Semaglutide in Metabolic Medicine: A Review on Clinical Applications and Emerging Therapeutics

Summary

Obesity and type 2 diabetes mellitus affect over 800 million and 537 million individuals worldwide. Semaglutide, a weekly glucagon-like peptide-1 receptor agonist, has advanced treatment of pathophysiological processes linked to metabolic dysregulation. This review consolidates evidence on its mechanisms of action, clinical effectiveness across established and emerging applications, safety, and prospects for personalized therapy. Clinical studies have shown that semaglutide sustains glycemic control, promotes substantial weight loss, and provides cardiovascular and renal protection. Recent FDA clearance marks the first therapeutic alternative for metabolic dysfunction-associated steatohepatitis among the emerging applications. Pharmacogenomic insights facilitate personalized therapy; however, clinical applications remain in experimental stage. Gastrointestinal side effects are the main tolerability concern, but the risk-benefit profile underscores its increasing significance in metabolic therapy. Therapies for diabetes and obesity are cost-effective; however, global accessibility challenges persist. Future priorities include refining combination medicines, promoting precision medicine, and addressing healthcare inequities to augment population-level effects.

Introduction

Type 2 diabetes mellitus (T2DM) and obesity form an interlocking epidemic affecting billions and challenging global healthcare systems. More than 537 million adults currently live with T2DM, and the International Diabetes Federation (IDF) projects 853 million by 2050. The World Health Organization (WHO) reports an almost three-fold increase in global obesity since 1975, now affecting 800 million people. These disorders often independently subject individuals to cardiovascular disease (CVD), renal failure, hepatic steatosis, and premature death. The aggregate economic burden exceeds $950 billion annually, ranking metabolic disorders among the most pressing challenges for healthcare and policy, as reported by the World Obesity Federation (2023) and the Centers for Disease Control and Prevention (2024).

Traditional diabetes therapies increase patient burden and complicate care. Standard therapies, including exogenous insulin and sulfonylureas, raise the risk of hypoglycemia and weight gain, undermining efforts to mitigate insulin resistance. Moreover, these agents provide limited cardiovascular protection, despite cardiovascular events being the leading cause of diabetes-related mortality. The progressive β-cell function decline requires complex regimens, resulting in multiple daily doses with limited clinical use, greater adverse events, and patient reluctance [1]. Obesity treatment has similarly relied on behavioral modifications, with limited long-term results. To date, pharmacotherapy has been restricted to agents that either produce modest weight loss or present safety liabilities that temper clinical enthusiasm. The complexity of metabolic diseases and limitations of current treatments underline the need for novel therapeutic approaches that offer durable solutions for diabetes and obesity.

Semaglutide is a major therapeutic advance for metabolic disorders. This long-acting GLP-1 receptor agonist mimics the body's natural GLP-1 hormone (94% identical sequence). For the first time, a single agent achieved glycemic control, adiposity reduction, and cardiovascular risk mitigation, three clinical objectives thought to be impossible without multiple pharmacological classes [2,3].

Clinical trials have confirmed semaglutide's broad metabolic benefits. However, its application in routine practice presents major challenges related to its persistence, accessibility, and cost-effectiveness. This review examines both the clinical benefits and practical challenges of semaglutide therapy. The analysis considers real-world evidence on treatment gaps, costs, and implementation barriers.

Molecular structure and mechanisms of action

Semaglutide is a second-generation glucagon-like peptide-1 receptor agonist (GLP-1RA) engineered for extended activity and enhanced pharmacokinetics [4,5]. Semaglutide incorporates three essential structural modifications. First, a substitution at position 8 confers protection against enzyme degradation. Second, the addition of a fatty acid chain enhances binding to blood albumin. Third, a substitution at position 34 prevents unwanted chemical modifications. These changes extend the drug's half-life from 2 minutes to 165 hours [4,5]. This resulted in a polypeptide that combines improved metabolic stability with effective GLP-1 receptor interactions [6].

Semaglutide selectively binds to GLP-1 receptors in the pancreas, central nervous system, cardiovascular system, and gastrointestinal tract, triggering Gs protein-coupled signalling cascades. Activation of these receptors elevates intracellular cAMP, which activates protein kinase A (PKA) and exchange protein activated by cAMP (Epac). These mechanisms promote glucose-dependent insulin secretion, suppress glucagon release under hyperglycemic conditions, delay gastric emptying, and reduce appetite while increasing satiety (Fig. 1). The widespread tissue distribution of the receptor supports additional effects, including the restoration of β-cell function and cardioprotective actions independent from alterations in glycemic levels (Fig. 1) [7]. Preclinical research suggests that semaglutide may influence the gut microbiota and modulate the gut–brain axis, thus enhancing metabolic regulation. These findings require validation in rigorously controlled human studies [8,9,10].

Fig. 1.

Multi-organ effects of semaglutide. Therapeutic effects of semaglutide on several organs due to GLP-1R activation. It promotes the release of insulin from the pancreas during hyperglycemia, inhibits glucagon secretion, and accelerates glucose clearance. Central nervous system effects include hunger reduction and fullness signals. Cardiovascular advantages include direct cardioprotection, whereas renal effects involve nephroprotection. Hepatic activities include MASH resolution, fibrosis reduction, and hepatoprotection. Gastric effects include delayed emptying and reduced fullness symptoms.

Pharmacological diversity of GLP-1 receptor agonists

The GLP-1 receptor agonists are a heterogeneous class distinguished by differences in their peptide sequences, pharmacokinetics, administration routes, and formulation. Semaglutide has the longest half-life in the GLP-1RA class (~165 hours), enabling once-weekly subcutaneous or daily oral dosing (Table 1). The oral formulation of semaglutide employed salcaprozate sodium (SNAC) as a permeability enhancer. This binds to the peptide, easing its mucosal transit and addressing the issue of low oral bioavailability (0.4–1%) [4,5]. Head-to-head studies show semaglutide achieves greater reductions in HbA1c levels and body weight than dulaglutide and liraglutide. However, tirzepatide, a novel dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, shown even greater efficacy on selected metabolic variables [11,12].

Table 1.

Comparative pharmacology of selected incretin-based agents.

Agent	Approximately half-life	Administration	Oral bioavailability	Key structural features
Semaglutide	∼7 d	SC weekly;oral daily (SNAC)	0.4–1%	C18 fatty-diacid, Ala8 to Aib substitution, and Lys34 to Arg substitution
Dulaglutide	∼5 d	SC weekly	–	GLP-1 analog fused to IgG4 Fc fragment
Liraglutide	∼13 h	SC daily	–	C16 fatty-acid acylation
Tirzepatide	∼5 d	SC weekly	–	Dual GIP/GLP-1 agonist
Exenatide (IR)	∼2.4 h	SC BID (ER: weekly)	–	Exendin-4 analogue

Clinical efficacy in established indications

Semaglutide has proven therapeutic value in several chronic diseases, with significant evidence from randomized studies validating its use in T2DM, obesity, cardiovascular protection, and kidney function (Table 2).

Table 2.

Major semaglutide clinical trials summary.

Trial	ClinicalTrials.gov (ID number)	Population	Number	Duration	Primary Outcome	Result	reference
SUSTAIN-1	NCT02054897	T2DM, drug-naive	388	30 weeks	HbA1c change	-1.55%	[7]
SUSTAIN-6	NCT01720446	T2DM + CVD	3,297	104 weeks	MACE	HR 0.74	[16]
STEP-1	NCT03548935	Obesity, no T2DM	1,961	68 weeks	Weight change	-14.9%	[13]
SELECT	NCT03574597	Obesity + CVD	17,604	∼160 weeks	MACE	HR 0.80	[18,19]
FLOW	NCT03819153	T2DM + CKD	3,533	∼168 weeks	Kidney composite	HR 0.76	[20]

Type 2 diabetes mellitus management

The SUSTAIN program is the largest evaluation of a glucagon-like peptide-1 receptor agonist conducted to date, with more than 8,000 participants from 7 prominent global studies. In SUSTAIN-1, the superiority of the pharmacological agent as a monotherapy in 388 treatment-naive adults with early stage T2DM was evident. Semaglutide treatment reduced HbA1c levels by 1.45-1.55% depending on the dose, compared to no significant change with placebo. Semaglutide caused significant weight loss, averaging 3.73 kg and 4.53 kg at higher doses. Semaglutide effectively enhanced glycemic control and facilitated weight loss in a single prescription. The trial confirms the agent's significant role in improving treatment options for diabetes [7].

Critical limitations and evidence gaps

Several limitations affect interpretation of SUSTAIN trial results for clinical practice. First, SUSTAIN-1 enrolled only treatment-naive patients with early-stage T2DM for 30 weeks. Real-world patients typically have more complex conditions requiring combination therapy. The trial used placebo comparisons instead of standard treatment and measured only HbA1c rather than actual complications. Furthermore, adherence rates in clinical practice are much lower than in trials due to reduced monitoring and support (Section 5.3). Consequently, these differences greatly limit how trial efficacy translates to everyday practice.

Obesity management

The STEP program established semaglutide as highly effective for obesity through the systematic investigation of diverse patient populations. In STEP-1, a trial of 1,961 adults with obesity or overweight and weight-related comorbidities but without diabetes, 2.4 mg weekly dosage of semaglutide, combined with lifestyle counselling, led to a mean weight change of -14.9% versus -2.4% in the placebo group over 68 weeks. Notably, 86.4% of participants given semaglutide lost ≥5% of their initial weight, 69.1% lost ≥10%, and 50.5% lost ≥15%, confirming semaglutide's capacity superiority over traditional take-up of lifestyle advice alone [13].

In STEP-2, among 1,210 adults with T2DM and obesity or overweight, a consistent weekly dose of semaglutide led to a 9.6% reduction in weight and a decrease in HbA1c, underscoring its benefits in a population at risk for obesity and hyperglycemia [14]. STEP-3 showed semaglutide with an intense behavioral weight management program caused a 16.0% weight reduction compared with 5.7% with a placebo. This improvement suggests that pharmacotherapy can make lifestyle-based interventions more effective and long-term in the clinical practice [15].

Critical limitations and evidence gaps

The STEP trial results have important limitations. Weight regains occurred rapidly after treatment discontinuation (two-thirds within one year), indicating the need for ongoing therapy [13]. Trials also excluded psychiatric patients common in obesity populations. Real-world weight loss is lower than trial outcomes (Section 5.3). This difference may reflect reduced lifestyle support in routine clinical practice.

Cardiovascular protection in diabetic populations

SUSTAIN-6, which included 3,297 participants at increased risk of CVD, demonstrated that semaglutide provided a 26% relative risk reduction in major adverse cardiovascular events (MACE) (hazard ratio (HR), 0.74) compared to placebo. Decomposing the composite endpoints revealed a 39% decline in nonfatal stroke; though cardiovascular mortality were similar between the groups. Therefore, the data demonstrated that semaglutide safeguards cardiovascular health independent of its capacity to lower glucose [16].

Meta-analysis of seven major studies confirmed GLP-1 receptor agonists reduce the incidence of severe cardiovascular events by 12% (HR 0.88, 95% CI 0.82–0.94), cardiovascular mortality by 12%, and stroke by 16%. The equity of the effect was preserved across all-cause mortality (12% reduction) and renal outcomes (17% reduction). These benefits were attained without signs of increased hypoglycemia severity, pancreatitis, or pancreatic malignancy [17].

Critical limitations and evidence gaps

SUSTAIN-6 revealed increased diabetic retinopathy complications with semaglutide treatment (Section 5.2). While rapid glucose reduction has been proposed as an explanation, other GLP-1 agonists with similar glucose-lowering effects do not show this pattern [16]. Ophthalmologic monitoring is recommended for high-risk patients until the cause is determined.

Cardiovascular protection in non-diabetic populations

The SELECT trial extended findings to obese non-diabetic patients with preexisting CVD. Among 17,604 individuals, MACE decreased by 20% after a median follow-up of 39.8 months (HR 0.80, P < 0.001)(18). At 208 weeks, participants had lost 10.2% of body weight, reduced waist circumference by 7.7 cm, and improved waist-to-height ratio by 6.9% versus placebo. These benefits exceed those from weight loss alone, suggesting additional direct cardioprotective effects, and were consistently noted irrespective of gender, race, adiposity, and region [19].

Critical limitations and evidence gaps

The SELECT participants were from a carefully selected group with pre-existing cardiovascular conditions, limiting their relevance to primary preventative scenarios. Despite a median follow-up of 39.8 months being substantial for a cardiovascular trial, it may not adequately reflect long-term safety signals or the sustainability of cardiovascular protection [18,19].

Kidney protection

The FLOW trial assessed semaglutide for renal protection in patients with T2DM and chronic kidney disease (CKD), independent of SGLT2 inhibition. In this multicenter, randomized trial encompassing 3,533 individuals with overt diabetic kidney disease, semaglutide administration correlated with a 24% decline in kidney failure, and a ≥50% decline in estimated glomerular filtration rate, renal death and cardiovascular death. The protective efficacy of semaglutide was consistent across participants treated with and without SGLT2 inhibitor use, with a ratio of 0.73 (P < 0.001) for the composite outcome in both groups [20].

Critical limitations and evidence gaps

Limited representation of SGLT2i users (15.6%) and early termination for efficacy may have biased the results [20]. Given that SGLT2 inhibitors are now standard of care for diabetic kidney disease, the clinical relevance to contemporary practice is uncertain, and the composite endpoint decomposition is unclear. Real-world adherence rates of 39% may substantially limit population-level benefit (Section 5.3).

Emerging clinical applications

Semaglutide shows potential in treating liver disease, addiction, and neurological conditions. However, evidence for these emerging applications ranges from early clinical approval to entirely preliminary, with substantial gaps compared to established metabolic indications.

Metabolic dysfunction-associated fatty liver disease

Semaglutide shows efficacy against Metabolic dysfunction-associated fatty liver disease (MAFLD) and its progressive variant, metabolic dysfunction-associated steatohepatitis (MASH). Phase II trials showed 59% achieved MASH resolution versus 17% of controls [21]. Building on these results, the ESSENCE Phase III trial evaluated 1,197 individuals with biopsy-confirmed MASH and fibrosis (stages 2-3). At 72-week interim analysis, semaglutide (2.4 mg) demonstrated superior efficacy across all endpoints. Steatohepatitis resolved in 63% versus 34% of controls, and fibrosis improved in 37% versus 22% (P < 0.001) [22]. In light of these findings, the FDA approved injectable semaglutide (Wegovy) 2.4 mg in August 2025 for non-cirrhotic MASH with moderate to advanced fibrosis. This is the first approved intervention for this condition.

Addiction disorders

Preliminary research indicates that GLP-1 receptor agonists may decrease consumption of alcohol via dopamine signaling pathways [23]. However, evidence is limited to one small trial (48 participants, 26 weeks), which is insufficient for clinical recommendations [24]. Therefore, off-label use for addiction is premature and needs further research.

Neuroprotection disorders

Early studies show brain protective effects through reduced inflammation and better glucose metabolism [25,26]. Two Phase III trials (EVOKE, EVOKE+) are currently assessing semaglutide in 3,680 Alzheimer's disease (AD) patients over three years; results are anticipated in September 2025 [27]. Nevertheless, historical context demands caution given the fact that 99.6% failure rate in Alzheimer's trials from 2002-2012 [28]. Phase III data must confirm efficacy before clinical application becomes justified.

Safety profile and clinical considerations

Semaglutide demonstrates a satisfactory safety profile, though gastrointestinal side effects are common. Monitoring for significant adverse effects is essential.

Adverse event profile

Gastrointestinal side effects

Gastrointestinal (GI) events that occur in a predictable and dose-dependent manner dominate the safety landscape of semaglutide. These symptoms are generally mild to moderate, self-limiting, and responsive to increasing incremental doses. In PIONEER 1, nausea, vomiting, and diarrhea were more frequent than in placebo, with early withdrawal linked to GI symptoms accounting for discontinuation rates of 2.3% at the 3 mg, 4.0% at the 7 mg, and 7.4% at the 14 mg doses, versus 2.2% with placebo, yet >90% of participants completed treatment [29]. The SELECT trial corroborated the GI-related withdrawal trend (10.0% for semaglutide versus 2.0% for placebo) but reported a lower incidence of serious adverse events with semaglutide (33.4% versus 36.4%), a pancreatitis rate of 0.2% versus 0.3%, and a marginal increase in gallbladder disorders (2.8% versus 2.3%), predominantly in those experiencing a weight reduction exceeding 10% [30].

Cardiovascular and metabolic safety

Meta-analyses of GLP-1 receptor agonists validate their cardiovascular safety, showing no rise in severe hypoglycemia, pancreatitis, or pancreatic cancer [17]. However, infrequent but clinically serious problems require continuous monitoring.

Serious and long-term safety considerations

Diabetic retinopathy

In SUSTAIN-6, semaglutide reduced MACE but increased incidence of complications pertaining to diabetic retinopathy (HR 1.76; 95% confidence interval 1.11–2.78). The clinical necessity of thorough ophthalmologic surveillance in this subgroup was highlighted by the fact that the relative risk was highest among those with a pre-existing retinopathy diagnosis [16]. Population-based analysis also found a slight but statistically significant increase in the risk of neovascular age-related macular degeneration among semaglutide recipients (0.2% versus 0.1% in controls); however, it is unclear whether this finding is due to the drug or confounding environmental or genetic factors [31].

Thyroid cancer risk assessment

The FDA maintains a black-box warning against use in individuals with personal or family histories of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 based on animal studies [32]. However, SUSTAIN-6 reported no cases of medullary thyroid cancer [16], whereas PIONEER-6 recorded one case in a patient with pre-existing nodular disease and increased calcitonin levels [33]. A 2024 systematic review confirmed a thyroid cancer incidence of less than 1% in semaglutide-treated participants and no increased risk in randomized controlled trials [34]. These results indicate that semaglutide is safe and generally well tolerated by most patients. Continuous surveillance is essential to identify adverse effects associated with thyroid disorders.

Real-world effectiveness and adherence challenges

Randomized controlled trials reported completion rates exceeding 90%. In contrast, real-world data reveal significantly lower persistence and adherence. Only 67% of patients continue treatment at 12 months. Adequate adherence reaches only 39% at this timepoint [35]. Table 3 summarizes these key differences between trial efficacy and real-world effectiveness. Several barriers contribute to this gap. Gastrointestinal side effects are the predominant cause for treatment discontinuation. Elevated pharmaceutical expenses and restricted insurance coverage create additional challenges. However, patients who persist achieve impressive outcomes. A U.S. cohort study of 343 adults showed promising results. Patients achieved 15% mean weight loss after treatment with semaglutide 2.4 mg [36]. The WeGoTogether support program reported even stronger outcomes. In this program, weight loss reached 17.6% and 20.4% at 12 and 24 months, respectively. Over half of participants achieved at least 20% weight loss [37].

Table 3.

Efficacy of semaglutide in clinical trials compared to real-world effectiveness.

Parameter	Clinical Trials	Real-World Data	Factors Contributing to Gap	Reference
Treatment Persistence (12 months)	>90% (SUSTAIN)	67%	Cost, GI side effects, and insurance lapses	[35]
Mean Weight Loss	14.9% (STEP-1)	∼10%	Less intensive lifestyle support	[36]
HbA1c Reduction	1.5-1.8% (SUSTAIN)	1.2-1.4%	Baseline differences and adherence	[38]
Discontinuation due to GI	3.5-4.5% (STEP)	∼10-11%	Slower titration in trials and support	[39,40]
Time to Target Dose	16 weeks (STEP)	20-24 weeks	Tolerability and conservative titration	[37]

Strategies for enhancing real-world effectiveness

Three interventions may advance the integration of trial outcomes into clinical practice.

Digital support programs

Digital tools can partly replace the close monitoring done within clinical trials. The WeGoTogether application allows the automation of reminders and tracking tools, and the integration of peer support networks. This approach positively impacts treatment adherence and leads to better weight loss outcomes [37].

Flexible dosing strategies

Individualized titration schedules with flexible dosing strategies tend to improve adherence compared to rigid protocols. SCOPE study results showed significant weight loss in adherent patients, supporting the use of patient-centered dosing strategies [36].

Systematic adherence interventions

Structured support systems significantly impact persistence rates. Programs for insurance navigation and patient assistance help reduce financial barriers. Clinical pharmacist support helps manage side effects [41].

Pharmacogenomics and future precision medicine approaches

Genetic variations may affect semaglutide responsiveness, though findings remain preliminary. For example, the GLP1R rs6923761 polymorphism may affect treatment outcomes. In a pilot trial of 112 severely obese people, homozygous A-allele carriers lost 1.64% per month compared with 1.04% for those with at least 1 G allele (P = 0.03) [42]. Women homozygous for the A allele showed higher reactions than men, indicating potential gender-specific genetic differences [42]. These associations, however, have not been validated in various populations and their clinical utility remains uncertain.

Further genetic variations may distinctively affect glycemic responses compared to weight outcomes. A genome-wide analysis of 4,571 individuals treated with different GLP-1 receptor agonists identified polymorphisms at the ARRB1 locus linked to improved HbA1c reduction; however, the variant rs6923761 was associated with fewer glycemic advantages [43]. These complicated gene-drug interactions explain only minor response variability and require confirmation prior to treatment decisions.

Clinical implementation challenges

Genetic testing lacks standardized methodologies, cost-effectiveness data, and regulatory endorsement. Machine learning utilizing high-dimensional clinical datasets exhibit the potential for response prediction; however, they remain experimental instruments that require further validation [44].

Current clinical recommendation

Genetic testing to guide semaglutide therapy should be considered exploratory. Clinicians should base treatment on recognized clinical criteria such as BMI, diabetes status, cardiovascular risk, and patient preferences, while monitoring emerging evidence for validated genetic biomarkers that may inform future clinical practice.

Strategies for combined therapeutic approaches

Semaglutide, similar to other antidiabetic agents, reduces cardiometabolic risk. For patients with T2DM and obesity, concurrent administration of semaglutide and metformin is the preferred initial therapy, outperforming metformin alone at regulating blood sugar levels, facilitating weight loss, and enhancing insulin efficacy [45]. In patients with concurrent MAFLD, the regimen further reduced hepatic inflammation, favored shifts in fibrosis scores, and enhanced β-cell resilience [46].

Among individuals with high cardiovascular and nephrological risk, pairing semaglutide with sodium–glucose cotransporter-2 inhibitors (SGLT2i) benefits from mechanistic synergy. Meta-analytic evaluations confirm that GLP-1 receptor-mediated cardiometabolic advantages complement the hemodynamic and renal protection of SGLT2i without measurable diminishing of either agent [20,47].

Life-long intensive glycemic control for selected patients can benefit from the combination of semaglutide with basal insulin. This approach not only decreases HbA1c levels but also curtails overall insulin doses, lowering the incidence of hypoglycemic events while stabilizing body weight. This therapy has been endorsed in the 2025 Standards of Care by the American Diabetes Association. SUSTAIN 5 confirmed the efficacy of this regimen, showing that the addition of semaglutide to a stable basal insulin regimen reduced HbA1c levels and body weight relative to placebo, and the associated increase in hypoglycemic episodes did not reach statistical significance [48].

Among very high-risk patients with T2DM, moderate-to-severe chronic kidney disease, and albuminuria, triple therapy with semaglutide, an SGLT2 inhibitor, and the nonsteroidal mineralocorticoid receptor antagonist finerenone, offers the most comprehensive modification of multiple atherosclerotic and nephroprotective pathways. Predictive modeling suggests that this regimen could yield an additional three years of freedom from MACE when benchmarked against current practices [49].

The various combination therapies and their implementations are outlined in Table 4, detailing the specified populations along with clinical outcomes, evidence, and evaluation criteria for each. These strategies mark a drastic shift in the approach toward personalization of treatment designed to enhance not only glycemic levels, but also the wider cardiometabolic health of patients with T2DM.

Table 4.

Framework for clinical adoption of combined semaglutide regimens.

Combination Type	Target Population	Primary Clinical Benefits	Key Evidence	Monitoring Requirements	Reference
Semaglutide + Metformin	First-line treatment for overweight/obese T2DM patients	Improved glycemic regulation Increased weight reduction Enhanced liver inflammation	Systematic review and meta-analysis confirm superior glycemic and metabolic outcomes vs. metformin alone;MAFLD benefit shown in observational studies	HbA1c every 3 months Weight monitoring eGFR assessment Liver function tests	[45,46]
Semaglutide + SGLT2i	High CV/kidney risk patients with T2DM	Independent CV protection Complementary kidney benefits Synergistic weight loss Heart failure risk reduction	FLOW trial and meta-analyses show consistent CV and renal benefits regardless of SGLT2i use	Volume status assessment eGFR and albuminuria Blood pressure monitoring Ketone testing if acutely unwell	[20,47]
Semaglutide + Insulin	Patients requiring intensive glycemic management	Superior glycemic control Weight neutrality or loss Reduced hypoglycemia risk Lower insulin requirements	SUSTAIN 5 trial demonstrates improved glycemic control with semaglutide and insulin combination;ADA guidelines recommend GLP-1 receptor agonists before insulin initiation	Frequent glucose monitoring Insulin dose adjustment Hypoglycemia risk assessment Weight monitoring	[48]
Triple Therapy (Semaglutide + SGLT2i + ns-MRA)	Very high-risk patients with multiple comorbidities (T2DM, CKD, albuminuria)	Maximal CV protection Optimal kidney preservation Comprehensive risk reduction Mortality benefit	Modeling studies estimate +3.2 years MACE-free survival with triple therapy vs. conventional care	Electrolyte checks Kidney function surveillance Blood prussure monitoring	[49]

Economic considerations and healthcare impact

The cost-effectiveness of semaglutide varies by indication. For T2DM, 45 economic evaluations found it cost-effective in 73.9% of cases, with incremental ratios of $40,100/QALY versus liraglutide and $117,500 versus conventional care [50,51]. For obesity, therapy varies from approximately $23,000–$144,500/QALY, below the standard $150,000 willingness-to-pay threshold [52]. Cardiovascular risk reduction produces higher ratios approaching $443,000 per QALY [53].

Population-level data indicates substantial healthcare savings. Following semaglutide treatment, patients with CVD exhibited a 65% reduction in inpatient healthcare costs and a 22% decrease in overall medical expenses, whereas patients with heart failure showed a 28.7% reduction in hospitalizations [54]. International analyses demonstrate that pricing substantially influences adoption, with modeling indicating that a 70% drop in prices would achieve cost-effectiveness in lower-income areas [55].

Saudi Arabia economic perspective

Economic analyses in Saudi Arabia indicate that semaglutide exhibits favorable cost-effectiveness across various studies. Initially, once-weekly semaglutide demonstrated the most favorable cost per patient in achieving HbA¹c targets compared to all GLP-1 receptor agonists [56]. Additionally, Oral semaglutide had minimal budget impact over five years. The net cost increase was only SAR 12.4 million (0.66%) after accounting for savings from better diabetes control and fewer cardiovascular complications [57]. Furthermore, five-year modeling showed semaglutide had the lowest budget impact (US $85.9 million) among GLP-1 agonists. The main savings came from reduced cardiovascular complications [58]. Current research indicates that semaglutide is economically viable for inclusion in the national formulary. This is consistent with the priorities of Vision 2030 regarding the prevention of non-communicable diseases.

Future directions and research priorities

In the future, research on semaglutide will target AD, MASH, and new methods of delivery. Priorities for development will include the integration of personalized medicine with digital health (Fig. 2).

Fig. 2.

Semaglutide Development Timeline and Future Horizons. A timeline illustrating semaglutide's regulatory milestones, beginning with FDA approval for T2DM in 2017, followed by obesity approval in 2021, cardiovascular benefits demonstrated in the SELECT trial (2023), renal protection established in the FLOW trial (2024), and concluding with the significant MASH approval in 2025. The research pipeline for 2025 and beyond includes further Alzheimer's trials and the application of addiction. Improvements in the next generation (2027+) include enhanced delivery methods, precision medical approaches, and integration of digital health. The ultimate aim is systems that provide cumulative clinical impact with multi-organ protection and reduced healthcare costs. This includes personalized therapy guided by biomarkers and genetics, and accessible health services using AI-integrated digital health systems and next-generation delivery platforms.

Enhanced approaches of delivery and combination

Advancements in delivery platforms have extended GLP-1 receptor agonism beyond subcutaneous injection. Future formulations must further simplify administration and enhance gastrointestinal tolerability. Combination regimens are central: co-prescription of semaglutide and SGLT2 inhibitors leverages intersecting cardiovascular and renal protective pathways, whereas novel dual agonists, including GLP-1/GIP constructs, signal expanded metabolic efficacy. Developing fixed combinations will enhance adherence and improve outcomes [47,49].

Precision medicine integration

Developing predictive computational algorithms in decision support systems and population-based testing of genomic anchors will remain a priority. Improvement of treatment outcomes will be achieved with integration of glucose monitoring and automated insulin delivery systems.

Economic accessibility and global equity

Addressing cost barriers remains critical, as detailed in Section 8. Future strategies must prioritize adaptive pricing and outcome-based reimbursement models. Additionally, technology transfer must enable local biosimilar production in resource-constrained regions with the highest metabolic disease burden.

Real-world implementation

Real-world data show reduced healthcare use and costs in high-risk patients [54]. When it comes to adherence and outcomes, real-world practice diverges from clinical trials, necessitating the conduct of long-term studies and the establishment of registries. Ensuring accessible and equitable availability requires

Conclusion

Semaglutide marks a significant advance in metabolic therapy, demonstrating efficacy in T2DM, obesity, and CVD treatment. The 2025 FDA approval for MASH marks the first pharmacological intervention for this condition, expanding its therapeutic scope. Recent findings also point to roles in neurological protection, though the current data remains insufficient for clinical use.

Several limitations constrain semaglutide's widespread implementation. Real-world data revealed significant deficiencies in treatment persistence and adherence, with considerable patient failure rates undermining therapeutic efficacy. Additionally, the unidentified increase in diabetic retinopathy complications requires careful patient monitoring. Rapid weight regain after discontinuation suggests metabolic suppression rather than durable correction. Lastly, high costs create significant access barriers in resource-limited settings where metabolic disease burden is greatest.

Successful future implementation must bridge this gap by enhancing patient support systems, optimizing combination therapy protocols, validating genetic biomarkers for treatment optimization. Additionally, dynamic pricing strategies and evidence-based coverage policies must ensure equitable access.

Funding declaration

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Acknowledgements

The authors knowledge Editage (www.editage.com) for the English language editing.