Disentangling Dual Threats: Premature Coronary Artery Disease and Early-Onset Type 2 Diabetes Mellitus in South Asians

South Asian individuals (SAs) face heightened risks of premature coronary artery disease (CAD) and early-onset type 2 diabetes mellitus (T2DM), with grave health, societal, and economic implications due to the region's dense population. Both conditions, influenced by cardiometabolic risk factors such as insulin resistance, hypertension, and central adiposity, manifest earlier and with unique thresholds in SAs. Epidemiological, demographic, nutritional, environmental, sociocultural, and economic transitions in SA have exacerbated the twin epidemic. The coupling of premature CAD and T2DM arises from increased obesity due to limited adipose storage, early-life undernutrition, distinct fat thresholds, reduced muscle mass, and a predisposition for hepatic fat accumulation from certain dietary choices cumulatively precipitating a decline in insulin sensitivity. As T2DM ensues, the beta-cell adaptive responses are suboptimal, precipitating a transition from compensatory hyperinsulinemia to beta-cell decompensation, underscoring a reduced functional beta-cell reserve in SAs. This review delves into the interplay of these mechanisms and highlights a prediabetes endotype tied to elevated vascular risk. Deciphering these mechanistic interconnections promises to refine stratification paradigms, surpassing extant risk-prediction strategies.