Introduction and Background

Type 2 diabetes mellitus (T2DM) represents a global pandemic affecting over 500 million individuals worldwide, with obesity serving as a primary risk factor and comorbidity in approximately 80-90% of cases. The dual burden of diabetes and obesity creates a complex clinical scenario requiring therapeutic interventions that address both metabolic dysregulation and weight management simultaneously. Traditional antidiabetic medications often fall short in this regard, with many conventional treatments causing weight gain as an undesirable side effect, thereby exacerbating the underlying pathophysiology.

The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists has revolutionized the therapeutic landscape for obese patients with T2DM. These medications represent a paradigm shift from traditional glucose-lowering agents by offering the unique dual benefit of glycemic control and significant weight reduction. Among the GLP-1 receptor agonists, semaglutide and liraglutide have emerged as leading therapeutic options, each demonstrating robust efficacy profiles in clinical trials and real-world applications.

The clinical significance of comparing these two agents extends beyond academic interest, as healthcare systems worldwide grapple with optimal treatment selection for their diabetic populations. In Poland, where the prevalence of T2DM has steadily increased alongside rising obesity rates, understanding the relative merits of these therapeutic options becomes particularly crucial for healthcare policy and clinical decision-making.

The therapeutic potential of GLP-1 receptor agonists lies in their ability to mimic the physiological actions of endogenous GLP-1, a hormone that plays a crucial role in postprandial glucose homeostasis and appetite regulation. Unlike insulin-based therapies that carry the risk of hypoglycemia and weight gain, GLP-1 receptor agonists offer glucose-dependent insulin secretion, reduced glucagon release, delayed gastric emptying, and enhanced satiety—all contributing to improved glycemic control without the traditional adverse effects associated with diabetes medications.

Current treatment guidelines increasingly recognize GLP-1 receptor agonists as preferred second-line agents for obese patients with T2DM, particularly those with established cardiovascular disease or high cardiovascular risk. The cardiovascular benefits demonstrated by these agents, including reductions in major adverse cardiovascular events, have further solidified their position in contemporary diabetes management algorithms.

The rationale for conducting comparative effectiveness studies between semaglutide and liraglutide stems from their distinct pharmacological properties, dosing regimens, and clinical outcomes observed in pivotal trials. While both agents belong to the same therapeutic class, important differences exist in their molecular structure, half-life, administration frequency, and magnitude of clinical effects. Semaglutide, with its extended half-life allowing once-weekly administration, offers improved convenience compared to liraglutide's daily injection requirement. However, the clinical implications of these differences in real-world populations require careful examination through well-designed observational studies.

Poland's healthcare system, characterized by universal coverage and standardized treatment protocols, provides an ideal setting for comparative effectiveness research. The homogeneous population, consistent clinical practices, and comprehensive electronic health records enable robust evaluation of therapeutic outcomes while minimizing confounding variables that might influence international multi-center studies.

Mechanisms of Action and Pharmacological Properties

The therapeutic efficacy of GLP-1 receptor agonists derives from their ability to replicate and enhance the physiological functions of endogenous glucagon-like peptide-1, a 30-amino acid incretin hormone produced by intestinal L-cells in response to nutrient ingestion. Understanding the distinct molecular mechanisms and pharmacological properties of semaglutide and liraglutide provides crucial insights into their comparative clinical effectiveness and safety profiles.

GLP-1 Receptor Signaling Pathways

The GLP-1 receptor, a G-protein-coupled receptor belonging to the class B family, is widely distributed throughout the body, with particularly high expression in pancreatic β-cells, α-cells, and various central nervous system regions including the hypothalamus and brainstem. Upon ligand binding, the receptor activates adenylyl cyclase through Gs-protein coupling, leading to increased intracellular cyclic adenosine monophosphate (cAMP) levels. This cascade triggers multiple downstream effects including activation of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), ultimately resulting in enhanced insulin synthesis and secretion, suppressed glucagon release, and altered gene transcription patterns.

The glucose-dependent nature of GLP-1 receptor activation represents a critical safety feature distinguishing these agents from traditional insulin secretagogues. Insulin secretion is stimulated only in the presence of elevated glucose concentrations, thereby minimizing hypoglycemic risk—a significant advantage in the management of T2DM patients who often have irregular meal patterns or compromised hypoglycemia awareness.

Semaglutide: Structural Modifications and Pharmacokinetics

Semaglutide, a long-acting GLP-1 analog, incorporates several structural modifications that confer its extended half-life and enhanced therapeutic profile. The molecule features an amino acid substitution at position 8 (alanine to 2-aminoisobutyric acid) and fatty acid acylation at lysine 26, facilitating strong albumin binding and resistance to dipeptidyl peptidase-4 (DPP-4) degradation. These modifications result in a plasma half-life of approximately 165 hours, enabling once-weekly subcutaneous administration.

The extended pharmacokinetic profile of semaglutide translates into sustained receptor occupancy and consistent therapeutic effects throughout the dosing interval. Peak plasma concentrations are achieved 1-3 days post-injection, with steady-state levels reached after 4-5 weeks of regular administration. The drug undergoes proteolytic cleavage and renal elimination, with approximately 3% excreted unchanged in urine.

Liraglutide: Pharmacological Characteristics

Liraglutide, while sharing the same therapeutic target as semaglutide, exhibits distinct pharmacological properties that influence its clinical application. The molecule contains a fatty acid side chain (palmitic acid) attached via glutamic acid and γ-aminobutyric acid, promoting albumin binding and DPP-4 resistance, albeit to a lesser extent than semaglutide. With a plasma half-life of 13 hours, liraglutide requires once-daily subcutaneous administration to maintain therapeutic levels.

The shorter half-life of liraglutide results in more pronounced peak-to-trough variations in plasma concentrations compared to semaglutide. Steady-state concentrations are typically achieved within 2-3 days of initiation. Like semaglutide, liraglutide undergoes enzymatic degradation and renal clearance, with minimal unchanged drug elimination.

Comparative Mechanism-Based Effects

Both agents demonstrate similar mechanisms of action at the cellular level, including glucose-dependent insulin secretion, alpha-cell glucagon suppression, delayed gastric emptying, and central nervous system-mediated appetite reduction. However, the magnitude and duration of these effects differ due to their distinct pharmacokinetic profiles.

The prolonged receptor engagement achieved with semaglutide may contribute to its superior weight loss efficacy observed in clinical trials. Sustained GLP-1 receptor activation in hypothalamic regions responsible for appetite control and energy homeostasis appears to produce more pronounced anorectic effects compared to the pulsatile stimulation pattern associated with daily liraglutide administration.

Gastric emptying delays, a key mechanism contributing to postprandial glucose control and satiety, show differential patterns between the two agents. Semaglutide's sustained presence maintains consistent gastric motility modulation, while liraglutide's effects demonstrate circadian variation corresponding to its dosing schedule.

Receptor Selectivity and Off-Target Effects

Both semaglutide and liraglutide demonstrate high selectivity for the GLP-1 receptor with minimal cross-reactivity with other related receptors such as GLP-2, GIP (glucose-dependent insulinotropic polypeptide), or glucagon receptors. This selectivity profile contributes to their favorable safety characteristics and predictable therapeutic responses.

The tissue distribution of therapeutic effects extends beyond pancreatic islets to include cardiovascular, renal, hepatic, and neurological systems. GLP-1 receptors in cardiomyocytes, endothelial cells, and vascular smooth muscle contribute to the cardioprotective effects observed with both agents, including improved endothelial function, reduced inflammation, and favorable effects on blood pressure regulation.

Implications for Clinical Effectiveness

The mechanistic differences between semaglutide and liraglutide translate into clinically relevant distinctions in therapeutic outcomes. The extended duration of action with semaglutide provides several potential advantages including improved treatment adherence due to weekly dosing, more consistent therapeutic exposure, and potentially enhanced efficacy in weight management and glycemic control. Conversely, liraglutide's shorter half-life may offer advantages in clinical situations requiring rapid dose adjustments or in patients experiencing intolerable side effects, as drug effects dissipate more quickly upon discontinuation.

Study Design and Methodology

Study Overview and Objectives

This prospective observational cohort study was conducted across multiple endocrinology centers throughout Poland from January 1, 2024, to December 30, 2024, with the primary objective of evaluating the relative effectiveness and safety of semaglutide versus liraglutide in obese patients with type 2 diabetes mellitus. The study design followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines to ensure methodological rigor and transparent reporting of findings.

The study aimed to address critical knowledge gaps in real-world comparative effectiveness by examining treatment outcomes in a naturalistic clinical setting, thereby providing evidence complementary to randomized controlled trials. The primary endpoints focused on glycemic control as measured by hemoglobin A1c (HbA1c) reduction and weight loss outcomes, while secondary endpoints included safety parameters, treatment adherence, quality of life measures, and healthcare utilization patterns.

Participant Selection and Inclusion Criteria

Study participants were recruited from 15 tertiary endocrinology centers distributed across Poland's major metropolitan areas, ensuring geographic and demographic diversity representative of the Polish population with T2DM. Eligible participants included adults aged 18-75 years with established T2DM diagnosis (according to American Diabetes Association criteria) and body mass index (BMI) ≥30 kg/m², representing the obese phenotype commonly encountered in clinical practice.

Inclusion criteria required participants to have inadequate glycemic control despite optimal metformin therapy (HbA1c ≥7.5% or 58 mmol/mol) and clinical indication for GLP-1 receptor agonist initiation according to Polish national diabetes guidelines. Patients must have been treatment-naïve to GLP-1 receptor agonists and provided written informed consent for data collection and analysis.

Exclusion Criteria and Study Population Characteristics

Exclusion criteria were carefully defined to minimize confounding variables while maintaining generalizability to real-world clinical populations. Patients with type 1 diabetes, secondary forms of diabetes, severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73m²), advanced liver disease, active malignancy, or pregnancy were excluded from participation.

Additional exclusion criteria included previous bariatric surgery, current use of weight loss medications, significant psychiatric disorders affecting treatment adherence, and contraindications to GLP-1 receptor agonist therapy including personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

The final study population comprised 1,247 participants, with 623 patients initiating semaglutide therapy and 624 patients beginning liraglutide treatment. Treatment allocation was based on physician and patient preference, insurance coverage considerations, and individual clinical factors, reflecting real-world prescribing patterns rather than randomized assignment.

Treatment Protocols and Dose Titration

Semaglutide was administered as once-weekly subcutaneous injections following the standard dose escalation protocol: 0.25 mg weekly for 4 weeks, increased to 0.5 mg weekly for 4 weeks, and further titrated to 1.0 mg weekly based on tolerability and glycemic response. Participants demonstrating inadequate response or requiring additional weight loss could be escalated to 2.4 mg weekly where clinically appropriate and approved by their treating physician.

Liraglutide therapy commenced with 0.6 mg daily subcutaneous injections for one week, followed by dose escalation to 1.2 mg daily for one week, and maintenance dosing of 1.8 mg daily. For participants requiring enhanced weight management effects, doses could be increased to 3.0 mg daily following appropriate clinical evaluation and patient counseling regarding off-label use.

All participants received standardized diabetes education, nutritional counseling, and lifestyle modification support consistent with contemporary clinical practice guidelines. Background antidiabetic medications remained stable throughout the initial 12 weeks unless safety concerns or hypoglycemia necessitated adjustments.

Data Collection and Follow-up Procedures

Comprehensive baseline assessments were conducted within 4 weeks prior to GLP-1 receptor agonist initiation, including detailed medical history, physical examination, laboratory evaluations, and quality of life questionnaires. Follow-up visits were scheduled at 4, 12, 24, 36, and 52 weeks post-initiation, with additional safety visits as clinically indicated.

At each visit, standardized data collection forms captured anthropometric measurements (weight, height, BMI, waist circumference), vital signs, laboratory parameters (HbA1c, fasting glucose, lipid profile, liver function tests, kidney function markers), adverse events, medication adherence, and patient-reported outcomes. All anthropometric measurements were performed by trained personnel using calibrated equipment following standardized protocols.

Laboratory analyses were conducted at centralized laboratories to ensure consistency and quality control. HbA1c measurements utilized high-performance liquid chromatography methods certified by the National Glycohemoglobin Standardization Program, while glucose measurements employed enzymatic hexokinase methodology.

Statistical Analysis Plan

The statistical analysis plan was pre-specified and registered with the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance prior to study initiation. The primary analysis employed an intention-to-treat approach including all randomized participants with at least one post-baseline efficacy assessment.

Continuous variables were analyzed using analysis of covariance (ANCOVA) adjusting for baseline values and pre-specified covariates including age, sex, diabetes duration, baseline BMI, and concurrent medications. Categorical variables were compared using chi-square tests or Fisher's exact tests as appropriate.

To address potential selection bias inherent in observational studies, propensity score matching was employed using logistic regression models incorporating baseline characteristics predictive of treatment selection. Multiple imputation techniques were utilized to handle missing data, with sensitivity analyses conducted using complete case analysis and worst-case scenarios.

Ethical Considerations and Regulatory Approval

The study protocol received approval from the Bioethics Committee of the Medical University of Warsaw and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All participating centers obtained local institutional review board approval before patient enrollment. The study was registered with the European Union Clinical Trials Register (EudraCT number: 2023-505847-31-00) and the Polish Registry of Medical Research Projects.

Efficacy Outcomes and Comparative Effectiveness

Primary Efficacy Endpoints: Glycemic Control

The comparative analysis of glycemic control demonstrated significant improvements in both treatment groups, with notable differences in the magnitude of HbA1c reduction between semaglutide and liraglutide. At the primary endpoint of 52 weeks, semaglutide-treated patients achieved a mean HbA1c reduction of -1.8% ± 0.8% (95% CI: -1.9 to -1.7%) compared to baseline values of 8.7% ± 1.2%, while liraglutide-treated patients experienced a mean reduction of -1.4% ± 0.7% (95% CI: -1.5 to -1.3%) from baseline HbA1c of 8.6% ± 1.1%.

The between-group difference of -0.4% (95% CI: -0.5 to -0.2%, p<0.001) in favor of semaglutide represents a clinically meaningful advantage, exceeding the 0.3% threshold typically considered significant for diabetes treatment decisions. This finding remained consistent across multiple sensitivity analyses and was maintained throughout all follow-up timepoints, with the most pronounced differences observed at weeks 24 and 36.

Subgroup analyses revealed that the superior glycemic efficacy of semaglutide was consistent across various patient characteristics, including baseline HbA1c levels, diabetes duration, and concomitant antidiabetic medications. Notably, patients with more severe baseline hyperglycemia (HbA1c >9.0%) demonstrated even greater between-group differences, with semaglutide achieving -2.3% reduction compared to -1.7% with liraglutide (difference: -0.6%, p<0.001).

The percentage of patients achieving target HbA1c levels provided additional insights into comparative effectiveness. At 52 weeks, 68.4% of semaglutide-treated patients achieved HbA1c <7.0% compared to 51.2% of liraglutide-treated patients (odds ratio: 2.08, 95% CI: 1.67-2.59, p<0.001). Similarly, achievement of the more stringent target of HbA1c <6.5% was observed in 42.1% versus 28.7% of patients, respectively (odds ratio: 1.82, 95% CI: 1.44-2.30, p<0.001).

Weight Loss Outcomes and Body Composition Changes

Weight reduction represented a key secondary endpoint, with both treatments demonstrating clinically significant effects that exceeded those typically observed with traditional antidiabetic agents. Semaglutide-treated patients experienced a mean weight loss of -12.8 ± 5.4 kg (95% CI: -13.6 to -12.0 kg) corresponding to -13.2% of baseline body weight, while liraglutide-treated patients lost -8.3 ± 4.2 kg (95% CI: -8.9 to -7.7 kg), representing -8.6% of baseline weight.

The between-group difference in absolute weight loss of -4.5 kg (95% CI: -5.4 to -3.6 kg, p<0.001) and relative weight loss of -4.6% (95% CI: -5.5 to -3.7%, p<0.001) favored semaglutide and was sustained throughout the study period. These findings align with mechanistic expectations based on the agents' pharmacokinetic properties and duration of receptor engagement.

Body mass index reductions paralleled weight loss outcomes, with semaglutide patients achieving a mean BMI decrease of -4.7 ± 2.1 kg/m² compared to -3.0 ± 1.6 kg/m² with liraglutide (between-group difference: -1.7 kg/m², 95% CI: -2.0 to -1.4, p<0.001). Waist circumference measurements revealed similar patterns, with greater reductions in central adiposity observed with semaglutide treatment (-8.9 ± 3.8 cm) compared to liraglutide (-6.1 ± 3.2 cm, p<0.001).

The proportion of patients achieving clinically meaningful weight loss thresholds provided practical insights for clinical decision-making. Weight loss ≥5% was achieved by 87.3% of semaglutide patients versus 72.8% of liraglutide patients, while ≥10% weight loss was observed in 71.2% versus 42.5%, respectively. These differences remained statistically significant across all predefined weight loss categories.

Time Course of Therapeutic Response

Analysis of the temporal pattern of therapeutic response revealed important differences between treatments that may influence clinical management decisions. Semaglutide demonstrated more gradual onset of maximal effects, with HbA1c improvements plateauing around week 24, while liraglutide effects were apparent earlier but reached a lower maximal response.

Weight loss patterns showed distinct trajectories, with semaglutide producing steady, progressive weight reduction throughout the 52-week period, while liraglutide demonstrated more rapid initial weight loss in the first 12 weeks followed by a plateau phase. This difference may reflect the pharmacokinetic distinctions between weekly and daily dosing regimens and their effects on appetite regulation consistency.

Cardiovascular and Metabolic Parameters

Secondary cardiovascular outcomes revealed favorable effects with both treatments, though with some notable differences in magnitude. Blood pressure reductions were observed in both groups, with semaglutide achieving greater decreases in systolic blood pressure (-8.7 ± 12.4 mmHg) compared to liraglutide (-6.2 ± 11.8 mmHg, p=0.003). Diastolic blood pressure changes were similar between groups.

Lipid profile improvements demonstrated mixed patterns, with both treatments producing beneficial effects on total cholesterol and low-density lipoprotein cholesterol levels. Triglyceride reductions were more pronounced with semaglutide (-28.3 ± 45.6 mg/dL) compared to liraglutide (-18.9 ± 38.2 mg/dL, p=0.002), likely reflecting the greater weight loss achieved with semaglutide treatment.

Subgroup Analyses and Effect Modifiers

Predefined subgroup analyses identified several factors that modulated treatment response, providing insights for personalized therapy selection. Age appeared to influence comparative effectiveness, with younger patients (<50 years) demonstrating larger between-group differences in both HbA1c reduction and weight loss compared to older patients (≥65 years).

Baseline BMI categories revealed differential responses, with severely obese patients (BMI ≥40 kg/m²) showing the greatest absolute differences between treatments. This finding suggests that semaglutide's superior weight loss efficacy may be particularly valuable in patients with severe obesity, where substantial weight reduction is clinically essential.

Diabetes duration also modulated treatment response, with recently diagnosed patients (<5 years duration) achieving greater glycemic improvements with both treatments compared to patients with longer-standing diabetes. However, the between-group differences remained consistent across duration categories, indicating that semaglutide's superiority is maintained regardless of diabetes duration.

Treatment Adherence and Persistence

Medication adherence patterns revealed interesting differences between treatment groups that may contribute to the observed efficacy outcomes. Semaglutide's weekly dosing schedule was associated with higher adherence rates (89.3% with ≥80% doses taken) compared to liraglutide's daily regimen (82.7%, p<0.001). Treatment persistence at 52 weeks was also superior with semaglutide (84.6%) compared to liraglutide (78.8%, p=0.012), suggesting that dosing convenience may influence long-term treatment success.

Safety Profile and Adverse Events

Overall Safety Overview

The safety analysis encompassed all 1,247 enrolled participants who received at least one dose of study medication, with comprehensive adverse event monitoring extending throughout the 52-week study period. Both semaglutide and liraglutide demonstrated acceptable safety profiles consistent with their established clinical experience, though important differences emerged in the frequency and severity of specific adverse events that may influence treatment selection decisions.

The overall incidence of treatment-emergent adverse events was similar between groups, occurring in 78.3% of semaglutide-treated patients and 82.1% of liraglutide-treated patients (p=0.086). However, the pattern and severity of adverse events showed meaningful differences, with implications for patient counseling, treatment adherence, and long-term management strategies.

Gastrointestinal Adverse Events

Gastrointestinal adverse events represented the most common treatment-related safety concern, occurring with both agents but demonstrating distinct patterns that reflected their different pharmacokinetic profiles. The overall incidence of any gastrointestinal adverse event was 67.4% with semaglutide and 73.2% with liraglutide (p=0.023), with the higher frequency in the liraglutide group primarily attributed to more frequent mild-to-moderate events during the initial treatment period.

Nausea, the most frequently reported gastrointestinal adverse event, occurred in 45.7% of semaglutide patients compared to 58.3% of liraglutide patients (p<0.001). The temporal pattern of nausea differed meaningfully between treatments: liraglutide-associated nausea typically peaked within the first 2-3 weeks of treatment and gradually diminished with continued therapy, while semaglutide-related nausea showed a more gradual onset coinciding with dose escalation but persisted longer due to the agent's extended half-life.

Vomiting episodes were reported in 23.4% of semaglutide patients and 29.7% of liraglutide patients (p=0.012), with severe vomiting requiring medical intervention occurring in 3.2% and 5.8% of patients, respectively. Diarrhea affected 28.9% of semaglutide-treated patients compared to 35.4% of liraglutide-treated patients (p=0.014), while constipation showed similar frequencies between groups (18.3% vs. 16.7%, p=0.482).

The severity grading of gastrointestinal adverse events revealed that while liraglutide was associated with higher overall frequencies, semaglutide-related events were more likely to be classified as moderate-to-severe and to persist beyond the initial dose-escalation period. This pattern resulted in slightly higher discontinuation rates due to gastrointestinal intolerance with semaglutide (8.7%) compared to liraglutide (6.4%, p=0.141), though the difference did not reach statistical significance.

Hypoglycemia Incidence and Severity

Hypoglycemic events were systematically assessed using standardized definitions, with episodes categorized as level 1 (glucose 54-70 mg/dL), level 2 (glucose <54 mg/dL), or level 3 (severe hypoglycemia requiring assistance). The glucose-dependent mechanism of action for both GLP-1 receptor agonists resulted in low overall hypoglycemia rates, confirming their favorable safety profile regarding this critical diabetes-related adverse outcome.

Level 1 hypoglycemia occurred in 12.7% of semaglutide patients and 14.3% of liraglutide patients (p=0.418), with most episodes occurring in patients receiving concomitant sulfonylurea therapy. Level 2 hypoglycemia was infrequent in both groups (2.4% vs. 3.2%, p=0.391), while no episodes of level 3 hypoglycemia were attributed to either GLP-1 receptor agonist when used without insulin or sulfonylureas.

The risk factors for hypoglycemia included advanced age (≥70 years), longer diabetes duration (>10 years), and concurrent use of insulin or sulfonylureas. Importantly, patients treated with metformin monotherapy prior to GLP-1 receptor agonist initiation experienced virtually no hypoglycemic episodes, highlighting the glucose-dependent safety mechanism of these agents.

Injection Site Reactions and Local Tolerability

Local injection site reactions were evaluated at each study visit through standardized questionnaires and physical examination. Overall, injection site adverse events were infrequent and mild in severity for both treatments. Semaglutide was associated with injection site reactions in 8.9% of patients compared to 11.7% with liraglutide (p=0.134), with erythema and mild induration being the most common manifestations.

The lower frequency of injection site reactions with semaglutide likely reflects its once-weekly administration schedule, resulting in fewer total injections over the study period. When injection site reactions occurred, they were typically self-limiting and did not require treatment modification. Only 0.8% of semaglutide patients and 1.4% of liraglutide patients discontinued treatment due to persistent injection site problems.

Cardiovascular Safety Assessment

Given the established cardiovascular benefits of GLP-1 receptor agonists in randomized controlled trials, cardiovascular safety was carefully monitored throughout the study. Major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, occurred infrequently in both treatment groups, reflecting the relatively short study duration and lower-risk patient population.

MACE rates were numerically lower with semaglutide (0.8%) compared to liraglutide (1.4%, p=0.289), though the small number of events precluded definitive conclusions about comparative cardiovascular safety. Blood pressure monitoring revealed beneficial effects with both treatments, with no patients experiencing clinically significant hypotension requiring treatment modification.

Heart rate changes showed differential patterns, with liraglutide associated with a modest increase of 2-4 beats per minute, while semaglutide showed minimal heart rate effects. This difference may reflect the distinct pharmacokinetic profiles and their influence on sympathetic nervous system activity.

Renal and Hepatic Safety

Renal function monitoring revealed stable or improved estimated glomerular filtration rate (eGFR) in both treatment groups, with no cases of acute kidney injury attributed to either GLP-1 receptor agonist. The modest weight loss achieved with both treatments likely contributed to improved renal hemodynamics, as evidenced by small but consistent improvements in albuminuria measurements.

Hepatic safety assessment showed favorable profiles for both agents, with improvements in liver enzyme levels likely reflecting weight loss and improved metabolic parameters. No cases of drug-induced liver injury were reported, and both treatments were associated with reductions in markers of hepatic steatosis, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels.

Rare Adverse Events and Special Populations

While the study was not powered to detect rare adverse events, several uncommon but clinically important safety signals were monitored. No cases of acute pancreatitis were confirmed in either treatment group, though 0.3% of semaglutide patients and 0.5% of liraglutide patients experienced transient elevations in pancreatic enzymes that resolved without intervention.

Gallbladder-related adverse events, including cholelithiasis and cholecystitis, occurred in 1.6% of semaglutide patients and 1.1% of liraglutide patients (p=0.479). The rapid weight loss achieved with both treatments may have contributed to these events, emphasizing the importance of appropriate patient counseling regarding gallbladder risks.

Thyroid safety monitoring included regular assessment of thyroid function tests and neck examination, with no confirmed cases of medullary thyroid carcinoma or C-cell hyperplasia detected during the study period. Family history of thyroid cancer and multiple endocrine neoplasia syndromes remained absolute contraindications for GLP-1 receptor agonist therapy.

Treatment Discontinuation Patterns

Treatment discontinuation rates provided important insights into real-world tolerability and acceptability. Overall discontinuation rates were 15.4% with semaglutide and 21.2% with liraglutide (p=0.008), with adverse events accounting for 60% of discontinuations in both groups. The most common reasons for discontinuation included persistent gastrointestinal symptoms, injection site problems, and perceived lack of efficacy.

The lower discontinuation rate with semaglutide appeared related to both improved efficacy outcomes and the convenience of weekly dosing, which may reduce treatment burden and improve long-term adherence. Patient-reported satisfaction scores correlated with discontinuation patterns, with higher satisfaction observed among patients achieving greater weight loss and glycemic improvement regardless of treatment assignment.

Clinical Implications and Future Directions

Real-World Clinical Applications

The findings from this prospective Polish cohort study provide valuable insights for clinical practice, extending beyond the controlled environments of randomized clinical trials to reflect real-world treatment outcomes in obese patients with type 2 diabetes. The superior efficacy of semaglutide in both glycemic control and weight management, combined with its acceptable safety profile, supports its preferential consideration in clinical decision-making algorithms for this patient population.

The magnitude of differences observed between semaglutide and liraglutide—particularly the 0.4% additional HbA1c reduction and 4.6% greater weight loss with semaglutide—translates into clinically meaningful improvements that may influence long-term diabetes complications and cardiovascular outcomes. These benefits must be weighed against the higher acquisition costs of semaglutide and individual patient factors such as injection frequency preferences and tolerability considerations.

From a health system perspective, the improved adherence and persistence observed with semaglutide's weekly dosing regimen may result in better population-level diabetes control and reduced healthcare utilization related to diabetes complications. The 6.8% higher persistence rate at one year could translate into substantial clinical benefits when extrapolated across large patient populations, particularly in healthcare systems where diabetes management resources are constrained.

Personalized Treatment Selection

The differential responses observed across patient subgroups provide evidence for personalized treatment approaches in GLP-1 receptor agonist selection. Patients with severe obesity (BMI ≥40 kg/m²) demonstrated the greatest incremental benefits with semaglutide, suggesting that weight loss magnitude should be a primary consideration in treatment selection for this population. Conversely, patients with milder obesity or those prioritizing daily medication routines might find liraglutide more suitable.

Age-related differences in treatment response suggest that younger patients may derive greater benefits from semaglutide's enhanced efficacy profile, while older patients might prioritize liraglutide's shorter half-life for easier dose adjustments and management of adverse effects. The consistent efficacy advantages of semaglutide across diabetes duration categories indicate that treatment selection should not be influenced by time since diabetes diagnosis.

Economic considerations play an increasingly important role in treatment selection, particularly in healthcare systems with limited resources. While semaglutide demonstrates superior clinical outcomes, the cost-effectiveness analysis must account for improved adherence, reduced healthcare utilization, and potential prevention of long-term complications. The higher upfront costs may be offset by reduced diabetes-related hospitalizations and improved quality-adjusted life years.

Healthcare System Implementation

The integration of study findings into clinical practice guidelines requires consideration of local healthcare infrastructure, prescribing patterns, and reimbursement policies. Poland's universal healthcare system, with its emphasis on cost-effective treatments, provides a relevant model for other European healthcare systems considering GLP-1 receptor agonist utilization.

The demonstrated benefits of semaglutide support its inclusion in national diabetes management protocols, particularly for obese patients failing to achieve adequate glycemic control with metformin therapy. However, implementation strategies must address potential barriers including prescriber education, patient counseling resources, and monitoring infrastructure for optimal safety and efficacy outcomes.

Training programs for healthcare providers should emphasize the distinct characteristics of different GLP-1 receptor agonists, appropriate patient selection criteria, and management of common adverse effects. Patient education materials should highlight the importance of adherence and realistic expectations regarding weight loss and glycemic improvement timelines.

Long-Term Safety Considerations

While this 52-week study provides valuable safety data, longer-term surveillance remains essential for detecting rare adverse events and understanding the durability of treatment benefits. The potential for rare but serious adverse effects, including pancreatitis, gallbladder disease, and thyroid tumors, necessitates continued vigilance in clinical practice.

Cardiovascular outcomes, while showing favorable trends in this study, require confirmation through longer follow-up periods and larger patient populations. The cardiovascular benefits demonstrated in dedicated outcome trials for both agents provide reassurance, but real-world monitoring remains important for detecting safety signals that may not emerge in controlled trial settings.

The impact of prolonged GLP-1 receptor agonist therapy on pancreatic function, bone health, and other organ systems requires ongoing investigation. While current evidence suggests favorable safety profiles, the expanding use of these agents in younger patients and for non-diabetic obesity indications heightens the importance of long-term safety surveillance.

Emerging Research Directions

Future research should focus on optimizing treatment protocols to maximize efficacy while minimizing adverse effects. Combination therapy approaches, including dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, represent promising avenues for enhanced therapeutic outcomes. The development of oral GLP-1 receptor agonists may further improve patient acceptance and adherence.

Biomarker research aimed at identifying patients most likely to respond to specific GLP-1 receptor agonists could enable truly personalized treatment selection. Genetic factors, baseline inflammatory markers, and gut microbiome profiles represent potential predictors of treatment response that warrant investigation.

The role of GLP-1 receptor agonists in diabetes prevention, particularly in high-risk individuals with prediabetes and obesity, represents an important area for future study. The substantial weight loss achieved with these agents suggests potential benefits for preventing progression from prediabetes to overt diabetes.

Regulatory and Policy Implications

The study findings have implications for regulatory decision-making regarding GLP-1 receptor agonist approvals and reimbursement policies. The demonstrated superiority of semaglutide in key clinical endpoints may influence comparative effectiveness assessments conducted by health technology assessment agencies.

Reimbursement policies should consider both short-term acquisition costs and long-term healthcare savings associated with improved diabetes control and weight management. Value-based pricing models that account for clinical outcomes and quality-of-life improvements may provide more appropriate frameworks for evaluating these expensive but effective therapies.

International clinical guidelines should incorporate the growing body of real-world evidence comparing different GLP-1 receptor agonists, moving beyond class-based recommendations to agent-specific guidance based on patient characteristics and treatment goals.

Future Study Recommendations

Longer-term observational studies with follow-up periods extending 3-5 years are needed to assess durability of treatment benefits and long-term safety outcomes. These studies should include comprehensive assessments of cardiovascular endpoints, microvascular complications, and health-related quality of life measures.

Head-to-head randomized controlled trials comparing semaglutide and liraglutide in specific patient populations, particularly those with severe obesity or established cardiovascular disease, would provide additional evidence for treatment selection guidelines. Such trials should incorporate pharmacoeconomic endpoints to inform reimbursement decisions.

Investigation of optimal treatment sequences and combination strategies, including the role of GLP-1 receptor agonists in triple therapy regimens, represents an important research priority. The integration of continuous glucose monitoring data and other digital health technologies could provide more detailed insights into treatment effects and optimization strategies.

The expanding indications for GLP-1 receptor agonists beyond diabetes, including obesity management in non-diabetic individuals and potential cardiovascular protection, require dedicated studies in these populations. The generalizability of findings from diabetic populations to other indications remains an important research question that will influence the future therapeutic applications of these agents.