Specific Classes Of Antihypertensive Drugs Research Articles

Abstract 16795: Blood Pressure Lowering Therapeutical Strategies Have Different Impact on Brain Functional Connectivity

Hypertension is a major risk factor for cognitive impairment and dementia. Using functional MRI, researchers have been able to study the brain’s functional connectivity in hypertensive patients. This has revealed that even before showing signs of vascular dementia, hypertensive patients have altered brain connections compared to normotensive patients. Our aim is now to characterize whether different classes of antihypertensive drugs, which vary in their mechanism of action and ability to cross the blood-brain barrier, have different effects on the brain’s functional organization. In this study, 42 hypertensive patients with controlled blood pressure underwent resting-state functional MRI. The data was analyzed using CONN to build functional connectivity network matrices and analyze the amplitude of spontaneous brain activity fluctuations (fALFF). These results were then evaluated using general linear models to identify connections that were modulated by specific classes of antihypertensive drugs. We applied regression models taking into account age, sex, BMI, alcohol, smoke and BP levels as covariates. Our results show that treatment with diuretics was associated with a large connectivity network among several brain networks (A). Treatment with ACE inhibitors (B), ARBs (C), and beta-blockers (D) was also associated with significant modulation of specific connections (all highlighted connections p<0.05, statistics in figure). Overall, diuretics had the greatest impact on brain function, possibly due to their effect on blood volume and cerebral circulation, with the effect further confirmed by fALFF analyses, showing a widespread reduction of the BOLD-signal intensity of spontaneous cerebral activity (all highlighted clusters p<0.05, statistics in figure E). These findings may help inform the choice of antihypertensive treatment for individual patients, taking into account the potential cognitive and functional impact of different drugs.

Effect of Different Classes of Antihypertensive Drugs on Arterial Stiffness.

To describe the physiological aspects of blood pressure and arterial stiffness, as well as explain how these processes are related. To review the available evidence on the effect of treatment with different classes of antihypertensive drugs on improving arterial stiffness. Specific classes of antihypertensive drugs may have effects directly on improving arterial stiffness independent of lowering blood pressure. The maintenance of normal blood pressure levels is essential for the homeostasis of the whole organism; the increase in blood pressure is directly related to the increased risk of cardiovascular diseases. Hypertension is characterized by structural and functional changes in blood vessels and is associated with a more accelerated progression of arterial stiffness. Randomized clinical trials have shown that some specific classes of antihypertensive drugs can improve arterial stiffness independently of their effect on lowering brachial blood pressure. These studies show that calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors have been shown to have a better effect on arterial stiffness compared to diuretics and beta-blockers in individuals with arterial hypertension and other cardiovascular risk factors. More real-world studies are needed to assess whether this effect on arterial stiffness can improve the prognosis of patients with hypertension.

Elevated blood pressure, antihypertensive medications and bone health in the population: revisiting old hypotheses and exploring future research directions

Blood pressure and bone metabolism appear to share commonalities in their physiologic regulation. Specific antihypertensive drug classes may also influence bone mineral density. However, current evidence from existing observational studies and randomised trials is insufficient to establish causal associations for blood pressure and use of blood pressure–lowering drugs with bone health outcomes, particularly with the risks of osteoporosis and fractures. The availability and access to relevant large-scale biomedical data sources as well as developments in study designs and analytical approaches provide opportunities to examine the nature of the association between blood pressure and bone health more reliably and in greater detail than has ever been possible. It is unlikely that a single source of data or study design can provide a definitive answer. However, with appropriate considerations of the strengths and limitations of the different data sources and analytical techniques, we should be able to advance our understanding of the role of raised blood pressure and its drug treatment on the risks of low bone mineral density and fractures. As elevated blood pressure is highly prevalent and blood pressure–lowering drugs are widely prescribed, even small effects of these exposures on bone health outcomes could be important at a population level.

Antihypertensive drugs demonstrate varying levels of hip fracture risk: A systematic review and meta-analysis

ObjectiveBy aggregating the literature, we evaluated the association between use of specific antihypertensive drugs and the risk of hip fractures compared with nonuse. Study design and settingWe systematically searched the Pubmed, Embase, and Cochrane databases from inception of each database until July 30, 2020 to identify articles including patients 18 years of age or older reporting on the association between antihypertensive drugs and the risk of hip fracture. Antihypertensive drugs were restricted to thiazides; beta-blockers; calcium-channel blockers; angiotensin-converting enzyme (ACE) inhibitors; and angiotensin receptor blockers. Nonusers encompass all patients that are not using the specific antihypertensive drug that has been reported. Unadjusted odds ratios with 95% confidence intervals (CIs) of the association between antihypertensive drug use and hip fractures were reported. Meta-analysis was performed when a minimum of five studies were identified for each antihypertensive drug class. Quality assessment was done using ROBINS-I tool. The GRADE approach was used to evaluate the certainty of the evidence. ResultsOf 962 citations, 22 observational studies were included; 9 studies had a cohort design and 13 studies were case-control studies. No randomized controlled trials were identified. We found very low certainty of evidence that both thiazides (pooled odds ratio: 0.85, 95% CI 0.73 to 0.99, p = 0.04) as well as beta-blockers (pooled odds ratio: 0.88, 95% CI 0.79 to 0.98, p = 0.02) were associated with a reduced hip fracture risk as compared to specific nonuse. One study, reporting on angiotensin receptor blockers, also suggested a protective effect for hip fractures, whereas we found conflicting findings in four studies for calcium-channel blockers and in two studies for ACE inhibitors. ConclusionAmong 22 observational studies, we found very low certainty of evidence that, compared to specific nonuse of antihypertensive drugs, use of thiazides, beta-blockers, and angiotensin receptor blockers were associated with a reduced protective hip fracture risk, while conflicting findings for calcium-channel blockers and ACE inhibitors were found. Given the low quality of included studies, further research –randomized controlled trials– are needed to definitively assess the causal relationship between specific antihypertensive drug classes and (relatively infrequent) hip fractures.

Elevated Blood Pressure, Antihypertensive Medications and Bone Health in the Population: Revisiting Old Hypotheses and Exploring Future Research Directions

Blood pressure and bone metabolism appear to share commonalities in their physiologic regulation. Specific antihypertensive drug classes may also influence bone mineral density. However, current evidence from existing observational studies and randomized trials is insufficient to definitely suggest likely causal associations between blood pressure levels and use of blood-pressure lowering drugs on bone health outcomes, particularly on the risks of osteoporosis and fractures. Nevertheless, the availability and access to relevant large-scale biomedical data sources as well as developments in study designs and analytical approaches are providing opportunities to examine the nature of the association between blood pressure and bone health more reliably and in greater detail than has ever been possible. It is unlikely that a single source of data or study design can provide a definitive answer. However, with appropriate considerations of the strengths and limitations of the different data sources and analytical approaches, we should be able to advance our understanding of the role of raised blood pressure and its drug treatment on bone health outcomes. As elevated blood pressure and use of blood pressure-lowering drugs are highly prevalent, even small effects of these exposures on bone health outcomes could be important at a population level.

Hypertension, antihypertensive medications use and risk of age-related macular degeneration in California Teachers Cohort.

Sustained and inadequately controlled hypertension can promote the development of age-related macular degeneration (AMD) through multiple biologic pathways. Epidemiologic studies of high blood pressure, antihypertensive therapies, and the risk of AMD thus far have been inconclusive. However, few studies evaluated risks according to the use of different classes of antihypertensive drugs or took combinations of use into account. We performed a prospective cohort study by linking the California Teachers Study (CTS) cohort (N = 88 481) to statewide hospital discharge records up to December 31, 2012. History of high blood pressure, regular use of antihypertensive medications, and comprehensive risk factor information was collected via self-administered questionnaires at baseline in 1995-1996, and information on specific classes of antihypertensive drugs was provided by a subsample of CTS participants who completed a follow-up questionnaire in 2000. We identified 1762 female teachers with AMD during 14.8 years of follow-up on average. Applying Cox proportional hazard regression, we estimated increased risks of AMD among women treated for hypertension at baseline (HR = 1.15, 95% CI: 1.03, 1.30); the magnitude of the association increased with longer duration of antihypertensive treatment. In the subsample with more specific information on type of medication use, we estimated a 45% increased risk of AMD among women receiving diuretics as monotherapy compared to women with medications more potent than diuretics (HR = 1.45, 95% CI 1.10, 1.90). In women treated with a combination of antihypertensive drugs, we observed no increased risk of AMD for any individual class of drugs.

Repurposing antihypertensive drugs for the prevention of Alzheimer's disease: a Mendelian randomization study.

BackgroundEvidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer’s disease.MethodsWe used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer’s disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer’s disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets.ResultsThere was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer’s disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 [95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17]. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153).ConclusionsMendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer’s disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer’s disease, they may not do so via systolic blood pressure.

Can treatments for hypertension be repurposed for the treatment of dementia?

Introduction There is evidence that hypertension in midlife can increase the risk of Alzheimer's disease and vascular dementia in late life. In addition, some treatments for hypertension have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose treatments for hypertension for dementia. This study systematically assessed ten antihypertensive drug classes for this purpose, using data on over 940,000 patients from the UK Clinical Practice Research Datalink. Methods Treatments for hypertension were assessed in an instrumental variable (IV) analysis to address potential confounding by indication. Physicians’ prescribing preference was used as a categorical instrument, defined by the physicians’ last seven prescriptions, and the analysis was adjusted for prescription year. A multivariable logistic regression analysis was also conducted to compare biases. Beta-adrenoceptor blockers were used as the control drug throughout. Results Treatments for hypertension had little effect reducing the risk of Alzheimer's disease, vascular dementia, and other dementias. These results differ from existing studies considering specific antihypertensive drug classes. For example, we estimated angiotensin converting enzyme inhibitors to result in 2.2 per 1000 (95% CI 8.1–3.6) fewer cases of Alzheimer's disease among those treated–a much smaller reduction than previously reported. Comparison of our IV and logistic regression analyses suggests that this is likely due to confounding in non-IV studies. Conclusions This study is the first to systematically assess all the major antihypertensive drug classes. The contradiction with previous studies suggests that continued research into the repurposing of these treatments for dementia is required. It also highlights the need for further research into the biological mechanisms that link hypertension and dementia so that we can better understand the confounding in such analyses.

Drug utilization and blood pressure control in ambulatory hypertensive patients: focus on those with compelling indications.

Compelling indications require the use of specific antihypertensive drug classes and often two or more antihypertensive medications for blood pressure (BP) control. This study assessed drug utilization patterns among hypertensive patients with compelling indications, conformity with recommended guidelines, and the effect on BP control. A prospective, cross-sectional study of hypertensive patients attending three subspecialty hospital clinics. Data on demographics, prescriptions, and BP were collected. BP control was defined as BP less than 140/90 mmHg in nondiabetic subjects and less than 130/80 for those with diabetes. Analysis was done with SPSS version 17. Of the 1,926 patients with hypertension, 877 (45.5%) had compelling indications. Patients were aged 59.3±11.5 years. The most frequently-encountered compelling indications were hypertensive heart disease (35.8%), diabetic mellitus (31.9%), and renal diseases (11.5%). The most prescribed drug was angiotensin-converting enzyme inhibitor (ACEIs), which was present in 22.6% of all prescriptions. Only 23.1% of patients had fully controlled BP. Poor BP control significantly correlated with the number of antihypertensive drugs r=0.205, p<0.001, but negatively correlated with age and duration of hypertension, r = -0.071, p = 0.038 and r = -0.448, p = 0.042, respectively. BP control was very poor in this study, and there was a high prevalence of compelling indications. Poor control was negatively correlated with increasing age and duration of hypertension. The most common compelling indications were hypertensive heart disease, diabetes mellitus, and renal disease.

Use of angiotensin converting enzyme inhibitors is associated with increased growth rate of abdominal aortic aneurysms

To evaluate whether either angiotensin converting enzyme (ACE) inhibitors or other classes of antihypertensive drug attenuate or increase growth rates of small infrarenal abdominal aortic aneurysms. Prospective cohort study of 1701 patients enrolled in the UK Small Aneurysm Trial or associated study at 93 hospitals between 1991 and 1995 and who had at least two ultrasound measurements of aneurysm diameter and baseline drug prescription data recorded. Abdominal aortic aneurysm diameter was measured in the anterior-posterior plane using ultrasound. The mean growth rate was estimated through a mixed-effects linear growth model. Mean aneurysm growth rate in 169 patients taking ACE inhibitors at baseline was 3.33 mm/y vs 2.77 mm/y in the remaining 1532 patients, P = .009. The significance of this finding did not alter after adjustment for known confounders. The prescription of any antihypertensive agent and other specific classes of antihypertensive drugs were not found to be associated with aneurysm growth rate. These results show that patients taking ACE inhibitors have faster aneurysm growth and are in conflict with the observation from a large Canadian data-base that aneurysm patients taking ACE inhibitors are less likely to present with aneurysm rupture. There is an urgent need for a randomized trial to assess whether ACE inhibitors are beneficial or harmful to patients with aneurysms below the threshold size for surgical intervention.

Obesity and Hypertension

The link between obesity and hypertension is well known, but there are still many questions to be answered: Is abdominal adiposity rather than overall obesity more closely associated with high blood pressure? Is obesity an independent cardiovascular risk factor even if not combined with hypertension? Can obesity be metabolically benign? To what extent weight reduction is expected to contribute to the management or the primary prevention of hypertension? Are there compelling indications and/or contraindications to the use of specific classes of antihypertensive drugs for the pharmacological treatment of obesity hypertension? Consequently, the present editorial seeks to answer these questions by briefly reviewing the current state of knowledge of the association of obesity with hypertension. Several tools are used to estimate obesity. The body mass index (BMI), or Quetelet index, is a statistical measurement which compares a person’s weight and height. BMI is body weight in kilograms divided by the height in meters squared, expressed as weight (in kg)/height (m). Overweight is defined as a BMI >25, obesity as a BMI >30, and morbid obesity is a BMI >35. Abdominal obesity is the accumulation of visceral fat resulting in an increase in waist size. It is often referred to as central, visceral, male-type or android obesity vs. female-type or gynoid obesity with a preferential gluteofemoral distribution. Abdominal obesity is diagnosed by a waist circumference >102 cm in men, and >88 cm in women or by a waist-to-hip ratio >0.95 in men and >0.85 in women. As early as in 1980, in the second National Health and Nutrition Examination Survey (NHANES II), it was noted that the prevalence of hypertension was 2.9 times higher in obese than in non-obese adult Americans. The Third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 to 1994 revealed a similar linear relationship despite a lower prevalence of hypertension. BMI was recently found to be positively associated with blood pressure even in active, American veteran football players. In a cross-sectional analysis of adults enrolled in NHANES 1999-2004, the odds ratio for hypertension for every 5-unit increase in BMI was 1.45 (95% CI 1.39-1.52). Although obesity was associated with hypertension in all age groups and both sexes, the odds for hypertension associated with obesity were relatively higher in younger people. With regard to hypertension subtypes, increasing BMI was a significant predictor of isolated diastolic hypertension or systodiastolic hypertension as opposed to isolated systolic hypertension. Isolated systolic hypertension represented a minority of hypertension cases in obese men, but remained the most prevalent type in obese women. There is substantial evidence that in addition to BMI, both waist circumference and waist-to-hip ratio are correlated with blood pressure, even after adjustment for BMI. The associations of BMI and waist circumference with systolic and diastolic blood pressure and their possible interactions with gender and age were assessed in a cohort of 10,928 non-smoking and never treated for hypertension adults, recruited from all regions of Greece during 1994–1999, within the context of the European From the Center for the Prevention of Cardiovascular Disease, “Hygieias Melathron,” Athens, Greece

Antihypertensive treatment and stroke prevention: are angiotensin receptor blockers superior to other antihypertensive agents?

Stroke remains a common vascular event with high mortality and morbidity. After heart disease, stroke is the second leading cause of death worldwide in adult persons. Silent or subclinical stroke is likely to occur with even greater frequency than clinical stroke and increases the risk of subsequent cerebrovascular events. Hypertension is by far the single most important controllable risk factor for stroke. The relationship between blood pressure (BP) and stroke mortality is strong, linear, and continuous in subjects with levels of BP higher than 115/75 mm Hg. Blood pressure reduction by antihypertensive treatment is clearly efficacious in the prevention of stroke (both primary and secondary). Although meta-analyses suggest that BP reduction, per se, is the most important determinant for stroke risk reduction, the question is if specific classes of antihypertensive drugs offer special protection against stroke is still controversial. Some studies have suggested that angiotensin receptors blockers (ARBs) appear to offer additional protection against stroke. This has been hypothesized in studies in hypertensives, such as LIFE and SCOPE, and especially in the only comparative trial focused on secondary stroke prevention. In the MOSES trial, the comparison of eprosartan versus nitrendipine in patients with a previous stroke resulted, despite a similar BP reduction, in a significant reduction in the primary composite endpoint of total mortality plus cardiovascular and cerebrovascular events, including recurrent events. These results may suggest a blood pressure-independent effect of ARBs, which can be mediated through several mechanisms, including their ability to counteract other markers of target organ damage, but also through a direct neuroprotective effect.

Are there Differences in Stroke Prevention with Different Blood Pressure Lowering Agents?

Hypertension is the major modifiable risk factor for fatal, nonfatal strokes and other vascular diseases. In a pooled analysis of 61 prospective studies including about one million individuals, the reported risk of stroke increased progressively with blood pressure from values as low as 115/75 mm/Hg. Each increment of 20/10 mm/Hg doubles the risk of cardiovascular disease and such a correlation is consistent at all ages. Blood pressure lowering strongly reduces the risk of either first stroke or recurrent stroke but the possibility that specific drugs may prevail over others for protection from stroke remains unclear. There is some evidence that specific classes of antihypertensive drugs have different effects and/or their pharmacological actions differ in patient subgroups. Currently, there are five classes of first-line blood pressure lowering drugs: diuretics, beta-blockers, calcium channel blockers, angiotensin-converting inhibitors and angiotensin II receptor blockers. This review evaluates the development of antihypertensive therapies and the latest studies of arterial hypertension and stroke prevention.

Blood pressure through aging and menopause

Together with the aging process, hypertension is the main risk factor contributing to the increase in cardiovascular morbidity and mortality in postmenopausal women, with a prevalence of around 60% in women older than 65 years. Considering that hypertension is a modifiable risk factor, the understanding of its epidemiology and pathophysiology and the development of appropriate therapeutic strategies are conceivably crucial in reducing cardiovascular risk. The high prevalence of hypertension in older women is largely due to the progressive stiffening of the arterial structure which accompanies the aging process in both sexes. However, the abrupt fall in circulating estrogen levels might independently contribute to the rise in blood pressure, through partly unknown mechanisms, such as a direct effect on the arterial wall, the activation of the renin–angiotensin system and of the sympathetic nervous system. Postmenopausal hypertension fosters the development of left ventricular hypertrophy and is the main factor contributing to coronary artery disease, chronic heart failure and stroke in older women. Recent analysis demonstrates that men and women receive a similar benefit from antihypertensive therapy in terms of reduction of cardiovascular morbidity and mortality and, considering that generally the response to different drugs is not different between the sexes, currently there is no need to use specific antihypertensive drug classes after menopause. Finally, although observational studies have shown that hormone replacement therapy is associated with lower cardiovascular risk and lower blood pressure values, randomized clinical trials have conversely denied this benefit and demonstrated rather that this therapeutical approach increases the risk of cardiovascular events.

Arterial Hypertension and Stroke Prevention: An Update

High blood pressure (BP) is the most important modifiable risk factor for stroke and other vascular diseases. Evidence from randomized controlled trials supports the use of antihypertensive drugs to lower blood pressure for stroke prevention. There is some evidence that specific classes of antihypertensive drugs have different effects and/or their pharmacological actions differ in patient subgroups. This review evaluates the development of antihypertensive therapies and the latest studies of arterial hypertension and stroke prevention: HOPE trial (ramipril versus placebo), ALLHAT trial (CCB or/and Angiotensin-Conventing enzyme Inhibitors (ACE-Is) versus diuretic), LIFE trial (losartan versus atenolol), and PROGRESS trial (perindopril or/and indapamide versus placebo). Despite the results of these relevant clinical trails, some aspects still remain unresolved. Future clinical trials on hypertension and stroke prevention should answer the following questions: Does lowering BP reduce stroke risk due to specific drug effect or class effect? Are angiotensin II receptor blockers (ARBs) better than ACE-Is? Should ACE-Is and ARBs be considered routinely for either high-risk stroke patients or patients with history of stroke or transient ischemic attack, irrespective of blood pressure? What is the role of lifestyle in BP control?

Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy

Little is known of the effects of blood pressure reduction by specific classes of antihypertensive drugs on the association between proteinuria reduction and progression of kidney insufficiency and development of end-stage kidney disease in patients with overt diabetic nephropathy in type 2 diabetes mellitus. Associations between baseline proteinuria and proteinuria reduction by either irbesartan, amlodipine, or control for similar decrements in blood pressure and the cumulative incidence of renal end points were examined using the Kaplan-Meier method in patients enrolled in the Irbesartan Diabetic Nephropathy Trial. Risk for kidney failure doubled for each doubling of baseline proteinuria level (hazard ratio, 2.04; 95% confidence interval, 1.87 to 2.22; P < 0.001). For each halving of proteinuria level between baseline and 12 months with treatment, risk for kidney failure was reduced by more than half (hazard ratio, 0.44; 95% confidence interval, 0.40 to 0.49; P < 0.001). For the same proportional change in proteinuria, the reduction in risk for kidney failure was significantly greater for irbesartan compared with amlodipine ( P = 0.048), but not control ( P = 0.245). Proteinuria reduction in the first 12 months of therapy with irbesartan is associated with 36% of the total renoprotective effect observed. Baseline proteinuria is an important risk factor for kidney failure and provides a means to identify patients at greatest risk. Halving proteinuria halves the kidney risk. Proteinuria reduction using an angiotensin receptor-blocking agent, such as irbesartan, should be regarded as an important therapeutic goal in renoprotective strategies.

Optimizing therapy in the diabetic patient with renal disease: antihypertensive treatment.

Hypertension, impaired renal function, and proteinuria are commonly associated to the presence of diabetes. They play a major role in the development of cardiovascular and renal damage. Effective antihypertensive treatment reduces the progression of diabetic nephropathy and improves cardiovascular prognosis. Accordingly, tight BP control (<130/80 mmHg) is currently recommended in diabetic patients. Achieving BP targets represents the most important determinant of cardiovascular and renal protection. However, it has been suggested that specific classes of antihypertensive drugs may exert additional organ protection beyond their BP control. The pharmacologic blockade of the renin-angiotensin-aldosterone system has been shown to convey greater renal and cardiovascular protection compared with other classes of drugs. In particular, studies focusing on renal end point suggest that angiotensin-converting enzyme inhibitors (ACEI) are the first-choice drugs in type 1 diabetes. Both ACEI and angiotensin II receptor blockers prevent the progression from microalbuminuria to clinical proteinuria in type 2 diabetes, but angiotensin blockers provide better renoprotection in patients with overt nephropathy. Regarding cardiovascular protection, several studies (but not all) have shown that ACEI exert a protective effect on diabetic patients. Recently, interesting results in favor of angiotensin receptor blockers have been reported in the IDNT, RENAAL, and LIFE studies. It should be noted that to achieve maximal renal and cardiovascular protection, most diabetic patients require integrated therapeutic intervention, including not only several antihypertensive drugs, but statins and antiplatelet therapy as well.

Antihypertensive drug therapy in the third millennium: are there benefits beyond blood pressure?

The classic outcome trials in hypertension, most of which used diuretics and b-blocking agents as first-line antihypertensive agents, have shown that antihypertensive drug treatment greatly reduces the risk of stroke, heart failure, and left ventricular hypertrophy (LVH). However, it is less successful in preventing fatal and nonfatal coronary heart disease (CHD) [1]. In the Framingham Heart Study, increased rates of use of antihypertensive medications, from 2.3% to 24.6% among men and from 5.7% to 27.7% among women, were associated with reduced prevalence of hypertension (blood pressure [BP]>160/100 mm Hg). Reductions were from 18.5% to 9.2% among men and from 28.0% to 7.7% among women. The prevalence of electrocardiographic evidence of LVH, an index of target organ damage, was reduced from 4.5% to 2.5% among men and from 3.6% to 1.1% among women. These findings suggest that the increasing use of antihypertensive medication may in part explain the major decline in mortality from cardiovascular disease observed in the United States since the late 1960s. Yet, despite these effective treatments, many important questions remain, some of which have been addressed by recently completed and ongoing clinical trials: • Are the newer classes of drugs, such as the calciumchannel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-II type-1 receptor blockers (ARBs), or a-adrenergic blockers (ABs) superior to diuretics or b-blockers in preventing cardiovascular disease and events? • Do specific classes of antihypertensive drugs, over and above their blood pressure–lowering effects, benefit specific subgroups of hypertensive patients? • What is the appropriate BP goal in various patient groups? • Are specific antihypertensive drugs indicated in special groups of patients, such as the very elderly (>80 years), normotensive persons at high cardiovascular risk, patients with type 2 diabetes, patients with stage 1 hypertension, or hypertensive patients of African-American extraction?