Does Legacy of Metformin Stand Tall in 2024?

Introduced in the 1950s, metformin has become a cornerstone in managing type 2 diabetes. Metformin has evolved through decades of research and clinical success, and its unique benefits, such as insulin sensitization without weight gain or hypoglycemia, led to its global adoption.(1) Metformin has been the most widely prescribed glucose-lowering agent, benefiting approximately 150 million people worldwide. Its enduring legacy is rooted in its primary role in managing hyperglycemia and its secondary advantages, including improved vascular function and reduced cardiovascular disease risk. This ongoing recognition demonstrated metformin’s remarkable contribution to diabetes care and its potential for further therapeutic applications.(2)

Metformin primarily works by reducing hepatic glucose production, thereby lowering blood glucose levels. Additionally, it enhances insulin-mediated glucose uptake and utilization in peripheral tissues. Recent evidence also suggests that metformin may influence gut microbiota, potentially contributing to its glucose-lowering effects.(3) Today, there are approximately 32,497 published articles on metformin, which speak volumes regarding the depth of continuous scientific research on this molecule.(4)

Long-Term Benefits of Early Metformin Use in T2DM - Data from the Latest UKPDS 2024

Recent data published in July 2024 from the UK Prospective Diabetes Study (UKPDS) highlights the enduring benefits of metformin in managing type 2 diabetes. Originally presented in 1998, the UKPDS demonstrated that metformin significantly reduced relative risks by 32% for any diabetes-related endpoint, 42% for diabetes-related deaths, and 36% for all-cause mortality. Follow-up results from 2008 showed that metformin continued to offer substantial benefits even after participants returned to usual care. The 2024 analyses affirm that metformin remains effective with legacy effects maintained over 24 years leading to significant reductions of 21% in diabetes-related endpoints, 33% in myocardial infarction, 12% in stroke, 45% in peripheral artery disease, and 27% in all-cause mortality, underscoring its long-term efficacy in diabetes management.(5)

Optimal Administration Time of Metformin & GLP-1 Response– 2024 Research Update

The timing of metformin administration is crucial for optimizing GLP-1 response and postprandial glucose control. Emerging data indicate that pre-meal administration significantly boosts GLP-1 secretion and improves glycaemic outcomes in individuals with type 2 diabetes.

A 2024 study by Xie, Cong et.al, found that administering metformin before meals enhances its glucose-lowering effects and increases GLP-1 levels, compared to taking it with glucose. This suggests that pre-meal metformin administration may optimize postprandial glycaemic control in type 2 diabetes.(6)

Metformin- Place in Eminent International & Indian Guidelines

The American Diabetes Association Standards of Care-Diabetes (2024) recommended metformin as the first-line therapy for type 2 diabetes and the beneficial effects of metformin on HbA1c, weight neutrality, lower risk of hypoglycemia, and reduction of cardiovascular mortality.(7) The ADA recommended considering metformin in prediabetes to prevent progression to type 2 diabetes, especially in patients with a BMI ≥35 kg/m2, those <60 years of age, and women with a history of gestational diabetes mellitus (GDM).(8)

The joint ADA/EASD (European Association for the Study of Diabetes) guidelines recommend using metformin for primary prevention of cardiovascular events in overweight patients with type 2 diabetes mellitus, provided they have no history of major cardiovascular events and among high-risk groups with a history of CV events.(9)

In India, the Research Society for the Study of Diabetes in India (Clinical Recommendation Guidelines-2022) recommended metformin as the first-line oral antidiabetic drug especially in obese people with diabetes, for the prevention of prediabetes in younger individuals with one or more risk factors for diabetes failed to achieve any benefit on lifestyle modification.(10)

Metformin – Milestones in Global Approvals

Metformin was approved for use in Europe for treating type 2 diabetes mellitus in 1957. Clinical trials from 1980 to 1998 established metformin’s safety and efficacy, showing a lower risk of lactic acidosis compared to other biguanides. This led to the US Food and Drug Administration (US-FDA) approving metformin for use in the United States in 1994, and it became widely prescribed by 1995. By the end of the 20th century, it had become the most commonly prescribed oral medication for controlling blood glucose levels. The World Health Organization further validated its importance by including it in its list of essential medications in 2011. (11) In India, the CDSCO has approved metformin for the treatment of type 2 diabetes. (12) The Drug Controller General of India also approved metformin in prediabetes for those with a BMI greater than 35 kg/m², those aged 60 years or older, and women with a history of gestational diabetes mellitus. Metformin may reduce the risk of T2D in individuals with impaired glucose tolerance (IGT).(13)

Take Home Messages

• Metformin remains essential in managing type 2 diabetes, benefiting around 150 million people with its insulin-sensitizing effects without causing weight gain or hypoglycemia.
• Metformin lowers blood glucose by reducing liver glucose production and enhancing insulin uptake in tissues, with emerging evidence suggesting it may also affect gut microbiota.
• Recent UKPDS 91 data published in 2024 confirms metformin’s long-term efficacy, showing significant reductions in diabetes-related endpoints, myocardial infarction, and all-cause mortality.
• Metformin is widely endorsed as a first-line therapy for type 2 diabetes by major global guidelines and scientific authorities, including the ADA, EASD, and the WHO, reflecting its established safety and effectiveness.
• Administering metformin 30 minutes before meals enhances glucose-lowering and GLP-1 responses, optimizing postprandial glycaemic control in type 2 diabetes.

References:

1. Bailey, Clifford J. “Metformin: historical overview.” Diabetologia vol. 60,9 (2017): 1566-1576. doi:10.1007/s00125-017-4318-z

2. Triggle, Chris R et al. “Metformin: Is it a drug for all reasons and diseases?.” Metabolism: clinical and experimental vol. 133 (2022): 155223. doi:10.1016/j.metabol.2022.155223

3. Schernthaner, Guntram, and Gerit-Holger Schernthaner. “The right place for metformin today.” Diabetes research and clinical practice vol. 159 (2020): 107946. doi:10.1016/j.diabres.2019.107946

4. PubMed. Metformin. Access on 13th September 2024 from https://pubmed.ncbi.nlm.nih.gov/?term=metformin

5. Adler, Amanda I et al. “Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91).” Lancet (London, England) vol. 404,10448 (2024): 145-155. doi:10.1016/S0140-6736(24)00537-3

6. Xie, Cong et al. “Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.” Diabetologia vol. 67,7 (2024): 1260-1270. doi:10.1007/s00125-024-06131-6

7. American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2024. Diabetes Care 1 January 2024; 47 (Supplement_1): S158–S178. https://doi.org/10.2337/dc24-S009

8. Inês H. Vieira, Luísa M. Barros, Carla F. Baptista, Dírcea M. Rodrigues, Isabel M. Paiva; Recommendations for Practical Use of Metformin, a Central Pharmacological Therapy in Type 2 Diabetes. Clin Diabetes 1 January 2022; 40 (1): 97–107. https://doi.org/10.2337/cd21-0043

9. Paolo Verdecchia, Giuseppe Murdolo, Stefano Coiro, Andrea Santucci, Francesco Notaristefano, Fabio Angeli, Claudio Cavallini, Therapy of Type 2 diabetes: more gliflozines and less metformin?, European Heart Journal Supplements, Volume 25, Issue Supplement_B, April 2023, Pages B171–B176, https://doi.org/10.1093/eurheartjsupp/suad098

10. RSSDI-Clinical-Practice-Recommendations-2022. Retrieved on 11 Sept 2024 from https://www.rssdi.in/newwebsite/RSSDI-Clinical-Practice-Recommendations-2022%20(1).pdf

11. Baker, Chelsea et al. “Should metformin remain the first-line therapy for treatment of type 2 diabetes?.” Therapeutic advances in endocrinology and metabolism vol. 12 2042018820980225. 13 Jan. 2021, doi:10.1177/2042018820980225

12. Evans, Valerie et al. “Adequacy of clinical trial evidence of metformin fixed-dose combinations for the treatment of type 2 diabetes mellitus in India.” BMJ global health vol. 3,2 e000263. 6 Mar. 2018, doi:10.1136/bmjgh-2016-000263

13. Das AK, Mohan V, Ramachandran A, et al. An Expert Group Consensus Statement on “Approach and Management of Prediabetes in India”. J Assoc Physicians India 2022;70(12):69–78.