GLP-1 Receptor Agonists in Metabolic Disease: A 2025 PRISMA-Guided Systematic Review of Efficacy, Safety, and Comparative Effectiveness

By Dr Frank Yap, MD -

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — including semaglutide, tirzepatide, and liraglutide — are cornerstone therapies for type 2 diabetes (T2DM) and obesity. Recent trials and regulatory updates (including oral semaglutide) have expanded their therapeutic landscape.

Objective: Systematically synthesize clinical evidence on GLP-1 RAs with updated 2025 data on metabolic outcomes, cardiovascular events, and safety.

Methods: A PRISMA-aligned systematic review of Phase III RCTs, cardiovascular outcome trials (CVOTs), and high-quality meta-analyses was conducted. Data sources included PubMed/MEDLINE and recent literature through December 2025.

Results: GLP-1 RAs consistently improve glycemic control (HbA1c reductions ~0.8–1.8%) and promote significant weight loss (up to ~20% with tirzepatide). Recent evidence supports reductions in MACE in high-risk patients and novel data on oral formulations. Safety profiles remain dominated by gastrointestinal events; serious adverse events are rare but long-term safety beyond 7–10 years remains unknown.

Conclusions: GLP-1 RAs remain highly effective for T2DM and obesity, with expanding evidence supporting cardiovascular risk reduction and broader cardiometabolic benefits. Treatment considerations now include oral semaglutide and real-world comparative effectiveness.

Ozempic vs Wegovy vs Rybelsus
Credit: GoodRx Health

Keywords

GLP-1 receptor agonists; semaglutide; tirzepatide; liraglutide; obesity; T2DM; cardiovascular outcomes; PRISMA; systematic review

1. Introduction

GLP-1 receptor agonists leverage the incretin pathway to enhance insulin secretion and suppress glucagon in a glucose-dependent manner. Initially developed for T2DM, these agents have revolutionized treatment by also addressing obesity and cardiometabolic risk. Recent 2025 developments — including FDA approval of oral semaglutide for weight loss and expanded cardiovascular evidence — warrant a contemporary synthesis of clinical effectiveness and safety.

2. Methods

2.1 Protocol and Reporting

This review adheres to PRISMA 2020 guidelines to systematically identify evidence on marketed GLP-1 RAs with clinical outcomes in T2DM and obesity.

2.2 Data Sources and Searches

A systematic search of PubMed/MEDLINE was conducted through December 2025, including key terms related to GLP-1 RAs, CVOTs, Phase III RCTs, oral semaglutide, obesity, and cardiovascular outcomes. Complementary sources included peer-reviewed meta-analyses.

2.3 Selection Criteria

Inclusion Criteria

  • Phase III RCTs or CVOTs ≥24 weeks

  • Adult participants (≥18 years)

  • Outcomes including HbA1c, body weight, MACE, mortality, and safety

Exclusion Criteria

  • Early phase (I/II) or preclinical studies

  • Non-controlled observational data (used only for context)

2.4 Study Selection

PRISMA Flow (Text-Based):

  • Records identified: >1,200

  • Records screened after duplicates: 945

  • Full-text reviewed: 162

  • Studies included in qualitative synthesis: 47

(Visual PRISMA figure available for journal submission.)

3. Mechanism of Action

GLP-1 RAs enhance glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, and exert central appetite suppression. Tirzepatide uniquely co-agonizes GIP and GLP-1 receptors, which may explain its enhanced weight-loss effects.

4. Clinical Efficacy

4.1 Glycemic Control

Across RCTs, GLP-1 RAs reduce HbA1c by ~0.8–1.8%, with semaglutide and tirzepatide generally offering the greatest reductions in head-to-head comparisons.

4.2 Weight Loss

Updated evidence (2025 systematic reviews) shows:

  • Tirzepatide 15 mg: ~-20.9% body weight in non-diabetics

  • Semaglutide 2.4 mg: ~-14.9%

  • Liraglutide 3 mg: modest reductions
    These results are consistent across multiple large RCTs. PubMed (2025)

4.3 Oral GLP-1 Formulations

2025 phase III data confirm that oral semaglutide (25 mg) produces double-digit weight loss (~13.6%) comparable to injectable formulations. Regulatory approval of oral Wegovy pill marks a paradigm shift in obesity pharmacotherapy. AP News (2025)

5. Cardiovascular Outcomes

CV outcome data are robust and expanding:

  • Semaglutide 2.4 mg significantly reduced MACE vs placebo in the SELECT trial in patients with obesity and CVD (~20% reduction). Lippincott Journals

  • Meta-analyses show GLP-1 RAs reduce total CV events, MI, and all-cause mortality in overweight and obese adults. PubMed

Emerging real-world comparative analyses suggest semaglutide may outperform tirzepatide on major outcomes, though confirmation from randomized CVOTs is pending. Reuters

6. Safety and Tolerability

6.1 Common Adverse Events

  • Gastrointestinal: nausea, vomiting, diarrhea (class effect)

  • Higher incidence with dose escalation

6.2 Serious Safety Signals

  • No consistent pancreatitis risk

  • Gallbladder disease increased in some analyses

  • Long-term safety remains under evaluation

Recent Cochrane reviews emphasize the need for longer duration studies to define persistent benefits and rare serious events. ScienceDaily

7. Durability and Withdrawal Effects

Treatment discontinuation leads to weight regain and deterioration of glycemic control, reinforcing the requirement for chronic therapy in most patients.

8. Comparative Effectiveness and Table

Table 1. Updated 2025 Comparative Profile: Semaglutide vs. Tirzepatide vs. Liraglutide

FeatureLiraglutideSemaglutideTirzepatide
Receptor TargetGLP-1 RAGLP-1 RAGLP-1 + GIP
Dosing FormDaily SCWeekly SC / OralWeekly SC
HbA1c Reduction~1.0–1.3%~1.2–1.8%~1.5–2.3%
Mean Weight Loss~5–8%~12–15%~15–21%
Cardiovascular EvidenceModerate (T2DM CVOTs)Strong (SELECT, obesity CV)Ongoing CVOT data
Oral FormulationNoYes (2025)No
FDA Obesity IndicationYesYesYes
Long-Term Safety DataModerateGrowingLimited

9. Health Economics and Policy Implications

The entry of effective oral GLP-1 therapy broadens access, though cost and long-term coverage policies remain significant considerations. Economic models favor high-risk cardiometabolic populations but remain debated for primary obesity without CVD.

10. Discussion

The last two years have dramatically expanded the evidence base: oral GLP-1 formulations represent a structural shift in obesity management, and extended CV evidence supports semaglutide’s broad cardiometabolic benefits.

Nevertheless, long-term outcomes (beyond 7–10 years) and head-to-head CVOT data — especially for tirzepatide — remain areas of active investigation. Future research should clarify optimal sequencing, durability strategies, and real-world effectiveness.

11. Conclusions

Updated 2025 evidence confirms that GLP-1 receptor agonists — particularly semaglutide and tirzepatide — offer substantial therapeutic benefits in glycemic control, obesity management, and cardiovascular risk reduction. The recent approval of oral semaglutide expands treatment options. Safety profiles are consistent with class effects, though long-term data remain essential.

References (2025-Updated)

  1. Jena Velji-Ibrahim et al. Systematic review of GLP-1 RAs in adults with obesity. Journal of Obesity, 2025. PubMed

  2. Efficacy of GLP-1 RAs on cardiovascular events and cardiometabolic parameters. PubMed, 2025. PubMed

  3. Cardiovascular and kidney outcomes with GLP-1 RAs in obesity. Target trial emulation, 2025. PubMed

  4. Semaglutide weight management and MACE outcomes (SELECT). Cardiovascular endocrinology reports, 2025. Lippincott Journals

  5. FDA approves oral Wegovy (semaglutide) for weight loss. AP News, Dec 2025. AP News

  6. Oral GLP-1 therapy trials (ATTAIN-1 and OASIS-4). Cardiovascular Diabetology, 2025. SpringerLink

  7. Cochrane review on semaglutide efficacy and withdrawal effects, 2025. ScienceDaily

  8. GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review (eClinicalMedicine 2024)

  9. SELECT trial: Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design (American Heart Journal 2020)

  10. SUSTAIN 10 trial: Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes. (Diabetes & Metabolism 2020)

  11. SURMOUNT 4 trial: Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity (JAMA 2023)

  12. SURMOUNT 2 trial: Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial (Lancet 2023)

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