Open research questions in Diabetes, Cardiovascular Risks, and Lipoproteins

What the literature leaves open

• There is a lack of comprehensive data on the prevalence of Metabolic Syndrome among adults in Pakistan. Existing studies have shown varying prevalence rates, highlighting the need for a systematic review and meta-analysis.

  Prevalence of Metabolic Syndrome among Adult Population in Pakistan: A Systematic Review and Meta-Analysis · 2026 · DOI

• The need to investigate the mediating role of BMI in the association between NHHR and cognitive impairment. The lack of studies examining the nonlinear relationship between NHHR and cognitive impairment.

  Association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and cognitive impairment in middle-aged and elderly Chinese population · 2026 · DOI

• Current primary screening tools have recognized limitations in sensitivity for detecting the earliest stages of glycemic dysregulation. The 2-h post-load glucose criterion can misclassify a significant number of high-risk individuals who later progress to type 2 diabetes.

  Clinical utility of 1-h post-load glucose in accelerating diagnosis of type 2 diabetes: a prospective cohort study · 2026 · DOI

• The study aims to investigate this gap using a multistate model with a large sample size and sufficient covariate data.

  Healthy lifestyle and related metabolomic signatures associated with decreased risk and delayed progression of type 2 diabetes mellitus transitions: a large prospective cohort study · 2026 · DOI

• The need for novel biomarkers that can quantify the metabolic 'load' imposed by adipose tissue and the metabolic 'capacity' provided by lean tissue. The lack of a systematic review and meta-analysis of the association between LCI and cardiometabolic risk.

  Load-capacity index and cardiometabolic risk: a longitudinal meta-analysis · 2026 · DOI

• Nationally representative data describing the CKM stage distribution and associated unhealthy lifestyle factors are lacking in Iran. Prior studies have reported varying prevalence of CKM syndrome in different countries, but there is a need for a comprehensive study in Iran.

  Patterns of cardiovascular-kidney-metabolic (CKM) syndrome stages and prevalence of lifestyle risk factors in a nationally representative iranian population study · 2026 · DOI

• The relationship between chronic pain phenotypes and vascular disease progression is uncertain. Prior studies have not jointly evaluated pain phenotype and spatial burden across cardiovascular and diabetic microvascular outcomes in T2DM.

  Pain phenotypes and chronic pain burden are associated with atherosclerotic cardiovascular disease and vascular disease progression in participants with type 2 diabetes: a UK Biobank cohort study with multistate analysis · 2026 · DOI

• The study identifies challenges in measuring insulin resistance, including the need for reliable and standardized methods. Another challenge is the complexity of the relationship between occupational context and insulin resistance risk, which involves multiple sociodemographic and lifestyle factors.

  Risk of Insulin Resistance: Comparison of the Commerce vs. Industry Sector and Associated Variables · 2025 · DOI

• Further research is needed to explore the differences in MetS prevalence according to metabolic syndrome component, population type, community setting, and diagnostic criteria. Studies should investigate the impact of MetS on non-communicable diseases in Pakistan and the continued epidemiological and nutritional transitions taking place across South Asia.

  Prevalence of Metabolic Syndrome among Adult Population in Pakistan: A Systematic Review and Meta-Analysis · 2026 · DOI

• The cardiovascular-kidney-metabolic syndrome (CKM) framework captures interconnected risks of adiposity, metabolic dysregulation, kidney disease, and cardiovascular disease, yet sex-specific differences in CKM stage distribution and lifestyle associations remain underexplored in adolescents.

  Sex Differences in Early Stages of Cardiovascular-Kidney-Metabolic Syndrome in Adolescents: Associations With Dietary and Lifestyle Factors · 2026 · DOI

• The association of cumulative triglyceride glucose–Chinese visceral adiposity index (TyG-CVAI) exposure with subsequent heart disease remains incompletely characterized.

  Association of cumulative triglyceride glucose–Chinese visceral adiposity index with incident heart disease in a Chinese cohort · 2026 · DOI

• Although the triglyceride–glucose (TyG) index has been associated with cardiovascular disease (CVD), its association with longer-term outcomes, including disability-free survival (DFS), has not been well characterised.

  Associations of the triglyceride-glucose index and its obesity-related derivative with all-cause mortality, cardiovascular events, and long-term survival and functioning in older adults · 2026 · DOI

• The association between the cholesterol, high-density lipoprotein, and glucose (CHG) index and stroke risk among individuals with cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 remains unclear.

  Association of the cholesterol, high-density lipoprotein, and glucose index with stroke risk in individuals with cardiovascular-kidney-metabolic syndrome stages 0-3: a national prospective cohort study · 2026 · DOI

• The prognostic significance of CVKLM profiles, their incremental value beyond established risk tools, and their clinical utility remain to be established.

  Redefining Cardiometabolic Disease: Expert Consensus on the CardioVascular–Kidney–Liver–Metabolic (CVKLM) Multiorgan Staging · 2026 · DOI

• However, whether plasma levels of Aβ40 are associated with metabolic traits in humans without established CVD remains poorly understood.

  Amyloid‐beta (1–40) peptide is associated with systemic metabolic health · 2026 · DOI

• The long-term burden, demographic drivers, and age-related heterogeneity of key cardiovascular-kidney-metabolic (CKM) syndrome components in China remain incompletely characterized.

  Burden, Drivers, and Age-related Heterogeneity of Key Components of Cardiovascular-kidney-metabolic Syndrome in China, 1990-2023: A National Burden Analysis with an Exploratory Patient-level Clinical Analysis · 2026 · DOI

• The clinical heterogeneity of MetS is not well understood. There is a need to identify distinct metabolic phenotypes and examine their association with MetS.

  Metabotype Risk Clustering Based on Metabolic Disease Biomarkers and Its Association with Metabolic Syndrome in Korean Adults: Findings from the 2016–2023 Korea National Health and Nutrition Examination Survey (KNHANES) · 2025 · DOI

• However, little is known about the suitability of the widely adopted T2D risk assessment tool, Canadian Diabetes Risk Questionnaire (CANRISK), for this population.

  Validation of the Canadian Diabetes Risk Questionnaire Tool Among Young African, Caribbean, and Black Adults Living in Canada · 2025 · DOI

• Individuals with severe obesity (SO) are at a high risk of developing cardiovascular disease, but traditional lipid parameters are insufficient for accurately assessing the risk.

  A Potential Ratio for Detecting Subclinical Atherosclerosis: Insight into Advanced NMR Lipid Profiles in Severe Obesity · 2025 · DOI

• Conventional definitions of metabolic syndrome may not adequately reflect its cumulative severity. The cumulative severity of metabolic dysfunction or the continuous nature of cardiometabolic risk may not be fully captured by conventional definitions.

  Association between metabolic syndrome severity score and coronary artery disease complexity assessed by the SYNTAX score in patients with chronic coronary syndrome · 2026 · DOI

• Further studies are needed to investigate the causes of geographic variations in CKM stage distribution, - Research should focus on the development of targeted interventions to reduce the prevalence of CKM syndrome, - Studies should explore the relationship between CKM syndrome and other health…

  Patterns of cardiovascular-kidney-metabolic (CKM) syndrome stages and prevalence of lifestyle risk factors in a nationally representative iranian population study · 2026 · DOI

• Pain was self-reported at a single baseline assessment, precluding evaluation of changes in pain over time, - information on pain severity, etiology, and pain treatment, including analgesic use and therapies for neuropathic pain…

  Pain phenotypes and chronic pain burden are associated with atherosclerotic cardiovascular disease and vascular disease progression in participants with type 2 diabetes: a UK Biobank cohort study with multistate analysis · 2026 · DOI

• The study identifies a gap in understanding the association between sociodemographic variables and healthy habits with insulin resistance risk scales. The global increase in obesity and associated metabolic diseases necessitates understanding the pathophysiological basis of insulin resistance.

  Risk of Insulin Resistance in 44,939 Spanish Healthcare Workers: Association with Sociodemographic Variables and Healthy Habits · 2025 · DOI

• Incorporate income-related variables to allow for a more comprehensive analysis - Include the assessment of molecular markers such as cortisol or high-sensitivity C-reactive…

  Risk of Insulin Resistance: Comparison of the Commerce vs. Industry Sector and Associated Variables · 2025 · DOI

• Further research is needed to validate the metabotyping approach in different populations, - Investigation of the underlying mechanisms driving the associations between metabotype risk clusters and MetS is necessary, - Development of personalized prevention strategies based on metabotyping…

  Metabotype Risk Clustering Based on Metabolic Disease Biomarkers and Its Association with Metabolic Syndrome in Korean Adults: Findings from the 2016–2023 Korea National Health and Nutrition Examination Survey (KNHANES) · 2025 · DOI

Most-cited papers in Diabetes, Cardiovascular Risks, and Lipoproteins

• Diabetes and Cardiovascular Disease · JAMA · 1979 · 6,306 citations
• Mortality from Coronary Heart Disease in Subjects with Type 2 Diabetes and in Nondiabetic Subjects with and without Prior Myocardial Infarction · New England Journal of Medicine · 1998 · 5,283 citations
• Prevalence of the Metabolic Syndrome Among US Adults · JAMA · 2002 · 5,035 citations
• Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies · The Lancet · 2010 · 4,265 citations
• Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001 · JAMA · 2003 · 4,173 citations
• Diabetes and cardiovascular disease. The Framingham study · JAMA · 1979 · 3,975 citations
• Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021 · The Lancet · 2023 · 3,857 citations
• The Metabolic Syndrome and Total and Cardiovascular Disease Mortality in Middle-aged Men · JAMA · 2002 · 3,593 citations
• The Disease Burden Associated With Overweight and Obesity · JAMA · 1999 · 3,352 citations
• Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4·4 million participants · The Lancet · 2016 · 2,868 citations

Most recent work

• Relationship between nine triglyceride-glucose-related indices and cardiometabolic multimorbidity incidence in patients with cardiovascular-kidney-metabolic syndrome stage 0–3: a nationwide prospective cohort study · Cardiovascular Diabetology · 2026
• Association of cumulative cholesterol-HDL-glucose index with blood pressure changes and risk of new-onset hypertension in middle-aged and older adults: a cohort study · Cardiovascular Diabetology · 2026
• Global, Regional, and National Estimates of Undiagnosed Diabetes in Adults: Findings From the 2025 IDF Diabetes Atlas · Diabetes Care · 2026
• Association between C-reactive protein-triglyceride glucose index (CTI) and cardiovascular and all-cause mortality risk among the elderly population: insights from three datasets · Clinical Research in Cardiology · 2026
• Joint assessment of insulin resistance surrogate indices and basal metabolic rate for primary prevention of cardiometabolic multimorbidity: evidence from the China Health and Retirement Longitudinal Study (2011–2020) · Cardiovascular Diabetology · 2026
• Akt, AS160, metabolic risk factors and aerobic fitness in middle-aged women · PubMed · 2026
• Prospective associations of triglyceride-glucose related indices with cardiovascular disease and mortality in individuals with metabolic syndrome: evidence from the UK biobank · Cardiovascular Diabetology · 2026
• The association of C-reactive protein–triglyceride–glucose index with cardiometabolic multimorbidity in middle-aged and older adults: evidence from two cohort studies · Cardiovascular Diabetology · 2026
• Associations of cumulative exposure and dynamic trajectories of cholesterol-HDL-glucose (CHG) index with cardiovascular disease in middle-aged and older Chinese adults: a longitudinal analysis · Cardiovascular Diabetology · 2026
• Asia at the Epicenter of the Global Cardiometabolic Shift · JACC Asia · 2026

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