How Does Metformin as First-Line Therapy Impact Long-Term Cardio- Vascular and Metabolic Outcomes in Patients with Type 2 Diabetes Mellitus over A 5-Year Period ? : A Systematic Review

How Does Metformin as First-Line Therapy Impact Long-Term Cardio- Vascular and Metabolic Outcomes in Patients with Type 2 Diabetes Mellitus over A 5-Year Period ? : A Systematic Review

Authors

  • Firman Gustina Faculty of Medicine, National Development University 'Veteran' Jakarta, Special Region of Jakarta, Indonesia
  • Amelinda Nur Amalina Faculty of Medicine, General Achmad Yani University, West Java, Indonesia
  • Fajar Nugraha Faculty of Medicine, General Achmad Yani University, West Java, Indonesia
  • Fitriah Hany Faculty of Medicine, Bandung Islamic University, West Java, Indonesia

Keywords:

Metformin, Type 2 Diabetes Mellitus, Long-Term Outcomes, Cardiovascular Disease, Metabolic Control, First-Line Therapy

Abstract

Introduction: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder requiring effective long-term management strategies.  Metformin is established as a first-line therapy, and understanding its long-term (≥5 years) cardiovascular and metabolic implications is crucial for optimizing patient care.  This systematic review aimed to synthesize existing academic literature on these long-term outcomes. Methods: This systematic review adhered to PRISMA 2020 guidelines. Results: Metformin demonstrated significant long-term cardiovascular benefits, including a notable reduction in heart failure incidence (Hazard Ratio [HR] 0.51)  and a lower overall cardiovascular risk (Odds Ratio [OR] 0.57).  Effects on specific events like myocardial infarction were modest (e.g., Risk Ratio [RR] 0.89, HR 0.88), and results for stroke were varied, though benefits were observed in specific subgroups such as patients with chronic kidney disease (CKD) (RR 0.76 for cardiovascular events)  or post-stroke (OR 0.66 for poor course).  Metabolically, metformin consistently led to reductions in HbA1c (ranging from 0.06% to 1.13%), modest decreases in BMI (up to 0.46 kg/m²), and reductions in LDL cholesterol (around 5-6 mg/dL).  Discussion: The substantial reduction in heart failure incidence and overall cardiovascular risk highlights metformin's role in primary prevention in T2DM patients.  While the impact on specific major adverse cardiovascular events like myocardial infarction and stroke is more nuanced, clear benefits emerge in high-risk subgroups.  Sustained improvements in glycemic control are crucial for long-term complication reduction.  Conclusion: First-line metformin therapy is associated with favorable long-term cardiovascular and metabolic profiles in adults with T2DM over five years or more.  Key benefits include significant reductions in heart failure incidence, improved overall cardiovascular risk, consistent glycemic control, and modest weight and lipid improvements.  Its well-established safety record, including a lower risk of hypoglycemia compared to sulfonylureas and manageable side effects with formulation adjustments, solidifies its foundational role in the comprehensive, long-term management of T2DM.

References

A. Pietraszek. “Cardiovascular Effects of Hypoglycemic Agents in Diabetes Mellitus.” Current Drug Safety, 2020.

B. Bergmark, Deepak L. Bhatt, Darren K Mcguire, Avivit Cahn, Ofri Mosenzon, P. Steg, K. Im, et al. “Metformin Use and Clinical Outcomes Among Patients with Diabetes with or Without Heart Failure or Kidney Dysfunction: Observations from the SAVOR-TIMI 53 Trial.” Circulation, 2019.

C. Aiken, J. Tarry-Adkins, I. Grant, R. Reynolds, and S. Ozanne. “An Update to the Article “Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis”.” Diabetes Therapy, 2021.

C. Thomopoulos, G. Katsimagklis, and T. Makris. “Metformin and Blood Pressure Lowering: A Questioned Association.” Journal of Hypertension, 2017.

Christine G. Lee, B. Heckman-Stoddard, D. Dabelea, K. Gadde, D. Ehrmann, L. Ford, P. Prorok, et al. “Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.” Diabetes Care, 2021.

F. Pérez-López, V. Pasupuleti, Ximena Gianuzzi, Gabriela Palma-Ardiles, Wendy Hernández-Fernández, and Adrian V. Hernández. “Systematic Review and Meta-Analysis of the Effect of Metformin Treatment on Overall Mortality Rates in Women with Endometrial Cancer and Type 2 Diabetes Mellitus.” Maturitas, 2017.

“Hypoglycaemic Therapy in Type 2 Diabetes. Part I. Metformin Is the Only Glucose-Lowering Drug Known to Prevent Complications of Diabetes.” Prescrire International, 2015.

I. Campbell. “Metformin: A 60-Year Odyssey with the Journey Still Continuing – a Personal Commentary from Professor Ian Campbell.” Current Medical Research and Opinion, 2021.

J. Fradkin, and G. Rodgers. “Glycemic Therapy for Type 2 Diabetes: Choices Expand, Data Lag Behind.”Annals of Internal Medicine, 2017.

J. Joo, Hyun-Soo Zhang, Jiyeon Chun, E. Park, and So-Yong Park. “Association of Metformin Treatment with Risk for Death in Diabetic Patients with Concomitant Gastric Cancer.” Cancers, 2023.

J. Sundström, R. Kristófi, O. Östlund, L. Bennet, B. Eliasson, S. Jansson, J. Leksell, K. Almby, M. Lundqvist, and J. Eriksson. “A Registry-Based Randomised Trial Comparing an SGLT2 Inhibitor and Metformin as Standard Treatment of Early Stage Type 2 Diabetes (SMARTEST): Rationale, Design and Protocol.” Journal of Diabetes and Its Complications, 2021.

J. Tan, Yang Wang, Song Liu, Qingyang Shi, Xu Zhou, Yiling Zhou, Xiaoling Yang, Pingshan Chen, and Sheyu Li. “Long-Acting Metformin Vs. Metformin Immediate Release in Patients With Type 2 Diabetes: A Systematic Review.” Frontiers in Pharmacology, 2021.

J. Tarry-Adkins, Imogen D. Grant, S. Ozanne, R. Reynolds, and C. Aiken. “Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis.” Diabetes Therapy, 2021.

Jared M. Campbell, Susan M. Bellman, M. Stephenson, and K. Lisy. “Metformin Reduces All-Cause Mortality and Diseases of Ageing Independent of Its Effect on Diabetes Control: A Systematic Review and Meta-Analysis.” Ageing Research Reviews, 2017.

Jian Zhou, Yang Ke, Xue-fen Lei, Tian-gen Wu, Yuehua Li, T. Bao, Haoran Tang, et al. “Meta-Analysis: The Efficacy of Metformin and Other Anti-Hyperglycemic Agents in Prolonging the Survival of Hepatocellular Carcinoma Patients with Type 2 Diabetes.” Annals of Hepatology, 2019.

Jianyi Liu, Zhihua Huang, Fuqun Luo, Yizhi Guo, Yandeng Li, Jun Wen, and Jianming Zhu. “Effect of Metformin on the Clinical Outcomes of Stroke in Patients with Diabetes: A Systematic Review and Meta-Analysis.” BMJ Open, 2025.

Karina Raygoza-Cortez, José Gerardo González-González, and R. Rodríguez‐Gutiérrez. “Letter to the Editor: ”Effect of Metformin on Microvascular Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis”.” Diabetes Research and Clinical Practice, 2022.

Kui Zhang, Wenxing Yang, H. Dai, and Z. Deng. “Cardiovascular Risk Following Metformin Treatment in Patients with Type 2 Diabetes Mellitus: Results from Meta-Analysis.” Diabetes Research and Clinical Practice, 2020.

L. Watson, R. Das, R. Farquhar, H. Langerman, and A. Barnett. “Consequences of Delaying Treatment Intensification in Type 2 Diabetes: Evidence from a UK Database.” Current Medical Research and Opinion, 2016.

Lisa Schlender, Yolanda V. Martinez, Charles Adeniji, D. Reeves, Barbara Faller, Christina Sommerauer, Thekraiat Al Qur an, et al. “Efficacy and Safety of Metformin in the Management of Type 2 Diabetes Mellitus in Older Adults: A Systematic Review for the Development of Recommendations to Reduce Potentially Inappropriate Prescribing.” BMC Geriatrics, 2017.

M. Pladevall, N. Riera‐Guardia, A. Margulis, C. Varas‐Lorenzo, B. Calingaert, and S. Perez-Gutthann. “Cardiovascular Risk Associated with the Use of Glitazones, Metformin and Sufonylureas: Meta-Analysis of Published Observational Studies.” BMC Cardiovascular Disorders, 2016.

N. Boulé. “Exercise Plus Metformin in the Fight Against Diabetes.” Exercise and Sport Sciences Reviews, 2016.

N. Maruthur, Eva Tseng, S. Hutfless, L. Wilson, C. Suarez‐Cuervo, Z. Berger, Yue Chu, Emmanuel Iyoha, J. Segal, and S. Bolen. “Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes.” Annals of Internal Medicine, 2016.

R. Romanelli, Sukyung Chung, J. Pu, Vani Nimbal, B. Zhao, and L. Palaniappan. “Comparative Effective- ness of Early Versus Delayed Metformin in the Treatment of Type 2 Diabetes.” Diabetes Research and Clinical Practice, 2015.

S. Elhini, A. Hussien, Ahmed Abd Elsamie Omran, Asmaa A Elsayed, and Haitham Saeed. “Efficacy and Safety Profile of Sitagliptin, Vildagliptin, and Metformin in Newly Diagnosed Type 2 Diabetic Subjects.” Clinical and Experimental Pharmacology and Physiology, 2021.

S. Gillani, S. S. Syed Sulaiman, V. Menon, Nazeerullah Rahamathullah, R. Elshafie, and H. Rathore. “Effect of Different Antidiabetic Medications on Atherosclerotic Cardiovascular Disease (ASCVD) Risk Score Among Patients with Type-2 Diabetes Mellitus: A Multicenter Non-Interventional Observational Study.” PLoS ONE, 2022.

S. Griffin, James K. Leaver, and G. Irving. “Impact of Metformin on Cardiovascular Disease: A Meta- Analysis of Randomised Trials Among People with Type 2 Diabetes.” Diabetologia, 2017.

S. Gu, Jihao Shi, Zhiliu Tang, M. Sawhney, Huimei Hu, Lizheng Shi, V. Fonseca, and Hengjin Dong. “Comparison of Glucose Lowering Effect of Metformin and Acarbose in Type 2 Diabetes Mellitus: A Meta-Analysis.” PLoS ONE, 2015.

T. Xu, S. Brandmaier, A. C. Messias, C. Herder, H. Draisma, A. Demirkan, Zhonghao Yu, et al. “Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes.” Diabetes Care, 2015.

T. Yue, Xulin Wang, Minzhe Zhao, J. Weng, S. Luo, and Xueying Zheng. “1362-P: The Long-Term Cardio- vascular Effects of Metformin on Patients with Newly Diagnosed Type 2 Diabetes.” Diabetes, 2023.

T. Zhao, Qize Yang, J. Feuerbacher, B. Yu, C. Brinkmann, S. Cheng, W. Bloch, and M. Schumann. “Effects of Exercise, Metformin and Their Combination on Glucose Metabolism in Individuals with Abnormal Gly- caemic Control: A Systematic Review and Network Meta-Analysis.” British Journal of Sports Medicine, 2024.

Wei-Wen Hung, Po Peng, Yi-Chun Tsai, Pei-Syuan Jhou, Chen-Chia Chang, Ching-Chun Hsieh, Yong-Chao Su, C. Dai, and Wei-Chun Hung. “Gut Microbiota Compositions and Metabolic Functions in Type 2 Diabetes Differ with Glycemic Durability to Metformin Monotherapy.” Diabetes Research and Clinical Practice, 2021.

Yao-chun Hu, Min Lei, Guibao Ke, Xin Huang, Xuan Peng, Lihui Zhong, and P. Fu. “Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease—A Systematic Review and Meta-Analysis.” Frontiers in Endocrinology, 2020.

Zhicheng Xu, Haidong Zhang, Chen-Ten Wu, Yuxiang Zheng, and Jingzhou Jiang. “Effect of Metformin on Adverse Outcomes in T2DM Patients: Systemic Review and Meta-Analysis of Observational Studies.” Frontiers in Cardiovascular Medicine, 2022.

Zhiwen Liu, Zhiguang Zhou, Gan Huang, Yang Xiao, Z. Li, Cong Liu, and Risu Na. “Long-Term Effects Intensive Medical Therapy on the Development and Progression of Subclinical Atherosclerosis and the Metabolic Syndrome in Chinese Patients with Type 2 Diabetes Mellitus.” Medicine, 2016.

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Published

2025-06-17

How to Cite

Firman Gustina, Amelinda Nur Amalina, Fajar Nugraha, and Fitriah Hany. 2025. “How Does Metformin As First-Line Therapy Impact Long-Term Cardio- Vascular and Metabolic Outcomes in Patients With Type 2 Diabetes Mellitus over A 5-Year Period ? : A Systematic Review”. The International Journal of Medical Science and Health Research 13 (2): 39-84. https://doi.org/10.70070/8c4yz749.