Lipids and apolipoproteins and the risk of vascular disease and mortality outcomes in women and men with type 2 diabetes in the ADVANCE study.

AIM: Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very-low-density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. The aim of this study was to assess the association between established risk markers, apolipoproteins and the risk of macro- and microvascular disease and death in a large study of women and men with diabetes and to assess the potential sex differences in the associations. MATERIALS AND METHODS: Established lipid risk markers were studied in 11 140 individuals with type 2 diabetes from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial, and apolipoproteins (A1, B, ApoB/ApoA1 ratio) and VLDL cholesterol from nuclear magnetic resonance (NMR) lipid analyses in biobanked samples from 3586 individuals included in the ADVANCE case-cohort study (ADVANCE CC). Primary outcomes were major macro- and microvascular events and death. Cox proportional hazards models adjusted for confounders were used to quantify the associations (hazard ratio [HR] and 95% confidence intervals [CIs]) between established lipid risk markers and apolipoproteins with study outcomes. To address potential effect modification by sex, we investigated the association between the lipid risk markers and outcomes in subgroup analyses by sex. RESULTS: There was a lower risk of macrovascular complications for high-density lipoprotein (HDL) cholesterol (HR [95%CI] 0.88 [0.82-0.95]), a higher risk for total cholesterol (1.10 [1.04-1.17]), low-density lipoprotein (LDL) cholesterol (1.15 [1.08-1.22]), non-HDL cholesterol (1.13 [1.07-1.20]) and the total cholesterol/HDL ratio (1.20 [1.14-1.27]) but no significant associations with triglycerides from ADVANCE. There was a higher risk of macrovascular complications for the ApoB/ApoA1 ratio (1.13 [1.03-1.24]) from the ADVANCE CC. Only the ApoB/ApoA1 ratio (1.19 [1.06-1.34]), but none of the established lipid risk markers, was associated with a higher risk of microvascular complications. There were no statistically significant sex differences for any of the established lipid risk markers or apolipoproteins with any outcome. Using C-statistics and net reclassification improvement (NRI) did not detect significant improvement in predicting all outcomes by adding lipids or apolipoproteins to the models with confounding factors only. CONCLUSIONS/INTERPRETATION: All established lipid risk markers, except triglycerides, were predictors of macrovascular complications, but not microvascular complications, in patients with type 2 diabetes. The ApoB/ApoA1 ratio was associated with major macro- and microvascular complications, but there was no evidence that apolipoproteins are better than established lipid risk markers in predicting cardiovascular complications in patients with type 2 diabetes.

The impact of the COVID-19 pandemic on blood pressure control in patients with treated hypertension-results of the European Society of Hypertension Study (ESH ABPM COVID-19 Study).

BACKGROUND: We aimed to determine the influence of coronavirus disease 2019 (COVID-19) pandemic on blood pressure (BP) control assessed by ambulatory blood pressure monitoring (ABPM). METHODS: Office BP and ABPM data from two visits conducted within a 9-15 months interval were collected from patients treated for hypertension. In the prepandemic group, both visits took place before, while in the pandemic group, Visit-1 was done before and Visit-2 during the pandemic period. RESULTS: Of 1811 collected patients 191 were excluded because they did not meet the required ABPM time frames. Thus, the study comprised 704 patients from the pandemic and 916 from the prepandemic group. Groups did not differ in sex, age, duration of hypertension, frequency of first line antihypertensive drug use and mean 24 h BP on Visit-1. The prevalence of sustained uncontrolled hypertension was similar in both groups. On Visit-2 mean 24 h BP, daytime and nighttime systolic BP and diastolic BP were higher in the pandemic compared to the prepandemic group ( P  < 0.034). The prevalence of sustained uncontrolled hypertension on Visit-2 was higher in the pandemic than in the prepandemic group [0.29 (95% confidence interval (95% CI): 0.26-0.33) vs. 0.25 (95% CI: 0.22-0.28), P  < 0.037]. In multivariable adjusted analyses a significant difference in BP visit-to-visit change was observed, with a more profound decline in BP between visits in the prepandemic group. CONCLUSIONS: This study using ABPM indicates a negative impact of the COVID-19 pandemic on BP control. It emphasizes the need of developing strategies to maintain BP control during a pandemic such as the one induced by COVID-19.

The impact of the COVID-19 Pandemic on hypertension phenotypes (ESH ABPM COVID-19 study).

OBJECTIVE: The COVID-19 pandemic had a major impact on medical care. This study evaluated the influence of the pandemic on blood pressure (BP) control and hypertension phenotypes as assessed by office and 24-hour ambulatory BP monitoring (ABPM). DESIGN AND METHODS: Data were collected from 33 centers including Excellence Centers of the European Society of Hypertension. Two groups of patients with treated hypertension were compared. Pandemic group: including participants who had ABPM twice - at visit 2 during the COVID-19 pandemic and visit 1 performed 9-15 months prior to visit 2. Pre-pandemic group: had ABPM at two visits, performed before the pandemic within 9-15 months interval. We determined the following hypertension phenotypes: masked hypertension, white coat hypertension, sustained controlled hypertension (SCH) and sustained uncontrolled hypertension (SUCH). We analyzed the prevalence of phenotypes and their changes between visits. RESULTS: Data of 1419 patients, 616 (43 %) in the pandemic group and 803 (57 %) in the pre-pandemic group, were analyzed. At baseline (visit 1), the prevalence of hypertension phenotypes did not differ between groups. In the pandemic group, the change in hypertension phenotypes between two visits was not significant (p = 0.08). In contrast, in the pre-pandemic group, the prevalence of SCH increased during follow-up (28.8 % vs 38.4 %, p < 0.01) while the prevalence of SUCH decreased (34.2 % vs 27.8 %, p < 0.01). In multivariable adjusted analysis, the only factor influencing negative changes of hypertension phenotypes was the COVID-19 pandemic period. CONCLUSION: These results indicate a negative impact of the COVID-19 pandemic on BP control assessed by hypertension phenotypes.

Combination blood pressure lowering therapy in patients with type 2 diabetes: messages from the ADVANCE trial.

The Action in Diabetes and Vascular disease: preterAx and diamicroN Controlled Evaluation (ADVANCE) trial investigated the effects of intensive blood pressure (BP) lowering using a fixed combination of perindopril-indapamide versus placebo in type 2 diabetes (T2D). The study showed that combination perindopril-indapamide had significant benefits in reducing cardiovascular, renal, and mortality events, with consistent relative risk reductions across different patient subgroups. Secondary analyses of ADVANCE have identified novel risk markers in T2D including cessation of BP lowering therapy, absent peripheral pulses and cardiac biomarkers to name a few. ADVANCE also shed light on practical aspects of hypertension management, including the limitations of office BP, tolerability of combination BP lowering therapy across the range of BP levels and the interpretation of changes in serum creatinine after treatment initiation. This review article summarizes the findings of ADVANCE and its subsequent substudies, which have been foundational in our understanding of BP management and the use of combination BP lowering therapy in T2D.

Long-term exposure to antihypertensive drugs and the risk of cancer occurrence: evidence from a large population-based study.

OBJECTIVE: Available data on the association between antihypertensive drugs and cancer are characterized by a few years follow-up. Our aim has been to evaluate the association between long-term exposure to antihypertensive drugs and the risk of cancer occurrence. METHODS: Using the healthcare utilization databases of the Lombardy region (Italy), individuals aged 40-85 years who had no previous history of cancer and were newly dispensed with at least one antihypertensive drug from the major drug classes between 2009 and 2011 were followed from the first drug dispensation to December 31, 2020. Data were analyzed according to the first drug used and the intention to treat principle, but also via an "as treated" approach, that is, by considering changes of and exposure to drugs during follow-up. The association between the duration of exposure to each drug class and the risk of cancer occurrence was evaluated using the adjusted Cox regression models. RESULTS: The study cohort included 338 910 new drug users (median age, 59 years; 49.5% males). During a median follow-up of 10.2 years, 36 556 cancers occurred. There was no consistent significant association between the risk of cancer occurrence and angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, or thiazides. A progressive, weak increase in cancer occurrence was associated with progressive exposure to calcium channel blockers and, limited to long-term exposure, to beta-blockers. A modest progressive increase in risk was observed also for thiazide-like and loop diuretics in the as treated, although not in the intention to treat approach. CONCLUSIONS: Long-term evaluation of exposure to antihypertensive drugs did not show consistent associations between thiazides, angiotensin-receptor blockers, or angiotensin-converting-enzyme inhibitors and the risk of cancer occurrence. A weak association was observed between cancer and the duration of exposure to calcium channel blockers and beta-blockers.

Ambulatory Blood Pressure Phenotypes, Arterial Stiffness And Cardiac Remodelling.

BACKGROUND: Evidence on the association of arterial stiffness and left ventricular (LV) concentric remodelling/ LVH assessed by echocardiography, with abnormal blood pressure (BP) phenotypes, defined by office and ambulatory BP monitoring (ABPM) in the community is scanty. We investigated this issue in the participants to the Pressioni Monitorate E Loro Associazioni (PAMELA) study. METHODS: The study included 491 participants who attended the second and third survey of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, blood examinations, office, ABPM, echocardiographic and Cardio-Ankle Vascular Index (CAVI) measurements. RESULTS: In the whole study sample (age 66 + 10 years, 50% males), the prevalence rates of sustained normotension (NT), white coat hypertension (WCH), masked hypertension (MH), sustained hypertension (SH) and non-dipping (ND) were 31.2, 10.0, 24.2, 34.6, and 35.8% and respectively. The likelihood of having SH, the BP phenotype carrying the greatest CV risk, was four times higher (OR= 4.31, CI:2.39-7.76, p<0.0001) in participants with increased CAVI and LV remodelling/LVH compared to their counterparts without organ damage. This association showed an incremental value in discriminating SH compared to both isolated markers of organ damage (OR=1.92,p=0.03 for increased CAVI and OR= 2.02, p=0.02 for LV remodelling/LVH). The presence of isolated but also combined organ damage was unrelated to ND. CONCLUSIONS: Our study provides new evidence of the incremental value of looking for both vascular and cardiac organ damage to optimize the identification and clinical management of SH in the general population.

Cost-effectiveness of single-pill and separate-pill administration of antihypertensive triple combination therapy: a population-based microsimulation study.

BACKGROUND: Single-pill combination (SPC) of three antihypertensive drugs has been shown to improve adherence to therapy compared with free combinations, but little is known about its long-term costs and health consequences. This study aimed to evaluate the lifetime cost-effectiveness profile of a three-drug SPC of an angiotensin-converting enzyme inhibitor, a calcium-channel blocker, and a diuretic vs the corresponding two-pill administration (a two-drug SPC plus a third drug separately) from the Italian payer perspective. METHODS: A cost-effectiveness analysis was conducted using multi-state semi-Markov modeling and microsimulation. Using the healthcare utilization database of the Lombardy Region (Italy), 30,172 and 65,817 patients aged ≥ 40 years who initiated SPC and two-pill combination, respectively, between 2015 and 2018 were identified. The observation period extended from the date of the first drug dispensation until death, emigration, or December 31, 2019. Disease and cost models were parametrized using the study cohort, and a lifetime microsimulation was applied to project costs and life expectancy for the compared strategies, assigning each of them to each cohort member. Costs and life-years gained were discounted by 3%. Probabilistic sensitivity analysis with 1,000 samples was performed to address parameter uncertainty. RESULTS: Compared with the two-pill combination, the SPC increased life expectancy by 0.86 years (95% confidence interval [CI] 0.61-1.14), with a mean cost differential of -€12 (95% CI -9,719-8,131), making it the dominant strategy (ICER = -14, 95% CI -€15,871-€7,113). The cost reduction associated with the SPC was primarily driven by savings in hospitalization costs, amounting to €1,850 (95% CI 17-7,813) and €2,027 (95% CI 19-8,603) for patients treated with the SPC and two-pill combination, respectively. Conversely, drug costs were higher for the SPC (€3,848, 95% CI 574-10,640 vs. €3,710, 95% CI 263-11,955). The cost-effectiveness profile did not significantly change according to age, sex, and clinical status. CONCLUSIONS: The SPC was projected to be cost-effective compared with the two-pill combination at almost all reasonable willingness-to-pay thresholds. As it is currently prescribed to only a few patients, the widespread use of this strategy could result in benefits for both patients and the healthcare system.

Cardio-Ankle Vascular Index and left ventricular mass as markers of nocturnal blood pressure fall in the general population.

BACKGROUND: Findings regarding the association between Cardio-Ankle Vascular Index (CAVI) and the extent of nocturnal blood pressure (BP) fall in the general population are scanty. We sought to investigate this issue in the participants enrolled in the Pressioni Monitorate E Loro Associazioni (PAMELA) study. METHODS: The study included 491 participants who attended the second and third surveys of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory blood pressure BP monitoring (ABPM), blood examinations, echocardiography, and CAVI measurements. RESULTS: In the whole study, both CAVI and left ventricular mass index (LVMI) were inversely correlated with nocturnal SBP fall, expressed as day-night percent change (r = - 0.152, p = 0.0007, and r = - 0.213, p < 0.0001, respectively). However, after adjustment for sex and age, the correlation remained significant only for LVMI (r = - 0.124, p = 0.006). Non-dipper participants exhibited significantly higher sex-age adjusted LVMI (91 ± 22 vs 82 ± 18 g/m2 (p < 0.0001)), but not of CAVI (9.07 ± 2.0 and 9.57 ± 2.2 m/s, p = ns). Similar results were found when classifying participants into quartiles of nocturnal SBP drop. Finally, both sex-age adjusted CAVI and LVMI were positively correlated with mean nocturnal SBP (r = 0.181, p < 0.001, and r = 0.240, p < 0.0001). CONCLUSIONS: Although arterial stiffness assessed by CAVI, unlike LVMI, is unrelated with the degree of nocturnal BP drop, this marker is useful in identifying nocturnal hypertension and optimizing cardiovascular risk stratification in the community.

Reliability of heart rate in reflecting cardiac sympathetic overdrive in type 2 diabetes mellitus.

PURPOSE: Clinical trials have shown that in type 2 diabetes mellitus (T2D) resting office heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk, a worse prognosis and an unfavorable outcome. The present study was aimed at investigating whether the above mentioned treshold HR values reflect a sympathetic overdrive of marked degree. METHODS: In 58 T2D patients (age range: 39-57 years) without signs of autonomic neuropathy and in 52 age-matched healthy controls, we assessed muscle sympathetic nerve activity (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC), subdividing the study population in different subgroups according to their clinic and 24-h HR values. RESULTS: In T2D progressively greater clinic and 24-h HR values were accompanied by progressive increases in MSNA and NE. HR cutoff values indicated by clinical trials as associated with an increased cardiovascular risk (> 70 beats/minute) were accompanied by MSNA values significantly higher than those detected in patients with lower HR, this being the case also for NE. In T2D both MSNA and NE were significantly related to clinic (r = 0.93, P < 0.0001 and r = 0.87, P < 0.0001, respectively) and 24-h (r = 0.92, P < 0.0001 and r = 0.84, P < 0.0001, respectively) HR. The MSNA and NE behaviour observed in T2D was not detected in healthy controls. CONCLUSIONS: In T2D clinic HR values allow to detect patients with a greater sympathetic overactivity. Considering the adverse clinical impact of the sympathetic overdrive on prognosis, our data emphasize the need of future studies investigating the potential usefulness of lifestyle and pharmacological interventions exerting sympathomodulatory effects.

Effects of acute carotid baroreceptor stimulation on sympathetic nerve traffic in resistant and uncontrolled hypertension: a systematic review and meta-analysis.

In resistant hypertensive patients acute carotid baroreflex stimulation is associated with a blood pressure (BP) reduction, believed to be mediated by a central sympathoinhbition.The evidence for this sympathomodulatory effect is limited, however. This meta-analysis is the first to examine the sympathomodulatory effects of acute carotid baroreflex stimulation in drug-resistant and uncontrolled hypertension, based on the results of microneurographic studies. The analysis included 3 studies assessing muscle sympathetic nerve activity (MSNA) and examining 41 resistant uncontrolled hypertensives. The evaluation included assessment of the relationships between MSNA and clinic heart rate and BP changes associated with the procedure. Carotid baroreflex stimulation induced an acute reduction in clinic systolic and diastolic BP which achieved statistical significance for the former variable only [systolic BP: -19.98 mmHg (90% CI, -30.52, -9.43), P < 0.002], [diastolic BP: -5.49 mmHg (90% CI, -11.38, 0.39), P = NS]. These BP changes were accompanied by a significant MSNA reduction [-4.28 bursts/min (90% CI, -8.62, 0.06), P < 0.07], and by a significant heart rate decrease [-3.65 beats/min (90% CI, -5.49, -1.81), P < 0.001]. No significant relationship was detected beween the MSNA, systolic and diastolic BP changes induced by the procedure, this being the case also for heart rate. Our data show that the acute BP lowering responses to carotid baroreflex stimulation, although associated with a significant MSNA reduction, are not quantitatively related to the sympathomoderating effects of the procedure. This may suggest that these BP effects depend only in part on central sympathoinhibition, at least in the acute phase following the intervention.

Habitual Regular Coffee Consumption and Arterial Stiffness: Data From the 3rd Pamela Survey.

BACKGROUND: We evaluated whether chronic coffee consumption affects arterial stiffness, assessed by cardio-ankle vascular index (CAVI). METHODS: In 514 subjects, aged 66.6 ±â€…9.9 years (mean ±â€…SD), recruited in the 3rd follow-up of the PAMELA study, subdivided into 3 groups according to the daily intake of regular coffee (0, 1-2, and ≥3 cups/day), we measured CAVI and clinic, ambulatory blood pressure (BP), and other variables. RESULTS: The 3 groups displayed similar age, gender, metabolic, and renal profile. Clinic and ambulatory BPs were similar in the 3 groups, this being the case for CAVI (0 cup: 9.1 ±â€…1.8, 1-2 cups: 9.5 ±â€…2.3, and ≥3 cups: 9.2 ±â€…2.1 m/s, P = NS). No significant gender difference in CAVI and in participants under antihypertensive treatment was detected. CONCLUSIONS: Our data show that chronic coffee consumption leaves unaffected arterial stiffness in the general population, this being the case in subgroups. The neutral vascular impact of coffee may favor the absence of any significant BP effect of habitual coffee intake.

Risk of recurrent stroke and dementia following acute stroke by changes in kidney function: results from the Perindopril Protection Against Recurrent Stroke Study.

BACKGROUND: Limited data exist on the relationship between declining kidney function and cardiovascular events, dementia, and mortality in patients with a history of stroke.Thus the aims of the study were to investigate functional relationships between dynamic kidney function change and cardiovascular outcomes, and clarify whether adding kidney parameters to conventional cardiovascular risk factors improves model discrimination. METHODS: Post hoc analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) clinical trial of blood pressure lowering for the secondary prevention of stroke. We examined the association between dynamic kidney function defined as percentage change (declines of >30%, and >0 to ≤30%, and increases of ≥0 to <30%, and ≥30%) in estimated glomerular filtration rate (eGFR) over 2 years and recurrent stroke, major cardiovascular events, dementia and all-cause death over the next 2 years using Cox proportional hazard models controlling for eGFR at registration and potential confounders. Restricted cubic splines were used to assess the functional relationships. C-statistics and Net Reclassification Improvement (NRI) at 2 years were used to assess model discrimination. RESULTS: In 4591 patients followed for a mean of approximately 2 years, 254 (5.5%) developed recurrent stroke, 391 (8.5%) had a major cardiovascular event, 221 (4.8%) developed dementia, and 271 (5.9%) died. Reverse J-like or U-like relationships were observed for percent declines in eGFR and outcomes. Using declines in eGFR of >0 to ≤30% as a reference, increased risks were evident for a greater decline (>30%) in relation to recurrent stroke [adjusted hazard ratio 1.85, 95% confidence interval (CI) 1.20-2.85], major cardiovascular event (2.24, 1.62-3.10) and all-cause death (2.09, 1.39-3.15). A larger increase (≥30%) in eGFR was also associated with a greater risk of all-cause death (1.96, 1.14-3.37). Improvements in the C-statistic were found by adding baseline eGFR and percent change compared with a model with conventional cardiovascular risk factors alone, for major cardiovascular events, dementia, and all-cause mortality. CONCLUSION: Declining kidney function following an incident cerebrovascular event is associated with additional risk of a major cardiovascular events, dementia, and 2-year mortality. However, a large increase in kidney function was also found to be associated with a higher risk of mortality.

Impact of seasonal blood pressure changes on visit-to-visit blood pressure variability and related cardiovascular outcomes.

BACKGROUND: Visit-to-visit blood pressure (BP) variability associates with an increased risk of cardiovascular events. We investigated the role of seasonal BP modifications on the magnitude of BP variability and its impact on cardiovascular risk. METHODS: In 25 390 patients included in the ONTARGET and TRANSCEND trials, the on-treatment systolic (S) BP values obtained by five visits during the first two years of the trials were grouped according to the month in which they were obtained. SBP differences between winter and summer months were calculated for BP variability quintiles (Qs), as quantified by the coefficient of variation (CV) of on-treatment mean SBP from the five visits. The relationship of BP variability with the risk of cardiovascular events and mortality was assessed by the Cox regression model. RESULTS: SBP was approximately 4 mmHg lower in summer than in winter regardless of confounders. Winter/summer SBP differences contributed significantly to each SBP-CV quintile. Increase of SBP-CV from Q1 to Q5 was associated with a progressive increase in the adjusted hazard ratio (HR) of the primary endpoint of the trials, i.e. morbid and fatal cardiovascular events. This association was even stronger after removal of the effect of seasonality from the calculation of SBP-CV. A similar trend was observed for secondary endpoints. CONCLUSIONS: Winter/summer SBP differences significantly contribute to visit-to-visit BP variability. However, this contribution does not participate in the adverse prognostic significance of visit-to-visit BP variations, which seems to be more evident after removal of the BP effects of seasonality from visit-to-visit BP variations.