The Prediabetes Wake-Up Call: Time for Proactive Endocrine Care

Long regarded as a transitional phase, prediabetes occupies a clinical grey zone—seemingly reversible, yet increasingly recognized as metabolically active and consequential. It represents more than a warning sign—it is a critical window for action. As endocrinologists, we find ourselves on the front lines of a global metabolic crisis, with nearly one in three adults meeting diagnostic criteria.

Prediabetes [also referred to as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), intermediate hyperglycaemia as preferred by the WHO, and an expert committee convened by the American Diabetes Association (ADA) has suggested high-risk state of developing diabetes] is defined by a fasting glucose level of 100–125 mg/dL, a glucose level of 140–199 mg/dL measured 2 hour after a 75 g oral glucose tolerance test, or an HbA1c of 5·7% to 6·4%. Individuals at the higher end of these thresholds face the greatest risk of progression to type 2 diabetes. The onset of prediabetes and type 2 diabetes mellitus (T2DM) is influenced by a combination of genetic, behavioural, and environmental factors. Key risk factors include excess body fat—especially central obesity—aging (typically over 35 years), physical inactivity, poor dietary patterns, and lower socioeconomic status.[1] Genetic predisposition significantly contributes to risk, and certain medical conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and a history of gestational diabetes mellitus (GDM), further increase vulnerability. Additionally, notable ethnic and racial disparities exist, with Asian, African American, and Hispanic populations experiencing a higher prevalence of T2DM.[2] The global prevalence of prediabetic conditions continues to rise at an alarming rate. In 2021, IGT affected 9.1% of adults—approximately 464 million people—while IFG was present in 5.8% (298 million). Projections for 2045 estimate a further increase, with IGT expected to affect 10.0% (638 million) and IFG 6.5% (414 million), underscoring the need for global public health interventions. According to the ICMR-INDIAB-17 study, India is witnessing a significant shift in its glycaemic profile, with the prevalence of prediabetes (15.3%) now exceeding that of diabetes (11.4%).[3] This trend reflects a substantial at-risk population and highlights the critical need for early detection, population-level prevention efforts, and robust healthcare infrastructure to manage the growing dysglycemia burden.

Prediabetes is not a harmless state—it represents an active stage in the progression toward T2DM, often advancing more rapidly than commonly perceived. Longitudinal studies indicate that more than 60% of individuals with prediabetes will transition to T2DM within 5 years, highlighting the urgency of early recognition and intervention.[4] Prediabetes, traditionally viewed as an intermediate stage between normoglycemia and T2DM, is now increasingly recognized as a clinically significant condition associated with early and progressive vascular damage. Substantial evidence suggests that macrovascular complications begin during the prediabetic phase, preceding the onset of clinically diagnosed diabetes.[5] A 2020 meta-analysis of 129 studies, involving over 10 million individuals revealed that prediabetes was associated with a 13% increase in all-cause mortality, a 15% increase in cardiovascular disease (CVD), a 16% increase in coronary heart disease, and a 14% increase in stroke, compared to normoglycemic individuals. In patients with pre-existing atherosclerotic cardiovascular disease (ASCVD), the presence of prediabetes significantly exacerbates risk. Over a median follow-up of 3.2 years, prediabetes was associated with a 36% increase in all-cause mortality (RR 1.36), a 37% increase in composite CVD outcomes (RR 1.37), and a 15% rise in coronary artery disease (CAD) events (RR 1.15). The burden of cerebrovascular disease is also heightened in prediabetes. Individuals with prediabetes are at increased risk for transient ischemic attacks (TIAs), ischemic strokes, and stroke recurrence. A study found that both diabetes and prediabetes were associated with poorer 30-day outcomes following acute ischemic stroke. Similarly, the IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone therapy in insulin-resistant patients without diabetes reduced the incidence of stroke, myocardial infarction, and progression to T2DM, emphasizing the potential benefits of early intervention in high-risk individuals.

Indians spend an average of 35 to 40 years in normoglycemia before dysglycemia begins. The rate of conversion from normal glucose tolerance (NGT) to IFG is 7.5% per year. Among those with IFG, 22.8% revert to NGT, while 8.6% progress to diabetes annually. Similarly, 5.1% of individuals progress to IGT annually, with 15.4% reverting to normal and 13.9% progressing to diabetes.[6] The average duration spent in IFG is 9.7 years, while for IGT it is 6.1 years. These timelines are significantly shorter than those reported in Western populations, where prediabetes often spans 10–15 years. Studies indicate that almost 50% of Indian prediabetics progress to type 2 diabetes within 5 years, suggesting a compressed natural history.[6] The annual incidence of diabetes among Indian prediabetics ranges from 6% to 14.7%. Interestingly, IFG is often more prevalent than IGT in Indian epidemiological surveys. In a cohort from Eastern India, the progression rate was as high as 71.5 per 1,000 person-years, translating to a 15%–19% annual risk, second only to that seen in Pima Indians. In contrast, the rate of direct progression from NGT to diabetes was much lower and similar to global norms.[6] The CURES study from Chennai showed a 58.9% conversion rate from prediabetes to diabetes over 9.1 years. Key predictors of this progression included: advancing age, family history of diabetes, 2-h plasma glucose, HbA1c, low HDL cholesterol, and physical inactivity.[7] A major reason for accelerated progression is that Indians exhibit β-cell dysfunction at milder levels of insulin resistance. Even in prediabetes, the insulin response is disproportionately elevated due to increased hepatic and peripheral insulin resistance. However, the β-cells fail to meet this demand, resulting in early decompensation. Studies show that the disposition index is significantly lower in Indian prediabetics, indicating early exhaustion of β-cell reserve.[6] At the same body mass index (BMI), Indians have higher total body fat and visceral adiposity, with less lean muscle mass compared to Westerners. This characteristic, termed the ‘Thin-Fat Indian Phenotype’, contributes to early insulin resistance and hepatic steatosis.[8] In susceptible individuals, positive caloric balance leads to adipocyte hypertrophy, inflammation, and adipogenesis failure—a condition known as adiposopathy. This results in lipid spillover into liver and muscle, contributing to metabolic dysfunction. Genome-wide studies have identified adipose tissue–specific transcriptomic abnormalities, including partial lipodystrophy patterns, in Indians.[9] Only 22% of T2DM-associated genes identified in European populations are replicated in Indian studies. Indian GWAS and meta-analyses have identified risk polymorphisms in TCF7L2 (rs7903146, rs12255372), ADIPOQ, CDKAL1, CDKN2A, and FTO.[10] However, significant heterogeneity exists within Indian subpopulations. For instance, people from Eastern and Northeastern India show different genetic profiles and prevalence rates compared to those from the South or West, due to diverse epigenetic, dietary, and environmental exposures.[11] India is undergoing a rapid nutrition transition, with total calorie intake increasing by 31%, mostly from dairy, animal products, and ultra-processed foods (UPFs). The contribution of UPFs to daily caloric intake rose from 3.6% to 11.6%, and animal-source foods from 15.1% to 24.3%.[12]

This dietary pattern causes exaggerated glycaemic spikes (causing β-cell stress), lipotoxicity from excess fats (causing hepatic insulin resistance) and ectopic fat deposition in lean, previously undernourished individuals.[13] Classically attributed to hyperglycaemia, microvascular complications are now seen in prediabetes, especially in IGT. Prevalence data include neuropathy: >10%, with one Indian IGT study showing 32% prevalence; Retinopathy: 5%–8% (NHANES, Funagata) and nephropathy: 10% (PREVEND study).[14,15,16] In India, low HDL—common even in lean subjects—is an independent predictor of neuropathy. Genetic variants like CETP polymorphisms may contribute to this susceptibility.[10] Studies using MR spectroscopy showed that Asian-Indian men have higher hepatic triglyceride content and insulin resistance compared to Caucasians, even at similar or lower BMI.[17] Intramyocellular lipid accumulation is also more pronounced, contributing to muscle insulin resistance.[18]

Despite these alarming statistics, the clinical response to prediabetes remains inconsistent and insufficient. We must reframe prediabetes not merely as a risk factor, but as a critical opportunity to reverse the metabolic trajectory and prevent downstream complications.

Testing should be overweight/obese adults (BMI more than 25 kg/m² or more than 23 kg/m² in Asians), who have one or more risk factors, including 1^st degree relatives with diabetes, age more than 35 years, CVDs, hypertension, triglycerides more than 250 mg/dl, HDL <35 mg/dl, individuals with PCOS, physical inactivity. It has suggested to use the Indian diabetes risk score (IDRS) which predicts the probability of diabetes based on age, abdominal obesity, family history of diabetes, physical inactivity. Latest IDF position statement advises using 1 hour post glucose load of more than 155 mg/dl to identify people at risk for developing type 2 diabetes.

Lifestyle modification is the cornerstone of prediabetes management, offering a cost-effective and evidence-based strategy to prevent or delay the onset of T2DM and reduce associated complications. Once diagnosed, timely and sustained intervention is critical. The ADA recommends a minimum of 7% weight reduction from baseline body weight through a calorie-restricted, balanced diet combined with at least 150 min of moderate-intensity aerobic physical activity per week (e.g., brisk walking, cycling). Numerous large-scale trials have validated this approach. The Diabetes Prevention Program (DPP), the Finnish Diabetes Prevention Study, the Da Qing Diabetes Prevention Study (DQDPS), and the DPP Outcomes Study (DPPOS) have consistently demonstrated that intensive lifestyle interventions can reduce the incidence of T2DM by 39%–58%.[19] Indian studies such as the Indian Diabetes Prevention Program (IDPP) and the Diabetes Community Lifestyle Improvement Program (D CLIP) also showed similar results.[7,20] A recent study from India has shown robust reduction in risk of diabetes from a yoga based intervention.[21] Low-carbohydrate diets primarily lower postprandial glucose excursions and reduce insulin demand. Beyond glycemic control, they promote satiety by suppressing hunger hormones (insulin and ghrelin) and stimulating satiety hormones (GLP-1 and peptide YY). In one study, 50% of participants following a low-carbohydrate diet achieved a ≥0.5% reduction in HbA1c, compared to 22% in those following traditional dietary guidelines. High-protein diets also enhance satiety through modulation of the gut-endocrine axis, decreasing ghrelin and increasing peptide YY levels. In a clinical trial, individuals consuming a high-protein diet (30% of total calories) over 6 months achieved a 100% reversion to normoglycemia, compared with 33% in the control group. Although no drug has yet received FDA approval specifically for diabetes prevention, several agents have demonstrated efficacy in delaying progression. While lifestyle modification remains the primary intervention for prediabetes, pharmacologic agents such as metformin have demonstrated efficacy in high-risk individuals, particularly when lifestyle changes alone are insufficient. The ADA advises considering metformin in individuals with prediabetes, who are at high risk, particularly those with BMI ≥35 kg/m², age >60 years, or a history of GDM. The American Association of Clinical Endocrinology (AACE) supports off-label metformin use for individuals with IFG, IGT, or elevated HbA1c, who do not respond to lifestyle modification after 3–6 months. The Drug Controller General of India (DCGI) has formally approved metformin for the management of prediabetes. In India, metformin is indicated for overweight adults with IGT, IFG, or elevated HbA1c. Other drugs-used include Glitazones-DREAM trial -Rosiglitazone used, Pioglitazone in Act Now Trial and AlphaGlucosidase inhibitor-Acarbose in STOP-NIDDM Trial. Semaglutide in STP10 trial showed that 81% of individuals with prediabetes and obesity, who received semaglutide 2.4 mg returned to normoglycemia, compared to just 14% in the control group.

Diabetes and its related complications can begin to develop even before the onset of prediabetes; therefore, initiating preventive interventions as early as the pre-prediabetic stage is crucial for effective risk reduction. Key strategies should include:

• 1) Promoting healthy weight and physical activity in women of reproductive age to prevent GDM. Encouraging to have a balanced diet with low GI foods before and during pregnancy and promoting breastfeeding and postnatal lifestyle counselling to reduce long-term diabetes risk.

• 2) In schools, encouraging daily physical activity, structured sports, healthy food environments and regulating screen time will help combat childhood obesity and insulin resistance.

• 3) Family-based approaches, including early screening, lifestyle counselling, and parental role modelling.

• 4) At the policy level, governments can support prevention through taxes on sugary drinks, subsidies for fruits and vegetables, urban planning that encourages active lifestyles in the form of development of parks, bicycle paths, and pedestrian-friendly neighbourhoods and to incorporate National surveillance programs.

Prediabetes remains an underexplored frontier in preventive endocrinology. Key areas for future research include: 1) More precise screening algorithms 2) Improved diagnostic tools 3) Risk stratification models for diabetes and ASCVD progression 5) Clinical trials assessing long-term outcomes of newer agents (e.g., GLP-1 RAs, SGLT2 inhibitors, dual agonists). Prediabetes is an active metabolic state that demands timely intervention. Early detection and targeted management can prevent progression, reduce complications, and ease the healthcare burden.