Prediabetes and CV Risk: Evidence Review in 2025

Prediabetes: Potential Cardiovascular (CV) Warning Sign: India has a high prediabetes prevalence (15.3%), nearly equal in urban (15.4%) and rural (15.2%) areas. (1) In India, isolated IFG predominates, with rapid progression to diabetes (55% in 3 years) even at lower BMI. Asian Indians have higher central adiposity and insulin resistance, worsening metabolic responses to weight gain; amplifying CV risk even in prediabetes, and highlighting the need for early interventions. (1,2) A recent study published in March 2025 included young acute myocardial infarction patients (<35 years) and found prediabetes in 22.1% of cases, with a significantly higher incidence of major adverse cardiovascular and cerebrovascular events (MACCE) compared to normoglycemic individuals (27.3% vs. 18.4%). After adjusting for confounders, prediabetes remained an independent predictor of adverse outcomes (HR 1.51; 95% CI 1.05–2.18; p=0.027), with risk comparable to diabetes.​ (3)

Pathophysiology Linking Prediabetes to CV Events: Prediabetes involves insulin resistance and β-cell dysfunction, leading to low-grade inflammation and endothelial damage. (4) Central obesity fuels cytokine release (e.g., tumor necrosis factor alpha, intercellular adhesion molecule-1), promoting atherosclerosis. Hyperglycemia worsens vascular injury via lipoprotein glycation and oxidative stress. These processes contribute to early cardiovascular disease. Surrogate markers like high-sensitivity C-reactive protein, carotid intima-media thickness, and microalbuminuria are often elevated, signaling subclinical vascular dysfunction and heightened CV risk even before progression to overt diabetes. (5)

Indian-Specific Risk Amplifiers: Indians suffer early CV risk, evident even before diabetes, with most newly diagnosed T2DM patients classified as high or very high risk and a mean 10-year CVD risk of 15.3%. (6) Indians exhibit a distinct "thin-fat" phenotype—marked by abdominal adiposity, insulin resistance, and dyslipidemia—even at low BMI. (7) This metabolic profile, seen from childhood, is compounded by high-carbohydrate diets and sedentary lifestyles. (8) Studies show higher truncal fat, insulin resistance, and beta-cell stress compared to whites, predisposing this group to early-onset diabetes and amplifying cardiovascular risk well before overt disease, as reflected in high-risk scores at diagnosis. (6)

Identifying High-Risk Individuals in Practice: Adults over 30 years with risk factors like family history, hypertension, PCOS, inactivity, or central obesity should be screened using HbA1c, fasting blood glucose (FBG), or oral glucose tolerance test (OGTT).(9) As per ADA 2025, the presence of prediabetes should prompt comprehensive cardiovascular risk assessment. (10)

Evidence for Metformin in CV Risk Reduction: The Diabetes Prevention Program (DPP) enrolled 3,234 high-risk adults to assess diabetes prevention using metformin (850 mg BID), lifestyle changes, or placebo. Over 2.8 years, metformin reduced diabetes incidence by 31% vs. placebo. Long-term follow-up in the DPPOS showed a sustained risk reduction of 18% over 10–15 years. Metformin was especially effective in individuals with obesity, elevated fasting glucose, or a history of gestational diabetes. (11)

The Indian Diabetes Prevention Programme (IDPP; n=531) was a randomized, controlled trial assessing diabetes prevention in Asian Indians with impaired glucose tolerance (IGT). Participants were assigned to control, lifestyle modification, metformin (250 mg BID), or both. Over 3 years, metformin alone reduced diabetes incidence from 55% to 40.5%, with a 26.4% relative risk reduction (p=0.029) and number needed to treat of 6.9, demonstrating efficacy of low-dose metformin in this high-risk population. (12)

Proactive Prediabetes Care: Integrating Lifestyle & Pharmacological Approach: Lifestyle modification is essential but often insufficient in Indian prediabetes due to early beta-cell dysfunction and rapid disease progression. The Indian Expert Consensus Statement (on Approach and Management of Prediabetes in India) suggests early consideration of metformin (250–850 mg/day), especially in younger individuals with additional risk factors such as BMI >35 kg/m² or prior GDM, and initiation after 6 months of failure of lifestyle interventions. Metformin is the only pharmacologic agent recommended to prevent or delay type 2 diabetes,8 and is approved for prediabetes in 66 countries. (13)

Take-Home Message

• Prediabetes is highly prevalent in India and significantly elevates CV risk—even in young adults- necessitating the need for early detection and intervention.
• Asian Indians are uniquely vulnerable due to early insulin resistance, central adiposity, and rapid progression to diabetes even at lower BMI.
• Screening high-risk adults and assessing cardiovascular risk may be essential even at the stage of prediabetes.
• Lifestyle modification plus early metformin use, supported by Indian & global guidelines, can effectively delay T2D and reduce CV complications when appropriately indicated.

References:

1. 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

2. Sandforth, Leontine et al. “Prediabetes remission to reduce the global burden of type 2 diabetes.” Trends in endocrinology and metabolism: TEM, S1043-2760(25)00004-9. 14 Feb. 2025, doi:10.1016/j.tem.2025.01.004

3. Zhao, X., Zhuang, Y., Tang, S. et al. Prognostic impact of prediabetes on long-term cardiovascular outcomes in patients under 35 with premature acute myocardial infarction. Diabetol Metab Syndr 17, 90 (2025). https://doi.org/10.1186/s13098-025-01662-3

4. Brannick B, Dagogo-Jack S. Prediabetes and Cardiovascular Disease: Pathophysiology and Interventions for Prevention and Risk Reduction. Endocrinol Metab Clin North Am. 2018;47(1):33-50. doi:10.1016/j.ecl.2017.10.001

5. Nanavaty D, Green R, Sanghvi A, et al. Prediabetes is an incremental risk factor for adverse cardiac events: A nationwide analysis. Atheroscler Plus. 2023;54:22-26. Published 2023 Sep 14. doi:10.1016/j.athplu.2023.08.002

6. Unnikrishnan, A G et al. “Cardiovascular risk in newly diagnosed type 2 diabetes patients in India.” PloS one vol. 17,3 e0263619. 31 Mar. 2022, doi:10.1371/journal.pone.0263619

7. Siddiqui MK, Anjana RM, Dawed AY, et al. Young-onset diabetes in Asian Indians is associated with lower measured and genetically determined beta cell function [published correction appears in Diabetologia. 2022 Jul;65(7):1237. doi: 10.1007/s00125-022-05707-4.]. Diabetologia. 2022;65(6):973-983. doi:10.1007/s00125-022-05671-z

8. 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.

9. Alvarez S, Coffey R, Mathias PM, et al. Prediabetes. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459332/

10. American Diabetes Association Professional Practice Committee; 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S27–S49. https://doi.org/10.2337/dc25-S002

11. Aroda VR, Knowler WC, Crandall JP, et al. Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study. Diabetologia. 2017;60(9):1601-1611. doi:10.1007/s00125-017-4361-9

12. Ramachandran, A et al. “The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1).” Diabetologia vol. 49,2 (2006): 289-97. doi:10.1007/s00125-005-0097-z

13. Petrie, John R. “Metformin beyond type 2 diabetes: Emerging and potential new indications.” Diabetes, obesity & metabolism vol. 26 Suppl 3 (2024): 31-41. doi:10.1111/dom.15756

14. American Diabetes Association Professional Practice Committee; 3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S50–S58. https://doi.org/10.2337/dc25-S003