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Orthostatic hypotension (OH) is associated with hypertension and diabetes mellitus. However, in populations with both hypertension and diabetes mellitus, its prevalence, the effect of intensive versus standard systolic blood pressure (BP) targets on incident OH, and its prognostic significance are unclear. In 4266 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial, seated BP was measured 3×, followed by readings every minute for 3 minutes after standing. Orthostatic BP change, calculated as the minimum standing minus the mean seated systolic BP and diastolic BP, was assessed at baseline, 12 months, and 48 months. The relationship between OH and clinical outcomes (total and cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization or death and the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) was assessed using proportional hazards analysis. Consensus OH, defined by orthostatic decline in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg, occurred at ≥1 time point in 20% of participants. Neither age nor systolic BP treatment target (intensive, <120 mm Hg versus standard, <140 mm Hg) was related to OH incidence. Over a median follow-up of 46.9 months, OH was associated with increased risk of total death (hazard ratio, 1.61; 95% confidence interval, 1.11-2.36) and heart failure death/hospitalization (hazard ratio, 1.85, 95% confidence interval, 1.17-2.93), but not with the primary outcome or other prespecified outcomes. In patients with type 2 diabetes mellitus and hypertension, OH was common, not associated with intensive versus standard BP treatment goals, and predicted increased mortality and heart failure events., (© 2016 American Heart Association, Inc.)

To evaluate the effects of achieved systolic blood pressure (SBP) during treatment on cardiovascular (CV) outcomes, the authors measured event rates of a composite primary endpoint (CV death or nonfatal myocardial infarction or stroke) at on-treatment SBPs of ≥140 mm Hg and the 10 mm Hg intervals of <140 mm Hg, <130 mm Hg, and <120 mm Hg in 6459 patients with diabetes (mean age, 67) and 4246 patients without diabetes (mean age, 69) from the Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. In the diabetic cohort, the primary endpoint was 49% lower (P<.001) at <140 mm Hg than at ≥140 mm Hg, and the separate components of this endpoint were also significantly reduced. Further SBP reductions did not improve outcomes, and at <120 mm Hg they were no longer different (except for stroke) from ≥140 mm Hg. In contrast, in the nondiabetic cohort, the primary endpoint event rate fell steadily (although not significantly) through the decreasing SBP categories until it was reduced by 45% (P=.0413) at <120 mm Hg. Total stroke rates for both the diabetic (-56%, P=.0120) and nondiabetic (-68%, P=.0067) cohorts were lowest at <120 mm Hg, and adverse renal events (serum creatinine increase ≥50%) were significantly lowest in the range of 130 mm Hg to 139 mm Hg for both cohorts. Diabetic patients (<140 mm Hg or <130 mm Hg) and nondiabetic patients (<120 mm Hg) may require different SBP targets for optimal CV protection, although stroke and renal considerations should also influence the selection of blood pressure targets., (© 2016 Wiley Periodicals, Inc.)

Background: Hypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD., Objectives: To compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT)., Design: Randomized, double-blind, active-control trial in high-risk hypertensive participants., Participants: Eight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT., Interventions/events: In-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years., Main Measures: Baseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups., Key Results: Following adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality., Conclusions: Neither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment.

Background: There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events., Methods: A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years., Results: After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001)., Conclusions: In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.), (2010 Massachusetts Medical Society)

Hypertension is a major risk factor for ischemic heart disease, stroke, and heart failure. Even moderate blood pressure (BP) elevation can have a significant impact on outcomes. Maintaining BP within recommended levels significantly reduces the risk of cardiovascular morbidity and mortality. Yet, more than one-third of people receiving treatment for hypertension in the United States have uncontrolled BP. When faced with a patient whose BP is no longer controlled, clinicians need to develop a differential diagnosis of potential contributing factors. These factors may include BP measurement issues, poor adherence to antihypertensive medications, therapeutic inertia on the part of clinicians, lifestyle changes, secondary causes of hypertension, or ingestion of substances that interfere with BP control. Patients who demonstrate a deterioration in BP control should be questioned about adherence, recent changes to diet and lifestyle, signs and symptoms of secondary causes of hypertension, and use of any concomitant medications or other substances that may be known to increase BP or interfere with antihypertensive therapy. Common substances that can interfere with BP control include nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, glucocorticoids, antidepressants, decongestants, alcohol, or other stimulants like cocaine and methamphetamines. Because of the high prevalence of both osteoarthritis and hypertension among elderly people, NSAIDs are a common potential factor in this age group. In the face of worsening BP control, clinicians must actively investigate potential contributing factors and appropriately increase or adjust antihypertensive therapy.

Background: Undefined pathophysiologic mechanisms likely contribute to unsuccessful antihypertensive drug therapy. The renin test-guided therapeutic (RTGT) algorithm is based on the concept that, irrespective of current drug treatments, subnormal plasma renin activity (PRA) (<0.65 ng/ml/h) indicates sodium-volume excess "V" hypertension, whereas values >or=0.65 indicate renin-angiotensin vasoconstriction excess "R" hypertension., Methods: The RTGT algorithm was applied to treated, uncontrolled hypertensives and compared to clinical hypertension specialists' care (CHSC) without access to PRA. RTGT protocol: "V" patients received natriuretic anti-"V" drugs (diuretics, spironolactone, calcium antagonists, or alpha(1)-blockers) while withdrawing antirenin "R" drugs (converting enzyme inhibitors, angiotensin receptor antagonists, or beta-blockers). Converse strategies were applied to "R" patients. Eighty-four ambulatory hypertensives were randomized and 77 qualified for the intention-to-treat analysis including 38 in RTGT (63.9 +/- 1.8 years; baseline blood pressure (BP) 157.0 +/- 2.6/87.1 +/- 2.0 mm Hg; PRA 5.8 +/- 1.6; 3.1 +/- 0.3 antihypertensive drugs) and 39 in CHSC (58.0 +/- 2.0 years; BP 153.6 +/- 2.3/91.9 +/- 2.0; PRA 4.6 +/- 1.1; 2.7 +/- 0.2 drugs)., Results: BP was controlled in 28/38 (74% (RTGT)) vs. 23/39 (59% (CHSC)), P = 0.17, falling to 127.9 +/- 2.3/73.1 +/- 1.8 vs. 134.0 +/- 2.8/79.8 +/- 1.9 mm Hg, respectively. Systolic BP (SBP) fell more with RTGT (-29.1 +/- 3.2 vs. -19.2 +/- 3.2 mm Hg, P = 0.03), whereas diastolic BP (DBP) declined similarly (P = 0.32). Although final antihypertensive drug numbers were similar (3.1 +/- 0.2 (RTGT) vs. 3.0 +/- 0.3 (CHSC), P = 0.73) in "V" patients, 60% (RTGT) vs. 11% (CHSC) of "R" drugs were withdrawn and BP medications were reduced (-0.5 +/- 0.3 vs. +0.7 +/- 0.3, P = 0.01)., Conclusions: In treated but uncontrolled hypertension, RTGT improves control and lowers BP equally well or better than CHSC, indicating that RTGT provides a reasonable strategy for correcting treated but uncontrolled hypertension.

Type 2 diabetes mellitus is a worldwide epidemic with considerable health and economic consequences. Diabetes is an important risk factor for cardiovascular disease, which is the leading cause of death in diabetic patients, and decreasing the incidence of diabetes may potentially reduce the burden of cardiovascular disease. This article discusses the clinical trial evidence for modalities associated with a reduction in the risk of new-onset diabetes, with a focus on the role of antihypertensive agents that block the renin-angiotensin system. Lifestyle interventions and the use of antidiabetic, anti-obesity, and lipid-lowering drugs are also reviewed. An unresolved question is whether decreasing the incidence of new-onset diabetes with non-pharmacologic or pharmacologic intervention will also lower the risk of cardiovascular disease. A large ongoing study is investigating whether the treatment with an oral antidiabetic drug or an angiotensin-receptor blocker will reduce the incidence of new-onset diabetes and cardiovascular disease in patients at high risk for developing diabetes.

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up, 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) in a randomized double-blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group-a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.

Expert committees in the United States and Europe formulated their currently recommended target blood pressures of <140/90 mm Hg or <130/80 mm Hg in persons with diabetes, chronic kidney disease, or coronary artery disease based on the totality of clinical data available at the time. However, accumulating evidence indicates that increased risk for cardiovascular and renal complications of hypertension may begin at a threshold of 115/75 mm Hg, suggesting that benefit from treatment may occur when blood pressure targets are lower than those currently recommended. Combination therapy with two or more agents having complementary mechanisms of action is the most effective method for achieving strict blood pressure goals in high-risk patients. Several clinical trials are under way to further determine the risks and benefits of lowering blood pressure beyond the currently recommended threshold.

Background: Antihypertensive drugs with favorable metabolic effects are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an alpha-blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril)., Methods: A subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind hypertension treatment trial of 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men or less than 50 mg/dL in women., Results: Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval, 1.18-1.90), 1.49 (1.17-1.90), and 1.88 (1.42-2.47) in black participants and 1.25 (1.06-1.47), 1.20 (1.01-1.41), and 1.82 (1.51-2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RRs, 1.24 [1.09-1.40] and 1.10 [1.02-1.19], respectively) and doxazosin-chlorthalidone comparisons (RRs, 1.37 [1.19-1.58] and 1.18 [1.08-1.30], respectively) in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [1.07-1.76] for the lisinopril-chlorthalidone comparison, and RR, 1.49 [1.09-2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 [1.13-2.55]) with lisinopril compared with chlorthalidone., Conclusions: The ALLHAT findings fail to support the preference for calcium channel blockers, alpha-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.

Desirable features of antihypertensive agents include efficacy, tolerability, prolonged duration of action and rapid achievement of target blood pressure (BP). Recent studies have examined the relationship between the onset of antihypertensive effect and cardiovascular events. Data from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE), the Study on Cognition and Prognosis in the Elderly (SCOPE), and the Systolic Hypertension in Europe (Syst-Eur) trials support the hypothesis that the time it takes to reach target BP influences cardiovascular outcomes. VALUE, which compared BP-lowering and clinical event rates between patients treated with the angiotensin II receptor blocker (ARB) valsartan or the calcium channel blocker (CCB) amlodipine as well as between those who achieved immediate or delayed BP control, provides the strongest evidence of this to date. Additional data from SCOPE and Syst-Eur suggest that delays of 3 months to 2 years in starting antihypertensive therapy can increase the risk of certain cardiovascular end points, especially stroke. These data suggest that it may be beneficial to examine the efficacy of antihypertensive agents, not only long term, but also at earlier times to assess the onset and impact of early antihypertensive effect. The ARB olmesartan medoxomil (olmesartan) and the CCB amlodipine were compared in a randomized, double-blind, placebo-controlled clinical trial, which demonstrated that the onset of antihypertensive effect of olmesartan is comparable with that of amlodipine. Another study demonstrated that more patients treated with olmesartan achieved target BPs within 2 weeks of treatment compared with the ARBs losartan, valsartan and irbesartan.

Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Alpha blockers decrease insulin resistance, whereas diuretics increase insulin resistance. The authors studied the effects of these two classes of hypertension medications (doxazosin, an a blocker, and chlorthalidone, a diuretic) on cardiovascular disease outcomes in adults aged >55 years with hypertension and glucose disorders who were participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (8749 had known diabetes mellitus and 1690 had a newly diagnosed glucose disorder [fasting glucose >/=110 mg/dL]). There was no difference in either group between the chlorthalidone- and doxazosin-based treatments with regard to fatal or nonfatal myocardial infarction or all-cause mortality. There was, however, a difference for combined cardiovascular disease (myocardial infarction, revascularization procedures, angina, stroke, heart failure, and peripheral arterial disease) in favor of the diuretic. This difference was due primarily to an increased heart failure risk in those treated with doxazosin (relative risk, 1.85; 95% confidence interval, 1.56-2.19) in the known diabetes mellitus group and a relative risk of 1.63 (95% confidence interval, 1.05-2.55) in those with a newly diagnosed glucose disorder despite lower glucose levels on follow-up in those treated with a blockers. The authors conclude that treatment of hypertension with doxazosin in adults with glucose disorders incurs the same risk of coronary heart disease as treatment with chlorthalidone; however, treatment with doxazosin increases the risk of combined cardiovascular disease and heart failure despite lower glucose levels.

Hypertension affects approximately 50 million individuals in the United States (US) and approximately 1 billion individuals worldwide. Blood pressure (BP) reduction significantly lowers the risk of cardiovascular (CV) disease-the most common cause of death in the US-yet only approximately one third of Americans with hypertension have their disease controlled to the minimum recommended level of <140/90 mm Hg. Clinical trials such as the Hypertension Optimal Treatment (HOT) study, and Treatment of Mild Hypertension Study (TOMHS) have shown that control of BP to targets of < or =140/90 mm Hg reduces the likelihood of CV disease and improves quality of life. This appears to be true even in patients at high risk, such as those with diabetes. Furthermore, it has become increasingly recognized that multiple BP-lowering agents are usually necessary to achieve BP control (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease). In fact, current hypertension guidelines clearly state that most hypertensive patients will require two or more agents, and recommend initiating treatment with two antihypertensive medications if the BP is >20/10 mm Hg above goal BP. A valuable class of drug in the management of hypertension, beta-blockers (betaB) play an important role-whether as initial agents or as add-on therapy. They are especially useful in hypertensive patients with certain comorbidities such as diabetes or heart failure, in patients post-myocardial infarction, or in those generally at high risk for coronary disease. This article explores the cardioprotective role of how betaB may be used to optimize antihypertensive treatment.

Objective: Hypertension (HTN) is a major risk factor for cardiovascular disease (CVD) in the setting of diabetes. There is no consensus on how best to treat hypertension among those with diabetes. Here we describe the characteristics of a cohort of hypertensive adults with diabetes who are part of a large prospective blood pressure study. This study will help clarify the treatment of HTN in the setting of diabetes., Research Design and Methods: The Antihypertensive and Lipid-Lowering high-risk hypertensive participants, ages > or = 55 years, designed to determine whether the incidence of fatal and nonfatal coronary heart disease (CHD) and combined cardiovascular events (fatal and nonfatal CHD, revascularization surgery, angina pectoris, congestive heart failure, and stroke) differs between diuretic (chlorthalidone) treatment and three alternative antihypertensive therapies: a calcium channel blocker (amlodipine), an ACE inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). The planned follow-up is an average of 6 years, to be completed March 2002., Results: There are 15,297 diabetic individuals in the ALLHAT study (36.0% of the entire cohort). Of these individuals, 50.2% are male, 39.4% are African-American, and 17.7% are Hispanic. Demographic and laboratory characteristics of the cohort are similar to those of other studies of the U.S. elderly population with HTN. The sample size has 42 and 93% confidence, treatments for the two study outcomes., Conclusions: The diabetic cohort in ALLHAT wil be able to provide valuable information about the treatment of hypertension in older diabetic patients at risk for incident CVD.