Prediabetes-The Sugary Iceberg Calls for Early Interventions With Metformin

Prediabetes, often a precursor to type 2 diabetes(T2D) and cardiovascular disease, is a harbinger of metabolic syndrome. Its high conversion rate to T2D of approximately 25% depicts it as the “sugary” iceberg (1). In primary care, prediabetes is a critical stage for intervention that gives a rare opportunity for early and efficient management (2).

Indians Are on High Pre-Diabetes Risk: The ICMR-INDIAB-17 (Indian Council of Medical Research–India Diabetes) data showed that the prevalence of prediabetes and diabetes in India was 15.3% and 11.49%, affecting 136 million and 101 million, respectively (3). A 10-year population-based prospective cohort study (n=1787), which assessed the incidence of dysglycaemia in Asian Indians, also showed that 55.7% of pre-diabetes individuals are converted to diabetes (p>0.05). With prediabetes affecting such a significant proportion of the population and increasing their risk for T2D, understanding the magnitude of this risk is crucial (4). Age and body mass index, physical inactivity, family history of T2D, hypertension (HT), and history of gestational diabetes are some common factors that predict prediabetes in Indians (5).

Benefits of Early Intervention:

Diagnosis, medication, lifestyle changes, and screening are all part of diabetes prevention strategies for high-risk individuals or populations. Apart from studies that demonstrate the benefits of lifestyle changes, several trials showed the significant effects of drug treatment in reducing the progression of T2D in high-risk individuals (6).

Early intervention can prevent the risk of diabetes by as much as 50% if normoglycemia can be achieved (7). Furthermore, the risk of microvascular complications such as retinopathy was reduced by 38% and the risk of cardiovascular disease (CVD) by 17% with early intervention (medication and lifestyle changes in prediabetes) (8).

The Diabetes Prevention Program Outcomes Study (DPPOS) showed a 28% lower incidence of the composite microvascular complications (retinopathy, nephropathy, and/or neuropathy) in participants who did not develop T2D, across treatment groups who had been randomised to intensive lifestyle intervention and followed for 15 years after randomization (9).

The 30-year follow-up of the Da Qing Study showed a 40% reduction in retinopathy despite the study cohort achieving a small average weight loss of 1.8 kg throughout the intervention period (10). Overall, there is mounting evidence that individuals with prediabetes are susceptible to the traditional problems of diabetes, which can be avoided with early intensification.

Metformin- Approved Agent in Prediabetes

Although both intensive lifestyle interventions have proven to be effective for the prevention or delay of diabetes in people with prediabetes,but challeging to adhere to, clinical trials have provided evidence that metformin is effective in preventing diabetes, particularly in younger, overweight patients (5).

A recently published 2024 meta-analysis analysing the effectiveness of metformin in delaying the progression of pre-diabetes to type 2 diabetes showed a 22% relative risk reduction with metformin compared to lifestyle modification or placebo, with a 95% confidence interval of 0.71–0.86. The result also noted that the metformin dose (low versus high) did not influence the outcome [p = 0.39] (1).

The Drug Controller General of India (DCGI) has approved metformin to prevent and delay T2D in prediabetes. Metformin has a strong safety record and positive effects on lipid levels and body mass index [BMI] (3). Metformin therapy for the prevention of T2D should be considered in those with prediabetes, especially those with BMI above 35 kg/m2, age above 60, and women with prior gestational diabetes mellitus, where lifestyle intervention is insufficiently effective in reducing body weight and improving glucose tolerance (3).

Key Takeaways

• Prediabetes not only signals the onset of metabolic syndrome but also presents a window to intervene before the development of more severe conditions like type 2 diabetes and cardiovascular disease.
• Prediabetes, with its high conversion rate of approximately 25%, depicts as the “sugary” iceberg.
• Asian Indians have a high risk of developing type 2 diabetes, with 55.7% of pre-diabetes individuals converted to diabetes.
• Early intervention can prevent diabetes in more than 50% of cases, if normoglycemia can be attained. It can also reduce the risk of CVD by 17% and microvascular complications, such as retinopathy, by 40%.
• Metformin is an effective drug for preventing diabetes. It has a strong safety record and positive effects on lipid levels and body mass index.
• The Drug Controller General of India (DCGI) approved metformin to prevent and delay T2D in prediabetes.

References:

1. Samit Ghosal, Surekha Tippisetty, Subhadra Polisetti, Krishna G. Seshadri. Metformin for the Prevention of Prediabetes Progression to Type 2 Diabetes: A Systematic Review and Meta-Analysis. Clinical Diabetology 2024, DOI: 10.5603/cd.99821

2. Gabison, Jonathan G. “Is Prediabetes Overdiagnosed? No: A Clinician's Perspective.” Annals of family medicine vol. 22,3 251-253. 28 May. 2024, doi:10.1370/afm.3101

3. Anjana, Ranjit Mohan et al. “Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17).” The Lancet. Diabetes & endocrinology vol. 11,7 (2023): 474-489. doi:10.1016/S2213-8587(23)00119-5

4. Gupta R, Jayant SS, Rastogi A, Bhadada SK, Bhansali A, Sachdeva N, Ram S. Incidence and risk factors for dysglycaemia in Asian-Indians: a 10-year population-based prospective cohort study. Postgrad Med J. 2023 May 19;99(1169):176-182. doi: 10.1136/postgradmedj-2021-141243. PMID: 37222055.

5. 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.

6. Del Prato, S., Bianchi, C., Miccoli, R. and Penno, G. (2007), Pharmacological intervention in prediabetes: considering the risks and benefits. Diabetes, Obesity and Metabolism, 9: 17-22. https://doi.org/10.1111/j.1463-1326.2007.00766.x

7. Perreault L. Prediabetes. [Updated 2022 Mar 3]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538537/

8. An X, Zhang Y, Sun W, et al. Early effective intervention can significantly reduce all-cause mortality in prediabetic patients: a systematic review and meta-analysis based on high-quality clinical studies. Front Endocrinol (Lausanne). 2024;15:1294819. Published 2024 Mar 1. doi:10.3389/fendo.2024.1294819

9. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015;3(11):866–875

10. Gong Q, Zhang P, Wang J, Ma J, An Y, Chen Y, Zhang B, Feng X, Li H, Chen X, Cheng YJ, Gregg EW, Hu Y, Bennett PH, Li G. Da Qing Diabetes Prevention Study G. Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study. Lancet Diabetes Endocrinol. 2019;7(6):452–461.