Twelve Co-morbidities' Association and Risks Associated with Prediabetes-Evidence Every Clinician Must Know

August 14 has been marked as World Prediabetes Day, set 90 days before World Diabetes Day (November 14), the typical timeframe needed to achieve a meaningful reduction in elevated HbA1c levels.

Prediabetes is a growing health concern in India, exceeding diabetes prevalence (11.4%) with a reported incidence of 15.3%. Its prevalence is comparable in urban (15.4%) and rural (15.2%) areas, but the absolute burden is higher in rural India (10,173 vs 4,783 cases) due to a larger population base, as shown in national data [n=113,043]. (1)

Prediabetes is commonly associated with multiple comorbidities, contributing to the overall disease burden. However, it also presents a crucial window for early intervention through lifestyle changes and, when needed, pharmacotherapy like metformin. Key comorbidities are discussed below-

1. Cardiovascular Diseases (CVD): Prediabetes increases CVD risk by coronary microvascular dysfunction, lipoprotein glycation, and early atherosclerosis. Insulin resistance, central obesity, and hyperinsulinemia contribute to a prothrombotic state and cardiac autonomic dysfunction. It increases risk of ACS by 2-fold (OR: 2.01; CI: 1.94–2.08), acute ischemic stroke by 2.2-fold (OR: 2.21; CI: 2.11–2.31), acute heart failure by 1.4-fold (OR: 1.41; CI: 1.29–1.55) [all p < 0.001].(2) In the PAMI cohort (n=7,512), 22.1% had prediabetes, which was linked to a higher MACCE risk [23.5%]. (3)

2. Dyslipidemia: Dyslipidemia associated with prediabetes contributes to atherogenesis through elevated triglycerides, reduced HDL-C, and small, dense LDL-C particles. In an Indian retrospective study (n=91,780), dyslipidemia was present in 40.36% of individuals with prediabetes, with the highest burden observed in those aged over 60 years. Significant lipid abnormalities included major-risk HDL (OR: 1.33), high triglycerides (OR: 1.89), very high non-HDL cholesterol (OR: 1.65), and high VLDL [OR: 1.31]. (4)

3. Chronic Kidney Disease (CKD): Prediabetes is associated with glomerular hyperfiltration, which may represent an early mechanistic link underlying the heightened susceptibility to CKD observed in prediabetes. In the CURE-CKD registry published in 2025, 3.6% (n=10,104) of 281,933 individuals with prediabetes developed CKD over a median follow-up of 2.5 years. (5)

4. Microvascular Complications: Prediabetes is associated with early microvascular damage, particularly retinopathy, CKD, and neuropathy. A meta-analysis of 35 studies found retinopathy as the most common, followed by CKD and neuropathy [e.g., sensory carpal tunnel syndrome]. (6)

5. Atrial Fibrillation (AF): Prediabetes and AF association stem from insulin resistance, oxidative stress, autonomic dysfunction, and prothrombotic states. Of 2.97 million AF-related MACCE hospitalizations, 1.6% involved prediabetics. Among 17,943 new AF cases, 20.7% had prediabetes. Prediabetics with AF had a 34% higher MACCE risk [OR: 1.34; p < 0.001]. (7)

6. Obesity (particularly abdominal obesity): Abdominal fat drives insulin resistance, β-cell dysfunction, and inflammation in prediabetes. In a study of 17,708 individuals, prediabetes incidence was 35.2%, while 21.6% regressed to normoglycemia over 4 years. Lower abdominal obesity (via BRI, WHtR, CVAI) was linked to ~1.45 times higher odds of regression. (8)

7. Non-Alcoholic Fatty Liver Disease (NAFLD) and MASLD: NAFLD, the hepatic manifestation of metabolic syndrome, is highly prevalent in prediabetes and linked to worse cardiometabolic outcomes and higher T2D risk. In overweight/obese prediabetics (n=202), NAFLD (FLI-defined) was found in 78%—far above the 30% general population rate. MASLD affects 37–50% of prediabetics and is 2.5 times more likely than in normoglycemics. Risks include 8.5 times for significant fibrosis, 6 times for advanced fibrosis, and 3.4 times for mortality. (9,10)

8. Erectile Dysfunction (ED) and Reproductive Issues in Men: Prediabetes impairs male fertility and erectile function via hormonal imbalance, oxidative stress, hyperglycemia, and microvascular dysfunction. In a cross-sectional study (75 prediabetics, 58 diabetics), semen parameters were significantly altered—low volume and concentration correlated with reduced testosterone (P = 0.004). Prediabetics had higher rates of abnormal semen pH (40.2% vs 31.5%), low vitality (38.6% vs 35.4%), and poor morphology (40.2% vs 33.0%) than diabeticsIn an Indian study (n=139), 50.3% of prediabetic men had ED, which showed significant correlation with HbA1c (p = 0.002) and random blood sugar [p = 0.003]. (11,12)

9. Polycystic Ovary Syndrome (PCOS) and Fertility Issues in Women: Insulin resistance plays a central role in the pathogenesis of PCOS, being present in 50–70% of cases. It leads to hyperinsulinemia, which enhances androgen synthesis and reduces SHBG levels. Prediabetes also increases the risk of PCOS-related infertility. (13)

10. Mental Health & Loneliness: In prediabetes, anxiety and depression are linked via inflammatory pathways and HPA axis dysregulation. In a study of 4,384 individuals, depression increased odds of prediabetes (OR: 1.83) and mortality (HR: 2.11). A 2025 (July) study (n=4,296) found 29.3% reported weekly loneliness; lonely individuals had a higher diabetes incidence (23.3 vs 18.4 per 1,000 person-years). Loneliness raised diabetes risk by 26% (HR: 1.26), and 53% with frequent loneliness (HR: 1.53), partly mediated by restless sleep [39.7%]. (14,15)

11. Cancers: Prediabetes is associated with a 15% higher overall cancer risk (RR: 1.15; 95% CI: 1.06–1.23) based on data from 891,426 individuals. Elevated site-specific risks include liver, endometrial, stomach/colorectal (16), pancreatic cancers [RR: 1.42; 95% CI: 1.36–1.49; p < 0.001] (17), and gallbladder cancer [aHR: 1.21; 95% CI: 1.04–1.41]. (18)

12. Mortality Risk: As per a 2025 published study, cardiovascular, renal, and acute diabetic mortality risks were significantly higher, with ADA-defined prediabetes accounting for 7%, 9%, and 31% of such deaths, respectively. In a cohort of 114,062 adults without diabetes followed for 18.4 years, ADA-defined prediabetes (26%) and IEC-defined prediabetes (7%) were associated with increased all-cause mortality (RR: 1.13 and 1.27, respectively) between ages 35–74. (19)

Metformin A Valuable Consideration

Most complications in prediabetes stem from insulin resistance and inflammation, leading to vascular disruption and increased cardiometabolic risk. Metformin—currently approved for prediabetes in 65 countries—is the only drug formally indicated to delay T2D. It targets core pathophysiologic mechanisms and provides added benefits such as improved lipids, BMI reduction, and long-term safety, making it especially valuable in early dysglycemia management. (20,21)

Takeaway for Clinicians:

• Prediabetes burden is substantial, affecting over 15% of the Indian population and rising across age groups and geographies.
• Prediabetes is not silent; it carries measurable risks for cardiovascular disease, kidney dysfunction, sexual and reproductive health issues, sleep disorders, mental health conditions, cancer, and more.
• Clinicians should be sensitized to these associations and adopt a proactive approach, screening high-risk individuals and early intervention.
• Lifestyle modification remains first-line, but early pharmacologic intervention with agents like metformin should be considered, especially in high-risk individuals.
• Timely detection and targeted action in prediabetes offer a valuable window to prevent disease progression and reduce long-term complications, which needs to be a highly relevant public health consideration in the Indian context.

Abbreviations: HbA1c – Glycated Hemoglobin, CVD – Cardiovascular Disease, ACS – Acute Coronary Syndrome, OR – Odds Ratio, CI – Confidence Interval, PAMI – Premature Acute Myocardial Infarction, MACCE – Major Adverse Cardiac and Cerebrovascular Events, CKD – Chronic Kidney Disease, CURE-CKD – Center for Kidney Disease Research and Education–Chronic Kidney Disease, HDL – High-Density Lipoprotein, LDL – Low-Density Lipoprotein, VLDL – Very Low-Density Lipoprotein, PCOS – Polycystic Ovary Syndrome, T2D / T2DM – Type 2 Diabetes Mellitus, BRI – Body Roundness Index, WHtR – Waist-to-Height Ratio, CVAI – Chinese Visceral Adiposity Index, HPA – Hypothalamic–Pituitary–Adrenal, HR – Hazard Ratio, IFG – Impaired Fasting Glucose, IGT – Impaired Glucose Tolerance, ADA – American Diabetes Association, IEC – International Expert Committee, NGT – Normal Glucose Tolerance, ED – Erectile Dysfunctionm, NAFLD – Non-Alcoholic Fatty Liver Disease, FLI – Fatty Liver Index, MASLD – Metabolic Dysfunction-Associated Steatotic Liver Disease, OSA – Obstructive Sleep Apnea, AHI – Apnea–Hypopnea Index, MACCE – Major Adverse Cardiac and Cerebrovascular Events, AF – Atrial Fibrillation, IGF-1 – Insulin-like Growth Factor 1

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. 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

3. Zhao, Xinlong et al. “Prognostic impact of prediabetes on long-term cardiovascular outcomes in patients under 35 with premature acute myocardial infarction.” Diabetology & metabolic syndrome vol. 17,1 90. 18 Mar. 2025, doi:10.1186/s13098-025-01662-3

4. Shimi Sundharan,Shibani Ramchandran, Raj Jatale et.al.Dyslipidemia in prediabetes population: a retrospective study of 91780 cases. Int J Health Sci Res. 2022; 12(10):132-139. DOI: https:// doi.org/10.52403/ijhsr.20221017

5. Alicic, Radica Z et al. “Incidence of chronic kidney disease among adults with prediabetes in the CURE-CKD registry, 2013-2020.” Diabetes, obesity & metabolism vol. 27,6 (2025): 3536-3541. doi:10.1111/dom.16365

6. Thiab, Sama et al. “Microvascular complications in prediabetes: a systematic review & meta-analysis.” Diabetes research and clinical practice vol. 225 (2025): 112261. doi:10.1016/j.diabres.2025.112261

7. Desai, Rupak et al. “Prediabetes: An overlooked risk factor for major adverse cardiac and cerebrovascular events in atrial fibrillation patients.” World journal of diabetes vol. 15,1 (2024): 24-33. doi:10.4239/wjd.v15.i1.24

8. Yang, Hongguang et al. “Associations of obesity-related indices with prediabetes regression to normoglycemia among Chinese middle-aged and older adults: a prospective study.” Frontiers in nutrition vol. 10 1075225. 19 May. 2023, doi:10.3389/fnut.2023.1075225

9. Arias-Fernández, María et al. “Fatty Liver Disease in Patients with Prediabetes and Overweight or Obesity.” Metabolites vol. 13,4 531. 7 Apr. 2023, doi:10.3390/metabo13040531

10. Cusi, Kenneth et al. “Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in People With Diabetes: The Need for Screening and Early Intervention. A Consensus Report of the American Diabetes Association.” Diabetes care vol. 48,7 (2025): 1057-1082. doi:10.2337/dci24-0094

11. Anyigor‐Ogah CS, Oboke OS, Okorocha AE, Anyigor‐Ogah O, Oboke HU, Ekechi AN, et al. The association between reproductive hormones and semen parameters: A cross-sectional comparative study of prediabetics in Southeast Nigeria. Ann Afr Med 0;0:0.

12. Vishwakarma RK, Patel NP, Goutam P. Evaluation of Erectile Dysfunction in Prediabetic Males at Tertiary Care Center in Central India. J Assoc Physicians India 2024;72(9):e10–e13.

13. Pani, Arianna et al. “From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management.” International journal of endocrinology vol. 2020 6276187. 8 Jun. 2020, doi:10.1155/2020/6276187

14. Zhou, Jin, and Xiaojiao Yang. “Association between depression and the prevalence and prognosis of prediabetes: Data from National Health and Nutrition Examination Survey (NHANES) 2013-2018.” PloS one vol. 20,1 e0304303. 13 Jan. 2025, doi:10.1371/journal.pone.0304303

15. Wang, Weiwei et al. “Could loneliness accelerate the progression of diabetes among adults with prediabetes: national longitudinal cohort.” BMC public health vol. 25,1 2441. 12 Jul. 2025, doi:10.1186/s12889-025-23675-3

16. Huang, Yi et al. “Prediabetes and the risk of cancer: a meta-analysis.” Diabetologia vol. 57,11 (2014): 2261-9. doi:10.1007/s00125-014-3361-2

17. Huang, Xuefang et al. “Prediabetes increases the risk of pancreatic cancer: A meta-analysis of longitudinal observational studies.” PloS one vol. 19,10 e0311911. 15 Oct. 2024, doi:10.1371/journal.pone.0311911

18. Park, Joo-Hyun et al. “Prediabetes persistence or remission and subsequent risk of gallbladder cancer: A nationwide cohort study.” European journal of cancer (Oxford, England : 1990) vol. 213 (2024): 114312. doi:10.1016/j.ejca.2024.114312

19. Fermín-Martínez, Carlos A et al. “Prediabetes and risk of all-cause and cause-specific mortality: a prospective study of 114,062 adults in Mexico City.” The Journal of clinical endocrinology and metabolism, dgaf225. 10 Apr. 2025, doi:10.1210/clinem/dgaf225

20. 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.

21. Lim, Beth Shi Yu et al. “Metformin use in prediabetes: A review of evidence and a focus on metabolic features among peri-menopausal women.” Diabetes, obesity & metabolism vol. 27 Suppl 3,Suppl 3 (2025): 3-15. doi:10.1111/dom.16442