The Risk of Type 2 Diabetes Mellitus: Cardiorenometabolic Syndrome and Its Components—A Call to Action

1. Introduction

Cardiorenometabolic syndrome, a constellation of interrelated risk factors including insulin resistance, central obesity, dyslipidemia, and hypertension, is rapidly becoming one of the defining global health challenges of our time. Metabolic syndrome (MetS), as the unifying clinical entity underpinning this syndrome, significantly increases the risk of development of both type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs)—the latter of which remains the leading cause of death and disability worldwide. Although equally important, renal complications such as chronic kidney disease are frequently underrecognized, despite their central role in disease progression and increased mortality. If MetS is left unaddressed, the downstream effects are devastating: escalating healthcare costs, diminished quality of life, and avoidable mortality [1].

Amidst this troubling epidemiological landscape, projections are sobering: global obesity rates are expected to rise from 650 million to over 2 billion individuals by 2035, and T2DM cases are estimated to increase from 500 million to 1.3 billion by 2050 [2]. These figures are not only alarming from a clinical perspective—they are also economic and social red flags, especially in low- and middle-income countries, where healthcare systems are already under strain. It is within this critical context that we present this Special Issue, which is dedicated to the evolving narrative of MetS and its increasingly complex web of determinants. The contributions included in this Issue span population health interventions, molecular mechanisms, pharmacogenetics, and behavioral sciences, reflecting the truly multidisciplinary nature of the challenge at hand [3].

2. A Sneak Peek at the Published Body of Literature

Understanding and managing MetS requires coordinated insight from multiple domains of research and clinical practice. One area of increasing importance is the role of healthcare delivery systems and population health initiatives in mitigating the glycemic burden and improving cardiometabolic outcomes. Models incorporating clinical pharmacists and multidisciplinary care teams have shown promise in improving key metabolic parameters, especially HbA1c, and may offer scalable solutions in both primary and secondary prevention. These approaches align closely with value-based care principles, where clinical efficacy must be matched by cost-effectiveness and system-level sustainability.

At the other end of the spectrum, the cellular and molecular mechanisms underlying MetS are gaining attention as targets for therapeutic innovation. Hyperglycemia, endothelial dysfunction, and post-translational protein modifications—such as O-GlcNAcylation—are increasingly understood to contribute directly to vascular pathology in diabetes and MetS [4]. Additionally, chronic hyperglycemia and systemic inflammation significantly impact glomerular filtration and renal endothelial integrity, further emphasizing the bidirectional relationship between metabolic dysregulation and kidney health. These insights not only improve our understanding of disease progression, but also provide new molecular targets for pharmacological intervention. The role of epigenetics and non-coding RNAs, particularly microRNAs released through exosomes, also presents exciting diagnostic and therapeutic possibilities. These circulating biomarkers have the potential to non-invasively reflect adipose and systemic metabolic dysfunction, thus bridging the gap between obesity, insulin resistance, and overt T2DM [5].

Genetic susceptibility remains a cornerstone of our understanding of MetS and T2DM risk. Advances in polygenic risk scoring and genome-wide association studies are contributing to a more refined stratification of at-risk individuals [6]. However, in order to move from population-level insights to patient-centered care, there is a need to translate genetic findings into actionable, individualized treatment strategies. This includes tailoring drug choices based on pharmacogenetic profiles and anticipating drug–drug or gene–environment interactions, which could significantly alter therapeutic outcomes in patients with multiple metabolic risk factors [7].

Behavioral and lifestyle determinants continue to be essential in determining both the origin and progression of MetS. Psychological eating patterns, emotional dysregulation, and sedentary lifestyles remain pervasive, and addressing these through integrated behavioral health strategies is critical. Exercise interventions, particularly those combining aerobic and resistance modalities, have been shown to improve not only glycemic control, but also broader cardiovascular outcomes. Coupling these interventions with patient education and adherence support can enhance their long-term efficacy and relevance across diverse populations [8].

In Croatia, for example, national organizations like the Croatian Hypertension League, in collaboration with several partner societies, are actively engaged in combating the cardiorenometabolic burden. Through public health campaigns such as “Mission 70/26” and “Do You Know What Is Your Number?”, the League and its collaborators focus on improving blood pressure, lipid control, and other modifiable risk factors by enhancing health literacy. These efforts serve as scalable models for community engagement and population-level risk reduction [9].

3. Conclusions: A Roadmap Going Forward

As the field of cardiorenometabolic syndrome continues to evolve, it is clear that no single intervention, biomarker, or therapeutic can offer a panacea. Rather, a cohesive, multidisciplinary, and personalized approach is required to meet the complexity of the disease. In this Special Issue, we have deliberately chosen to highlight studies that either already impact or are poised to reshape current clinical practices.

Given the global rise of obesity and T2DM and their intertwined relationship with cardiovascular and renal outcomes, a holistic approach to individuals with obesity, metabolic syndrome, or prediabetes is essential to curb progression to type 2 diabetes and mitigate downstream cardiorenal complications [10]. Efforts such as those by the Croatian Hypertension League serve as inspiring examples of how local leadership and targeted education can drive meaningful change [9]. Moreover, this Special Issue serves not only as a scholarly update, but also as a strategic call to action for healthcare providers, researchers, policymakers, and patients alike. The field is brimming with innovation—from molecular biomarkers to digital health interventions—and it is imperative that all stakeholders remain vigilant and informed. We hope that the work presented here will engage a broad readership—from students and early-career scientists to seasoned clinicians and decision-makers—and ultimately lead to meaningful improvements in patient care, policy development, and global health outcomes.