Blood Pressure Control In Diabetes Research Articles

Evaluation and Treatment of Patients With Systemic Hypertension

A 65-year-old man presented for evaluation of high blood pressure found on screening at a local health fair. History and physical examination did not show any signs or symptoms suggestive of a secondary cause, nor was there evidence of target end-organ damage except for grade 1 Keith-Wagener-Barker retinopathy. The patient denied taking any prescription or over-the-counter medications. Hypertension is the most common disease-specific reason Americans visit a physician. Despite the risks associated with an elevated blood pressure (BP), there is still woefully low achievement of recommended BP goals. From 1991 to 1994, only 27.4% of hypertensive Americans aged 18 to 74 years had a BP <140/90 mm Hg, the current stated goal for most people with hypertension, and in those with diabetes, less than half that number (11%) were controlled to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI (JNC VI) recommended goal of <130/85 mm Hg.1 The present update will provide an overview of the evaluation and management of essential hypertension and help to guide clinicians in developing a management plan for a patient like the one described above. Taking a proper BP is an important first step in the diagnosis of hypertension.2 Using the proper cuff size with patients resting quietly and comfortably (with back support if seated) for at least 5 minutes before measurement, 2 or more readings separated by 2 minutes should be taken and averaged. Initial elevated BP readings should be confirmed on at least 2 subsequent visits over a period of 1 week or more. A value that is consistently ≥140/90 mm Hg is diagnostic in healthy patients; a value >130/80 mm Hg should be used for those with diabetes or kidney disease and proteinuria. Initial evaluation of the hypertensive patient focuses on the presence …

Manipulation of the renin-angiotensin system.

Since the initial description of angiotensin II–mediated hypertension >40 years ago, basic and clinical investigations of the renin-angiotensin system (RAS) have resulted in a broader understanding of cardiovascular pathophysiology and significant advances in therapy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are now widely prescribed for the treatment of hypertension and left ventricular (LV) dysfunction; more recently, the aldosterone receptor antagonist, spironolactone, has proven beneficial in severe heart failure. This article will focus on our current understanding of the RAS and how pharmacological manipulation of this system can improve clinical outcomes in patients with cardiovascular disease. ### Pathophysiological Rationale for RAS Manipulation Renin is released by juxtuloglomerular cells in the kidney in response to renal hypoperfusion, decreased sodium delivery, and sympathetic activation (Figure 1). Angiotensinogen produced by the liver is cleaved by renin to yield the inactive decapeptide angiotensin I. Circulating angiotensin I is, in turn, converted to angiotensin II in the lungs by the action of ACE. ACE, or kininase II, also plays a key role in the kallikrein-kinin system by cleaving bradykinin to inactive peptides. In addition to the hormonal effects of circulating angiotensin II, all of the necessary components of the RAS exist in several organs and tissues, including the heart, kidneys, and vasculature. Figure 1. Pathophysiology of the RAS. SMC indicates smooth muscle cell. Angiotensin II exerts its actions in target organs and tissues by binding to both angiotensin II type 1 and 2 (AT1 and AT2) receptors, although adverse effects in humans seem to be mediated primarily by the AT1 receptor (Figure 1). In the kidney, angiotensin II causes sodium and water retention and efferent arteriolar vasoconstriction. Constriction of the systemic vasculature by angiotensin II causes hypertension, whereas coronary vasoconstriction may cause myocardial ischemia and arrhythmias. Angiotensin II–stimulated secretion of aldosterone by the adrenal cortex and arginine …

Increasing homocysteine levels and diabetic autonomic neuropathy

Objective: To determine if hyperhomocysteinemia is a risk factor for the development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DAN). Background: Hyperhomocysteinemia and non-insulin-dependent diabetes mellitus (NIDDM) are both associated with premature vascular disease. Microvascular ischemia may be a risk factor for DSPN and DAN; therefore, the relationship of hyperhomocysteinemia to DSPN and DAN was investigated. Methods: Baseline neurological tests and homocysteine levels were determined in patients from a large prospective study of diabetic complications, the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Results: Total homocysteine (tHcy) was independently associated with DAN; for each 1 μmol/l increase in tHcy, there was a 7.1% increased risk of developing DAN ( P<0.05). There was no association between tHcy and DSPN. Conclusions: Hyperhomocysteinemia may be a risk factor for DAN but not for DSPN. This relationship may be related to differential small fiber injury. Further studies are needed to investigate this relationship between tHcy and DAN, specifically whether treatment of hyperhomocysteinemia may modify DAN.

A Bayesian approach to stochastic cost-effectiveness analysis. An illustration and application to blood pressure control in type 2 diabetes.

The aim of this paper is to discuss the use of Bayesian methods in cost-effectiveness analysis (CEA) and the common ground between Bayesian and traditional frequentist approaches. A further aim is to explore the use of the net benefit statistic and its advantages over the incremental cost-effectiveness ratio (ICER) statistic. In particular, the use of cost-effectiveness acceptability curves is examined as a device for presenting the implications of uncertainty in a CEA to decision makers. Although it is argued that the interpretation of such curves as the probability that an intervention is cost-effective given the data requires a Bayesian approach, this should generate no misgivings for the frequentist. Furthermore, cost-effectiveness acceptability curves estimated using the net benefit statistic are exactly equivalent to those estimated from an appropriate analysis of ICERs on the cost-effectiveness plane. The principles examined in this paper are illustrated by application to the cost-effectiveness of blood pressure control in the U.K. Prospective Diabetes Study (UKPDS 40). Due to a lack of good-quality prior information on the cost and effectiveness of blood pressure control in diabetes, a Bayesian analysis assuming an uninformative prior is argued to be most appropriate. This generates exactly the same cost-effectiveness results as a standard frequentist analysis.

Microvascular complications of diabetes: the role of angiotensin converting enzyme inhibitors Proceedings of a Round Table Meeting, June 1999, San Diego, USA

Microvascular complications of diabetes: the role of angiotensin converting enzyme inhibitors Proceedings of a Round Table Meeting, June 1999, San Diego, USA

Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes.

To assess whether ACE inhibitors are superior to alternative agents for the prevention of cardiovascular events in patients with hypertension and type 2 diabetes. This study is a review and meta-analysis of randomized controlled trials that included patients with type 2 diabetes and hypertension who were randomized to an ACE inhibitor or an alternative drug, were followed for > or =2 years, and had adjudicated cardiovascular events. A total of 4 trials were eligible. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial (n = 470) compared enalapril with nisoldipine, the Captopril Prevention Project (CAPPP) (n = 572) compared captopril with diuretics or beta-blockers, the Fosinopril Versus Amlodipine Cardiovascular Events Trial (FACET) (n = 380) compared fosinopril with amlodipine, and the U.K. Prospective Diabetes Study (UKPDS) (n = 758) compared captopril with atenolol. The cumulative results of the first 3 trials showed a significant benefit of ACE inhibitors compared with alternative treatments on the outcomes of acute myocardial infarction (63% reduction, P < 0.001), cardiovascular events (51% reduction, P < 0.001), and all-cause mortality (62% reduction, P = 0.010). These findings were not observed in the UKPDS. The ACE inhibitors did not appear to be superior to other agents for the outcome of stroke in any of the trials. None of the findings were explained by differences in blood pressure control. Compared with the alternative agents tested, ACE inhibitors may provide a special advantage in addition to blood pressure control. The question of whether atenolol is equivalent to captopril remains open. Conclusive evidence on the comparative effects of antihypertensive treatments will come from large prospective randomized trials.

Improving the prognosis of diabetic patients: Evaluating the role of intensive versus moderate blood pressure control with selective angiotensin II receptor blocker (ARB) therapy

The ABCD (Appropriate Blood Pressure Control in Diabetes) and ABCD-2V (Part 2 with Valsartan) are prospective, randomised clinical trials which will provide important data on the impact of intensive vs. moderate blood pressure (BP) control on microvascular and macrovascular complications in normotensive and hypertensive patients with type 2 diabetes mellitus (DM). The ABCD trial was a five-year study that compared the effects of intensive vs. moderate BP control on the endpoints of nephropathy, retinopathy, neuropathy, and cardiovascular disease events using a calcium channel blocker (CCB) and an angiotensin-converting enzyme (ACE) inhibitor as the primary antihypertensive agents. The recently published results of the hypertensive cohort of ABCD are reviewed herein. The follow-up study, ABCD-2V, is ongoing and was designed to compare intensive vs. moderate BP control on the same endpoints as the ABCD study, using the highly selective angiotensin II receptor blocker (ARB) valsartan as the primary antihypertensive agent. First results of ABCD-2V are expected in 2004. The baseline characteristics for the patients enrolled thus far in the hypertensive cohort of ABCD-2V are reviewed. These studies will provide insight into the role of intensive vs. moderate BP control in the management of normotensive and hypertensive patients with type 2 DM.

Treatment of diabetic patients with hypertension

This review attempts to highlight the potential of calcium-channel blockers in the prevention of sequelae of diabetes mellitus and hypertension in patients who have both disorders. Evidence-based medicine is driven by the results of randomized, clinical trials. Major contributions were therefore derived from post hoc analyses of the diabetic patients enrolled in placebo-controlled trials, such as Systolic Hypertension in the Elderly Program (SHEP), Systolic Hypertension in Europe (Syst-Eur), and Systolic Hypertension in China (Syst-China), and stepped-care blood-pressure-oriented trials, such as the Hypertension Optimal Treatment (HOT) and United Kingdom Prospective Diabetes Study (UKPDS). Several studies, such as the Fosiniprl; versus Amlodipine Cardiovascular Events Trial (FACET) and Appropriate Blood Pressure Control in Diabetes (ABCD) Trial, have compared the relative merits of angiotensin-converting enzyme and calcium-channel blockers in preserving renal function and metabolic balance in diabetic patients with hypertension, but their publications focused on cardiovascular disorders, which were only secondary end points. On balance, the articles reviewed prove that dihydropyridine calcium-channel blockers score particularly well in the prevention of cardiovascular complications in diabetic patients with hypertension.

Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial

As the population ages, the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications. Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes. Results from the recent Appropriate Blood Pressure Control in Diabetes (ABCD) trial demonstrated an advantage of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) over a long-acting calcium antagonist (nisoldipine) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes. This trial was a prospective, randomized, blinded study comparing the effects of moderate blood pressure control (target diastolic pressure 80–89 mm Hg) with those of intensive control (target diastolic pressure 75 mm Hg) on the incidence and progression of diabetic vascular complications. The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes. In 470 hypertensive patients, the incidence of fatal and nonfatal myocardial infarctions was significantly (p = 0.001) higher among those receiving nisoldipine (n = 25) compared with those receiving enalapril (n = 5). Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril resulted from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine. Since these findings in the ABCD trial are based on a secondary endpoint, they require confirmation. Nevertheless, they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension.

Calcium antagonists and the diabetic patient: a response to recent controversies

The results of 2 recently published studies have been interpreted as suggesting that calcium antagonists are unsafe for the management of hypertension in patients with diabetes. These 2 studies, the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) and Appropriate Blood Pressure Control in Diabetes (ABCD), showed that angiotensin-converting enzyme (ACE) inhibitors may be preferable to calcium antagonists for managing hypertension in diabetic patients; they do not, however, show any harm attributable to calcium antagonists. Indeed, results of the FACET study suggest that the combination of an ACE inhibitor and a calcium antagonist is effective antihypertensive therapy. This suggestion is supported by findings in the Systolic Hypertension in Europe (Syst-Eur) Study, which revealed outstanding benefits of either a calcium antagonist alone or a calcium antagonist combined with an ACE inhibitor among diabetic patients with hypertension. The premature termination of the hypertensive arm of the ABCD study was puzzling because, although 2 of 13 subgroups of 1 of the 5 possible secondary endpoints in this part of the trial were apparently favorably affected by the use of the ACE inhibitor rather than the calcium antagonist, such a finding was compatible with chance alone. If the results of the FACET and ABCD studies are considered in the context of the best available data arising from large randomized controlled trials, one may conclude that calcium antagonists are not harmful or contraindicated in hypertensive patients with diabetes and that the combination of an ACE inhibitor and a calcium antagonist is effective for the management of hypertension in diabetic patients.

Calcium antagonists and cardiovascular risk in diabetes

Recent trials have linked calcium antagonists with adverse cardiovascular events in hypertensive patients with diabetes. A closer examination of these trials (in particular the Appropriate Blood Pressure Control in Diabetes [ABCD] trial and the Fosinopril Versus Amlodipine Cardiovascular Events Trial [FACET]) reveals a lack of data from which to draw conclusions of harm. In fact, based on the results of these trials and the recent Hypertension Optimal Treatment (HOT) Trial, one may conclude that the combination of a calcium antagonist with an ACE inhibitor is a rational therapeutic choice in patients with coexisting hypertension and diabetes.

New evidence on the prevention of cardiovascular events in hypertensive patients with type 2 diabetes.

Recent trials in hypertensive patients with type 2 diabetes reveal important differences in the risk for major cardiovascular events when individual agents are compared. In the Fosinopril Amlodipine Cardiovascular Events Trial (FACET), 380 patients with hypertension and type 2 diabetes were randomized to fosinopril or amlodipine and followed for up to 3.5 years to assess effects on serum lipids. Although both agents effectively controlled blood pressure, amlodipine caused a significantly greater decrease in systolic pressure. At the end of the trial, serum cholesterol, high-density lipoprotein cholesterol, triglycerides, HbA1c, serum glucose, plasma insulin, serum creatinine, and microalbuminuria were similar in both groups. The patients randomized to fosinopril were significantly less likely to experience the prospectively defined combined outcome of acute myocardial infarction (MI), hospitalized angina, or stroke compared to those randomized to amlodipine (RR 0.49; 95% CI 0.26-0.95). In the Appropriate Blood pressure Control in Diabetes (ABCD) trial, 470 patients with hypertension and type 2 diabetes who were randomized to long-acting nisoldipine had an adjusted sevenfold increased risk for acute MI compared to those randomized to enalapril (RR 7.0; 95% CI 2.3-21.4). In the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) trial, the patients with hypertension and above the median of HbA1c (> or =6.7%) randomized to isradipine had a threefold increased risk for major cardiovascular events compared to those randomized to hydrochlorothiazide (RR 2.81; 95% CI 1.09-7.26). These findings are supported by several observational studies. Therefore, evidence is emerging that angiotensin-converting enzyme inhibitors and low-dose diuretics may be more effective than calcium antagonists for prevention of cardiovascular events in hypertensive patients with diabetes or impaired glucose control.

Personal viewpoint: new developments in the therapy of diabetic hypertensive disease. The ABCD study adds to strong evidence favoring the prime use of ACE inhibitors. Appropriate Blood Pressure Control in Diabetes.

Personal viewpoint: new developments in the therapy of diabetic hypertensive disease. The ABCD study adds to strong evidence favoring the prime use of ACE inhibitors. Appropriate Blood Pressure Control in Diabetes.

Angiotensin-converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus and its relationship with diabetic nephropathy

Previous studies have shown that the angiotensin-converting enzyme (ACE) gene polymorphism is associated with an increased risk of vascular disease in non-diabetic patients. The present study was conducted on 509 NIDDM patients who underwent a screening test to determine their ACE genotype for the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Various baseline indices were correlated with the three ACE polymorphisms. The genotype was determined through polymerase chain reaction amplification of the angiotensin-converting enzyme polymorphism. The univariate relationship between the presence of the DD genotype with nephropathy as measured by urinary albumin excretion (UAE), and a history coronary artery disease (CAD) was then examined. Finally, a multiple model for each UAE and CAD was created so as to determine the independent effects of the presence of the DD genotype on each diabetic complication. Univariately, the presence of the DD genotype was associated with diabetic nephropathy. Furthermore, in a multiple model predicting diabetic nephropathy, the presence of the DD genotype was independently associated with diabetic nephropathy (odds ratio = 2.8, 95% confidence interval 1.4 to 5.5) but not CAD. Thus, the ACE DD genotype in 509 non-Hispanic white NIDDM patients in a metropolitan area in the U.S. was independently associated with the presence of diabetic nephropathy and, therefore, may be potentially used as a marker for NIDDM patients at risk for developing diabetic nephropathy.

Associations of hypertension and complications in non-insulin-dependent diabetes mellitus

Hypertension is a common comorbidity with non-insulin-dependent diabetes mellitus (NIDDM). Data are somewhat inconsistent as to whether hypertension exacerbates diabetic complications in this population. Therefore, we examined the relationship between hypertension and vascular complications of NIDDM in the 950 patients enrolled in the prospective and randomized Appropriate Blood Pressure Control in Diabetes (ABCD) study. We found both systolic and diastolic hypertension to be associated with diabetic nephropathy ( P < .001) as well as with its macrovascular complications ( P < .05). Our present results also demonstrated that there was a significant relationship between hypertension and peripheral vascular disease ( P < .05), and left ventricular hypertrophy ( P < .001). There was, however, no apparent relationship between hypertension and diabetic neuropathy. Thus, arterial pressure may be a major determinant of complications in NIDDM.

How far should blood pressure be reduced in diabetic hypertensive patients?

EPIDEMIOLOGY OF DIABETES: Diabetes mellitus and arterial hypertension are closely related diseases that strongly predispose an individual to atherosclerotic cardiovascular disease and to renal failure. High blood pressure is twice as frequent in diabetics compared with the general population, and often precedes and contributes to the development of diabetic nephropathy. The prevalence of coexisting arterial hypertension and non-insulin-dependent diabetes mellitus (NIDDM) is increasing as populations age, giving an increased prevalence of both diseases. TREATMENT OF HYPERTENSIVE DIABETIC PATIENTS: The goal of treating arterial hypertension in diabetic patients is to prevent death and disability associated with high blood pressure. In addition, other reversible risk factors for cardiovascular disease, seen so frequently in hypertensive diabetics, also need to be addressed. The optimal goal of blood pressure control in diabetics has not been established, but there are indications that it should be lower than the 130/85 mmHg systolic/diastolic pressure recommended by current guidelines. In the presence of multiple associated risk factors, most guidelines suggest a threshold for intervention of > or = 140/90 mmHg. In particular, in hypertensive diabetic patients intervention must be early and aggressive.

Baseline characteristics of participants in the appropriate blood pressure control in diabetes trial

The ABCD (Appropriate Blood Pressure Control in Diabetes) trial is a large, prospective, randomized clinical trial designed to compare the effects of intensive with moderate blood pressure control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease, and neuropathy in non-insulin-dependent diabetes (NIDDM). The secondary objective is to determine equivalency of the effects of a calcium channel blocker (nisoldipine) and of an angiotensin-converting enzyme inhibitor (enalapril) as a first-line antihypertensive agent in the prevention and/or progression of these diabetic vascular complications. The study consists of two study populations: a hypertensive one (diastolic blood pressure of⩾90.0 mm Hg at the time of randomization) and a normotensive one (diastolic blood pressure of 80.0–89.0 mm Hg at the time of randomization). A total of 950 men and women aged 40–74 years were randomized and are being followed for 5 years at a single center. There were 470 randomized participants in the hypertensive population and 480 randomized participants in the normotensive population. This report summarizes the demographic, biochemical, and clinical characteristics of the randomized patients at the time of entry into the trial and evaluates the balance between the treatment groups within each population.

The sympathetic nervous system in diabetic neuropathy. A clinical and pathological study.

Tests of autonomic function were performed on 16 subjects with diabetic neuropathy. Abnormal sweating occurred in 10/10 (100 per cent), postural hypotension in 7/16 (44 per cent), an abnormal Valsalva ratio in 7/11 (64 per cent), and denervation hypersensitivity to phenylephrine in 2/8 (25 per cent) of patients tested. A quantitative assessment of baroreceptor function was made. In diabetics, there was a reduced resting heart period, heart period range and mean gain. Quantitative histological studies were performed on the greater splanchnic nerves removed at autopsy from 9 control subjects and from 8 subjects with diabetic neuropathy. The fibre density was significantly reduced in the greater splanchnic nerve of diabetics. The predominant pathology on teased fibre preparations was that of demyelination. Disordered blood pressure control in diabetes correlated with the pathological abnormalities in the sympathetic nervous system. Light and electronmicroscopic studies were performed on the sural nerves of 2 diabetic subjects with autonomic dysfunction. The predominant change was active axonal degeneration affecting mainly unmyelinated and small myelinated fibres.