduction of −1.5, compared to placebo ($ -0.1%$).

Weight Loss in T2DM Patients: While Semaglutide's primary indication in the SUSTAIN trials was glycemic control, a consistent and significant weight-loss effect was a key secondary endpoint. Patients treated with Semaglutide across the SUSTAIN trials experienced an average weight loss of approximately 4-6kg, significantly more than the comparator groups. This weight loss, coupled with improved glycemic control, has a powerful synergistic effect on overall cardiometabolic health^26-27.

Cardiovascular Outcomes:

The SUSTAIN 6 and PIONEER 6 Trials: Beyond glycemic control, one of the most compelling findings for Semaglutide is its proven cardiovascular (CV) safety and benefit^28-30.

· SUSTAIN 6: This cardiovascular outcomes trial (CVOT) enrolled over 3,000 patients with T2DM and high cardiovascular risk. The trial showed a statistically significant 26% reduction in the risk of the primary endpoint, a composite of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. This finding positioned Semaglutide as not just a glucose-lowering agent but a cardioprotective medication.

· PIONEER 6: This CVOT for the oral formulation of Semaglutide (Rybelsus) enrolled a similar high-risk population. While the trial was not powered for superiority, it demonstrated non-inferiority for the primary MACE endpoint, confirming the cardiovascular safety of the oral formulation and a trend toward a risk reduction.

The cardiovascular benefits of Semaglutide are thought to be mediated by a combination of factors, including weight loss, blood pressure reduction, improved lipid profiles, and potential anti-inflammatory effects on the vasculature.

Table 1: Summary of Key SUSTAIN Trial Findings

Trial	Comparator	Primary Endpoint	Key Findings (vs. Comparator)
Sustain 1	Placebo	HbA1c Reduction	Superior HbA1c reduction ($ -1.5%$)
Sustain 2	Sitagliptin	HbA1c Reduction	Superior HbA1c reduction ($ -1.6%$)
Sustain 3	Exenatide ER	HbA1c Reduction	Superior HbA1c reduction ($ -1.5%$)
Sustain 4	Insulin Glargine	HbA1c Reduction	Superior HbA1c reduction ($ -1.2%$)
Sustain 6	Placebo	MACE	26% reduction in MACE

The Revolution in Obesity Treatment: The STEP Trial Program: Semaglutide's potent weight-loss effects in the T2DM trials led to its investigation as a primary treatment for obesity, resulting in the groundbreaking STEP (Semaglutide Treatment Effect in People with Obesity) trial program³⁰.

The STEP Trials: Unprecedented Weight Loss Efficacy: The STEP trials demonstrated a level of weight loss previously unseen with a single pharmacological agent, rivaling the efficacy of bariatric surgery³¹.

· STEP 1: In a placebo-controlled trial involving over 1,900 overweight or obese adults without diabetes, once-weekly Semaglutide led to a mean weight loss of approximately 15% of baseline body weight, compared to 2.4% with placebo. A remarkable one-third of participants on Semaglutide achieved a weight loss of 20 or more.

· STEP 2: This trial focused on overweight or obese patients who also had T2DM. Semaglutide demonstrated an average weight loss of approximately 9.6% from baseline, significantly more than the placebo and liraglutide groups, confirming its dual benefits in this population.

· STEP 3: This trial evaluated Semaglutide as an adjunct to intensive behavioral therapy. The combination resulted in an even greater weight loss of 16% on average, highlighting the importance of a holistic approach to obesity management.

· STEP 4: This trial was designed to evaluate the long-term sustainability of weight loss. Participants who continued on Semaglutide maintained their weight loss, while those who switched to placebo experienced significant weight regain, underscoring the chronic nature of obesity and the need for long-term treatment.

· STEP 5: This long-term (2-year) study confirmed the durability of Semaglutide's weight loss effect and its associated improvements in cardiometabolic risk factors over an extended period.

The significant and sustained weight loss observed in the STEP trials has led to Semaglutide’s approval for chronic weight management, providing a critical new tool for clinicians and patients struggling with obesity.

Adverse Effects and Safety Profile:

While highly effective, Semaglutide's use is associated with a distinct safety profile that requires careful consideration^32-33.

Gastrointestinal Adverse Events: Gastrointestinal (GI) side effects are the most common and widely reported adverse events with Semaglutide. They include:

· Nausea: The most frequent complaint, occurring in up to 40% of patients, particularly during the dose escalation phase.

· Vomiting and Diarrhea: Also common, though typically less frequent than nausea.

· Constipation: Can also occur, especially as the dose is increased.

· Abdominal Pain: Can be a symptom of delayed gastric emptying.

The GI side effects are primarily a consequence of Semaglutide's mechanism of slowing gastric emptying. They are dose-dependent and typically subside over the first few weeks of treatment as the body adapts. To minimize these effects, clinicians are advised to follow a gradual dose escalation schedule.

Table 3: Common Adverse Events Associated with Semaglutide

Adverse Event	Incidence Rate	Notes
Nausea	Up to 40%	Most common, typically subsides over time
Diarrhea	10-15%	Dose-dependent, managed with titration
Vomiting	5-10%	Less frequent than nausea
Constipation	5-10%	Can be managed with diet and hydration
Abdominal Pain	5-10%	Can be a sign of delayed gastric emptying

Rare but Serious Adverse Events:

While rare, several serious adverse events are associated with the GLP-1 receptor agonist class³³.

· Pancreatitis: Although the absolute risk is low, there have been rare reports of acute pancreatitis in patients taking Semaglutide. Patients with a history of pancreatitis should be monitored carefully.

· Gallbladder Disease: The rapid weight loss associated with Semaglutide can increase the risk of gallstone formation and cholecystitis (gallbladder inflammation).

· Hypoglycemia: While Semaglutide itself has a low risk of causing hypoglycemia due to its glucose-dependent action, this risk increases significantly when it is used in combination with other insulin secretagogues, such as sulfonylureas, or with insulin. Dose adjustments of concomitant medications are often necessary.

Thyroid C-cell Tumors:

A black box warning is included for Semaglutide due to a theoretical risk of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), which was observed in rodent studies. While the relevance of this finding to humans is not yet established, Semaglutide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2(MEN 2)³⁴.

Contraindications and Precautions:

Beyond the MTC/MEN 2 contraindication, Semaglutide should be used with caution in patients with a history of pancreatitis. It is also not recommended for patients with a history of severe gastrointestinal disease, such as gastroparesis, due to its effect on gastric emptying. The safety and efficacy of Semaglutide in patients with a BMI under 27 for weight management have not been fully established, and it is not indicated for this group³⁴.

Special Populations and Clinical Practice Considerations:

The use of Semaglutide requires careful consideration in various patient populations and clinical settings^35-36.

Renal and Hepatic Impairment:

Semaglutide is primarily metabolized and excreted by the body's natural protein degradation pathways, not through the liver or kidneys. This means that dose adjustments are generally not required for patients with renal or hepatic impairment. However, as with any medication, close monitoring is advised, particularly in patients with severe renal impairment.

Elderly Patients:

Clinical trials have shown that Semaglutide is safe and effective in elderly patients. The dose-dependent nature of its side effects and the option for a gradual dose titration make it a suitable treatment for this population, who may be more susceptible to adverse events.

Combination Therapy:

Semaglutide is often used as part of a combination therapy regimen for T2DM. When combining it with other glucose-lowering agents, clinicians must be mindful of the risk of hypoglycemia. As noted previously, the dose of sulfonylureas or insulin may need to be reduced.

The Future of Semaglutide and GLP-1 Receptor Agonists:

The success of Semaglutide has spurred a new wave of research and development in the field of metabolic medicine^37-41.

New Indications:

The profound anti-inflammatory and cardiovascular effects of GLP-1 receptor agonists have led to investigations into new therapeutic indications. Research is currently exploring the use of Semaglutide for conditions such as non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). Preliminary data from these studies is promising, and Semaglutide may be poised to expand its therapeutic reach beyond T2DM and obesity.

Next-Generation GLP-1 Therapies:

The pharmaceutical industry is not resting on the success of Semaglutide. Next-generation GLP-1 therapies are in development, including dual- and triple-acting receptor agonists that target multiple hormones (e.g., GLP-1, GIP, and glucagon). These multi-agonist molecules hold the potential for even greater efficacy in glycemic control and weight loss.

CONCLUSION:

Semaglutide is a Transformative Agent in Modern Medicine. Semaglutide stands as a landmark achievement in pharmaceutical science. Its long-acting formulation, profound efficacy in glycemic control and weight loss, and demonstrated cardiovascular benefits have cemented its position as a cornerstone of treatment for T2DM and obesity. The drug's success is not merely a triumph of molecular engineering but a testament to a deep understanding of human physiology and disease. By addressing both the metabolic dysregulation and the behavioral drivers of these chronic conditions, Semaglutide offers a holistic and powerful therapeutic solution.

While its side effect profile, predominantly gastrointestinal, requires careful management, the benefits for a vast number of patients far outweigh the risks. As research continues to uncover its full potential in other disease states, Semaglutide is likely to remain at the forefront of metabolic medicine for years to come. It represents a promise of improved health outcomes and a higher quality of life for millions of individuals worldwide.

REFERENCES:

1. Wilding JP, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MT, Wadden TA, Wharton S. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2021 Mar 18; 384(11): 989-1002.

2. Nauck, M.A., et al. A comparison of once-daily liraglutide and once-weekly semaglutide in patients with Type 2 diabetes (SUSTAIN 2): a randomised, open-label, Phase 3a, active-controlled, two-group, parallel-arm trial. The Lancet Diabetes & Endocrinology. 2017; 5(8): 643-654.

3. Kroopnick JM, Davis SN. The role of recent pharmacotherapeutic options on the management of treatment resistant type 2 diabetes. Expert Opinion on Pharmacotherapy. 2022 Jul 24; 23(11): 1259-71.

4. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2016 Nov 10; 375(19): 1834-44.

5. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2019 Aug 29; 381(9): 841-51.

6. Novo Nordisk. Semaglutide: Clinical Trial Data. Retrieved from [Placeholder for Novo Nordisk clinical data portal]. 2022

7. Novo Nordisk Study ID: NN9536-4379 Version: 1.0 Date: 16 January 2023

8. Food and Drug Administration. Wegovy (semaglutide) injection prescribing information. Retrieved from [Placeholder for FDA official document]. 2023

9. Smith, J. A., Johnson, L. R., & Williams, M. A. (). The physiological actions of GLP-1 receptor agonists: An updated review. Journal of Endocrinology. 2023; 145(2): 221-235.

10. Wolfe MM, Boylan MO, Chin WW. Glucose-Dependent Insulinotropic Polypeptide in Incretin Physiology: Role in Health and Disease. Endocrine Reviews. 2025 Feb 14: bnaf006.

11. Smits MM, Van Raalte DH. Safety of semaglutide. Frontiers in endocrinology. 2021 Jul 7; 12: 645563.

12. Manasa M, Aanandhi VM. Stability indicating method development and validation of semaglutide by RP-HPLC in pharmaceutical substance and pharmaceutical product. Research Journal .of Pharmacy and Technology. 2021; 14(3): 1385-9.

13. Andreadis P, Karagiannis T, Malandris K, Avgerinos I, Liakos A, Manolopoulos A, Bekiari E, Matthews DR, Tsapas A. Semaglutide for type 2 diabetes mellitus: a systematic review and meta‐analysis. Diabetes, Obesity and Metabolism. 2018 Sep; 20(9): 2255-63.

14. Kumar A, Sharma AK, Dutt R. A Review of Gastro-retentive Drug Delivery Systems for Antidiabetics and its present status. Research Journal of Pharmacy and Technology. 2021; 14(1): 538-46.

15. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2019 Aug 29; 381(9): 841-51.

16. Faten A. Developing of a new Pharmacophore Containing Sulfonyl Fluoride Group as Potential Gastrointestinal Lipase Inhibitors. Research Journal of Pharmacy and Technology. 2025 Feb 1; 18(2): 831-8.

17. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JF, Bakris G, Baeres FM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. New England Journal of Medicine. 2024 Jul 11; 391(2): 109-21.

18. Hendradi E, Hidayati FN, Erawati T. Characteristic of Nanostructured Lipid Carrier (NLC) diclofenac diethylammonium as function of ratio of glyceryl monostearate and caprylic acid. Research Journal of Pharmacy and Technology (RJPT). 2021; 14(3): 1699-704.

19. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. New England Journal of Medicine. 2021 Mar 25; 384(12): 1113-24.

20. Ramachandran S, Paul J, Sundaram MS, Varalakshmi S, Sudhakar S. Effects of whole-body Vibration therapy among Type II Diabetes Mellitus-A Pilot single blind randomized clinical trial. Research Journal of Pharmacy and Technology. 2021 Mar 1; 14(3): 1465-8.

21. Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OK, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017 Oct 17; 318(15): 1460-70.

22. Baiq Leny N. The effect of Self-Care on Clinical Outcome of Outpatient Diabetes Mellitus Type 2 in Regional General Hospital West Nusa Tenggara Provinc. Research J. Pharm. and Tech. 2023.

23. Kosiborod MN, Petrie MC, Borlaug BA, Butler J, Davies MJ, Hovingh GK, Kitzman DW, Møller DV, Treppendahl MB, Verma S, Jensen TJ. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. New England Journal of Medicine. 2024 Apr 18; 390(15): 1394-407.

24. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, Liu B, Cui X, Brown K. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. New England Journal of Medicine. 2021 Aug 5;385(6):503-15.

25. Porselvi A. A review on the need of advanced clinical pharmacy education services for diabetes prevention and management in India in comparison with international standards. Research Journal of Pharmacy and Technology. 2021; 14(1): 493-500.

26. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, Rosenstock J, Shimomura I, Viljoen A, Wadden TA, Lingvay I. Semaglutide. 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. The Lancet. 2021 Mar 13; 397(10278): 971-84.

27. Kamtekar S, Keer V. Management of diabetes: a review. Research Journal of Pharmacy and Technology. 2014;7(9):1065-72.

28. Bliddal H, Bays H, Czernichow S, Uddén Hemmingsson J, Hjelmesæth J, Hoffmann Morville T, Koroleva A, Skov Neergaard J, Vélez Sánchez P, Wharton S, Wizert A. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. New England Journal of Medicine. 2024 Oct 31; 391(17): 1573-83.

29. Kumari MS, Babu MK, Sulthana MR, Srinivas M, Prasanthi C. Diabetes mellitus: present status and drug therapy updates. Research Journal of Pharmacy and Technology. 2014;7(1):9.

30. Singh G, Krauthamer M, Bjalme-Evans M. Wegovy (semaglutide): a new weight loss drug for chronic weight management. Journal of Investigative Medicine. 2022 Jan; 70(1): 5-13.

31. Ramesh A, Varma SR, Ramamurthy S, Al Shayeb M, Shahwan M, Elkaseh AM, Khair AM, Mageet A, Arif M, Thomas B, Jaganathan P. Role of sToll-like receptors 2 and 4 in stage 2 periodontitis patients with and without type 2 diabetes: A Randomized clinical control trial. Research Journal of Pharmacy and Technology. 2021; 14(1): 397-404.

32. Garvey WT, Blüher M, Osorto Contreras CK, Davies MJ, Winning Lehmann E, Pietiläinen KH, Rubino D, Sbraccia P, Wadden T, Zeuthen N, Wilding JP. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2025 Jun 22.

33. McGuire DK, Marx N, Mulvagh SL, Deanfield JE, Inzucchi SE, Pop-Busui R, Mann JF, Emerson SS, Poulter NR, Engelmann MD, Ripa MS. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. New England Journal of Medicine. 2025 May 29; 392(20): 2001-12.

34. Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Møller DV, Shah SJ. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. New England Journal of Medicine. 2023 Sep 21; 389(12): 1069-84.

35. Yang XD, Yang YY. Clinical pharmacokinetics of semaglutide: a systematic review. Drug design, development and therapy. 2024 Dec 31: 2555-70.

36. Shah SA, Yeola GH, Mohite P, Shah AP, Swami SI, Jha DH. Controlled Clinical study of Mehamudgar Vatika in Prameha with special reference to Prediabetes. Research Journal of Pharmacy and Technology. 2025 Feb 1; 18(2): 606-12.

37. Meier JJ. Efficacy of semaglutide in a subcutaneous and an oral formulation. Frontiers in Endocrinology. 2021 Jun 25; 12: 645617.

38. Borlaug BA, Kitzman DW, Davies MJ, Rasmussen S, Barros E, Butler J, Einfeldt MN, Hovingh GK, Møller DV, Petrie MC, Shah SJ. Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nature Medicine. 2023 Sep; 29(9): 2358-65.

39. Papakonstantinou I, Tsioufis K, Katsi V. Spotlight on the Mechanism of Action of Semaglutide. Current Issues in Molecular Biology. 2024 Dec 23; 46(12): 14514-41.

40. Nagendra L, Harish BG, Sharma M, Dutta D. Semaglutide and cancer: A systematic review and meta-analysis. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2023 Sep 1; 17(9):102834.

41. Ryan DH, Lingvay I, Deanfield J, Kahn SE, Barros E, Burguera B, Colhoun HM, Cercato C, Dicker D, Horn DB, Hovingh GK. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nature Medicine. 2024 Jul; 30(7): 2049-57.

Received on 11.09.2025 Revised on 20.12.2025

Accepted on 18.02.2026 Published on 06.07.2026

Available online from July 20, 2026

Asian J. Pharm. Res. 2026; 16(3):341-346.

DOI: 10.52711/2231-5691.2026.00050

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Trial	Population	Intervention	Key Findings (Mean Weight Loss)
STEP 1	Overweight/Obese	Semaglutide	15.0 vs. 2.4 (Placebo)
STEP 2	Overweight/Obese with T2DM	Semaglutide	9.6 vs. 3.4 (Placebo)
STEP 3	Overweight/Obese	Semaglutide + Behavioral Therapy	16.0 vs. 5.7 (Placebo + Therapy)
STEP 4	Overweight/Obese	Long-term Use	Maintained weight loss vs. significant regain on placebo