Protective Effect Of Angiotensin-converting Enzyme Inhibitors Research Articles

Risk of pneumonia-related hospitalization after initiating angiotensin-converting enzyme inhibitors compared with angiotensin II receptor blockers: a retrospective cohort study using LIFE Study data.

There is insufficient evidence that angiotensin-converting enzyme inhibitors (ACEIs) can reduce pneumonia by inducing a dry cough that confers a protective effect on the airway. To increase the evidence base on the clinical use of ACEIs for pneumonia prevention, this retrospective cohort study aimed to comparatively examine the risk of pneumonia-related hospitalization between ACEI initiators and angiotensin II receptor blocker (ARB) initiators using claims data from two Japanese municipalities. We identified persons who were newly prescribed any ACEI or ARB as their first antihypertensive agent between April 2016 and March 2020. The Fine-Gray method was applied to a Cox proportional hazards model to estimate the subdistribution hazard ratio (HR) of ACEI use (reference: ARB use) for pneumonia-related hospitalization, with death treated as a competing risk. Sex, age, comorbidities, medications, and pneumococcal immunization were included as covariates. The analysis was conducted on 1421 ACEI initiators and 9040 ARB initiators, and the adjusted subdistribution HR of ACEI use was estimated to be 1.21 (95% confidence interval: 0.89-1.65; P = 0.22). ACEI initiation did not demonstrate any significant preventive effect against pneumonia-related hospitalization relative to ARB initiation. There remains a lack of strong evidence on the protective effects of ACEIs, and further research is needed to ascertain the benefits of their use in preventing pneumonia. We conducted a large-scale retrospective cohort study using real-world healthcare data from a Japanese population. In this study, ACEI initiation did not indicate a significant preventive effect against pneumonia-related hospitalization.

Use of Angiotensin Converting Enzyme Inhibitors and Risk of Late Bladder Toxicity Following Radiotherapy for Prostate Cancer

Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) near AGT associated with late hematuria following radiotherapy (RT) for prostate cancer. AGT encodes angiotensinogen and, in pre-clinical models, angiotensin pathway inhibition protects against late radiation toxicity in some tissues. Effects on the bladder have not been investigated. We tested the hypothesis that angiotensin converting enzyme inhibitors (ACEi) reduce risk of late hematuria following RT. We additionally investigated the effect of genetically-defined hypertension on hematuria.Prostate cancer patients (N = 268) undergoing curative RT (alone or with surgery and/or androgen deprivation therapy) were enrolled from each of two cancer centers pre-RT and followed prospectively for development of hematuria for up to four years using patient reported outcome questionnaires. Hematuria was defined as gross bleeding or medication use for hematuria. Demographic, treatment, and medication data were abstracted from medical records. The cumulative probability of hematuria was estimated by Kaplan-Meier methods, and the log rank test assessed differences by ACEi/ARB, use stratified by enrollment center. Multivariable analyses used Cox models of time to onset of hematuria stratified by enrollment center. A polygenic risk score (PRS) comprising 882 SNPs previously associated with blood pressure was tested for association with time to onset of hematuria in our Radiogenomics Consortium GWAS cohorts (N = 3,608).The cumulative probability of hematuria among all participants was 17.1% (N = 19) at four years (median follow-up of two years). Hematuria was seen in 1.4% of those taking vs 22.9% in those not taking ACEi (P = 0.01) at the start of RT, resulting in a hazard ratio (HR) of 0.11 (95% CI 0.01 to 0.83). The protective effect of ACEi on hematuria remained when adjusted for factors associated with ACEi use, including body mass index, hypertension, or diabetes. The protective effect also remained after stratifying by risk factors for hematuria, including prior transurethral prostate resection, smoking status, or prior prostatectomy. A blood pressure PRS was strongly associated with hypertension (odds ratio per standard deviation 1.40, 95% CI 1.30 to 1.50, P < 0.001) but not with hematuria (HR per standard deviation 0.97, 95% CI 0.87 to 1.07, P = 0.52).Our study is the first to show a radioprotective effect of ACEi on bladder toxicity. This effect appears distinct from presence of hypertension, which is not itself a risk factor. These results point to a promising radioprotector readily available for testing in a randomized clinical trial. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects normal tissues to reduce RT toxicity.

240-LB: Angiotensin-Converting Enzyme and Type 2 Diabetes Risk: A Mendelian Randomization Study

The causal relationship between angiotensin-converting enzyme (ACE) inhibition and protection from type 2 diabetes (T2D) remains uncertain. While three large randomized control trials (RCTs) suggested a protective effect of ACE inhibitors compared to placebo, three other RCTs failed to observe an effect, including the only trial dedicated to this question. We hypothesized that ACE concentration-lowering genetic variants could be used to infer the pharmacological effect of ACE inhibitors on T2D risk using a Mendelian Randomization (MR) approach. We first assessed the association between T2D prevalence and ACE serum level in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (N=8,197). We next investigated whether genetically lowered ACE level was causally linked to the risk of T2D using (i) a two-sample MR analysis applied to the DIAbetes Genetics Replication And Meta-analysis consortium (n=26,676 T2D cases; 132,532 controls), and (ii) an ACE concentration-lowering genetic risk score in the UK Biobank cohort (N=341,872). We then compared the genetically determined effect of lower ACE level on T2D risk to the pharmacological inhibition of ACE vs. placebo, which was evaluated through a meta-analysis of six RCTs (N=31,200). Lower ACE serum level was associated with reduced T2D prevalence (OR, 0.89; 95% CI, 0.82-0.96; P=3.50x10-3) in the ORIGIN trial. Through MR analyses, a 1 SD lower genetically determined ACE level predicted a lower risk of T2D (OR, 0.92; 95% CI, 0.89-0.95; P=1.79x10-7). This result was replicated in the UK Biobank (OR, 0.97; 95% CI, 0.96-0.99, P=8.73x10-4). RCT meta-analysis showed a reduction in T2D incidence on ACE inhibitors vs. placebo (OR, 0.76; 95% CI, 0.60-0.97; P=2.59x10-2), which was consistent with the findings from MR analyses (P for comparison=0.95). Our results support a protective effect of long-term ACE inhibition on T2D risk and suggest to consider patient's risk for T2D when prescribing blood-pressure lowering drugs. Disclosure M. Pigeyre: None. J. Sjaarda: None. M. Chong: None. S. Hess: None. J. Bosch: Advisory Panel; Self; Bayer AG. S. Yusuf: None. H. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Sanofi. G. Pare: Consultant; Self; Amgen Inc., Bristol-Myers Squibb Company, Lexicomp, Sanofi. Research Support; Self; Canada Research Chair in Genetic and Molecular Epidemiology, CISCO Professorship in Integrated Health Biosystems, Sanofi. Funding Sanofi; Canadian Institutes of Health Research

Primary prevention of myocardial infarction with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in hypertensive patients with rheumatoid arthritis-A nationwide cohort study.

BackgroundRheumatoid arthritis (RA) is regarded as a high risk factor for myocardial infarction. Hypertension is a major modifiable risk factor contributing to increased risk of myocardial infarction (MI). Dual blood pressure (BP)-lowering and anti-inflammatory effect of renin-angiotensin-system (RAS) inhibitors may possess protective effect from MI in RA population. However, treatment of hypertension with RAS inhibitors and MI in RA population remains unclear.MethodsWe investigated whether RAS blockade could decrease risk of incident MI in hypertensive patients with RA. We identified patients with RA and hypertension from the Registry for Catastrophic Illness, a nation-wide database encompassing almost all of the RA patients in Taiwan from 1995 to 2008. The primary endpoint was MI and the median duration of follow up was 2,986 days. Propensity score weighting and Cox proportional hazards regression models were used to estimate hazard ratios for MI.ResultsAmong 27,335 subjects, 9.9% received angiotensin-converting enzyme inhibitors (ACEIs), 25.9% received angiotensin II receptor blockers (ARBs) and 20.0% received ACEIs or ARBs alternatively. The incidence of MI significantly decreased in patients treated with ACEIs (hazard ratio 0.707; 95% confidence interval 0.595–0.840), ARBs (0.641; 0.550–0.747) and ACEIs/ARBs (0.631; 0.539–0.739). The protective effect of ACEI or ARB therapy was significantly better in patients taking longer duration. The effect remained robust in subgroup analyses.ConclusionsTherapy of ACEIs or ARBs is associated with a lower risk of MI among patients with RA. Hence, hypertension in patients with RA could comprise a compelling indication for RAS inhibitors.

Comparison of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockade for the prevention of premalignant changes in the liver

Aim We investigate and compare the possible antitumor activity of clinically used angiotensin converting enzyme (ACE) inhibitors; captopril, perindopril and angiotensin II type 1 receptor (AT1R) blocker, losartan against hepatocarcinogenesis initiated by diethylnitrosoamines (DENA) and promoted by carbon tetrachloride (CCl 4). Main methods Diethylnitrosamine (DENA) (200 mg/kg i.p.) initiated and carbon tetrachloride (CCl 4) (2 ml/kg i.p.) promoted hepatocarcinogenesis in male Wistar rats after 8 weeks. Results Hepatocarcinogenesis was manifested biochemically by elevation of serum hepatic tumor markers tested; α-feto protein (AFP) and carcinoembryonic antigen (CEA). In addition, hepatic carcinogenesis was further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF). Moreover a marked increase in matrix metalloproteinase-2 and hydroxyproline content were also observed. Hepatocarcinogenesis was further confirmed by a significant decrease in hepatic endostatin and metallothonein level. Key findings Long-term administration of the selected drugs for 2 weeks before and throughout the experimental period produced a significant protection against hepatic carcinogenesis. The present results claimed that different doses of the selected drugs succeeded in normalization of serum tumor markers. Furthermore, the drugs reduced the elevated level in the hepatic growth factors, matrix metalloproteinase-2 and hydroxyproline induced by the hepatocarcinogen. Moreover, the amelioration was also accompanied by augmentation of hepatic content of metallothionein and endostatin. Histopathological examination of liver tissues of rats treated with DENA–CCl 4 correlated with the biochemical observations. Significance These findings suggest a similar protective effect of ACE inhibitors; captopril; perindopril and AT1R blocker, losartan against premalignant stages of liver cancer in the DENA initiated and CCl 4 promoted hepatocarcinogenesis model in rats. Therefore, RAS especially angiotensin II (Ang II) and AT1R interaction plays a pivotal role hepatocarcinogenesis development.

Are There Effects of Renin–Angiotensin System Antagonists Beyond Blood Pressure Control?

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are recognized to reduce cardiovascular and renal morbidity and mortality, which is primarily attributed to their antihypertensive effects. Activation of the renin-angiotensin system (RAS) may also play an important role in the pathogenesis of cardiovascular and renal disease through blood pressure-independent mechanisms mediated by angiotensin II. Thus, inhibiting the RAS with either an ARB or an ACE inhibitor may confer additional benefit in people with advanced nephropathy that cannot be explained totally by reductions in blood pressure. Preclinical evidence suggests that blood pressure lowering is not solely responsible for the organ and tissue protective effects of ACE inhibitors or ARBs. Furthermore, clinical studies evaluating effects on end organs and surrogate markers have shown that these agents have blood pressure-independent effects. There is also intriguing evidence that agents in the same class may differ in their effects on renal function despite similar blood pressure control. Support for blood pressure-independent effects comes from outcome studies. Agents evaluated in such studies and that appear to have effects independent of blood pressure lowering include irbesartan, losartan, ramipril, and telmisartan. Taken together, this body of evidence indicates that the clinical benefits of ARBs and ACE inhibitors in patients with advanced nephropathy extend beyond blood pressure reduction. Therefore, although antihypertensive efficacy is of primary importance in choosing a treatment to provide cardiovascular and renal protection, consideration should be given to the effects of an agent that extend beyond blood pressure.

Cellular protective action of angiotensin converting enzyme inhibitors.

In several studies organ protective effects of ACE inhibitors independent from their antihypertensive action have been demonstrated. The mechanisms of the protective effects of angiotensin converting enzyme (ACE) inhibitors on vasculature and kidney are largely unknown. In the present study the modulatory action of captopril on the angiotensin II (AngII), arginine vasopressin (AVP), and platelet derived growth factor (PDGF)-induced increase of cytosolic free calcium concentration ([Ca2+]i) was investigated in cultured vascular smooth muscle cells (VSMC) and cultured glomerular mesangial cells (MC) from rats using the fluorescent dye technique. Resting [Ca2+]i in VSMC or MC was not significantly affected by captopril. The preincubation of VSMC with 1 mumol/l captopril significantly reduced the AngII-induced [Ca2+]i increase in VSMC from 90 +/- 10 nmol/l (n = 78; mean +/- SEM) to 51 +/- 16 nmol/l (n = 53; p < 0.05) and in MC from 102 +/- 42 nmol/l (n = 14) to 43 +/- 12 nmol/l (n = 7; p < 0.05). In the absence of extracellular calcium captopril produced no effect on AngII induced changes of [Ca2+]i. Captopril significantly attenuated the AVP-induced [Ca2+]i increase in VSMC and MC. The preincubation of MC with 1 mumol/l captopril for 40 min significantly reduced the PDGF-induced [Ca2+]i increase in MC from 127 +/- 31 nmol/l (n = 11) to 61 +/- 32 nmol/l (n = 5, p < 0.05). The present results may indicate that part of the protective effects of ACE inhibitors on vasculature and kidney may be promoted by inhibition of growth-factor induced changes of calcium homeostasis.

Protective Effect of Perindopril on Diabetic Retinopathy Is Associated With Decreased Vascular Endothelial Growth Factor–to–Pigment Epithelium–Derived Factor Ratio

OBJECTIVEThis study aimed to verify whether the decreased vascular endothelial growth factor (VEGF)–to–pigment epithelium–derived factor (PEDF) ratio can serve as an indicator for the protective effect of angiotensin-converting enzyme inhibitors (ACEIs) on diabetic retinopathy (DR) and to investigate the role of mitochondrial reactive oxygen species (ROS) in the downregulated VEGF-to-PEDF ratio.RESEARCH DESIGN AND METHODSDiabetic rats and control animals were randomly assigned to receive perindopril or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without perindopril. VEGF, PEDF, PPARγ, and uncoupling protein-2 (UCP-2) in the rat retinas or BREC extracts were examined by Western blotting and real-time RT-PCR. The levels of VEGF and PEDF in cell culture media were examined by ELISA. Mitochondrial membrane potential (Δψm) and ROS production were assayed using JC-1 or CM-H2DCFDA.RESULTSThe VEGF-to-PEDF ratio was increased in the retina of diabetic rats; perindopril lowered the increased VEGF-to-PEDF ratio in diabetic rats and ameliorated the retinal damage. In BRECs, perindopril lowered the hyperglycemia-induced elevation of VEGF-to-PEDF ratio by reducing mitochondrial ROS. We found the decreased ROS production was a result of perindopril-induced upregulation of PPARγ and UCP-2 expression and the subsequent decrease of Δψm.CONCLUSIONSIt is concluded that the protective effect of ACEI on DR is associated with a decreased VEGF-to-PEDF ratio, which involves the mitochondria-ROS pathway through PPARγ-mediated changes of UCP-2. This study paves a way for future application of ACEI in treatment of DR.

Blood pressure reduction and renin-angiotensin system inhibition for prevention of congestive heart failure: a meta-analysis

It is unclear whether prevention of congestive heart failure (CHF) by drugs that inhibit the renin-angiotensin system (RAS) occurs over and beyond the reduction in blood pressure (BP) achieved by these drugs. We conducted a meta-analysis of trials comparing angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), or calcium-channel blockers (CCBs), with diuretics, beta-blockers, or placebo in hypertensive or high-risk subjects without CHF at entry. Both fixed- and random-effect models were used. In trials vs. placebo, the risk of CHF was reduced by 21% with ACEIs (P = 0.007), whereas the effect of ARBs and CCBs was not significant (random-effect models). Thus, CCBs did not increase the risk of CHF. In trials vs. diuretics/beta-blockers, no differences were found between ACEIs and comparators [odds ratio (OR) 1.02; 95% confidence interval (CI) 0.84-1.24], whereas CCBs were associated with an 18% higher risk of CHF (OR 1.18; 95% CI 1.00-1.39; P = 0.048). Therefore, ACEIs were not superior to diuretics/beta-blockers for the prevention of CHF. Because heterogeneity between trials was significant, we investigated potential sources of heterogeneity by meta-regression. The risk of CHF decreased by 24% (P < 0.001) for each 5 mmHg reduction in systolic BP. The risk of CHF was 19% less with ACEIs/ARBs than CCBs (P < 0.001) and 16% less in studies without multiple risk factors required for entry (P = 0.009). BP reduction is beneficial for the prevention of CHF. Over and beyond BP reduction, the protective effect of ACEIs and ARBs is greater than that of CCBs.

Protective effects of ACE inhibitors on vascular endothelial dysfunction induced by exogenous advanced oxidation protein products in rats

To explore detrimental effects of advanced oxidation protein products-bovine serum albumin (BSA) on endothelial function and compare the favorable effects of angiotensin-converting enzyme (ACE) inhibitors: captopril and enalapril. Male Sprague–Dawley rats were randomly divided into groups: control, advanced oxidation protein products-BSA, captopril (10, 20 mg/kg/day), enalapril (15 mg/kg/day), and NG-nitro-l-arginine methyl ester (l-NAME, 300 mg/kg/day) plus captopril (20 mg/kg/day) groups. All animals were given advanced oxidation protein products-BSA (100 mg/kg/day, i.v.) except for control group (iv. equal volume of PBS). Rats in other groups were received different drugs intragastrically after advanced oxidation protein products-BSA administration. Endothelium-dependent relaxation of thoracic aorta was assayed. Content of nitrite/nitrate (NO), malondialdehyde (MDA), activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and of ACE in Sera, as well as renal function index including blood urea nitrogen and creatinine were measured. After 30 days, the endothelium-dependent relaxation of blood vessels in received advanced oxidation protein products-BSA rats was significantly impaired compared with control rats. The impairment was accompanied by decreases of serum NO, activity of GSH-Px and SOD. Administration of captopril and enalapril not only decreased damage of endothelium-dependent relaxation, but also reverse the changes of MDA levels, NO content and activity of SOD. The protective effect of captopril was abolished by l-NAME. Blood urea nitrogen and creatinine had no significant differences between various groups. ACE activities were decreased in high captopril and enalapril groups, but did not significantly change in other groups. The results suggested that captopril and enalapril have similar effects on endothelial dysfunction induced by advanced oxidation protein products-BSA, which indicated that protective effects of captopril are not related to sulfhydryl group.

Angiotensin-Converting Enzyme Inhibitors and Risk of Esophageal and Gastric Cancer: A Nested Case-Control Study

There are contradictory results regarding the association between angiotensin-converting enzyme (ACE) inhibitors and cancer. We aimed to investigate whether ACE inhibitors protect against esophageal and gastric cancer. We conducted a population-based case-control study nested within the General Practitioners' Research Database in the United Kingdom. All individuals in the General Practitioners' Research Database aged 40-84 years between 1994 and 2001 were followed up until detection of an esophageal or gastric cancer (cases), other cancer, age of 85 years, death, or end of study period. Among 4.34 million person-years, 909 cases of esophageal and 1023 cases of gastric cancer were identified, and 10,000 matched controls were selected at random. Adjustments included smoking, body mass index, concurrent medication, and gastrointestinal disorders. Current use of ACE inhibitors decreased the risk of esophageal adenocarcinoma by 29% (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.43-1.17), but not of squamous-cell carcinoma (OR, 1.27; 95% CI, 0.71-2.28) compared with nonusers. A high daily dose of ACE inhibitors decreased the risk of both adenocarcinoma and squamous-cell cancer of the esophagus and rendered a 45% decrease of total esophageal cancer (OR, 0.55; 95% CI, 0.33-0.93). Our data showed no clear association between the use of ACE inhibitors and risk of gastric cancer (OR, 1.07; 95% CI, 0.84-1.36). The use of ACE inhibitors may decrease the risk of developing esophageal cancer, particularly among users with a high daily dose. No association was found between gastric cancer and ACE inhibitors.

Proposal for mapping renal failure in Japan and its application for strategy to arrest endstage renal disease

Remarkable regional differences in the annual incidence of endstage renal disease (ESRD) was found within Japan, which has a relatively homogeneous ethnic composition. In addition, there existed no regional difference in the incidence of ESRD due to polycystic kidney disease, the major genetic disorder of the kidneys. These findings suggest that the presence of factors other than genetic disposition contribute to the differences. On the other hand, there were similar regional variations in the incidences of ESRD between two causes of ESRD: chronic glomerulonephritis and diabetic nephropathy. Because it is unlikely that the regional distribution of underlying disease incidence and the disease-specific progression rate would be similar for two different causes, this observation suggests that factors governing the progression rate, which operate commonly for all causes of ESRD but differ among regions, may play an important role in generating the regional differences. Finally, we examined regional differences in the amounts of inhibitors of the renin-angiotensin system used, especially angiotensin-converting enzyme (ACE) inhibitors, in our search for an explanation of the regional differences in ESRD dynamics. Among antihypertensive agents examined, only ACE inhibitors were negatively correlated with the annual incidence of ESRD. The renal protective effects of ACE inhibitors have been established by results with animal models of progressive nephropathy and by large-scale clinical trials. Our epidemiological results for Japan as a whole show the same protective effects still more convincingly from a different approach. It is not completely clear yet at present, however, how regional variations in the incidence of ESRD are generated. If we could identify in future the factors that contribute to the regional differences, strategies for the treatment of renal disease will become available from different angles. Thus, much effort will be encouraged for the further analysis of regional differences in ESRD dynamics.

Bone marrow transplant nephropathy successfully treated with angiotensin-converting enzyme inhibitor

We report a patient who developed chronic renal failure 11 months after an allogeneic hematopoietic stem-cell transplantation (HSCT) for Ph1(+) acute lymphocytic leukemia. Renal biopsy showed typical pathological findings compatible with a bone marrow transplant nephropathy (BMT nephropathy). The general course of BMT nephropathy is slowly progressive, eventually reaching endstage renal failure. Intervention therapy with an angiotensin-converting enzyme inhibitor (ACE-I), temocapril, was started for this patient, based on several experimental reports showing the protective effects of ACE-Is on BMT nephropathy. After the induction of ACE-I in this patient, the rate of regression of renal function was significantly reduced and his serum creatinine was maintained at almost the same level for 18 months. Although the course of observation in this patient was short, we clearly showed the effects of an ACE-I on preventing BMT nephropathy from progressing to endstage renal failure in a human rather than in an experimental model.

A Fiveyear Comparison of the Renal Protective Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients with NonDiabeticNephropathy

Evidence suggests that the effectiveness of angiotensin-converting enzyme (ACE) inhibition diminishes with time, resulting in increasing angiotensin II levels, the action of which can be inhibited by the addition of an angiotensin receptor blocker (ARB). In the present study, the renal protective effects of ACE inhibitors and ARBs were compared over a five-year period in a prospective, randomized, open-blind study in 68 nondiabetic Japanese patients with elevated serum creatinine levels. Japanese patients with renal insufficiency were randomly assigned to receive either an ACE inhibitor (benazepril 1.25 to 5 mg daily or trandolapril 0.5 to 4 mg daily) or ARB (candesartan 2 to 8 mg daily or losartan 25 to 100 mg daily) at the Kidney Disease Center at Saitama Medical School Hospital. The primary study endpoint was a change in glomerular filtration rate (GFR) between the baseline value and the last available value obtained during the five-year treatment period, as estimated by the Cockcraft-Gault equation. Secondary endpoints included the annual changes in GFR, serum creatinine level, urinary protein excretion, and blood pressure, as well as the rate of development of endstage renal disease. There were no significant differences in the primary endpoint between the two groups. However, after 4 years, the decline in GFR in patients treated with ARBs was significantly greater than that seen in patients treated with an ACE inhibitor (p<0.05). Furthermore, the rate of introduction of dialysis therapy was also significantly greater in the ARB-treated patients (52.7% in ACE inhibitor and 81.2% in ARB group at year 5. p<0.01). While our data suggested that ARB, like ACE, treatment might slow the progression of renal dysfunction, it also pointed to the necessity to be alerted to the progression to endstage renal disease with longterm medication.

Anti‐diabetic effect of blockade of the renin‐angiotensin system

Diabetes, which is frequently associated with hypertension, accelerates the development of hypertension-induced cardiovascular disease. Thus, the prevention of diabetes is important in the management of hypertension. Recent clinical megastudies have suggested that the blockade of the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) inhibits new onset of diabetes. Thus, the agents to inhibit the RAS should be beneficial for glucose metabolism. However, the cardiovascular protective effects of ACE inhibitors and ARBs are not always superior to other classes of drugs. Further long-term clinical trials are necessary to clarify the anti-diabetic effect of the RAS-inhibiting agents.

Angiotensinogen Met235Thr polymorphism, angiotensin-converting enzyme inhibitor therapy, and the risk of nonfatal stroke or myocardial infarction in hypertensive patients

Background The ThrThr genotype of the angiotensinogen (AGT) Met235Thr polymorphism has been associated with elevated AGT levels, hypertension, increased heart disease risk, and improved blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitors. We hypothesized that risk of stroke or myocardial infarction (MI) associated with ACE inhibitor use varies by AGT genotype, with a larger protective effect of ACE inhibitors in individuals with the ThrThr genotype than individuals who are carriers of the Met allele. Methods We conducted a population-based case-control study. Participants were health maintenance organization members aged 30 to 79 years with treated hypertension. Those who survived incident stroke (n = 116) or MI (n = 208) during the study period were designated as cases. Control subjects (n = 717) were randomly sampled and frequency-matched to MI cases on age, sex, and calendar year. Health history, medication use, and AGT genotype were assessed. Results ThrThr genotype was present in 21% of stroke cases, 26% of MI cases, and 19% of control subjects. Compared with nonuse, ACE inhibitor use was associated with lower stroke risk among Thr homozygotes (odds ratio [OR] = 0.37, 95% CI = 0.14 to 0.99) than among Met carriers (OR = 1.4, 95% CI = 0.88 to 2.4; P for interaction = .02). Compared with nonuse, ACE inhibitor use was associated with similar MI risk among Thr homozygotes (OR = 0.90, 95% CI = 0.62 to 1.3) and among Met carriers (OR = 1.2, 95% CI = 0.60 to 2.5; P for interaction = 0.5). Conclusions In this hypertensive population, the association of ACE inhibitor use with risk of nonfatal stroke varied by genotype. The protective association between ACE inhibitor use and nonfatal stroke risk among individuals with ThrThr genotype was not observed for nonfatal MI.

Connective tissue growth factor is up-regulated in the diabetic retina: amelioration by angiotensin-converting enzyme inhibition.

Connective tissue growth factor (CTGF) has been postulated to have prosclerotic and angiogenic properties. The aim of this present study was to characterize retinal CTGF expression in the absence and presence of diabetes and in the context of treatment with the angiotensin-converting enzyme (ACE) inhibitor, perindopril. Retinas were obtained from control, diabetic, and diabetic plus perindopril-treated (3 mg/d) rats. CTGF gene expression was quantitated by RT-PCR and localized by in situ hybridization. CTGF protein expression was analyzed by Western blotting and localized by immunohistochemistry. Diabetes was associated with a greater than 2-fold increase in CTGF mRNA levels, which was attenuated by perindopril treatment. CTGF immunoreactivity was increased almost 2-fold in diabetes and was ameliorated by the ACE inhibitor perindopril. By in situ hybridization and immunohistochemistry, the major site of CTGF gene expression in the retina of diabetic rats was the ganglion cell layer. Based on the known in vivo effects of CTGF, it is postulated that this growth factor plays a pivotal role in mediating diabetes-associated retinal pathology. Furthermore, the protective effects of ACE inhibitors on retinal pathology may partly be mediated via effects on retinal CTGF expression.

Maps of end-stage renal disease and amounts of angiotensin-converting enzyme inhibitors prescribed in Japan

We recently found regional differences in the incidence of end-stage renal disease (ESRD) in Japan, which is generally ethnically homogeneous, suggesting that factors other than genetic may contribute to the difference. Here, we examined regional differences in the amounts of expenses spent on antihypertensives, especially angiotensin-converting enzyme (ACE) inhibitors, in our search for an explanation. Annually, the Japanese Society for Dialysis Therapy reports the numbers of patients entering maintenance dialysis in each prefecture of Japan since 1982. We used the findings for 1995 to 2000 to calculate the annual incidence of ESRD in each of the 11 regions of Japan. In addition, regional differences in annual amounts paid for antihypertensive drugs, presumably corresponding to the amounts used, during the same 6 years, corrected for population, were estimated. As in our 1982 to 1998 study, the incidence of ESRD was high in Okinawa, Kyushu, and Shikoku, while low in Hokuriku, Koshinetsu, and Tohoku (P < 0.0001) [one-way repeated measures analysis of variance (ANOVA)]. We found regional differences in the corrected sum paid for total antihypertensive drugs, ACE inhibitors and calcium antagonists. Only ACE inhibitors were negatively correlated with the incidence of ESRD by linear and multiple regression analyses. The renal protective effects of ACE inhibitors have been established by results with animal models of progressive nephropathy and large-scale clinical trials. Our epidemiologic results for Japan as a whole show the same protective effects still more convincingly from a different approach.

The use of ACE inhibitors on diabetic patients without renal disease.

Strategies that interrupt the renin-angiotensin system, especially with angiotensin-converting enzyme (ACE) inhibition, reduce cardiovascular disease mortality and morbidity in high-risk persons such as those with the insulin resistance syndrome and diabetes mellitus. In the 1980s emphasis was placed on the renal protective effects of ACE inhibitors in patients with diabetes and proteinuria. During the past several years controlled clinical trials have demonstrated that ACE inhibition reduces cardiovascular disease (CVD) mortality and morbidity. This is especially important in patients in the United States, where 80% of excess mortality for diabetes mellitus is attributed to CVD. This article reviews the clinical trials in high-risk patients, especially those with diabetes, that shown beneficial CVD risk reduction with ACE inhibitors.

Angiotensin-converting enzyme inhibitors and the risk of cancer: a population-based cohort study in Denmark.

A recent observational study suggested that the use of angiotensin-converting enzyme (ACE) inhibitors protects against cancer in general and against breast and female reproductive tract cancers in particular. To explore these hypotheses, the authors examined cancer risk among users of ACE inhibitors in North Jutland County, Denmark. Using data from the population-based Prescription Database of North Jutland County and the Danish Cancer Registry, cancer incidence among 17,897 individuals prescribed ACE inhibitors was compared with expected incidence based on county specific cancer rates during an 8-year study period with a mean follow-up of 3.7 years. Standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (95% CIs) were calculated for cancers overall and at selected sites. In addition, the authors performed a direct comparison of users of ACE inhibitors with users of beta-blockers or calcium channel blockers (n = 47,579 individuals) by means of a Cox proportional hazards model. Overall, 909 cancer cases were observed among users of ACE inhibitors, with 846 expected based on general population rates, yielding an SIR of 1.07 (95% CI, 1.01-1.15). No risk reductions were observed for cancers of the breast and female reproductive tract, whereas nonsignificantly decreased SIRs were observed for cancers of the esophagus, stomach, and liver. Cancer of the kidney was found in significant excess (SIR, 1.6; 95% CI, 1.1-2.2). Stratification by duration of follow-up or number of prescriptions revealed no apparent trends, except for a tendency toward decreasing risk with increasing length of follow-up for smoking-related cancers. The direct comparison of users of ACE inhibitors with users of beta-blockers or calcium channel blockers yielded results comparable to those derived from the comparison with the general population, with a hazard ratio for cancer overall of 1.01 (95% CI, 0.93-1.09). This large, population-based cohort study did not confirm a protective effect of ACE inhibitors on the development of cancer. The excess of kidney cancer observed likely reflects a correlation between hypertension and kidney cancer. Further investigation is needed to evaluate the long-term effects of ACE inhibitors beyond the observation period of this and previous studies. Also, the suggestive evidence of decreased risks for upper digestive system cancers and for smoking-related cancers over time may warrant additional investigation.