Ten-year legacy effects of baseline blood pressure ‘treatment naivety’ in the Second Australian National Blood Pressure study Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. Legacy Effect of Delayed Blood Pressure-Lowering Pharmacotherapy in Middle-Aged Individuals Stratified by Absolute Cardiovascular Disease Risk: Protocol for a Systematic Review Benefits of adherence to anti-hypertensive drug therapy. Chocolate and Prevention of Cardiovascular Disease: A Systematic Review Fish oil affects blood pressure and the plasma lipid profile in healthy Danish infants. Mortality and morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the U.K. Effectiveness of blood pressure-lowering drug treatment by levels of absolute risk: post hoc analysis of the Australian National Blood Pressure Study Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality Plasma Fatty Acid Composition as a Predictor of Arterial Stiffness and Mortality Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Long-term effect of calcium-vitamin D3 fortified milk on blood pressure and serum lipid concentrations in healthy older men Statins and Fibrates for Diabetic Retinopathy: Protocol for a Systematic Review Association between different lipid-lowering treatment strategies and blood pressure control in the Brisighella Heart Study. No excess 12-year mortality in men with impaired glucose tolerance who participated in the Malmö Preventive Trial with diet and exercise The long-term effects of lifestyle change on blood pressure: One-year follow-up of the ENCORE study. Long-term effects of stress reduction on mortality in persons > or = 55 years of age with systemic hypertension. Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride: results from the European exenatide study Outcomes of Combined Cardiovascular Risk Factor Management Strategies in Type 2 Diabetes: The ACCORD Randomized Trial Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Effects of medical therapies on retinopathy progression in type 2 diabetes: Is blood pressure control the lower the better?
Objectives : Current blood pressure ( BP ) management guidelines recommend that treatment thresholds for BP be based on absolute cardiovascular disease ( CVD ) risk rather than on elevated BP levels alone . Clinicians are concerned that delayed pharmacotherapy in individuals with high BP , but low CVD risk , may increase long-term CVD events . To investigate this , we examined differences in CVD events within the Second Australian National BP study ( ANBP2 ) for those previously on pharmacotherapy and those who were not , as well as fatal events in the 6-year post-trial period . Methods : Population consisted of ANBP2 participants without a prior CVD event . Adjusted Cox-regression hazard models were used to assess the effects of prior BP pharmacotherapy use on cardiovascular endpoints within ANBP2 . An extended 6-year follow-up analysis for cardiovascular and all-cause mortality was also conducted . Results : We found a higher in-trial CVD and all-cause mortality rate and incidence of new-onset diabetes for those on previous treatment versus those who were treatment-naive . We investigated whether this was an effect of the in-trial protocol , but this did not explain the observed differences . No difference in CVD or all-cause mortality at 10 years was observed between ‘ treatment-naive ’ and ‘ previous treatment ’ groups . Conclusion : We found no long-term adverse mortality associated with treatment naivety of elevated BP in an elderly hypertensive cohort , but this finding is likely to be confounded as seen by the lower in-trial mortality in the ‘ treatment-naive ’ group . Legacy effects need to be explored in r and omized trials of middle-aged population s where the clinical concern lies The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infa rct ion . The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects . No evidence of efficacy was found for the clofibrate treatment . Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infa rct ion but did not decrease total mortality . With a mean follow-up of 15 years , nearly 9 years after termination of the trial , mortality from all causes in each of the drug groups , except for niacin , was similar to that in the placebo group . Mortality in the niacin group was 11 % lower than in the placebo group ( 52.0 versus 58.2 % ; p = 0.0004 ) . This late benefit of niacin , occurring after discontinuation of the drug , may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfa rct ion or a result of the cholesterol-lowering effect of niacin , or both Background Many national and international guidelines recommend that the initiation of blood pressure (BP)-lowering drug treatment for the primary prevention of cardiovascular disease ( CVD ) should no longer be based on BP level alone , but on absolute cardiovascular risk . While BP-lowering drug treatment is beneficial in high-risk individuals at any level of elevated BP , clinicians are concerned about legacy effects on patients with low-to-moderate risk and mildly elevated BP who remain “ untreated ” . Objective We aim to investigate the legacy effect of delayed BP-lowering pharmacotherapy in middle-aged individuals ( 45 - 65 years ) with mildly elevated BP ( systolic BP 140 - 159 mmHg and /or diastolic BP 90 - 99 mmHg ) stratified by absolute risk for primary prevention of CVD , but particularly in the low-risk ( < 10 % five-year absolute risk ) group . Methods R and omized trials of BP-lowering therapy versus placebo or pretreated subjects in active comparator studies with posttrial follow-up will be identified using a 2-step process . First , r and omized trials of BP-lowering therapy will be identified by ( 1 ) retrieving the references of trials included in published systematic review s of BP-lowering therapy , ( 2 ) retrieving studies published by the Blood Pressure Lowering Treatment Trialists ’ Collaboration ( BPLTTC ) , and ( 3 ) checking studies referenced in the 1993 World Health Organization/International Society of Hypertension meeting memor and um on BP management . Posttrial follow-up studies will then be identified by forward citation search ing the r and omized trials identified in step 1 through Web of Science . The search will include r and omized controlled trials with at least 1-year in-trial period and a posttrial follow-up phase . Age is the major determinant of absolute cardiovascular risk , so the participants in our review will be restricted to middle-aged adults who are more likely to have a lower cardiovascular risk profile . The primary outcome will be all-cause mortality . Secondary outcomes will include cardiovascular mortality , fatal stroke , fatal myocardial infa rct ion , and death due to heart failure . Results The search es for existing systematic review s and BPLTTC studies were piloted and modified . The study is expected to be completed before June 2018 . Conclusions The findings of this study will contribute to the body of knowledge concerning the beneficial , neutral , or harmful effects of delayed BP-lowering drug treatment on the primary prevention of CVD in patients with mildly elevated BP and low-to-moderate CVD risk . Trial Registration PROSPERO International Prospect i ve Register of Systematic Review s : CRD42017058414 ; https://www.crd.york.ac.uk/ PROSPERO /display_record.asp?ID = CRD42017058414 ( Archived by WebCite ® at http://www.webcitation.org/6t6sa8O2Q Long-term adherence or compliance with anti-hypertensive drug therapy is poor . It has been estimated that within the first year of treatment 16 - 50 % of hypertensives discontinue their anti-hypertensive medications . Even among those who remain on therapy long term , missed medication doses are common . Epidemiological studies have shown that drug-treated hypertensives have higher blood pressures than age- , gender- and body mass index-matched normotensives . In addition , drug-treated hypertensive men and women who achieve blood pressure normalization are less likely to die over a 9.5-year period than those whose blood pressure remains elevated while taking anti-hypertensive drugs . Thus , one reason for less than optimal reduction of blood pressure-related cardiovascular-renal risk in drug-treated hypertensives is inadequate blood pressure lowering . Quantifiable excess risk has been documented even in the short term ( < 1 year ) after interruption or discontinuation of anti-hypertensive medications as total healthcare costs are higher , mostly because of higher hospitalization rates . Data from the Treatment of Mild Hypertension Study ( TOMHS ) are relevant to long-term adherence to various anti-hypertensive drug monotherapies . At 48 months , 82.5 % and 77.8 % of participants remained on  amlodipine and acebutolol  , respectively ( both P < 0.01 compared with placebo ) . However , only 67.5 % , 66.1 % and 68.1 % , respectively , of chlorthalidone , doxazosin and enalapril participants remained on these drugs as monotherapy at 48 months . Differential adherence to long-term anti-hypertensive drug therapy could translate into a greater risk of blood pressure-related complications and higher overall healthcare expenditures . Strategies to minimize the deleterious impact of therapeutic non-adherence with anti-hypertensive medications as well as the clinical and cost implication s of the TOMHS data will be discussed Background Consumption of chocolate has been often hypothesized to reduce the risk of cardiovascular disease ( CVD ) due to chocolate 's high levels of stearic acid and antioxidant flavonoids . However , debate still lingers regarding the true long term beneficial cardiovascular effects of chocolate overall . Methods We review ed English- language MEDLINE publications from 1966 through January 2005 for experimental , observational , and clinical studies of relations between cocoa , cacao , chocolate , stearic acid , flavonoids ( including flavonols , flavanols , catechins , epicatechins , and procynadins ) and the risk of cardiovascular disease ( coronary heart disease ( CHD ) , stroke ) . A total of 136 publications were selected based on relevance , and quality of design and methods . An up date d meta- analysis of flavonoid intake and CHD mortality was also conducted . Results The body of short-term r and omized feeding trials suggests cocoa and chocolate may exert beneficial effects on cardiovascular risk via effects on lowering blood pressure , anti-inflammation , anti-platelet function , higher HDL , decreased LDL oxidation . Additionally , a large body of trials of stearic acid suggests it is indeed cholesterol-neutral . However , epidemiologic studies of serum and dietary stearic acid are inconclusive due to many method ologic limitations . Meanwhile , the large body of prospect i ve studies of flavonoids suggests the flavonoid content of chocolate may reduce risk of cardiovascular mortality . Our up date d meta- analysis indicates that intake of flavonoids may lower risk of CHD mortality , RR = 0.81 ( 95 % CI : 0.71–0.92 ) comparing highest and lowest tertiles . Conclusion Multiple lines of evidence from laboratory experiments and r and omized trials suggest stearic acid may be neutral , while flavonoids are likely protective against CHD mortality . The highest priority now is to conduct larger r and omized trials to definitively investigate the impact of chocolate consumption on long-term cardiovascular outcomes Animal and epidemiologic studies indicate that early nutrition has lasting effects on metabolism and cardiovascular disease risk . In adults , ( n-3 ) long-chain PUFA ( LCPUFA ) from fish oils improve blood pressure , the lipid profile , and possibly cardiovascular disease mortality . This r and omized trial is the first to investigate the effects of fish oil on blood pressure and the lipid profile in infancy . Healthy term 9-mo old infants ( n = 83 ) were r and omly assigned to 5 mL fish oil daily or no fish oil for 3 mo and to 2 different milk types . Before and after the intervention , blood pressure was measured with an oscillometric device , and blood was sample d for analysis of erythrocyte fatty acid composition and the plasma lipid profile . This paper examines the effects of the fish oil supplement , with adjustment for the effects of the milk intervention when relevant . The fish oil intervention increased erythrocyte ( n-3 ) LCPUFA content ( P < 0.001 ) . At 12 mo , infants administered fish oil had a lower systolic blood pressure [ adjusted mean difference ( 95 % CI ) ] 6.3 mm Hg ( 0.9 , 11.7 ) ( P = 0.02 ) , a 0.51 mmol/L ( 0.07 , 0.95 ) higher plasma total cholesterol ( P = 0.02 ) , and a 0.52 mmol/L ( 0.02,1.01 ) higher LDL cholesterol ( P = 0.04 ) than infants not administered fish oil . Plasma triacylglycerol was inversely associated with the erythrocyte content of eicosapentaenoic acid ( r = 0.34 , P < 0.01 ) , a biomarker of fish oil dose . The observed effects of fish oil are in accordance with findings in adults . The long-term health implication s warrant further investigation A r and omized , double-blind , active-controlled , multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone ( n=15,002 ) , amlodipine ( n=8898 ) , or lisinopril ( n=8904 ) for 4 to 8 years , when double-blinded therapy was discontinued . Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative data bases to ascertain deaths and hospitalizations . During the post-trial period , fatal outcomes and nonfatal outcomes were available for 98 % and 65 % of participants , respectively , due to lack of access to administrative data bases for the remainder . This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up . Primary outcome was cardiovascular mortality and secondary outcomes were mortality , stroke , coronary heart disease , heart failure , cardiovascular disease , and end-stage renal disease . For the post-trial period , data are not available on medications or blood pressure levels . No significant differences ( P<.05 ) appeared in cardiovascular mortality for amlodipine ( hazard ratio [ HR ] , 1.00 ; 95 % confidence interval [ CI ] , 0.93 - 1.06 ) or lisinopril ( HR , 0.97 ; CI , 0.90 - 1.03 ) , each compared with chlorthalidone . The only significant differences in secondary outcomes were for heart failure , which was higher with amlodipine ( HR , 1.12 ; CI , 1.02 - 1.22 ) , and stroke mortality , which was higher with lisinopril ( HR , 1.20 ; CI , 1.01 - 1.41 ) , each compared with chlorthalidone . Similar to the previously reported in-trial result , there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone .  Black participants had higher risk than non-black participants  taking lisinopril compared with chlorthalidone . After accounting for multiple comparisons , none of these results were significant . These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension AIMS The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in the Anglo-Sc and inavian Cardiac Outcomes Trial-8 years after closure of the lipid-lowering arm ( LLA ) of the trial ( ASCOT-LLA ) among the U.K. population . METHODS AND RESULTS ASCOT-LLA was a factorially design ed double-blind placebo-controlled trial of atorvastatin in 10 305 hypertensive patients enrolled into the ASCOT-Blood Pressure Lowering Arm ( BPLA ) of the trial and with total cholesterol concentrations , at baseline , of < 6.5 mmol/L. ASCOT-LLA was stopped prematurely after a median 3.3-year follow-up because of a 36 % relative risk reduction ( RRR ) in non-fatal myocardial infa rct ion and fatal coronary heart disease ( CHD ) ( the primary outcome ) in favour of atorvastatin and a non-significant reduction in CV deaths ( 16 % ) and all-cause mortality ( 13 % ) . After a further 2.2 years at the end of ASCOT-BPLA , despite extensive crossovers from and to statin usage , the RRR in all endpoints remained essentially unchanged . A median 11 years after initial r and omization and ∼8 years after closure of LLA , all-cause mortality ( n=520 and 460 in placebo and atorvastatin , respectively ) remained significantly lower in those originally assigned atorvastatin ( HR 0.86 , CI 0.76 - 0.98 , P=0.02 ) . CV deaths were fewer , but not significant ( HR 0.89 , CI 0.72 - 1.11 , P=0.32 ) and non-CV deaths were significantly lower ( HR 0.85 , CI 0.73 - 0.99 , P=0.03 ) in those formerly assigned atorvastatin attributed to a reduction in deaths due to infection and respiratory illness . CONCLUSION Legacy effects of those originally assigned atorvastatin may contribute to long-term benefits on all-cause mortality . An explanation for long-term benefits on non-CV deaths has not been established Objectives In many current guidelines , blood pressure (BP)-lowering drug treatment for primary prevention of cardiovascular disease ( CVD ) is based on absolute risk . However , in clinical practice , therapeutic decisions are often based on BP levels alone . We sought to investigate which approach was superior by conducting a post hoc analysis of the Australian National Blood Pressure ( ANBP ) cohort , a seminal study establishing the efficacy of BP lowering in ‘ mild hypertensive ’ persons . Design A post hoc subgroup analysis of the ANBP trial results by baseline absolute risk tertile . Setting and participants 3244 participants aged 35–69 years in a community-based r and omised placebo controlled trial of blood pressure-lowering medication . Interventions Chlorothiazide500 mg versus placebo . Primary outcome measures All-cause mortality and non-fatal events ( non-fatal CVD , congestive cardiac failure , renal failure , hypertensive retinopathy or encephalopathy ) . Results Treatment effects were assessed by HR , absolute risk reduction and number needed to treat . Participants had an average 5-year CVD risk in the intermediate range ( 10.5±6.5 ) with moderately elevated BP ( mean 159/103 mmHg ) and were middle aged ( 52±8 years ) . In a subgroup analysis , the relative effects ( HR ) and absolute effects ( absolute risk reduction and number needed to treat ) did not statistically differ across the three risk groups except for the absolute benefit in all-cause mortality ( p for heterogeneity=0.04 ) . With respect to absolute benefit , drug treatment significantly reduced the number of events in the high-risk group regarding any event with a number needed to treat of 18 ( 10 to 64 ) , death from any cause with 45 ( 25 to 196 ) and major CVD events with 23 ( 12 to 193 ) . Conclusion Our analysis confirms that the benefit of treatment was substantial only in the high-risk tertile , reaffirming the rationale of treating elevated blood pressure in the setting of all risk factors rather than in isolation Context It is not clear whether variability in a patient 's outpatient blood pressure ( BP ) measurements has prognostic importance . Contribution Patients with greater visit-to-visit variability in BP readings had an increased risk for cardiovascular events and mortality , which was independent of their overall degree of BP control . Implication Further studies are warranted to assess whether reducing visit-to-visit BP variations will alter the risk for adverse cardiovascular outcomes . The prognostic value of blood pressure ( BP ) is mainly based on measurements obtained in a clinical setting , typically from a few visits ( 1 ) . Until recently , variability of BP across outpatient visits was dismissed as r and om fluctuation around a patient 's true underlying BP ( 2 , 3 ) . Although some studies have reported associations between higher visit-to-visit variability ( VVV ) of systolic BP ( SBP ) and an increased risk for stroke and coronary heart disease ( CHD ) , other analyses have failed to show such associations ( 410 ) . The method applied in estimating VVV of BP varied widely across previous studies . In addition , studies have used as few as 3 visits and as many as 56 visits to estimate the VVV of BP , and the time between visits has ranged from 2 days to as long as 4 years ( 5 , 11 , 12 ) . These factors not only influence VVV of BP but could also affect the strength of its association with cardiovascular disease ( CVD ) outcomes ( 4 , 13 ) . To address the inconsistent findings from previous studies , we did a secondary data analysis of ALLHAT ( Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ) to examine whether VVV of BP is associated with CVD and mortality events . ALLHAT provides the opportunity to evaluate the association between VVV of BP and major clinical outcomes in a large and diverse population with hypertension in which visits were conducted at set time intervals , BP was measured by following a st and ardized protocol , and outcomes were evaluated over several years of follow-up . Methods Study Design We did a cohort study as a secondary analysis using data from ALLHAT . Figure 1 shows the timeline for assessment of VVV of BP and outcome events within ALLHAT . The primary exposure of interest , VVV of SBP , was ascertained at the 7 study visits conducted between 6 and 28 months after r and omization . We studied 4 outcomes : fatal CHD or nonfatal myocardial infa rct ion ( MI ) , all-cause mortality , stroke , and heart failure . Participants were followed from their 28-month visit until the occurrence of an outcome event or the end of active ALLHAT follow-up ( October 2001 to March 2002 ) . Participants who had an event before their 28-month visit were excluded from all analyses . Figure 1 . Study design evaluating the association between VVV of BP and cardiovascular outcomes and all-cause mortality in ALLHAT . ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ; BP = blood pressure ; DBP = diastolic blood pressure ; SBP = systolic blood pressure ; VVV = visit-to-visit variability . * Participants were followed for a mean of 2.7 to 2.9 y ( maximum , 5.7 y ) depending on the outcome after assessment of VVV of BP . ALLHAT was a multicenter , double-blind , r and omized clinical trial sponsored by the National Heart , Lung , and Blood Institute of the National Institutes of Health . A complete description of the rationale and design of ALLHAT has been previously published ( 14 ) . In brief , ALLHAT was design ed to determine whether treatment initiated with a calcium-channel blocker ( amlodipine ) , angiotensin-converting enzyme inhibitor ( lisinopril ) , or -blocker (doxazosin)each compared with treatment initiated with a diuretic (chlorthalidone)would lower major cardiovascular outcomes . The primary end point was incidence of fatal CHD or nonfatal MI .  A total of 42418 hypertensive adults aged 55 years or older with 1 or more additional risk factor for CVD were enrolled at 623 clinical sites across the United States , Canada , Puerto Rico , and the U.S. Virgin Isl and s between February 1994 and January 1998 . The doxazosin treatment group was discontinued in 2000 because of the small chance of finding a benefit on CHD outcomes and an increased risk for CVD than in the chlorthalidone group ( 15 ) . The main results comparing participants r and omly assigned to chlorthalidone , amlodipine , or lisinopril were published in December 2002 ( 16 ) . The trial was approved by local institutional review boards , and all participants provided written informed consent . Our current analysis was approved by the Institutional Review Board at the University of Alabama at Birmingham . Study Visits , BP Measurements , and Calculation of VVV of BP To calculate intraindividual VVV of SBP and diastolic BP ( DBP ) , we used data from 7 follow-up visits that occurred 6 , 9 , 12 , 16 , 20 , 24 , and 28 months after r and omization . We chose to begin the assessment period at the 6-month follow-up visit to avoid confounding by the initial reduction in BP that occurred between r and omization and this visit ( SBP , 6 to 10 mm Hg ; DBP , approximately 5 mm Hg ) due to early medication titration . To increase the precision of estimates , we calculated VVV of BP for participants with BP measurements at 5 , 6 , or 7 visits conducted between month 6 and 28 after r and omization . The VVV of BP was imputed for participants who attended fewer than 5 visits between months 6 and 28 . To maximize follow-up time , we did not extend the assessment past the 28-month follow-up visit . At each follow-up visit ,  BP was measured twice by a trained observer by means of a st and ardized technique ( 17 ) . Using the average BP at each visit , we defined VVV of BP by the intraindividual SD across visits . Average real variability ( ARV ) and SD independent of the mean ( SDIM ) were calculated as alternative metrics for VVV of BP ( Appendix Figure ) ( 18 ) . The VVV of DBP was also calculated in secondary analyses . Appendix Figure . Formulas used to calculate VVV of BP metrics . ARV = average real variability ; BP = blood pressure ; SDIM = SD independent of the mean ; VVV = visit-to-visit variability . Outcome Ascertainment We studied 4 outcomes , including fatal CHD or nonfatal MI , all-cause mortality , stroke , and heart failure . The event ascertainment process is detailed elsewhere ( 14 , 16 ) . Participants were followed from the end of the assessment period to the date of each outcome , their date of death , or the end of active ALLHAT follow-up ( 1 October 2001 through 31 March 2002 ) . Covariate Information Covariates used for adjustment were selected a priori on the basis of their potential role as confounders . Baseline ( before r and omization ) variables included age , sex , race/ethnicity , education , current cigarette smoking status , body mass index , use of aspirin , high-density lipoprotein cholesterol level less than 0.91 mmol/L ( < 35 mg/dL ) ( at 2 occasions in the 5 years before ALLHAT enrollment ) ,  total cholesterol level , estimated glomerular filtration rate ( eGFR ) , diabetes , history of MI or stroke , documentation of other atherosclerotic CVD , history of revascularization , atrial fibrillation by electrocardiography , left ventricular hypertrophy ( LVH ) , the presence of ST depression and T-wave inversion , and use of antihypertensive medication  before ALLHAT r and omization . The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation ( 19 ) . Data collected at visits conducted 6 to 28 months after r and omization were used to calculate mean SBP and DBP ; pulse pressure ; the use of antihypertensive medications beyond the r and omization drug ; changes in antihypertensive medication regimen ( adding , stopping , or changing antihypertensive medications ) ; use of statins ; and low adherence , which is defined as a report of a participant receiving less than 80 % of the r and omization drug at any visit between months 6 and 28 . Participants who reported taking 80 % or more of their r and omization drug at every visit between months 6 and 28 were considered to have high adherence . Statistical Analysis Because of limited follow-up available after the assessment period for participants r and omly assigned to receive doxazosin , we restricted our analyses to the 33357 ALLHAT participants r and omly assigned to receive chlorthalidone , amlodipine , or lisinopril .  We excluded 7543 participants who had CVD events or died before the 28-month visit . We imputed VVV of BP for participants with fewer than 5 visits and BP measurements between months 6 and 28 of follow-up . In addition , missing data for covariates were imputed ( Appendix Table 1 ) . Imputation was performed with 10 data sets using chained equations . Appendix Table 1 . Percentage of Missing Data for Participants Included in the Current Analyses Characteristics of participants included in the current analyses were calculated after participants were stratified into a quintile of SD of SBP . The KaplanMeier method was used to calculate the cumulative incidence of each outcome by quintile of SD of SBP . Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios ( HRs ) for each outcome associated with a quintile of SD of SBP , with the lowest quintile serving as the reference . Four nested models were constructed . Model 1 included adjustment for age , race/ethnicity , sex , region of residence , and antihypertensive r and omization assignment . Model 2 includes the variables in model 1 and additional adjustment for education , smoking status , body mass index , use of aspirin , low high-density lipoprotein cholesterol level , total cholesterol level , eGFR , diabetes , history of MI or stroke , history of other atherosclerotic CVD , history of coronary revascularization , atrial fibrillation by electrocardiography , major ST depression or T-wave inversion , LVH , use of antihypertensive medications before ALLHAT r and omization , and  statin use during the assessment period ( months 6 through 28 of follow-up ) . Model 3 includes the variables in model 2 and additional adjustment for mean pulse pressure , Aortic stiffness predicts  cardiovascular mortality  and may be influenced by dietary fat composition . The hypothesis that plasma fat composition influences arterial stiffness and subsequent mortality was tested here in a prospect i ve study . A total of 174 r and omly sample d nondiabetic participants aged 45 to 74 years were recruited from local population s , stratified by ethnicity and gender , and followed up for mortality . Aortic pulse wave velocity ( PWV ) , blood pressure , and fatty acid composition of plasma lipids were measured at baseline . PWV was associated with increased cardiovascular mortality and inversely related to the proportions of docosahexaenoic ( & rgr;=−0.22 ; P=0.02 ) and arachidonic acids ( & rgr;=−0.25 ; P<0.001 ) in plasma lipids . Principal component analyses identified a cluster characterized by higher proportions of palmitate , palmitoleic and oleic acid and lower proportions of linoleic , dihomo-γ linolenic , and arachidonic acids . This cluster was positively associated with PWV , central adiposity , smoking , and increased mortality ( hazard ratio : 1.13 ; 95 % CI : 1.01 to 1.27 ) . A second cluster , with higher proportions of arachidonic , eicosapentaenoic , and docosahexaenoic and lower proportions of oleic , palmitic , and linoleic acid levels , was associated with lower PWV and systolic blood pressure but also decreased risk of mortality ( hazard ratio : 0.57 ; 95 % CI : 0.39 to 0.82 ) , independent of PWV and blood pressure . These data suggest that plasma fatty acid profiles characterized by a higher proportion of long-chain polyunsaturated fatty acids are associated with decreased cardiovascular mortality , independent of the impact of aortic PWV . The results are consistent with an effect of dietary sources of n-3 long-chain polyunsaturates influencing arterial stiffness and mortality AIMS Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown . The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group . METHODS This long-term follow-up ( median 10 years , interquartile range 9.0 - 10.5 ) of the three-arm Diabetes Prevention Program r and omized controlled clinical trial ( metformin , intensive lifestyle and placebo ) , performed on 2766 ( 88 % ) of the Diabetes Prevention Program participants ( who originally had impaired glucose tolerance ) , comprised a mean of 3.2 years of r and omized treatment , approximately 1-year transition ( during which all participants were offered intensive lifestyle intervention ) and 5 years follow-up ( Diabetes Prevention Program Outcomes Study ) . During the study , participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting . The study determined lipoprotein profiles and blood pressure and medication use annually . RESULTS After 10 years ' follow-up from Diabetes Prevention Program baseline , major reductions were seen for systolic ( -2 to -3 ) and diastolic ( -6 to -6.5 mmHg ) blood pressure , and for LDL cholesterol ( -0.51 to -0.6 mmol/l ) and triglycerides ( -0.23 to -0.25 mmol/l ) in all groups , with no between-group differences . HDL cholesterol also rose significantly ( 0.14 to 0.15 mmol/l ) in all groups . Lipid ( P = 0.01 ) and blood pressure ( P = 0.09 ) medication use , however , were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study . CONCLUSION Overall , intensive lifestyle intervention achieved , with less medication , a comparable long-term effect on cardiovascular disease risk factors , to that seen in the metformin and placebo groups Background / Objectives : Some epidemiological and clinical studies have shown that increased dairy consumption or calcium and /or vitamin D supplementation can have a beneficial effect on blood pressure , and lipid and lipoprotein concentrations . The aim of this study was to assess the long-term effects of calcium-vitamin D3 fortified milk on blood pressure and lipid-lipoprotein concentrations in community-dwelling older men . Subjects/ Methods : This is a sub study of a 2-year r and omized controlled trial in which 167 men aged > 50 years were assigned to receive either 400 ml per day of reduced fat ( ∼1 % ) milk fortified with approximately 1000 mg of calcium and 800 IU of vitamin D3 or to a control group receiving no additional fortified milk . Weight , blood pressure , lipid and lipoprotein concentrations were measured every 6 months . Participants on lipid-lowering ( n=32 ) or antihypertensive medication ( n=39 ) were included , but those who commenced , increased or decreased their medication throughout the intervention were excluded ( n=27 ) . Results : In the 140 men included in this study ( milk , n=73 ; control , n=67 ) , there were no significant effects of the calcium-vitamin D3 fortified milk  on weight , systolic or diastolic blood pressure , total cholesterol , high-density lipoprotein or low-density lipoprotein cholesterol or triglyceride concentrations at any time throughout the intervention . Similar results were observed after excluding men taking antihypertensive or lipid-lowering medication or limiting the analysis to those with baseline calcium intakes < 1000 mg per day and /or with hypovitaminosis D ( 25(OH)D < 75 nmol/l ) . Conclusions : Supplementation with reduced-fat calcium-vitamin D3 fortified milk did not have a beneficial ( nor detrimental ) effect on blood pressure , lipid or lipoprotein concentrations in healthy community-dwelling older men Background Diabetic retinopathy ( DR ) is a common microvascular complication of diabetes mellitus , and more than 75 % of patients who have had diabetes for more than 20 years will have some degree of DR . This disease is highly destructive to self-esteem and puts a high burden on public health and pension systems due to the effects that it has on people of working age . The current mainstay of treatment is laser photocoagulation , which causes impairment of vision and discomfort to patients . Thus , finding a systemic drug that could act on all microcirculation and prevent direct manipulation of the eyes would be highly desirable . Objective To assess the efficacy and safety of the drugs in the statin and /or fibrate groups for the prevention and treatment of DR . Methods In this systematic review , we will select r and omized controlled trials of fibrates or statins used for the treatment or prevention of DR . Our search strategy will include free text terms and controlled vocabulary ( eg , MeSH , Emtree ) for , “ diabetic retinopathy ” , “ statins ” , “ fibrates ” , “ hypolipidemic agents ” , and for drugs from both groups . Data bases that will be used include Medical Literature Analysis and Retrieval System/ PubMed , Embase , Cochrane Central Register of Controlled Trials , Latin American and Caribbean Center on Health Sciences Information , Clinical trials.gov , World Health Organization International Clinical Trials Registry Platform , and OpenGrey , and we will not have language or date limits . Two review authors will independently select eligible studies and assess the risk of bias using the Cochrane Collaboration ’s tool . We will report structured summaries of the included studies and , if possible , conduct meta-analyses . Results This is a protocol for a systematic review , therefore results are not available . We registered a short version of this protocol before progressing in the review and we are currently in the process of selecting the studies for inclusion . Conclusions Intensive glucose control and lowering blood pressure and lipids are mechanisms that protect macrocirculation in diabetic patients . Both macrovascular and microvascular events in diabetic patients appear to have a common pathway , starting with endothelial injury . Thus , prevention and treatment of microvascular events may benefit from the same interventions . In the review for which we have written this protocol , we will assess whether the use of lipid-lowering oral drugs of the statin and /or fibrate groups may prevent and /or retard progression of DR , with the added benefit of preserving visual acuity . Trial Registration PROSPERO BACKGROUND Small studies have suggested that lipid-lowering strategies , and particularly statins , could influence blood pressure ( BP ) control . The aim of the present study was to evaluate the effect of different lipid-lowering strategies on BP control of subjects with hypercholesterolemia who were enrolled in the prospect i ve , population -based , longitudinal Brisighella Heart Study . METHODS A total of 1356 subjects with total cholesterol levels > or=239 mg/dL were r and omly treated for 5 years ( 1988 - 1993 ) with 1 of these lipid-lowering regimens : low-fat diet , cholestyramine , gemfibrozil , or simvastatin . Participants were divided at baseline into 4 quartiles according to systolic BP level and examined for the percent change in systolic and diastolic BP during the 5 years of treatment . RESULTS A significant decrease in BP was observed in the 2 upper quartiles of systolic BP ( > or=140 mm Hg ) and was greater in subjects treated with cholesterol-lowering drugs who also had a greater reduction in plasma levels of low-density lipoprotein cholesterol . The BP decrease was greater in patients treated with statin drugs and , among those treated with antihypertensive drugs , in subjects in the fourth quartile . CONCLUSION The use of lipid-lowering measures could significantly improve BP control in subjects with both hypercholesterolemia and hypertension . The reduction in BP seems to be enhanced in subjects treated with statins Summary Impaired glucose tolerance ( IGT ) is associated with increased mortality due to ischaemic heart disease ( IHD ) , but as it is not known whether this excess mortality can be reduced by preventing or delaying the development of non-insulin-dependent diabetes mellitus ( NIDDM ) , a long-term NIDDM prevention trial of dietary counselling and physical exercise was launched at Malmö , Sweden , the 12-year follow-up of which is reported here . At 12-year follow-up of 6956 men who underwent health screening at 48 years of age , an IGT intervention group ( n = 288 ) who participated in a long-term NIDDM prevention programme were compared with an IGT non-r and omised routine treatment group ( n = 135 ) , a diabetic group ( n = 144 ) , and the remainder , the normal glucose tolerance ( NGT ) group ( n = 6389 ) . The variables studied included the levels of blood glucose , plasma insulin , blood pressure , blood lipids , lung function and maximum oxygen uptake .  Subjects with IGT were characterised by overweight , poor vital capacity , hypertension , hypertriglyceridaemia and hyperinsulinaemia . The mortality rate in the IGT intervention group was similar to that in the NGT group ( 6.5 vs 6.2 per 1000 person years at risk ) and lower than that in the IGT routine treatment group ( 6.5 vs 14.0 , p = 0.009 ) . In the two IGT groups taken together , intervention but not body mass index , systolic blood pressure , smoking , cholesterol or the 2-h glucose level predicted mortality . Systolic blood pressure was a predictor of IHD mortality among IGT subjects ; and in the cohort as a whole , body mass index , systolic blood pressure , hypercholesterolaemica , diabetes and smoking were predictors of IHD mortality . The findings suggest that a long-term intervention programme , with an emphasis on lifestyle changes , including dietary counselling and physical exercise , will reduce mortality in subjects with IGT who are at an increased risk of both developing NIDDM and of premature death due to IHD and other causes . [ Diabetologia ( 1998 ) 41 : 1010–1016 BACKGROUND There is a paucity of data describing the sustained benefits of lifestyle interventions on health behaviors and blood pressure ( BP ) . METHODS We examined the persistence of changes in health habits and BP in the ENCORE study , a trial in which 144 overweight individuals with above-normal BP were r and omized to one of the following 16-week interventions : Dietary Approaches to Stop Hypertension ( DASH ) diet alone ( DASH-A ) , DASH diet plus a behavioral weight management intervention ( DASH-WM ) , or Usual Care . Follow-up assessment s were conducted 8 months after the end of treatment . RESULTS At 16 weeks , systolic BP was reduced by 16.1 ( 95 % confidence interval ( CI ) = 13.0 - 19.2 ) mm Hg in the DASH-WM group , 11.2 ( 95 % CI = 8.1 - 14.3 ) mm Hg in the DASH-A group , and 3.4 ( 95 % CI = 0.4 - 6.4 ) mm Hg in the Usual Care group . A decrease in BP persisted for 8 months , with systolic BP lower than baseline by 11.7 ( 95 % CI = 8.1 - 15.3 ) mm Hg in the DASH-WM group , 9.5 ( 95 % CI = 6.7 - 12.1 ) mm Hg in the DASH-A group , and 3.9 ( 95 % CI = 0.5 - 7.3 ) mm Hg in the Usual Care group ( P < 0.001 for active treatments vs. Usual Care ) . DASH-WM subjects lost 8.7 kg during the intervention and remained 6.3 kg lighter on follow-up examination . Changes in diet content were sustained in both DASH intervention groups . Among those who participated in DASH-WM , however , caloric intake was no longer lower , and only 21 % reported still exercising regularly 8 months after completing the intervention . CONCLUSIONS Changes in dietary habits , weight , and BP persisted for 8 months after completion of the 16-week ENCORE program , with some attenuation of the benefits . Additional research is needed to identify effective methods to promote long-term maintenance of the benefits of lifestyle modification programs . CLINICAL TRIAL REGISTRATION Clinical trials.gov identifier : NCT00571844 Psychosocial stress contributes to high blood pressure and subsequent cardiovascular morbidity and mortality . Previous controlled studies have associated decreasing stress with the Transcendental Meditation ( TM ) program with lower blood pressure . The objective of the present study was to evaluate , over the long term , all-cause and cause-specific mortality in older subjects who had high blood pressure and who participated in r and omized controlled trials that included the TM program and other behavioral stress-decreasing interventions .  Patient data were pooled from 2 published r and omized controlled trials that compared TM , other behavioral interventions , and usual therapy for high blood pressure .  There were 202 subjects , including 77 whites ( mean age 81 years ) and 125 African-American ( mean age 66 years ) men and women . In these studies , average baseline blood pressure was in the prehypertensive or stage I hypertension range . Follow-up of vital status and cause of death over a maximum of 18.8 years was determined from the National Death Index . Survival analysis was used to compare intervention groups on mortality rates after adjusting for study location . Mean follow-up was 7.6 + /- 3.5 years . Compared with combined controls , the TM group showed a 23 % decrease in the primary outcome of all-cause mortality after maximum follow-up ( relative risk 0.77 , p = 0.039 ) . Secondary analyses showed a 30 % decrease in the rate of cardiovascular mortality ( relative risk 0.70 , p = 0.045 ) and a 49 % decrease in the rate of mortality due to cancer ( relative risk 0.49 , p = 0.16 ) in the TM group compared with combined controls . These results suggest that a specific stress-decreasing approach used in the prevention and control of high blood pressure , such as the TM program , may contribute to decreased mortality from all causes and cardiovascular disease in older subjects who have systemic hypertension Objective The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes ; thus , it is important to determine whether glucose-lowering therapy affects this risk over time . Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily ( a glucagon-like peptide-1 receptor agonist ) or glimepiride ( a sulfonylurea ) added to metformin in the EURopean EXenAtide ( EUREXA ) study . Research design and methods Patients with type 2 diabetes failing metformin were r and omized to add-on exenatide twice daily ( n = 515 ) or glimepiride ( n = 514 ) until treatment failure defined by hemoglobin A1C . Anthropomorphic measures , blood pressure ( BP ) , heart rate , lipids , and high-sensitivity C-reactive protein ( hsCRP ) over time were evaluated . Results Over 36 months , twice-daily exenatide was associated with improved body weight ( −3.9 kg ) , waist circumference ( −3.6 cm ) , systolic/diastolic BP ( −2.5/−2.6 mmHg ) , high-density lipoprotein (HDL)-cholesterol ( 0.05 mmol/L ) , triglycerides ( −0.2 mmol/L ) , and hsCRP ( −1.7 mg/L ) . Heart rate did not increase ( −0.3 beats/minute ) , and low-density lipoprotein-cholesterol ( 0.2 mmol/L ) and total cholesterol ( 0.1 mmol/L ) increased slightly . Between-group differences were significantly in favor of exenatide for body weight ( P < 0.0001 ) , waist circumference ( P < 0.001 ) , systolic BP ( P < 0.001 ) , diastolic BP ( P = 0.023 ) , HDL-cholesterol ( P = 0.001 ) , and hsCRP ( P = 0.004 ) . Fewer patients r and omized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive ( 20.4 vs 26.4 % ; P = 0.026 ) or lipid-lowering medication ( 8.4 vs 12.8 % ; P = 0.025 ) . Conclusions Add-on exenatide twice daily was associated with significant , sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride . Clinical trial registration : NCT00359762 , http://www . Clinical OBJECTIVE To compare effects of combinations of st and ard and intensive treatment of glycemia and either blood pressure ( BP ) or lipids in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial . RESEARCH DESIGN AND METHODS ACCORD enrolled 10,251 type 2 diabetes patients aged 40–79 years at high risk for cardiovascular disease ( CVD ) events . Participants were r and omly assigned to hemoglobin A1c goals of < 6.0 % ( < 42 mmol/mol ; intensive glycemia ) or 7.0–7.9 % ( 53–63 mmol/mol ; st and ard glycemia ) and then r and omized a second time to either 1 ) systolic BP goals of < 120 mmHg ( intensive BP ) or < 140 mmHg ( st and ard BP ) or 2 ) simvastatin plus fenofibrate ( intensive lipid ) or simvastatin plus placebo ( st and ard lipid ) . Proportional hazards models were used to assess combinations of treatment assignments on the composite primary ( deaths due to CVD , nonfatal myocardial infa rct ion [ MI ] , and nonfatal stroke ) and secondary outcomes . RESULTS In the BP trial , risk of the primary outcome was lower in the groups intensively treated for glycemia ( hazard ratio [ HR ] 0.67 ; 95 % CI 0.50–0.91 ) , BP ( HR 0.74 ; 95 % CI 0.55–1.00 ) , or both ( HR 0.71 ; 95 % CI 0.52–0.96 ) compared with combined st and ard BP and glycemia treatment . For secondary outcomes , MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment ; most other HRs were neutral or favored intensive treatment groups . In the lipid trial , the general pattern of results showed no evidence of benefit of intensive regimens ( whether single or combined ) compared with combined st and ard lipid and glycemia treatment . The mortality HR was 1.33 ( 95 % CI 1.02–1.74 ) in the st and ard lipid/intensive glycemia group compared with the st and ard lipid/st and ard glycemia group . CONCLUSIONS In the ACCORD BP trial , compared with combined st and ard treatment , intensive BP or intensive glycemia treatment alone improved major CVD outcomes , without additional benefit from combining the two . In the ACCORD lipid trial , neither intensive lipid nor glycemia treatment produced an overall benefit , but intensive glycemia treatment increased mortality BACKGROUND n-3 Fatty acids lower blood pressure , improve lipids , and benefit other cardiovascular disease risk factors . Effects on glycemia in patients with type 2 diabetes are uncertain . OBJECTIVE We determined whether purified eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) have differential effects on glycemic control , including insulin sensitivity and stimulated insulin secretion ; 24-h ambulatory blood pressure ; and serum lipids in type 2 diabetic patients with treated hypertension . DESIGN In a double-blind , placebo-controlled trial of parallel design , 59 subjects were r and omly assigned to consume 4 g EPA , DHA , or olive oil/d for 6 wk while continuing to consume their usual diet . RESULTS Thirty-nine men and 12 postmenopausal women with a mean ( + /- SE ) age of 61.2 + /- 1.2 y completed the study . In comparison with the change from baseline in fasting glucose in the olive oil group , fasting glucose in the EPA and DHA groups increased 1.40 + /- 0.29 mmol/L ( P = 0.002 ) and 0.98 + /- 0.29 mmol/L ( P = 0.002 ) , respectively . Neither EPA nor DHA had significant effects on glycated hemoglobin , fasting insulin or C-peptide , insulin sensitivity or secretion , or blood pressure . Serum triacylglycerols in the EPA and DHA groups decreased 19 % ( P = 0.022 ) and 15 % ( P = 0.022 ) , respectively . There were no significant changes in serum total , LDL , or HDL cholesterol , although HDL(2 ) cholesterol in the EPA and DHA groups increased 16 % ( P = 0.026 ) and 12 % ( P = 0.05 ) , respectively . HDL(3 ) cholesterol decreased 11 % ( P = 0.026 ) with EPA supplementation . CONCLUSIONS EPA and DHA had similar benefits on lipids but adverse effects on short-term glycemic control in hypertensive diabetic patients . The overall implication s for cardiovascular disease require long-term evaluation The authors conducted a r and omized , controlled , multicenter trial , in which they assigned well-controlled hypertensive participants aged 55 years and older with moderate hypercholesterolemia to receive pravastatin ( n=5170 ) or usual care ( n=5185 ) for 4 to 8 years , when trial therapy was discontinued . Passive surveillance using national data bases to ascertain deaths and hospitalizations continued for a total follow-up of 8 to 13 years to assess whether mortality and morbidity differences persisted or new differences developed . During the post-trial period , fatal and nonfatal outcomes were available for 98 % and 64 % of participants , respectively . The primary outcome was all-cause mortality and the secondary outcomes included cardiovascular mortality , coronary heart disease ( CHD ) , stroke , heart failure , cardiovascular disease , and end-stage renal disease . No significant differences appeared in mortality for pravastatin vs usual care ( hazard ratio [ HR ] , 0.96 ; 95 % confidence interval [ CI ] , 0.89 - 1.03 ) or other secondary outcomes . Similar to the previously reported in-trial result , there was a significant treatment effect for CHD in black patients ( HR , 0.79 ; 95 % CI , 0.64 - 0.98 ) . However , the in-trial result showing a significant treatment by race effect did not remain significant during the entire follow-up ( P=.08 ) . These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in black patients Type 2 diabetes has become an important public health challenge worldwide and , in particular , in Asian population s , which are characterized by onset at a relatively young age and low body mass index . These patients have long disease duration and thus are associated with a higher risk of long‐term complications . Diabetic retinopathy is one of the major microvascular complications and is the most common cause of blindness . The Diabcare‐Asia study carried out in Indonesia , Malaysia , the Philippines , Singapore , South Korea , Taiwan , Thail and and Vietnam has found that in 2001 , up to 8 % of type 2 diabetic patients aged 30 years or above had retinopathy , 4 % has received photocoagulation and 0.7 % were legally blind . For most type 2 diabetes patients , the frequency and severity of diabetic retinopathy increase over time , which substantially impacts on quality of life . Therefore , there is an urgent need for effective and safe treatment regimens against the occurrence and to slow the progression of diabetic retinopathy . Substantial evidence has found that in addition to the degree of glycemia , the level of blood pressure and dyslipidemia , including elevated total cholesterol , low‐density lipoprotein (LDL)‐cholesterol , triglycerides and decreased high‐density lipoprotein (HDL)‐cholesterol levels , were important risk factors for retinopathy in type 2 diabetes patients . A multifactorial approach optimizing all these risk factors has become the current st and ard in diabetes management . The concept of this multifactorial intervention to reduce the incidence and progression of diabetic retinopathy is supported by findings from the Steno type 2 r and omized trial . An intensive combined treatment targeting hyperglycemia , hypertension , dyslipidemia and microalbuminuria can reduce the risk of retinopathy progression by 55 % in the follow‐up period of 3.8 years . However , there are still questions that remain to be answered . First , the optimal target for blood pressure , glucose and lipid level remains unclear , in particular for different risk population s. Whether further intensification of treatments provide additional benefits needs to be evaluated . Second , it is not known whether combining blood pressure lowering , glucose control and improving lipid profile can reduce the risk of retinopathy to a greater extent than either treatment alone . There are also concerns about whether intensive treatment of one of the risk factors could modify or even negate the benefits from treatment of the other risk factors . The recently published the Action to Control Cardiovascular Risk in Diabetes Eye study ( ACCORD‐EYE ) sheds new light on the optimal treatment for diabetic retinopathy1 . The original ACCORD study was a r and omized controlled trial with three components , assessing the effects of intensive glycemic control ( targeted HbA1c level < 6.0 % ) vs st and ard glycemic control ( targeted HbA1c 7.0–7.9 % ) ; intensive blood pressure control ( targeted systolic blood pressure < 120 mmHg ) vs st and ard blood pressure control ( targeted systolic blood pressure < 140 mmHg ) ; and using fibrates to lower triglycerides and raise HDL‐cholesterol vs the placebo after LDL‐cholesterol has been decreased by statin therapy on macro‐ and microvascular complications . A total of 10,251 participants were enrolled for glycemia therapy .  Of them , 5518 with dyslipidemia were also r and omly assigned , in a 2 × 2 factorial design , to receive simvastatin plus either fenofibrate or a placebo . The remaining 4733 participants , without further requirement for blood pressure level , were enrolled for evaluating the blood pressure lowering effect . The ACCORD‐EYE trial is a study of a subset of the original ACCORD trial participants to evaluate the effects of the aforementioned interventions at 4 years on the progression of diabetic retinopathy by three or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale , or the development of diabetic retinopathy leading to laser photocoagulation or vitrectomy . By this complex study design , it is planned that a sample size of 4056 recruited patients would have a power of 88 , 91 and 80 % for the effect of glycemic control , lipid control and blood pressure control , respectively . However , only 2856 participants completed the evaluation and were included for analyses . In contrast to the original ACCORD study reporting excess mortality in intensive glucose control , results from the ACCORD‐EYE glycemic trial are reassuring . The median HbA1c levels in the intensive treatment arm were 6.4 % , compared with 7.5 % in the st and ard treatment arm , and were associated with a reduced rate of progression of diabetic retinopathy by 33 % . This beneficial effect was consistent across baseline levels of HbA1c , retinopathy at baseline and duration of diabetes , and was independent of effects as a result of the blood pressure and lipid intervention . This finding , in addition to previous large‐scale r and omized controlled trials , such as the United Kingdom Prospect i ve Diabetes Study ( UKPDS ) , Kumamoto study and the Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ( ADVANCE trial ) , confirms that tight glucose control can reduce the risk of microvascular complications . The unexpected finding comes from evaluation of blood pressure lowering . Intensive blood pressure control , instead of providing a beneficial effect , is associated with a trend of increased risk for diabetic retinopathy progression by 23 % at 4 years . As shown in Table 1 , a trend of beneficial effect by intensive blood pressure control was found in four other r and omized trials2–5 . Significant results were found by UKPDS , characterized by enrolling patients with short diabetic duration , substantial blood pressure lowering and long treatment duration 2 . The Appropriate Blood Pressure Control in Diabetes (ABCD)‐Normotensive study showed a favorable effect , even among patients with long diabetic duration and who had a ‘ normal ’ blood pressure level4 . Instead of targeting a specific blood pressure level , the ADVANCE Retinal Measurement Study examined the effect of the combination treatment of perindopril – indapamide vs the placebo5 . A favorable result was found , although not statistically significant , probably as a result of the magnitude of blood pressure lowering was modest and the follow‐up duration was relatively short . In the ACCORD‐EYE study , an even more intensive treatment strategy targeting systolic blood pressure below 120 mmHg was used . This raises the concern that the optimal target for blood pressure against retinopathy worsening might not be ‘ the lower the better ’ . This argument is further substantiated by the finding from a subgroup analysis showing that the detrimental effect of intensive blood pressure lowering is greater among participants with systolic blood pressure 144 mmHg . The implication that the magnitude of blood pressure reduction should be individualized based on baseline blood pressure level needs to be clarified in a future study . Table 1 R and omized controlled trials evaluating effect of blood pressure control on diabetic retinopathy The ACCORD‐EYE study was design ed to answer the question whether a more intensive blood pressure control , rather than specific pharmacotherapy , had a beneficial effect on retinopathy improvement . All major classes of antihypertensive agents were used , although diuretics combined with either an angiotensin‐converting enzyme ( ACE ) inhibitor or beta‐blocker are recommended as initial therapy in the intensive treatment arm . Recently , there has been increasing evidence suggesting the role of the rennin‐angiotensin system in diabetic retinopathy . In animal models , angiotensin has been shown to be an angiogenic growth factor . In patients with diabetic retinopathy , plasma and intravitreal prorenin levels are increased and correlate with its severity . Several r and omized placebo‐controlled trials have found the beneficial effect of certain ACE inhibitors or angiotensin receptor blockers on retinopathy worsening among type 1 and type 2 patients with normal blood pressure , normal microalbuminuria and mild to moderately severe retinopathy at baseline . Whether it is a class effect or specific to particular medications should be explored in properly design ed studies . Results from the ACCORD‐EYE dyslipidemia control were inspiring in terms of the addition of 160 mg fenofibrate per day to statins conferring an additional 40 % reduced risk among type 2 diabetic patients with a mean baseline triglycerides level of approximately 200 mg/dL , HDL‐cholesterol level of approximately 40 mg/dL and LDL‐cholesterol of approximately 100 mg/dL. This finding substantiates the observation from the Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study showing the beneficial effects of fenofibrate vs the placebo in reducing laser therapy , particularly in preventing disease progression in patients with pre‐existing diabetic retinopathy . In contrast to no clinical ly important difference in blood lipid concentrations between two treatment groups at FIELD study completion , the ACCORD‐EYE study showed a medium triglyceride levels reduction from 162 to 120 mg/dL in the fenofibrate group , as compared with 147 mg/dL in the placebo group . The optimal dosage , blood lipid target and the safety of this combination therapy in the Asian population require further studies . In conclusion , the ACCORD‐EYE study has extended our knowledge of strategies to lessen diabetic retinopathy progression . Although physicians who take care of diabetic patients should continue emphasizing the importance of glycemic control , a more intensified approach for elevated plasma triglyceride levels , but judicious blood pressure lowering , might be considered based on individual patients ’ risk of this condition
Results : BP and lipid levels tended to come together soon in the post-trial period .
Conclusion : Benefits of BPL and lipid lowering on all-cause and cardiovascular mortality were persistent , but attenuated , after discontinuation of r and omized treatment , indicating the importance of continuing therapy
Objective : Persistent long-term benefits after discontinuation of treatment have been suggested for blood pressure-lowering and lipid-lowering treatment .
We conducted a systematic review to assess the long-term effects of  blood pressure ( BP ) lowering ( BPL ) and lipid lowering on all-cause and cardiovascular mortality after discontinuation of r and omized treatment .