Developing technologies to assess vascular ageing: a roadmap from VascAgeNet.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges.

Association between changes in cardiovascular health and the risk of multimorbidity: community-based cohort studies in the UK and Finland.

Background: Better cardiovascular health is associated with lower risk of various chronic diseases, but its association with multimorbidity is poorly understood. We aimed to examine whether change in cardiovascular health is associated with multimorbidity risk. Methods: The primary analysis was conducted in the Whitehall II multiwave prospective cohort study (UK) and the validation analysis in the Finnish Public Sector cohort study (Finland). Change in cardiovascular health was assessed using the American Heart Association Life's Simple 7 (LS7) and Life's Essential 8 (LE8) at baseline and re-assessments, using objective measures in Whitehall II and self-reports and pharmacy claims in the Finnish Public Sector cohort study, respectively. Multimorbidity was defined as the presence of two or more of 12 chronic diseases during follow-up. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox's proportional hazard models with age as time scale, adjusting for sex, education, occupation, marital status, and ethnicity. Findings: In the primary analysis among 9715 participants, mean age was 44.8 (standard deviation 6.0) years and 67.6% participants were men at baseline. During the median follow-up of 31.4 (interquartile range 26.8-32.3) years, 2751 participants developed multimorbidity. The hazard of multimorbidity decreased by 8% (HR 0.92, 95% CI 0.88-0.96) per ideal LS7 metric increment over 5 years and by 14% (HR 0.86, 95% CI 0.80-0.93) per ten points increase in LE8 score over 10 years. These findings were replicated in the validation analysis among 75,377 participants in terms of 4-year change in cardiovascular health. Interpretation: Improvement in cardiovascular health was associated with lower multimorbidity risk in two community-based cohort studies. Interventions improving cardiovascular health of the community may contribute to multimorbidity prevention. Funding: None.

Development and validation of a lifetime prediction model for incident type 2 diabetes in patients with established cardiovascular disease: the CVD2DM model.

AIMS: Identifying patients with established cardiovascular disease (CVD) who are at high risk of type 2 diabetes (T2D) may allow for early interventions, reducing the development of T2D and associated morbidity. The aim of this study was to develop and externally validate the CVD2DM model to estimate the 10-year and lifetime risks of T2D in patients with established CVD. METHODS AND RESULTS: Sex-specific, competing risk-adjusted Cox proportional hazard models were derived in 19 281 participants with established CVD and without diabetes at baseline from the UK Biobank. The core model's pre-specified predictors were age, current smoking, family history of diabetes mellitus, body mass index, systolic blood pressure, fasting plasma glucose, and HDL cholesterol. The extended model also included HbA1c. The model was externally validated in 3481 patients from the UCC-SMART study. During a median follow-up of 12.2 years (interquartile interval 11.3-13.1), 1628 participants with established CVD were diagnosed with T2D in the UK Biobank. External validation c-statistics were 0.79 [95% confidence interval (CI) 0.76-0.82] for the core model and 0.81 (95% CI 0.78-0.84) for the extended model. Calibration plots showed agreement between predicted and observed 10-year risk of T2D. CONCLUSION: The 10-year and lifetime risks of T2D can be estimated with the CVD2DM model in patients with established CVD, using readily available clinical predictors. The model would benefit from further validation across diverse ethnic groups to enhance its applicability. Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle.

In this study, we developed and externally validated the CVD2DM model, which predicts the 10-year and lifetime risk of type 2 diabetes (T2D) in individuals who already have cardiovascular disease (CVD). The key findings are as follows: The CVD2DM model is the first model to estimate the risk of developing T2D applicable in all patients with atherosclerotic CVD. The model is based on several factors available in clinical practice, such as age, fasting plasma glucose, family history of diabetes, and body mass index. It was developed in 19 281 patients from the UK Biobank. The model performed well in 3481 patients from the UCC-SMART study.Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle.

Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

BACKGROUND: Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. METHODS: Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). RESULTS: After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43]). CONCLUSIONS: These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

HbA1c and fasting plasma glucose levels are equally related to incident cardiovascular risk in a high CVD risk population without known diabetes.

OBJECTIVES: Type 2 diabetes (T2DM) is associated with increased risk for cardiovascular disease (CVD). Whether screen-detected T2DM, based on fasting plasma glucose (FPG) or on HbA1c, are associated with different risks of incident CVD in high-risk populations and which one is preferable for diabetes screening in these populations, remains unclear. METHODS: 8,274 high-risk CVD participants were included from the UCC-SMART cohort. Participants were divided into groups based on prior T2DM diagnosis, and combinations of elevated/non-elevated FPG and HbA1c (cut-offs at 7 mmol/L and 48 mmol/mol, respectively): Group 0: known T2DM; group 1: elevated FPG/HbA1c; group 2: elevated FPG, non-elevated HbA1c; group 3: non-elevated FPG, elevated HbA1c; group 1 + 2: elevated FPG, regardless of HbA1c; group 1 + 3: elevated HbA1c, regardless of FPG; and group 4 (reference), non-elevated FPG/HbA1c. RESULTS: During a median follow-up of 6.3 years (IQR 3.3-9.8), 712 cardiovascular events occurred. Compared to the reference (group 4), group 0 was at increased risk (HR 1.40; 95 % CI 1.16-1.68), but group 1 (HR 1.16; 95 % CI 0.62-2.18), 2 (HR 1.18; 95 % CI 0.84-1.67), 3 (HR 0.61; 95 % CI 0.15-2.44), 1 + 2 (HR 1.17; 95 % CI 0.86-1.59) and 1 + 3 (HR 1.01; 95 % CI 0.57-1.79) were not. However, spline interpolation showed a linearly increasing risk with increasing HbA1c/FPG, but did not allow for identification of other cut-off points. CONCLUSIONS: Based on current cut-offs, FPG and HbA1c at screening were equally related to incident CVD in high-risk populations without known T2DM. Hence, neither FPG, nor HbA1c, is preferential for diabetes screening in this population with respect to risk of incident CVD.

Continuous glucose monitoring in adults with type 2 diabetes: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) is increasingly used in the treatment of type 2 diabetes, but the effects on glycaemic control are unclear. The aim of this systematic review and meta-analysis is to provide a comprehensive overview of the effect of CGM on glycaemic control in adults with type 2 diabetes. METHODS: We performed a systematic review using Embase, MEDLINE, Web of Science, Scopus and ClinicalTrials.gov from inception until 2 May 2023. We included RCTs investigating real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) compared with self-monitoring of blood glucose (SMBG) in adults with type 2 diabetes. Studies with an intervention duration <6 weeks or investigating professional CGM, a combination of CGM and additional glucose-lowering treatment strategies or GlucoWatch were not eligible. Change in HbA1c and the CGM metrics time in range (TIR), time below range (TBR), time above range (TAR) and glycaemic variability were extracted. We evaluated the risk of bias using the Cochrane risk-of-bias tool version 2. Data were synthesised by performing a meta-analysis. We also explored the effects of CGM on severe hypoglycaemia and micro- and macrovascular complications. RESULTS: We found 12 RCTs comprising 1248 participants, with eight investigating rtCGM and four isCGM. Compared with SMBG, CGM use (rtCGM or isCGM) led to a mean difference (MD) in HbA1c of -3.43 mmol/mol (-0.31%; 95% CI -4.75, -2.11, p<0.00001, I2=15%; moderate certainty). This effect was comparable in studies that included individuals using insulin with or without oral agents (MD -3.27 mmol/mol [-0.30%]; 95% CI -6.22, -0.31, p=0.03, I2=55%), and individuals using oral agents only (MD -3.22 mmol/mol [-0.29%]; 95% CI -5.39, -1.05, p=0.004, I2=0%). Use of rtCGM showed a trend towards a larger effect (MD -3.95 mmol/mol [-0.36%]; 95% CI -5.46 to -2.44, p<0.00001, I2=0%) than use of isCGM (MD -1.79 mmol/mol [-0.16%]; 95% CI -5.28, 1.69, p=0.31, I2=64%). CGM was also associated with an increase in TIR (+6.36%; 95% CI +2.48, +10.24, p=0.001, I2=9%) and a decrease in TBR (-0.66%; 95% CI -1.21, -0.12, p=0.02, I2=45%), TAR (-5.86%; 95% CI -10.88, -0.84, p=0.02, I2=37%) and glycaemic variability (-1.47%; 95% CI -2.94, -0.01, p=0.05, I2=0%). Three studies reported one or more events of severe hypoglycaemia and macrovascular complications. In comparison with SMBG, CGM use led to a non-statistically significant difference in the incidence of severe hypoglycaemia (RR 0.66, 95% CI 0.15, 3.00, p=0.57, I2=0%) and macrovascular complications (RR 1.54, 95% CI 0.42, 5.72, p=0.52, I2=29%). No trials reported data on microvascular complications. CONCLUSIONS/INTERPRETATION: CGM use compared with SMBG is associated with improvements in glycaemic control in adults with type 2 diabetes. However, all studies were open label. In addition, outcome data on incident severe hypoglycaemia and incident microvascular and macrovascular complications were scarce. REGISTRATION: This systematic review was registered on PROSPERO (ID CRD42023418005).

Microvascular Dysfunction and Whole-Brain White Matter Connectivity: The Maastricht Study.

BACKGROUND: Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity. METHODS AND RESULTS: Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (ß per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. CONCLUSIONS: These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.

Associations of plasma NfL, GFAP, and t-tau with cerebral small vessel disease and incident dementia: longitudinal data of the AGES-Reykjavik Study.

We investigated the associations of plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau) with markers of cerebral small vessel disease (SVD) and with incident dementia. We also investigated whether associations of NfL, GFAP, and t-tau with incident dementia were explained by SVD. Data are from a random subsample (n = 1069) of the population-based AGES-Reykjavik Study who underwent brain MRI and in whom plasma NfL, GFAP, and t-tau were measured at baseline (76.1 ± 5.4 years/55.9% women/baseline 2002-2006/follow-up until 2015). A composite SVD burden score was calculated using white matter hyperintensity volume (WMHV), subcortical infarcts, cerebral microbleeds, and large perivascular spaces. Dementia was assessed in a 3-step process and adjudicated by specialists. Higher NfL was associated with a higher SVD burden score. Dementia occurred in 225 (21.0%) individuals. The SVD burden score significantly explained part of the association between NfL and incident dementia. WMHV mostly strongly contributed to the explained effect. GFAP was not associated with the SVD burden score, but was associated with WMHV, and WMHV significantly explained part of the association between GFAP and incident dementia. T-tau was associated with WMHV, but not with incident dementia. In conclusion, the marker most strongly related to SVD is plasma NfL, for which the association with WMHV appeared to explain part of its association with incident dementia. This study suggests that plasma NfL may reflect the contribution of co-morbid vascular disease to dementia. However, the magnitude of the explained effect was relatively small, and further research is required to investigate the clinical implications of this finding.

Age at cardiovascular disease onset, dementia risk, and the role of lifestyle factors.

INTRODUCTION: We first examined the role of age at cardiovascular disease (CVD) onset for incident dementia, and then examined whether lifestyle factors at guideline-recommended levels in individuals with CVD mitigates dementia risk. METHODS: We used population-based data (Whitehall II: n = 10,308/baseline 1985-1988/examinations every 4-5 years). Lifestyle factors (non-smoking, body mass index [BMI], physical activity, diet) were extracted post-CVD. RESULTS: Over a median of 31.6 years, 3275 (32.1%) developed CVD. At age 70, risk of dementia was higher in individuals with CVD onset before (hazard ratio [HR] of incident dementia for participants with CVD before age 60, using participants without CVD at age 70 as the reference: 1.56, 95% confidence interal [CI] 1.18-2.08) but not after 60 years. In participants with CVD, a greater number of lifestyle factors at recommended levels post-CVD was associated with a lower dementia risk (per lifestyle factor at recommended level HR: 0.73, 95% CI 0.59-0.92). DISCUSSION: Our results suggest that early onset CVD is associated with a higher dementia risk at older ages. In those with CVD, the dementia risk was lower if lifestyle factors are at recommended levels following CVD diagnosis. HIGHLIGHTS: CVD in midlife but not in late life is associated with a higher risk of dementia. Dementia risk in CVD patients is lower if their lifestyle factors are at recommended levels. These findings provide evidence to promote CVD prevention in midlife or earlier. Study findings also show the importance of a healthy lifestyle in those with CVD.

Long-term lifestyle change and risk of mortality and Type 2 diabetes in patients with cardiovascular disease.

AIMS: To quantify the relationship between self-reported, long-term lifestyle changes (smoking, waist circumference, physical activity, and alcohol consumption) and clinical outcomes in patients with established cardiovascular disease (CVD). METHODS AND RESULTS: Data were used from 2011 participants (78% male, age 57 ± 9 years) from the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort who returned for a re-assessment visit (SMART2) after ∼10 years. Self-reported lifestyle change was classified as persistently healthy, improved, worsened, or persistently unhealthy. Cox proportional hazard models were used to quantify the relationship between lifestyle changes and the risk of (cardiovascular) mortality and incident Type 2 diabetes (T2D). Fifty-seven per cent of participants was persistently healthy, 17% improved their lifestyle, 8% worsened, and 17% was persistently unhealthy. During a median follow-up time of 6.1 (inter-quartile range 3.6-9.6) years after the SMART2 visit, 285 deaths occurred, and 99 new T2D diagnoses were made. Compared with a persistently unhealthy lifestyle, individuals who maintained a healthy lifestyle had a lower risk of all-cause mortality [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.36-0.63], cardiovascular mortality (HR 0.57, 95% CI 0.38-0.87), and incident T2D (HR 0.46, 95% CI 0.28-0.73). Similarly, those who improved their lifestyle had a lower risk of all-cause mortality (HR 0.52, 95% CI 0.37-0.74), cardiovascular mortality (HR 0.46, 95% CI 0.26-0.81), and incident T2D (HR 0.50, 95% CI 0.27-0.92). CONCLUSION: These findings suggest that maintaining or adopting a healthy lifestyle can significantly lower mortality and incident T2D risk in CVD patients. This study emphasizes the importance of ongoing lifestyle optimization in CVD patients, highlighting the potential for positive change regardless of previous lifestyle habits.

In this study, we investigated whether lifestyle changes were related to improved health outcomes in individuals with cardiovascular disease (CVD). We assessed self-reported lifestyle behaviours (smoking, waist circumference, alcohol consumption, and physical activity), at inclusion in the cohort and again ∼10 years later. The results emphasize the importance of making healthy lifestyle choices, even for individuals already diagnosed with CVD, and suggest that it is never too late to improve one's lifestyle.

Thinner inner retinal layers are associated with lower cognitive performance, lower brain volume, and altered white matter network structure-The Maastricht Study.

INTRODUCTION: The retina may provide non-invasive, scalable biomarkers for monitoring cerebral neurodegeneration. METHODS: We used cross-sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency). RESULTS: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency. DISCUSSION: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia.

Dual hormone fully closed loop in type 1 diabetes: a randomised trial in the Netherlands - study protocol.

INTRODUCTION: The management of type 1 diabetes (T1DM) has undergone significant advancements with the availability of novel technologies, notably continuous and flash glucose monitoring (CGM and FGM, respectively) and hybrid closed loop (HCL) therapy. The dual hormone fully closed loop (DHFCL) approach with insulin and glucagon infusion has shown promising effects in small studies on glycaemic regulation and quality of life in T1DM. METHODS AND ANALYSIS: The Dual Hormone Fully Closed Loop for Type 1 Diabetes (DARE) study is a non-commercial 12-month open-label, two-arm randomised parallel-group trial. The primary aim of this study is to determine the long-term effects on glycaemic control, patient-reported outcome measurements and cost-effectiveness of the DHFCL compared with usual care, that is, HCL or treatment with multiple daily insulin injections+FGM/CGM. We will include 240 adult patients with T1DM in 14 hospitals in the Netherlands. Individuals will be randomised 1:1 to the DHFCL or continuation of their current care. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Medical Research Ethics Committee NedMec, Utrecht, the Netherlands. Findings will be disseminated through peer-reviewed publications and presentations at local, national and international conferences. TRIAL REGISTRATION NUMBER: NCT05669547.

Is the number of ideal cardiovascular health metrics in midlife associated with lower risk of cancer? Evidence from 3 European prospective cohorts.

BACKGROUND: Primordial prevention may be a relevant strategy for the prevention of cancer. Given the commonality of risk factors and mechanisms between cancer and cardiovascular disease, we examined the associations between the number of ideal cardiovascular health metrics in midlife and incident cancer. METHODS: In 3 European cohorts (NutriNet-Santé and GAZEL, France; Whitehall II, United Kingdom), the number of ideal cardiovascular health metrics was determined at baseline (range 0-7). Follow-up for cancer events was until October 2020 (NutriNet-Santé), March 2017 (Whitehall II) and December 2015 (GAZEL). Cox regression was conducted in each cohort, and results were thereafter pooled using a random-effects model. RESULTS: Data were available on 39 718 participants. A total of 16 237 were from NutriNet-Santé (mean age 51.3 yr; 28% men), 9418 were from Whitehall II (mean age 44.8 yr; 68% men) and 14 063 were from GAZEL (mean age 45.2 yr; 75% men). The median follow-up was 8.1 years in NutriNet-Santé, 29.6 years in Whitehall II and 24.8 years in GAZEL, and yielded a total of 4889 cancer events. A greater number of ideal cardiovascular health metrics was associated with a lower overall cancer risk in each cohort, with an aggregate hazard ratio (HR) per 1 increment in number of ideal metrics of 0.91 (95% confidence interval [CI] 0.88-0.93). This association remained after removal of the smoking metric (aggregate HR per unit increment in number of ideal metrics: 0.94, 95% CI 0.90-0.97), and site-specific analysis demonstrated a significant association with lung cancer. INTERPRETATION: A greater number of ideal cardiovascular health metrics in midlife was associated with lower cancer risk, notably lung cancer. Primordial prevention of cardiovascular risk factors in midlife may be a complementary strategy to prevent the onset of cancer.

Variability in benefit from intensive insulin therapy on cardiovascular events in individuals with type 1 diabetes: A post hoc analysis of the DCCT/EDIC study.

AIM: To evaluate presence of treatment effect heterogeneity of intensive insulin therapy (INT) on occurrence of major adverse cardiovascular events (MACE) in individuals with type 1 diabetes. METHODS: In participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, individual treatment effect of INT (≥3 daily insulin injections/insulin pump therapy) versus conventional therapy (once/twice daily insulin) on the risk of MACE was estimated using a penalized Cox regression model including treatment-by-covariate interaction terms. RESULTS: In 1441 participants, 120 first MACE events were observed and 1279 individuals (89%) were predicted to benefit from INT with regard to MACE risk reduction. The study population was divided into four groups based on predicted treatment effect: one group with no predicted benefit and three tertiles with predicted treatment benefit. The median absolute reduction in 30-year risk of MACE across groups of predicted treatment effect ranged from -0.2% (i.e. risk increase; interquartile range [IQR] -0.1% to -0.3%) in the group with no predicted benefit to 6.6% (i.e. risk reduction; IQR 3.8%-10.9%; number needed to treat 15) in the highest tertile of predicted benefit. The observed benefit of preventing microvascular complications was stable across all subgroups of predicted MACE benefit. CONCLUSIONS: Although INT reduces the risk of MACE in the majority of individuals with type 1 diabetes, benefit varies substantially. These individual differences in the effect of INT underline the necessity for a better understanding of the individual response to intensive treatment.

[The PROMINENT trial: swan song of the fibrates]. / De PROMINENT-studie: zwanenzang van de fibraten.

Post hoc analyses of previous fibrate trials have suggested that individuals with type 2 diabetes mellitus with high triglyceride levels and low HDL-cholesterol levels benefit from fibrate therapy even when the overall trial results were neutral. However the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) trial seems to close the door for fibrates. The trial found that fibrates do not reduce the risk of cardiovascular disease among individuals with type 2 diabetes and high triglyceride levels and low HDL cholesterol levels, despite triglyceride lowering. The results of PROMINENT suggest that triglyceride lowering without decreases in the plasma concentration of atherogenic lipoproteins are unlikely to decrease the risk of cardiovascular disease. These results also highlight the importance of rigorously confirmation of post hoc findings before implementation in clinical practice.

Association of Midlife Cardiovascular Health and Subsequent Change in Cardiovascular Health With Incident Cancer.

Background: The commonality of risk factors between cancer and cardiovascular disease suggests that primordial prevention (preventing the onset of risk factors) is a relevant strategy for cancer prevention. Objectives: This study sought to examine the association between baseline and change in the cardiovascular health (CVH) score and incident cancer. Methods: Using serial examinations of the GAZEL (GAZ et ELECTRICITE de France) study in France, we examined the associations between the American Heart Association's Life's Simple 7 CVH score (range: 0-to 14 [poor, intermediate, and ideal level of smoking, physical activity, body mass index, diet, blood pressure, diabetes status, or lipids]) in 1989/1990, their change over 7 years, and incident cancer and cardiac events up to 2015. Results: The study population included 13,933 participants (mean age: 45.3 ± 3.4 years, 24% women). After a median follow-up of 24.8 years (Q1-Q3: 19.4-24.9 years), 2,010 participants had an incident cancer and 899 a cardiac event. The risk of cancer (any site) decreased by 9% (HR: 0.91; 95% CI: 0.88-0.93) per 1-point increase in the CVH score in 1989/1990 compared with a 20% (HR: 0.80; 95% CI: 0.77-0.83) risk reduction for cardiac events. The risk of cancer decreased by 5% (HR: 0.95; 95% CI: 0.92-0.99) per unit of change in the CVH score between 1989/1990 and 1996/1997 compared with a 7% risk reduction for cardiac events (HR: 0.93; 95% CI: 0.88-0.98). These associations remained after omitting the smoking metric from the CVH score. Conclusions: Primordial prevention is a relevant strategy for the prevention of cancer in the population.

Person-centered and measured life's simple 7 cardiovascular health concordance and association with incident cardiovascular disease.

Person-centered cardiovascular health (CVH) may facilitate cardiovascular disease primordial prevention in low resources settings. The study aims to assess the validity of person-centered CVH compared to gold standard measured CVH by examining the concordance between person-centered vs. measured CVH together with their respective association with incident cardiovascular disease events (CVD). Life's Simple 7 (LS7) CVH metrics, including non-smoking, Body Mass Index, diet, physical activity, blood glycemia, blood pressure, and blood cholesterol were collected from 19,473 adults participating in the e-cohort NutriNet-Santé study from 2011 to 2014 and were followed until September 2020. Clinical examinations and blood analyses defined the measured biological metrics, while diagnoses, medication, or treatment for type 2 diabetes, hypertension, and hypercholesterolemia defined person-centered biological metrics. Declared behavioral metrics were common for both measured and person-centered CVH. The study included 18,714 CVD-free participants (mean age 51 years, 73% women), among whom 16.52% and 38.75% had 5-7 ideal LS7 metrics according to measured and person-centered CVH, respectively. Weighted concordance of person-centered and measured CVH was 0.87 [0.86; 0.88]. Over median follow-up of 8.05 years, 749 CVD events occurred. There was a 7% (HR 0.93 [0.88; 0.99]) and 13% (HR 0.87 [0.83; 0.92]) risk reduction of CVD risk by additional measured and person-centered ideal metrics, respectively. In conclusion, person-centered CVH may represent a reliable alternative to measured CVH.

Changes in Cardiovascular Health Across Midlife and Late-Life and Magnetic Resonance Imaging Markers of Cerebral Vascular Disease in Late-Life.

BACKGROUND: Cardiovascular health may be used for prevention of cerebral vascular disease; however, data on the association of cardiovascular health across midlife and late-life with late-life cerebral vascular disease are lacking. Our aim was to examine whether midlife or late-life cardiovascular health as well as changes of cardiovascular health within midlife and between midlife and late-life were associated with prevalence of magnetic resonance imaging markers of cerebral vascular disease at late-life. METHODS: Prospective cohort study including 1638 participants from the Atherosclerosis Risk in Communities Study who took part in 2 visits at midlife (mean ages, 53 and 59 years), and a late-life visit (mean age, 76 years). A cardiovascular health Life's Simple 7 score (range, 0-12/0-14, depending on diet availability) including 6 out of 7 items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain magnetic resonance imaging scans in late-life visit. Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health in midlife and late-life, and improvement of cardiovascular health within midlife, and from midlife to late-life with magnetic resonance imaging markers of cerebral vascular disease, adjusting for potential confounders. RESULTS: A higher cardiovascular health in midlife, improvement of cardiovascular health within midlife, higher cardiovascular health at late-life, and improvement of cardiovascular health from midlife to late-life were associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (ß, -0.07 [95% CI, -0.10 to -0.04]) and lower odds of microbleeds (odds ratio, 0.93 [0.90-0.97]), lacunar (odds ratio, 0.93 [0.89-0.97]), subcortical (odds ratio, 0.93 [0.89-0.97]), and cortical infarcts (odds ratio, 0.92 [0.87-0.97]). CONCLUSIONS: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Association of type 2 diabetes according to the number of risk factors within the recommended range with incidence of major depression and clinically relevant depressive symptoms: a prospective analysis.

BACKGROUND: Type 2 diabetes is associated with an increased risk of depression, but the extent to which risk factor modification can mitigate this risk is unclear. We aimed to examine the association between the incidence of major depression and clinically relevant depressive symptoms among individuals with type 2 diabetes, according to the number of risk factors within the recommended target range, compared with individuals without diabetes. METHODS: We did a prospective analysis of population-based data from the UK Biobank and the Maastricht Study. Individuals with type 2 diabetes were categorised according to the number of risk factors within the recommended target range (non-smoking, guideline-recommended levels of glycated haemoglobin (HbA1c), blood pressure, BMI, albuminuria, physical activity, and diet). The primary outcome, based on data from the UK Biobank, was the incidence of major depression ascertained from hospital records; the secondary outcome, based on data from the UK Biobank and the Maastricht Study, was clinically relevant depressive symptoms based on a score of 10 or higher on the Patient Health Questionnaire (PHQ-9). FINDINGS: The study population of the UK Biobank comprised 77 786 individuals (9047 with type 2 diabetes and 68 739 without diabetes; median age 59 years [IQR 51-64]; 34 136 [43·9%] women and 43 650 [56·1%] men). A median of 12·7 years (IQR 11·8-13·4) after recruitment (between March 13, 2006, and Oct 1, 2010), 493 (5·5%) of 9047 individuals with type 2 diabetes and 2574 (3·7%) of 68 739 individuals without diabetes developed major depression. Compared with individuals without diabetes, those with type 2 diabetes had a higher risk of major depression (hazard ratio [HR] 1·61 [95% CI 1·49-1·77]). Among individuals with type 2 diabetes, the excess risk of depression decreased stepwise with an increasing number of risk factors within the recommended target range (HR 2·04 [95% CI 1·65-2·52] for up to two risk factors within the recommended target range; 1·95 [1·65-2·30] for three risk factors within the recommended target range; 1·38 [1·16-1·65] for four risk factors within the recommended target range; and 1·34 [1·12-1·62] for five to seven risk factors within the recommended target range). In the UK Biobank dataset, a median of 7·5 years (IQR 6·8-8·2) after the baseline examination, 147 (7·5%) of 1953 individuals with type 2 diabetes and 954 (4·5%) of 21 413 individuals without diabetes had developed clinically relevant depressive symptoms. The study population of the Maastricht Study comprised 4530 individuals (1158 with type 2 diabetes and 3372 without diabetes; median age 60 years [IQR 53-66]; 2244 [49·5%] women and 2286 [50·1%] men). A median of 5·1 years (IQR 4·1-6·1) after recruitment (between Sept 1, 2010, and Dec 7, 2017), 170 (14·7%) of 1158 individuals with type 2 diabetes and 227 (6·7%) of 3372 individuals without diabetes developed clinically relevant depressive symptoms. Similarly, in both the UK Biobank dataset and the Maastricht Study cohort, among individuals with type 2 diabetes, the excess risk of clinically relevant depressive symptoms decreased stepwise with an increasing number of risk factors within the recommended target range. INTERPRETATION: Among individuals with type 2 diabetes, the excess risk of major depression and clinically relevant depressive symptoms decreased stepwise with an increasing number of risk factors within the recommended target range. This study provides further evidence to promote risk factor modification strategies in individuals with type 2 diabetes and to encourage the adoption of a healthy lifestyle. FUNDING: ZonMW, Hartstichting, and Diabetes Fonds.