Metformin in Prediabetes: Guideline-Directed Therapy in India

A robust evidenced pharmacological approach to type 2 diabetes prevention would benefit the community and healthcare in India. There is increasing evidence to support the use of metformin in prediabetes, when it is prescribed as first line of treatment following diagnosis and after diet and exercise fail to restore blood glucose control. (1) Based on such durable evidence, the Drug Controller General India (DCGI) in India has approved the use of metformin for the prevention and delaying of T2D. (2)

Who Should Receive Metformin for Diabetes Prevention?

ICMR Guidelines for Diabetes: The Indian Council of Medical Research (ICMR) Guidelines for Management of T2D stressed that metformin treatment, in addition to lifestyle modifications, may be taken into consideration when lifestyle alone is insufficient, particularly in those with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) where the development of T2D is imminent; relevant in Indians who move quickly from the prediabetes stage to diabetes. (3)

RSSDI Guidelines: The Research Society for the Study of Diabetes in India (RSSDI) recommended starting oral anti-diabetic medications (OADs) in individuals with prediabetes who did not show any benefit from lifestyle changes after six months. Regardless of BMI, the guidelines suggested metformin for younger people with one or more additional diabetes risk factors. If the patient was overweight or obese and had an IFG + IGT or IFG + HbA1c >5.7%, metformin should be added after six months of follow-up. (4)

ADA Standards of Care: The American Diabetes Association (ADA) has advised all patients with prediabetes to follow an intense diet and exercise regimen and to take metformin if they have additional risk factors, such as a body mass index of 35 kg/m2, age less than 60 years old, or a history of gestational diabetes. Metformin is also advised for individuals whose HbA1c values are steadily increasing despite attempts at lifestyle change. (5)

The Indian Expert Group Consensus Statement on the Management of Prediabetes in India also indicated the use of metformin in prediabetes, primarily to prevent diabetes, secondary prevention of prediabetes and primordial prevention of vascular ill health in prediabetes. It also stressed that metformin should be given in prediabetes with BMI above 35 kg/m2, age 60 years or above and women with prior gestational diabetes mellitus. (2)

Therapeutic Use of Metformin for Diabetes Prevention:

Metformin plays a regulatory role in multiple systems including, regulation of hepatic gluconeogenesis through a variety of mechanisms; reduction of obesity-related inflammation; and various influences on the gastrointestinal tract and gut microbiota. Insulin resistance is a contributing factor to the reduction of β-cell function, which is another important component linked to the development of type 2 diabetes. Intervention is advantageous at any point of the progression to type 2 diabetes, as metformin treats insulin resistance; however, it may be more effective if undertaken early, before β-cell function is impaired. (1)

Diabetes Prevention Trials with Metformin in People with Prediabetes

Metformin has been tested in various clinical trials for diabetes prevention, providing vital evidence of its efficacy and safety.

Landmark DPP & DPPOS Trial: The Diabetes Prevention Program (DPP) tested the efficacy of metformin, lifestyle changes, and placebo in people with prediabetes. Over a two-year and eight-month average follow-up period, metformin lowered the chance of developing diabetes by 31% compared to a placebo group. (6) Furthermore, a 10-year follow-up trial called the DPP outcomes trial (DPPOS) investigated the long-term benefits of metformin and found a persistent reduction in the incidence of diabetes. Metformin lowered the risk of acquiring diabetes by 18% over 10 years. (7) Another study, that investigated using the dataset from the DPP study; the effectiveness of metformin in preventing type 2 diabetes in prediabetes patients with a lower FPG at baseline and more pronounced IFG relative to IGT found that metformin reduced the incidence of diabetes by 26% (RR 74%, CI 0.65–0.83) and by 43% (RR 0.57, CI 0.4–0.9) in those prediabetic persons whose IFG was more pronounced. (1) These findings consistently demonstrate that metformin supplementation reduces the likelihood of developing T2DM. The effectiveness of metformin in preventing prediabetes was also cited in a meta-analysis by Patel D et al where using metformin had a 42% lower risk of getting diabetes than those in the control group. (8)

Is Metformin Underused in Prediabetes Population?

A retrospective observational study described prescribing patterns of metformin in low-income and Medicaid insured (Medicaid is South Carolina’s aid program where federal and state governments share the costs of providing medical care for needy persons who have a low income. More than 1 million South Carolinians enrol in Medicaid each fiscal year.) patients with prediabetes. The utilization of metformin prescription to treat prediabetes in a low-income population remains low. Less than 8% of studied patients (n=7102) received metformin to treat prediabetes. (9) Despite the fact that metformin can help delay the onset of type 2 diabetes, only 3.7% of patients with prediabetes received a prescription for it throughout the course of a three-year retrospective cohort research. (10) Metformin appears to be underused among the population of subjects eligible for it.

The UKPDS follow-up determined that the metformin clinical effects would wane by extending the follow-up for another 14 years. The median follow-up time from baseline in the sulfonylurea or insulin group was 17·3 years, and in the metformin group, it was 19·1 years. The result showed that metformin legacy effects seen during the post-trial monitoring study in the metformin group, compared with the conventional therapy group, did not wane over the following 14 years. The overall relative risk reductions from baseline in the metformin group were 20% (95% CI 5–32; p=0·010) for death from any cause and 31% (12–46; p=0·003) for myocardial infarction. These results highlight how critical it is for individuals with type 2 diabetes to attain optimal glycaemic control as early as feasible. (11)

Key Takeaways

Diabetes can be avoided in up to one-third of people with prediabetes. (2)

Studies to date suggest that only a small proportion of people with non-diabetic hyperglycemia receive metformin for prediabetes prevention.

Metformin has been tested in various clinical trials for diabetes prevention, providing vital evidence of its efficacy and safety.

Metformin lowered the risk of acquiring diabetes by 18% over 10 years in the DPPOS trial.

Metformin reduces the risk of T2D in subjects with IGT, effectively reduces body weight and improves glucose tolerance.

The Drug Controller General of India (DCGI) has approved the use of metformin to prevent and delay T2D.

Reference:

1. Warrilow A, Somerset S, Pumpa K, Fleet R. Metformin use in prediabetes: is earlier intervention better? Acta Diabetol. 2020 Nov;57(11):1359-1366. doi: 10.1007/s00592-020-01559-9.

2. 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.

3. ICMR Guidelines for Management of T2D 2018. Retrieved on 20th May 2024 from https://main.icmr.nic.in/sites/default/files/guidelines/ICMR_GuidelinesType2diabetes2018_0.pdf

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

5. American Diabetes Association Professional Practice Committee; Summary of Revisions: Standards of Care in Diabetes—2024. Diabetes Care 1 January 2024; 47 (Supplement_1): S5–S10. https://doi.org/10.2337/dc24-SREV

6. Diabetes Prevention Program (DPP). Retrieved on 20th May 2024 from https://www.niddk.nih.gov/about-niddk/research-areas/diabetes/diabetes-prevention-program-dpp

7. Diabetes Prevention Program Research Group; Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R, Venditti E, Nathan DM. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009 Nov 14;374(9702):1677-86. doi: 10.1016/S0140-6736(09)61457-4.

8. Patel D, Ayesha IE, Monson NR, Klair N, Patel U, Saxena A, Hamid P. The Effectiveness of Metformin in Diabetes Prevention: A Systematic Review and Meta-Analysis. Cureus. 2023 Sep 28;15(9):e46108. doi: 10.7759/cureus.46108.

10. Wu J, Ward E, Threatt T, Lu ZK. Metformin prescribing in low-income and insured patients with prediabetes. J Am Pharm Assoc (2003). 2017 Jul-Aug;57(4):483-487. doi: 10.1016/j.japh.2017.04.008.

11. Moin T, Li J, Duru OK, Ettner S, Turk N, Keckhafer A, Ho S, Mangione CM. Metformin prescription for insured adults with prediabetes from 2010 to 2012: a retrospective cohort study. Ann Intern Med. 2015 Apr 21;162(8):542-8. doi: 10.7326/M14-1773. PMID: 25894024; PMCID: PMC4682357.

12. Amanda I Adler, Ruth L Coleman, Jose Leal, William N Whiteley, Philip Clarke, Rury R Holman. 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). May 17, 2024DOI:https://doi.org/10.1016/S0140-6736(24)00537-3