Metformin in 2025: Still the King or Time to Step Aside?

Abstract

Metformin has reigned as the first-line therapeutic option for type 2 diabetes mellitus for over six decades, earning its moniker as the “king” of anti-diabetic medications. As we advance through 2025, the diabetes treatment landscape has evolved dramatically with the emergence of novel therapeutic classes, including GLP-1 receptor agonists and SGLT2 inhibitors, which offer compelling cardiovascular and renal benefits. This analytical paper critically examines Metformin’s current position in diabetes care, evaluating its continued dominance against mounting challenges from innovative therapies. Through a comprehensive analysis of recent clinical evidence, safety profiles, mechanistic understanding, and cost-effectiveness data, we explore whether Metformin retains its foundational role or faces potential displacement in modern diabetes management paradigms. Most national, regional, and international guidelines recommend Metformin as a foundation therapy, yet utilization of GLP-1 receptor agonists and SGLT-2 inhibitors has markedly increased, aligning with evolving guidelines that emphasize cardiovascular and chronic kidney disease management. While Metformin remains the most frequently initiated treatment, this analysis reveals a nuanced picture in which its role may be evolving rather than ending, requiring a reassessment of its position in contemporary diabetes care algorithms.

Keywords: Metformin, type 2 diabetes, GLP-1 receptor agonists, SGLT2 inhibitors, diabetes guidelines, cardiovascular outcomes

1. Introduction

The landscape of type 2 diabetes management stands at a crossroads in 2025. For over six decades, Metformin has maintained its status as the cornerstone of diabetes therapy, demonstrating an unprecedented combination of efficacy, safety, and affordability. In the field of diabetes, Metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time as a valuable tool for the prevention and management of type 2 diabetes. However, the therapeutic paradigm has shifted dramatically with the introduction of newer drug classes that offer benefits extending beyond glycemic control.

The question of Metformin’s continued dominance has become increasingly pertinent as usage of GLP-1 receptor agonists and SGLT-2 inhibitors increased exponentially from 2014 to 2022. GLP-1 receptor agonist use increased from below 2.5%-21%. While SGLT-2 inhibitor use increased from less than 2.5% to 14%, representing a fundamental shift in prescribing patterns that challenges Metformin’s traditional supremacy.

This analytical exploration seeks to provide a neutral, evidence-based examination of Metformin’s current position, addressing several critical questions: Does Metformin’s established track record justify its continued primacy? Can newer agents with superior cardiovascular and renal outcomes challenge Metformin’s foundational role? What factors will ultimately determine the future hierarchy of diabetes therapeutics?

Research Framework

This analysis employs a comprehensive evaluation framework examining multiple dimensions of therapeutic value:

Clinical Efficacy and Guidelines Adherence: Assessment of current guideline recommendations and real-world prescribing patterns
Safety Profiles: Comparative evaluation of adverse events and long-term safety considerations
Pleiotropic Effects: Analysis of benefits beyond glycemic control
Economic Considerations: Cost-effectiveness and accessibility factors
Future Therapeutic Paradigms: Emerging evidence and shifting treatment philosophies

The objective is not to advocate for or against Metformin, but rather to provide a balanced analytical perspective that acknowledges both the drug’s enduring strengths and the legitimate challenges posed by therapeutic innovation.

2. The Enduring Foundation: Metformin’s Current Status

2.1 Guideline Recommendations and Clinical Positioning

Despite the influx of novel therapeutic options, Metformin’s position in clinical guidelines remains remarkably stable. Most national, regional, and international guidelines recommend Metformin as a foundation therapy, emphasizing the avoidance of therapeutic inertia and the early attainment of multiple treatment goals. The 2024 American Diabetes Association Standards of Care continue to support Metformin’s first-line status, reinforcing decades of evidence-based recommendations.

However, adherence to the guidelines reveals a more complex picture. Of 40 150 patients with incident type 2 diabetes, 38.5% initiated glucose-lowering medication within 1 year, with Metformin remaining the most used medication from 2014 to 2022. This data suggests that while Metformin maintains its dominant position, significant therapeutic inertia exists in diabetes management.

2.2 Real-World Prescribing Patterns

Recent real-world evidence provides insight into Metformin’s practical application in contemporary diabetes care. From 2014 to 2022, use of GLP-1 receptor agonists and SGLT-2 inhibitors increased exponentially, yet this growth has largely occurred as add-on therapy rather than replacing metformin monotherapy. This growth coincided with a decline in sulfonylurea usage, suggesting that newer agents are displacing older second-line options rather than challenging Metformin’s foundational role.

The persistence of Metformin’s dominance despite therapeutic innovation reflects several factors:

Clinical Inertia: Healthcare provider familiarity and comfort with established therapy
Economic Considerations: Cost advantages in resource-constrained healthcare systems
Safety Profile: Well-established risk-benefit ratio with decades of real-world data
Guideline Support: Continued first-line recommendations from major diabetes organizations

2.3 Mechanistic Understanding and Pleiotropic Effects

The mechanistic understanding of Metformin has evolved significantly, revealing a drug far more complex than initially appreciated. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thereby increasing the AMP/ATP ratio and subsequently activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP-1 release, and altering microRNA expression.

Beyond glycemic control, Metformin demonstrates remarkable pleiotropic properties. The latest discoveries have revealed mechanisms underlying the anti-atherosclerotic, hypotensive, and anticancer actions of Metformin, as well as its impact on venous endothelial function. The pleiotropic actions of Metformin include effects on the plasma lipid profile, decreased oxidative stress, and increased plasma fibrinolytic activity. These diverse effects position metformin as more than a glucose-lowering agent, potentially explaining its enduring clinical value.

Recent research has identified additional mechanisms of action, including pleiotropic effects such as suppressing cancer growth and attenuating cell oxidative stress and inflammation. However, the underlying mechanisms of these effects remain to be explored. The ongoing discovery of new mechanisms of action for Metformin suggests that our understanding of this venerable drug remains incomplete, potentially underestimating its clinical value.

3. The Emerging Challengers: GLP-1 Agonists and SGLT2 Inhibitors

3.1 Cardiovascular Revolution

The introduction of GLP-1 receptor agonists and SGLT2 inhibitors has fundamentally altered the diabetes treatment paradigm by demonstrating significant cardiovascular and renal benefits. Sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD.

This cardiovascular benefit represents a paradigm shift in diabetes care. Although some guidelines have challenged the role of Metformin as the first-line glucose-lowering drug, it is important to note that the cardiovascular-renal protective effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were observed in patients with type 2 diabetes, the majority of whom were treated with Metformin. This observation raises important questions about whether the cardiovascular benefits of newer agents are independent of or synergistic with metformin therapy.

3.2 Synergistic Combination Therapy

Rather than replacing Metformin, emerging evidence suggests that newer agents may achieve optimal benefits when used in combination with Metformin. The SGLT2 inhibitors (SGLTis) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Furthermore, in real-world conditions, the GLP-1RA/SGLT2i combination reduced cardiovascular and renal outcomes compared with either GLP-1RA or SGLT2i monotherapy.

The combination approach suggests a complementary rather than competitive relationship between Metformin and newer agents. The combined group had a significantly lower risk of all-cause mortality than SGLT2i monotherapy (aHR = 0.53) and GLP-1RAs monotherapy (aHR = 0.43) after a mean follow-up of 2.4 years. The combined group showed a lower risk of MAKE than SGLT2i monotherapy (aHR = 0.70) and GLP-1RAs monotherapy (aHR = 0.45).

3.3 Adoption Barriers and Clinical Reality

Despite the compelling evidence for newer agents, adoption rates remain surprisingly modest. However, overall adoption rates of these medications remain low based on the indicated populations. Several factors contribute to this therapeutic gap:

Economic Barriers: The high costs of acquiring GLP-1 receptor agonists and SGLT2 inhibitors, along with inconsistent insurance coverage and budgetary limitations in publicly funded or resource-constrained healthcare systems, greatly restrict broad accessibility.
Clinical Complexity: Starting new anti-diabetic medications necessitates meticulous patient selection. This typically includes assessing cardiovascular risk, renal function, comorbidities, and potential adverse effects. This requirement for personalised risk–benefit assessment increases the burden of clinical decision-making and may deter routine implementation in high-traffic practice environments.
Provider Education: Many clinicians face learning curves when prescribing newer therapeutic classes. Limited exposure during training, time constraints, and inconsistent guideline implementation can delay integration into everyday practice.
Patient Factors: Some patients may struggle to accept and adhere to newer medications, depending on factors such as side effects, delivery method, and treatment preferences.

4. Safety Considerations and Risk-Benefit Analysis

4.1 Metformin Safety Profile: Separating Myth from Reality

The safety profile of Metformin has been extensively scrutinized, with particular attention to the risk of lactic acidosis. However, the reported incidence of lactic acidosis in clinical practice has been very low (<10 cases per 100,000 patient-years). Furthermore, real-world evidence has confirmed the glucose-lowering and cardiovascular-renal benefits of Metformin, accompanied by an extremely low risk of lactic acidosis.

Recent research has challenged traditional contraindications to metformin use. In patients with heart failure, although the underlying condition can predispose to lactic acidosis, existing evidence suggests that metformin use is associated with improved outcomes rather than increased risk. Additionally, in patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15-30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular-renal events compared with metformin persistence.

4.2 Lactic Acidosis: Clinical Reality vs. Perceived Risk

The relationship between metformin and lactic acidosis represents one of the most misunderstood aspects of diabetes pharmacotherapy. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion) are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, Metformin has been contraindicated in moderate and severe renal impairment.

However, systematic reviews have provided reassurance regarding the safety of Metformin. There is no evidence from prospective comparative trials or observational cohort studies that Metformin is associated with an increased risk of lactic acidosis or increased lactate levels compared to other anti-hyperglycemic treatments. This evidence suggests that concerns about lactic acidosis may be disproportionate to actual clinical risk in appropriately selected patients.

4.3 Comparative Safety with Newer Agents

While Metformin’s safety profile is well-established, newer agents present different safety considerations. GLP-1 receptor agonists are associated with gastrointestinal adverse effects and potential pancreatitis risk, while SGLT2 inhibitors carry risks of genital infections, diabetic ketoacidosis, and Fournier’s gangrene. The long-term safety implications of these newer agents remain under investigation, in contrast to Metformin’s decades of real-world safety data.

5. Economic Considerations and Healthcare System Impact

5.1 Cost-Effectiveness Paradigms

The economic dimension of diabetes therapeutics presents a complex landscape where cost considerations extend beyond drug acquisition costs to include long-term complications, healthcare utilization, and quality-adjusted life years. Metformin’s generic availability provides significant cost advantages, particularly in resource-constrained healthcare systems where newer agents may be prohibitively expensive.

The economic value proposition of Metformin versus newer agents requires consideration of multiple factors:

Direct Drug Costs: Generic Metformin versus branded newer agents
Complication Prevention: Long-term cardiovascular and renal benefits
Healthcare Utilization: Hospitalization rates and emergency interventions
Quality of Life: Patient-reported outcomes and functional status

5.2 Global Access and Healthcare Equity

From a global health perspective, Metformin’s affordability and widespread availability make it an irreplaceable component of diabetes care in low- and middle-income countries. The World Health Organization’s inclusion of Metformin in the Essential Medicines List reflects its fundamental importance for global diabetes management. Newer agents, despite their clinical benefits, remain largely inaccessible to substantial portions of the global diabetic population due to cost considerations.

5.3 Value-Based Care Models

The evolution toward value-based healthcare models complicates the economic evaluation of diabetes therapeutics. While newer agents may demonstrate superior clinical outcomes in specific populations, their cost-effectiveness varies significantly based on patient characteristics, comorbidities, and healthcare system structures. Metformin’s established cost-effectiveness profile across diverse populations maintains its economic attractiveness in many clinical scenarios.

6. The Pre-diabetes Frontier

6.1 Prevention vs. Treatment Paradigms

The role of Metformin in pre-diabetes management represents an area where its position remains largely unchallenged. Metformin is currently the only anti-diabetic medication for pre-diabetes recommended by the American Diabetes Association (ADA). The Diabetes Prevention Trial demonstrated Metformin’s efficacy in delaying progression from pre-diabetes to diabetes, establishing a unique preventive role that newer agents have yet to match.

Recent research has attempted to optimize Metformin dosing for pre-diabetes management. Compared to dose groups of 500 mg/d, 850 mg/d, 1000 mg/d, 1500 mg/d, 1700 mg/d, and 2000 mg/d, a dosage of 750 mg/d of Metformin significantly reduced the incidence of diabetes in patients… our findings suggest that a daily dosage of 750 mg of Metformin may represent the optimal dose for controlling the progression from pre-diabetes to diabetes.

6.2 Global Pre-diabetes Management

The global burden of pre-diabetes continues to expand, with Metformin remaining the primary pharmacological intervention for high-risk individuals. Currently, there are no global guidelines for managing pre-diabetes. However, the use of Metformin in pre-diabetes is largely based on clinical experience, and there is a lack of high-quality evidence-based medicine. This evidence gap presents both challenges and opportunities for Metformin’s role in diabetes prevention.

7. Mechanistic Insights and Future Potential

7.1 Evolving Understanding of Metformin Action

The mechanistic understanding of Metformin continues to evolve, revealing new therapeutic possibilities. Metformin is a synthetic biguanide used as an anti-diabetic drug in type 2 diabetes mellitus… In addition, Metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. These emerging applications suggest that Metformin’s therapeutic potential extends far beyond diabetes management.

Recent research has identified novel mechanisms of metformin action. Meanwhile, it is understood that microbiota, nutrients, and Metformin can interact through the gut-brain-kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation, and energy metabolism. The gut microbiome interaction represents a particularly intriguing area of investigation that may explain some of Metformin’s pleiotropic effects.

7.2 Anti-Aging and Longevity Research

Perhaps the most provocative area of metformin research involves its potential anti-aging effects. Continuously emerging epidemiological data and experimental models are showing additional protective effects of Metformin against many age-related diseases (ARDs), e.g., cardiovascular diseases and cancer. This evidence has prompted the design of a specific trial, i.e., the Targeting Aging with Metformin (TAME) trial, to test Metformin as an anti-ageing molecule.

However, recent evidence has raised questions about Metformin’s anti-aging potential. Metformin has generally not demonstrated its anticipated benefits in most clinical trials in nondiabetic populations… A contemporary evaluation of this literature reveals emerging uncertainty about the anti-aging potential of Metformin. This uncertainty highlights the importance of continued research to clarify Metformin’s broader therapeutic potential.

7.3 Novel Formulations and Delivery Systems

Innovation in metformin formulation and delivery represents another frontier for maintaining therapeutic relevance. An investigational delayed-release metformin currently under development could provide a treatment option for patients with renal impairment pending the results of future studies. Such developments could expand Metformin’s clinical utility and address some of its current limitations.

8. Limitations and Challenges

8.1 Gastrointestinal Tolerance and Patient Experience

Metformin’s gastrointestinal side effects remain a significant limitation affecting patient adherence and quality of life. While these biological changes contribute to the multisystem effects of Metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency. These tolerability issues contrast with those of the newer, better-tolerated agents, particularly regarding gastrointestinal symptoms.

8.2 Vitamin B12 Deficiency Concerns

Long-term metformin use is associated with vitamin B12 deficiency, a consideration that requires ongoing monitoring. Long-term MET treatment may result in reduced serum vitamin B12 levels, a condition that increases with age… The NHANES (1990–2006) survey examined the prevalence of vitamin B12 deficiency among 1,621 adults with T2DM, treated with or without Metformin. This side effect necessitates additional clinical monitoring and potential supplementation, adding complexity to long-term metformin therapy.

8.3 Renal Function Limitations

Traditional renal function limitations continue to restrict metformin use in certain populations, despite evolving evidence regarding safety in mild to moderate renal impairment. Several groups have suggested that current renal function cutoffs for Metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. This conservative approach may unnecessarily limit Metformin’s therapeutic reach.

9. Future Perspectives and Paradigm Shifts

9.1 Personalized Medicine Approaches

The future of diabetes management increasingly emphasizes personalized therapeutic approaches based on individual patient characteristics, comorbidities, and genetic factors. Metformin’s role in this personalized landscape will likely depend on its ability to demonstrate specific benefits in particular patient subgroups rather than universal first-line applicability.

Emerging research on pharmacogenomics may help identify patients who derive the greatest benefit from metformin therapy versus those who would benefit more from alternative first-line options. Polymorphisms in the SLC22A1 (OCT1) Gene… genetic variation in the organic cation transporters OCT1, OCT2, and multidrug and toxin extrusion 1 transporter protein genes suggest that genetic factors influence metformin response and tolerability.

9.2 Combination Therapy as the New Standard

The evolving evidence suggests that the future of diabetes management may not involve replacing Metformin but rather optimizing combination therapies that leverage the complementary mechanisms of different drug classes. Effect of GLP-1 RAs (column 1) and SGLT2 inhibitors (column 2) on metabolic/cardiovascular/renal parameters. The potential of combined GLP-1 RA/SGLT2i therapy to produce an additive effect is shown in column 3.

This combined approach recognizes that diabetes is a complex, multifactorial disease that requires multifaceted therapeutic intervention. Metformin’s role may evolve from monotherapy dominance to an essential component of multidrug regimens optimized for individual patient needs.

9.3 Healthcare System Evolution

The evolution of the healthcare system toward value-based care, population health management, and chronic disease prevention will influence Metformin’s future role. Its established safety profile, cost-effectiveness, and preventive potential position it favorably in healthcare systems focused on long-term outcomes and resource optimization.

10. Discussion

10.1 Synthesis of Evidence

The analysis reveals a nuanced picture of Metformin’s position in 2025 diabetes care. Rather than facing displacement, Metformin appears to be experiencing an evolution in its therapeutic role. The drug maintains its foundational importance while adapting to a more complex therapeutic landscape characterized by combination therapies and personalized medicine approaches.

Several key findings emerge from this analysis:

Guideline Stability: Metformin retains strong support in clinical guidelines despite therapeutic innovation
Complementary Role: Newer agents appear to complement rather than replace Metformin in most clinical scenarios
Safety Reassurance: Evolving safety evidence supports broader metformin use than previously recognized
Economic Value: Cost-effectiveness remains a compelling argument for Metformin’s continued use
Mechanistic Complexity: Ongoing discovery of metformin mechanisms suggests underappreciated therapeutic potential

10.2 The King Adapts: Evolution vs. Revolution

The question of whether Metformin remains the “king” or should “step aside” may be framed incorrectly. The evidence suggests that Metformin is adapting to maintain its relevance rather than facing obsolescence. This adaptation involves:

Role Diversification: Expanding from monotherapy to combination therapy foundation
Population Targeting: Enhanced focus on specific patient populations where benefits are maximized
Formulation Innovation: Development of improved delivery systems and formulations
Mechanistic Understanding: Leveraging new knowledge of pleiotropic effects

10.3 Clinical Implications

For clinicians, the evidence supports a continued foundational role for Metformin while embracing the benefits of newer therapeutic options. The optimal approach appears to involve:

Initial Assessment: Comprehensive evaluation of patient characteristics and comorbidities
Risk Stratification: Identification of patients requiring immediate cardiovascular or renal protection
Combination Planning: Strategic use of multiple agents with complementary mechanisms
Long-term Monitoring: Attention to vitamin B12 status and renal function evolution

10.4 Research Priorities

Several research priorities emerge from this analysis:

Optimal Combination Strategies: Defining the most effective multidrug approaches
Personalized Medicine: Identifying genetic and phenotypic predictors of metformin response
Global Health Applications: Addressing Metformin’s role in resource-limited settings
Novel Indications: Exploring anti-aging and cancer prevention potential
Formulation Development: Creating improved delivery systems for enhanced tolerability

Conclusion

The analysis of Metformin’s position in 2025 reveals a drug that has successfully adapted to maintain its therapeutic relevance despite significant challenges from newer, more innovative agents. Rather than stepping aside, Metformin appears to be evolving its role from monotherapy dominance to serving as a foundational component of personalized, combination-based diabetes management strategies.

The evidence supports several key conclusions:

Metformin Retains Foundational Value: Most national, regional, and international guidelines recommend Metformin as a foundation therapy, and this position appears justified by continued clinical benefits, safety reassurance, and economic value.

Combination Therapy Represents the Future: The optimal therapeutic approach increasingly involves combining Metformin with newer agents to leverage complementary mechanisms rather than replacing Metformin entirely.

Personalized Medicine Will Define Roles: Future metformin use will likely be guided by individual patient characteristics, genetic factors, and comorbidity profiles rather than universal first-line application.

Global Health Considerations Matter: Metformin’s affordability and accessibility make it irreplaceable for global diabetes management, particularly in resource-limited settings.

Research Opportunities Abound: Continued investigation into Metformin’s mechanisms, optimal dosing strategies, and novel applications may reveal additional therapeutic potential.

The question of whether Metformin should “step aside” appears premature. Instead, the evidence suggests that Metformin is successfully adapting to maintain its relevance in an evolving therapeutic landscape. The drug’s future lies not in monotherapy dominance but in serving as a versatile, foundational component of sophisticated, personalized diabetes management strategies.

As we progress through 2025 and beyond, Metformin’s legacy will likely be defined not by its resistance to change but by its adaptability to new therapeutic paradigms. The “king” may be evolving, but abdication appears neither necessary nor advisable based on current evidence. Instead, Metformin’s reign continues through adaptation, combination, and continued discovery of its therapeutic potential.

The diabetes care community benefits from embracing both Metformin’s established value and the innovations offered by newer therapeutic classes. This balanced approach, supported by evidence and guided by individual patient needs, represents the optimal path forward for diabetes management in 2025 and beyond.

References:

Chan, J. C. N., Yang, A., Chu, N., & Chow, E. (2024). Current type 2 diabetes guidelines: Individualized treatment and how to make the most of Metformin. Diabetes, Obesity and Metabolism, 26 Suppl 3, 55-74. https://doi.org/10.1111/dom.15700
American Diabetes Association Professional Practice Committee. (2024). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care, 47(Suppl 1), S158-S178. https://doi.org/10.2337/dc24-S009
Hou, W., Tuttle, K. R., Shen, W., Reikes, A., & Watanabe, J. H. (2025). Trends in Pharmacological Treatment of Patients With New Onset Type 2 Diabetes: Usage Patterns in an Evolving Guideline Landscape. Journal of Diabetes, 17(6), e70108. https://doi.org/10.1111/1753-0407.70108
American Diabetes Association Professional Practice Committee. (2025). 3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes-2025. Diabetes Care, 48(1 Suppl 1), S50-S58. https://doi.org/10.2337/dc25-S003
Li, Y., & Zhang, M. (2025). Evidence-based pharmacological investigation of the clinical practice and rational use of Metformin in pre-diabetes mellitus. Diabetes Research and Clinical Practice, 185, 109234.
Rodríguez-Gutiérrez, R., & Montori, V. M. (2025). Metformin: Paradigm of therapeutic pleiotropism (1922–2025). Medicina Clínica, 164(5), 228-235.
Corcoran, C., & Jacobs, T. F. (2025). Metformin. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK518983/
Bailey, C. J. (2024). Metformin: Therapeutic profile in the treatment of type 2 diabetes. Diabetes, Obesity and Metabolism, 26 Suppl 3, 3-19. https://doi.org/10.1111/dom.15663
Sinclair, A. J., & Abdelhafiz, A. H. (2025). Emerging uncertainty on the anti-aging potential of Metformin. Ageing Research Reviews, 78, 101645.
Wang, L., & Chen, X. (2024). The optimal dose of Metformin to control conversion to diabetes in patients with pre-diabetes: A meta-analysis. Journal of Clinical Medicine, 13(16), 4721.
Kumar, S., et al. (2023). Efficacy and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in overweight/obese patients with or without diabetes mellitus: a systematic review and network meta-analysis. Frontiers in Endocrinology, 14, 1156123.
Montvida, O., & Paul, S. K. (2024). Efficacy and safety of the combination or monotherapy with GLP-1 receptor agonists and SGLT-2 inhibitors in Type 2 diabetes mellitus: An update systematic review and meta-analysis. The American Journal of the Medical Sciences, 368(6), 621-627.
Scheen, A. J. (2019). SGLT2 inhibitor or GLP-1 receptor agonist in type 2 diabetes? The Lancet Diabetes & Endocrinology, 7(11), 834-836.
DeFronzo, R. A. (2017). Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes, Obesity and Metabolism, 19(10), 1353-1362.
Phung, O. J., et al. (2016). SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives. Vascular Health and Risk Management, 12, 239-249.
[Same as reference 3]
Gupta, V., & Kumar, A. (2024). GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review. The Lancet Diabetes & Endocrinology, 12(8), 545-561.
Verma, S., & McMurray, J. J. V. (2020). Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar. Journal of the American College of Cardiology, 75(16), 1956-1974.
Palmer, S. C., et al. (2021). In type 2 diabetes, SGLT2 inhibitors reduce all-cause mortality but not cardiovascular mortality vs. GLP-1 RAs. Annals of Internal Medicine, 174(6), JC63.
Pfeffer, M. A., et al. (2015). An overview of new GLP-1 receptor agonists for type 2 diabetes. Clinical Medicine Insights: Endocrinology and Diabetes, 8, 15-22.
Lin, K. J., et al. (2022). Metformin-associated lactic acidosis and factors associated with 30-day mortality. PLOS ONE, 17(8), e0273534.
Eurich, D. T., et al. (2009). Metformin: safety in cardiac patients. Expert Opinion on Drug Safety, 8(4), 405-414.
Lalau, J. D., & Kajbaf, F. (2015). Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism, 65(2), 20-29.
[Same as reference 23]
See, K. C. (2024). Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis, and management in critically ill patients. World Journal of Diabetes, 15(6), 1178-1186.
Khurana, R., et al. (2017). Metformin is not associated with lactic acidosis in patients with diabetes undergoing coronary artery bypass graft surgery: a case-control study. Journal of Cardiothoracic Surgery, 12, 46.
Kwon, K. S., et al. (2015). Metformin-associated lactic acidosis: predisposing factors and outcome. Endocrinology and Metabolism, 30(1), 78-83.
Bodmer, M., et al. (2007). Metformin, heart failure, and lactic acidosis: Is Metformin absolutely contraindicated? BMJ, 335(7618), 508-509.
Salpeter, S. R., et al. (2010). Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews, (4), CD002967.
Salvatori, M., et al. (2015). [Lactic acidosis, acute renal failure, and heart failure during treatment with Metformin: what do we know?] Giornale Italiano di Nefrologia, 32(5), gin/32.5.9.
Menichetti, F., et al. (2024). View on Metformin: Anti-diabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences. Pharmaceuticals, 17(4), 478.
Krysiak, R., & Okopień, B. (2011). [Metformin – mechanisms of action and use for the treatment of type 2 diabetes mellitus]. Wiadomości Lekarskie, 64(2), 67-74.
Giunti, S., et al. (2017). Metformin overcomes high glucose-induced insulin resistance of podocytes by pleiotropic effects on SIRT1 and AMPK. Journal of Cellular and Molecular Medicine, 21(11), 2637-2649.
Li, X., et al. (2024). Systematic Investigation of Dose-Dependent Protein Thermal Stability Changes to Uncover the Mechanisms of the Pleiotropic Effects of Metformin. Journal of Proteome Research, 23(2), 567-580.
Vancura, A., et al. (2018). Pleiotropic Effects of Metformin on Cancer. International Journal of Molecular Sciences, 19(10), 2863.
Ko, M., et al. (2024). The anticancer effect of metformin targets VDAC1 via ER-mitochondria interactions-mediated autophagy in HCC. Experimental & Molecular Medicine, 56(12), 2714-2725.
Kulkarni, A. S., et al. (2018). Pleiotropic effects of Metformin: Shaping the microbiome to manage type 2 diabetes and postpone ageing. Ageing Research Reviews, 49, 88-102.
Bell, D. S. H., & Goncalves, E. (2015). The pleiotropic effects of Metformin: time for prospective studies. Clinical Medicine Insights: Endocrinology and Diabetes, 8, 43-49.
[Same as reference 37]
Fahed, G., et al. (2023). Anti-Obesity Effects of Metformin: A Scoping Review Evaluating the Feasibility of Brown Adipose Tissue as a Therapeutic Target. Nutrients, 15(2), 439.

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