Ib A. Jacobsen

Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial

Background: The increased risk of cardiovascular morbidity and mortality associated with arterial hypertension is particularly pronounced in patients with type 2 diabetes mellitus. Blood pressure control is, therefore, decisively important but often not sufficiently achieved. Objective: The primary objective of this study was to evaluate the antihypertensive effect of low dose spironolactone added to triple therapy for resistant hypertension in patients with type 2 diabetes measured by ambulatory monitoring. Secondary objectives were to evaluate the effects on glycaemic control and urinary albumin excretion as well as adverse effects. Methods: In a multicentre, double-blind, randomized, placebo-controlled study 119 patients with blood pressure at or above 130/80 mmHg despite triple antihypertensive therapy were included. One tablet of 25 mg spironolactone or placebo was added to previous treatment and increased to two if blood pressure below 130/80 mmHg was not achieved after 4 weeks. Blood pressure was measured by ambulatory monitoring at baseline and after 16 weeks. Results: The study was completed by 112 patients, 57 randomized to spironolactone and 55 to placebo. Average daytime placebo-corrected blood pressure was reduced by 8.9 (4.7–13.2)/3.7 (1.5–5.8) mmHg. Also office blood pressure, night-time, 24-h and pulse pressures were reduced significantly. Urinary albumin/creatinine ratio was significantly reduced in the spironolactone group. Glycaemic control remained unchanged. Hyperkalemia was the most frequent adverse event leading to dose reduction in three cases and discontinuation in one, whereas gynaecomastia was not reported. Conclusion: Low dose spironolactone exerts significant BP and urinary albumin creatinine ratio lowering effects in high-risk patients with resistant hypertension and type 2 diabetes mellitus.

The effect of low-dose spironolactone on resistant hypertension.

Our objective was to estimate the effect of addition of low-dose spironolactone to previous antihypertensive therapy in patients with resistant hypertension. Patients had 25 to 50 mg of spironolactone once daily added to the treatment of hypertension that was uncontrolled despite previous treatment with three classes of antihypertensive drugs. The effect on blood pressure was estimated by office measurements together with serum potassium and adverse effects. The data were analyzed retrospectively. A total of 544 patients were identified; 200 were excluded because of secondary hypertension, other indications for spironolactone than hypertension, previous antihypertensive therapy with less than three drugs unless demonstrated intolerance to a third drug, insufficient compliance, and lack of follow-up data. Thus, 344 cases were included in the analysis. The population was 62.1 ± 12.8 years old, 45.1% were males, and 43% had cardiovascular comorbidity. Mean blood pressure before the addition of spironolactone was 169/88 mm Hg. At 1, 3, and 6 months after the addition, blood pressure was decreased by an average of 16.6/7.0, 23.9/9.7, and 26.0/10.7 mm Hg (all P < .001). Serum potassium increased from an average of 3.7 mmol/L to 4.1 mmol/L (P < .001). Spironolactone was discontinued because of hyperkalemia in 4.1% of the cases. A total of 18% of all patients had adverse effects, which in 9.9% led to discontinuation of the drug. A total of 5.2% of the males developed gynecomastia. In conclusion, low-dose spironolactone is highly effective when added to previous treatment of patients with resistant hypertension.

Prevalence, awareness, and control of arterial hypertension in Denmark

Hypertension is an important modifiable risk factor for cardiovascular disease. Risk is reduced by reduction of blood pressure (BP). The present survey estimated the prevalence of hypertension, awareness, treatment, and BP control in Denmark. BP was measured three times on one occasion in a representative sample (n = 7,767) of the Danish population ages 20 to 89 years. Persons with screening BP >/=140/90 mm Hg also measured BP at home. Participants with home BP >/=135/85 mm Hg in general and >/=125/75 mm Hg for patients with diabetes or renal disease were categorized as hypertensive together with those already on antihypertensive treatment. Awareness was registered by questionnaire. Treated patients with BP below relevant limits were categorized as controlled. Age-adjusted prevalence of hypertension was on the basis of screening BP 25.7% and by home BP 22.3%. Seventy-two percent of patients found hypertensive by home BP were aware of it, 64% were treated, and 57% of those treated were controlled by office BP and 68% by home BP. One-fifth of the adult Danish population was found to be hypertensive, Awareness and control of hypertension was better than in most previous reports. Control rates similar to those of clinical trials are achievable in clinical practice.

Tracking and factors predicting rising in ‘tracking quartile’ in blood pressure from childhood to adulthood: Odense Schoolchild Study

This prospective study determines the degree of tracking and investigates factors predicting a rise in blood pressure (BP) quartile in a cohort of 1369 subjects who were followed for 11 years from childhood into young adulthood. In 900 of these subjects BP, height, weight, physical fitness and BP responses to a maximal exercise testing were measured both at baseline and at follow-up. BP, weight, height and body mass index (BMI) were divided into sex-specific quartiles at both examinations. Tracking was evaluated by examining the tendency of remaining in the same quartile from baseline to follow-up and by measuring product-moment correlation coefficients. Tracking in the upper and lower quartile for BP, weight, height and BMI were significant. Odds ratios for staying in the upper or lower quartile through the follow-up period ranged from 1.6 to 2.4 for diastolic BP and from 2.1 to 3.1 for systolic BP. The range of correlation coefficients for the anthropometric measurements were 0.57–0.75, for diastolic BP 0.12–0.22 and for systolic BP 0.34–0.36 respectively. Changes in weight or relative weight as well as BP response to an exercise test were the factors which predicted a rise in quartile through the 11 years of follow-up. The existence of the inevitable regression to the mean problem in large longitudinal studies of BP was demonstrated by the finding of baseline BP being a significant factor in the prediction of rising in systolic, diastolic or both systolic and diastolic BP quartiles.

Plasmin in urine from patients with type 2 diabetes and treatment-resistant hypertension activates ENaC in vitro.

Background: Aberrant filtration of plasminogen from plasma and subsequent activation to plasmin in the urinary space may activate proteolytically the epithelial sodium channel, ENaC. In conditions with chronic albuminuria, this may cause hypertension. It was hypothesized that patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension excrete plasmin(ogen) in urine in proportion to albumin and that plasmin confers to urine the ability to activate ENaC. Method: Patients (n = 113) with T2DM and resistant hypertension, defined as systolic blood pressure (SBP) more than 130 mmHg and/or diastolic blood pressure (DBP) more than 80 mmHg despite use of at least three drugs with one diuretic and one renin–angiotensin system inhibitor, were included. Urine was analyzed for albumin, creatinine, plasmin(ogen), protease activity, and ability to activate inward current in single collecting duct cells. Results: Mean ambulatory SBP/DBP was 143 ± 1/77 ± 0.7 mmHg; HbA1c 7.35%; and eGFR 81.0 ml/min per 1.73 m2 (geometric means). Patients with microalbuminuria (39%) and macroalbuminuria (13%) displayed significantly elevated levels of urinary plasmin(ogen) normalized to urine creatinine compared with patients with normal excretion of albumin (48%). Urinary plasminogen correlated significantly to urine albumin. Western immunoblotting and gelatine zymography confirmed active plasmin in urine samples from patients with microalbuminuria and macroalbuminuria. Single collecting duct cells displayed significantly increased, amiloride-sensitive, inward current when superfused with urine from albuminuric patients compared with patients with normal albumin excretion. Urinary plasminogen/creatinine ratio correlated significantly with 24-h ambulatory blood pressure. Conclusion: Aberrant presence of plasmin in preurine may inappropriately activate ENaC in patients with type 2 diabetes and microalbuminuria. This may contribute to treatment-resistant hypertension.

Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment-resistant hypertension

In conditions with albuminuria, plasminogen is aberrantly filtered across the glomerular barrier and activated along the tubular system to plasmin. In the collecting duct, plasmin activates epithelial sodium channels (ENaC) proteolytically. Hyperactivity of ENaC could link microalbuminuria/proteinuria to resistant hypertension. Amiloride, an ENaC inhibitor, inhibits urokinase-type plasminogen activator. We hypothesized that amiloride (1) reduces blood pressure (BP); (2) attenuates plasminogen-to-plasmin activation; and (3) inhibits urine urokinase-type plasminogen activator in patients with resistant hypertension and type 2 diabetes mellitus (T2DM).In an open-label, non-randomized, 8-week intervention study, a cohort (n = 80) of patients with resistant hypertension and T2DM were included. Amiloride (5 mg/d) was added to previous triple antihypertensive treatment (including a diuretic and an inhibitor of the renin-angiotensin-aldosterone system) and increased to 10 mg if BP control was not achieved at 4 weeks. Complete dataset for urine analysis was available in 60 patients. Systolic and diastolic BP measured by ambulatory BP monitoring and office monitoring were significantly reduced. Average daytime BP was reduced by 6.3/3.0 mm Hg. Seven of 80 cases (9%) discontinued amiloride due to hyperkalemia >5.5 mol/L, the most frequent adverse event. Urinary plasmin(ogen) and albumin excretions were significantly reduced after amiloride treatment (P < .0001). Urokinase activity was detectable in macroalbuminuric urine, with a tendency toward reduction in activity after amiloride treatment. Amiloride lowers BP, urine plasminogen excretion and activation, and albumin/creatinine ratio, and is a relevant add-on medication for the treatment of resistant hypertension in patients with T2DM and microalbuminuria.

Multimorbidity and Blood Pressure Control in 37 651 Hypertensive Patients From Danish General Practice

Background Patients with hypertension are primarily treated in general practice. However, major studies of patients with hypertension are rarely based on populations from primary care. Knowledge of blood pressure (BP) control rates in patients with diabetes and/or cardiovascular diseases (CVDs), who have additional comorbidities, is lacking. We aimed to investigate the association of comorbidities with BP control using a large cohort of hypertensive patients from primary care practices. Methods and Results Using the Danish General Practice Database, we included 37 651 patients with hypertension from 231 general practices in Denmark. Recommended BP control was defined as BP <140/90 mm Hg in general and <130/80 mm Hg in patients with diabetes. The overall control rate was 33.2% (95% CI: 32.7 to 33.7). Only 16.5% (95% CI: 15.8 to 17.3) of patients with diabetes achieved BP control, whereas control rates ranged from 42.9% to 51.4% for patients with ischemic heart diseases or cerebrovascular or peripheral vascular diseases. A diagnosis of cardiac heart failure in addition to diabetes and/or CVD was associated with higher BP control rates, compared with men and women having only diabetes and/or CVD. A diagnosis of asthma in addition to diabetes and CVD was associated with higher BP control rates in men. Conclusion In Danish general practice, only 1 of 3 patients diagnosed with hypertension had a BP below target. BP control rates differ substantially within comorbidities. Other serious comorbidities in addition to diabetes and/or CVD were not associated with lower BP control rates; on the contrary, in some cases the BP control rates were higher when the patient was diagnosed with other serious comorbidities in addition to diabetes and/or CVD.

Selective renal vasoconstriction, exaggerated natriuresis and excretion rates of exosomic proteins in essential hypertension.

In essential hypertension (EH), the regulation of renal sodium excretion is aberrant. We hypothesized that in mild EH, (i) abnormal dynamics of plasma renin concentration (PRC) and atrial natriuretic peptide (ANP) are responsible for the exaggerated natriuresis, and (ii) exosomic protein patterns reflect the renal tubular abnormality involved in the dysregulation of sodium excretion.

Treatment of 5413 hypertensive patients: a cross-sectional study

BACKGROUND Most hypertensive patients are managed in primary care in Denmark, but previous studies have shown that only 21-43% of hypertensive patients achieve optimal blood pressure (BP) control. Antihypertensive drug treatment, risk factors and cardiovascular disease (CVD) are some of the important factors to consider when optimizing the individual treatment strategy in hypertensive patients. OBJECTIVE To examine treatment of BP according to Danish guidelines (BP < 140/90 mmHg generally and <130/80 mmHg for diabetics) in a population from general practice in relation to risk factors, CVD and diagnosis of diabetes. METHODS A cross-sectional study comprising 184 practices and 5413 hypertensive patients was carried out in Denmark. The general practitioners filled in information on each patients risk factors, CVD and antihypertensive drug treatment. Patients filled in a questionnaire on risk factors. The outcome measures were optimal BP control according to Danish guidelines and antihypertensive drug treatment. RESULTS Mean patient age was 65.9 years [95% confidence interval (CI): 65.6-66.1]. Optimal BP control was achieved in 29.1% (95% CI: 27.9-30.3) of the study population. Among 842 diabetics with or without CVD, optimal BP control was achieved in 10.9% (95% CI: 8.8-10.3), while 38.7% (35.5-41.9) of patients with CVD achieved optimal BP control. The majority of all patients were treated with 1 (32.5%, 95% CI: 32.5 (31.3-33.8)) or two antihypertensive drugs (39.0%, 95% CI: 38.2-40.8). In hypertensive diabetics, 17.7% were not treated with an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. CONCLUSION In general practice, the proportion of hypertensive patients achieving optimal BP control is inadequate. The majority of hypertensive patients are treated with only one or two antihypertensive drugs.

Angiotensin Converting Enzyme Inhibitor Therapy and Acute Pancreatitis

Angiotensin converting enzyme (ACE) inhibitors are generally well tolerated. Worldwide, only few reports have been published associating pancreatitis with ACE inhibitor therapy. We report a case in whom there was no other likely explanation for the acute pancreatitis than enalapril therapy, which was temporally associated with the symptoms. Possible mechanisms underlying the induction of pancreatitis by ACE inhibitors are discussed. With the increasing use of ACE inhibitors, the incidence of rare adverse effects such as potentially lethal pancreatitis is likely to increase. Clinicians need to be aware of this association.