Volume 3, Number 4, December 2002

POPULAR
TOPICPAPERThe DIabetic Retinopathy Candesartan Trials (DIRECT) Programme, rationale and study design
The DIRECT Programme Study Group

The DIabetic Retinopathy Candesartan Trials (DIRECT) Programme consists of three randomised, double-masked, parallel, placebo-controlled studies to determine the impact of treatment with candesartan on diabetic retinopathy. In Type 1 diabetes, 1,700 patients without retinopathy will be randomised into a primary prevention study, and 1,200 with non-proliferative retinopathy into a secondary prevention study. In Type 2 diabetes, 1,600 patients with non-proliferative retinopathy will be randomised. Patients will be followed for at least three years. Eligible patients must be normotensive (systolic blood pressure [SBP] < 130 mmHg and diastolic blood pressure [DBP] < 85 mmHg) without antihypertensive medication in Type 1 diabetes, and either normotensive or treated hypertensive (SBP < 160 mmHg and SBP < 90 mmHg) and not taking angiotensin-converting enzyme inhibitors or AT₁-receptor blockers in Type 2 diabetes. All patients will be normoalbuminuric, based on two overnight urine collections. The primary endpoint is based upon retinal photographs, graded to the Early Treatment of Diabetic Retinopathy Study scale. A two-step increase on this scale defines incidence, and a three-step increase defines progression of retinopathy. The main secondary endpoint for each study is change in urinary albumin excretion rate. A positive outcome of the DIRECT Programme would be an important step forward in the clinical management of patients with diabetes.

JRAAS 2002;3:255-261.

PAPERACE-I and ARBs in early diabetic nephropathy
Michael Mauer, Bernard Zinman, Robert Gardiner, Keith N Drummond, Samy Suissa, Sandra M Donnelly, Trudy D Strand, Michael S Kramer, Ronald Klein, Alan R Sinaiko

Introduction: Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy, and especially, renin-angiotensin system (RAS) inhibition, slows, but may not fully arrest progression towards end-stage renal disease. Studies using ‘hard’ endpoints such as doubling of serum creatinine, dialysis, or death that are initiated before emergence of any renal functional abnormalities in diabetes, would be of impractical length and size. We therefore undertook a primary prevention study (The Renin-Angiotensin System Study or RASS) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint, increase in mesangial fractional volume (Vv[Mes/glom]).
Methods: This is a parallel group, double-blind, placebo-controlled trial with 285 patients with Type 1 diabetes mellitus (95 per group) randomised to receive the angiotensin-converting enzyme inhibitor, enalapril, the angiotensin II receptor blocker, losartan, or placebo. All patients are normotensive, normoalbuminuric and have normal or increased glomerular filtration rates at study entry. The study is based on primary endpoint of change in Vv(Mes/glom) from baseline to the five-year renal biopsy, with baseline and interval measures of albumin excretion rate, glomerular filtration rate, blood pressure, and glycaemia. Baseline, mid-point, and five-year retinal fundus photography are also performed.
Results: One thousand and sixty-five patients were interviewed, 707 refused participation and 73 were excluded. The target of 285 subjects were randomised and their clinical and demographic characteristics are described. Biopsy complications occurred in 17 (6%), only one of which required hospitalisation. There were no permanent biopsy-related sequelae.
Conclusions: Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy. Although requiring substantial recruitment effort, diabetic nephropathy primary prevention trials based on change in renal structure are feasible.

JRAAS 2002;3:262-269.

PAPEREffects of the vasopeptidase inhibitor, omapatrilat, in 723 patients with coronary heart disease
Pacific study group

Introduction: Among individuals with a history of myocardial infarction (MI), higher levels of blood pressure (BP) are associated with increased long-term risks of death from coronary heart disease. Treatment with a BP-lowering regimen, based on omapatrilat may result in greater clinical benefits than treatment with a regimen based on a regular angiotensin-converting enzyme (ACE) inhibitor because of more favourable effects on the renin-angiotensin-aldosterone system.
Methods: Seven hundred and twenty-three clinically stable patients with a history of MI or unstable angina, and a mean entry BP of 134/77 mmHg, were randomised to six months treatment with omapatrilat 40 mg, omapatrilat 20 mg, or matching placebo.
Results: After six months, mean BP levels (systolic/diastolic) in the omapatrilat 40 mg group were reduced by 4.3/2.9 mmHg (95% confidence interval 1.3 to 7.2/1.2 to 4.6). Mean BP levels in the omapatrilat 20 mg group were reduced by 4.6/1.0 mmHg (1.6 to 7.6/–0.7 to 2.6) in comparison with the placebo group. Both doses of omapatrilat also produced significant decreases in plasma ACE activity and significant increases in levels of plasma renin activity, atrial natriuretic peptide, endothelin and homocysteine (p<0.05 for all). Premature discontinuations were more frequent with omapatrilat than with placebo (p<0.001 for 20 mg and 40 mg).
Conclusions: Omapatrilat produced changes in BP, neurohormone and biochemical parameters that were similar for the two doses. The long-term clinical implications of the observed effects are uncertain and a large-scale randomised trial would be required to reliably establish the effects of omapatrilat on the risks of major vascular disease events among patients with coronary heart disease.

JRAAS 2002;3:270-276.

POPULAR
TOPICEDITORIAL REVIEWCellular targets for angiotensin II fragments: pharmacological and molecular evidence
Georges Vauquelin, Yvette Michotte, Ilse Smolders, Sophie Sarre, Guy Ebinger, Alain Dupont, Patrick Vanderheyden

Although angiotensin II has long been considered to represent the end product of the renin-angiotensin system (RAS), there is accumulating evidence that it encompasses additional effector peptides with diverse functions. In this respect, angiotensin IV (Ang IV) formed by deletion of the two N terminal amino acids, has sparked great interest because of its wide range of physiological effects. Among those, its facilitatory role in memory acquisition and retrieval is of special therapeutic relevance. High affinity binding sites for this peptide have been denoted as ‘AT₄- receptors’ and, very recently, they have been proposed to correspond to the membrane-associated OTase/ IRAP aminopeptidase. This offers new opportunities for examining physiological roles of Ang IV in the fields of cognition, cardiovascular and renal metabolism and pathophysiological conditions like diabetes and hypertension. Still new recognition sites may be unveiled for this and other angiotensin fragments. Recognition sites for Ang-(1-7) (deletion of the C terminal amino acid) are still elusive and some of the actions of angiotensin III (deletion of the N terminal amino acid) in the CNS are hard to explain on the basis of their interaction with AT₁-receptors only. A more thorough cross-talk between in vitro investigations on native and transfected cell lines and in vivo investigations on healthy, diseased and transgenic animals may prove to be essential to further unravel the molecular basis of the physiological actions of these small endogenous angiotensin fragments.

JRAAS 2002;3:195-204.

EDITORIAL REVIEWBetween-patient differences in the renal response to renin-angiotensin system intervention: clue to optimising renoprotective therapy?
Gozewijn D Laverman, Dick de Zeeuw, Gerjan Navis

Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT₁-receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide, prompting the search for improved renoprotective strategies.
In spite of proven efficacy at group level, the long-term renoprotective effect of RAAS blockade displays a marked between-patient heterogeneity, which is closely linked to between-patient differences in the intermediate parameters of blood pressure, proteinuria and renal haemodynamics. Of note, the between-patient differences by far exceed the between-regimen differences, and thus may provide a novel target for exploration and intervention.
The responsiveness to RAAS blockade appears to be an individual characteristic – as demonstrated by studies applying a rotation-schedule design. The type and severity of renal disease, obesity, insulin-resistance, glycaemic control, and genetic factors may all be involved in individual differences in responsiveness, as well as dietary factors, such as dietary sodium and protein intake.
Several strategies, such as dietary sodium restriction and diuretic therapy, dose-titration for proteinuria, and dual RAAS blockade with ACE-I and ARB, can improve the response to therapy at a group level. However, when analysed for their effect in individuals, it appears that these measures do not allow poor responders to catch up with the good responders, i.e. in spite of their efficacy at group level, the available measures are usually not sufficient to overcome individual resistance to RAAS blockade.
We conclude that between-patient differences in responsiveness to renoprotective intervention should get specific attention as a target for intervention. Unravelling of the underlying mechanisms may allow development of specific intervention. Based on the currently available data, we propose that response-based treatment schedules, with a multidrug approach titrated and adapted at individual responses rather than fixed treatment schedules, may provide a fruitful strategy for more effective renoprotection.

JRAAS 2002;3:205-213.

EDITORIAL REVIEWLocal renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production
Scott M MacKenzie, Robert Fraser, John MC Connell, Eleanor Davies

Adrenal aldosterone production is regulated by the renin-angiotensin system (RAS). It is now known that several other tissues are capable of extra-adrenal aldosterone biosynthesis and that these tissues can also generate angiotensin II through local RAS. Therefore, the regulation of local aldosterone production by the local RAS is a distinct possibility. In this review, we present evidence for the existence of such systems in the vascular system, heart and brain. We then discuss the possibility of interactions between the RAS and aldosterone synthesis at the local level and speculate on the possible physiological effects of such systems in these tissues.

JRAAS 2002;3:214-221.

EDITORIAL REVIEWBlood pressure and cardiac autonomic function in relation to risk factors and treatment perspectives in Type 1 diabetes
Per Løgstrup Poulsen

The cumulative incidence of diabetic nephropathy in Type 1 diabetes mellitus is in the order of 25–30%. The recognition that elevated blood pressure (BP) is a major factor in the progression of these patients to end-stage renal failure has led to the widespread use of antihypertensive therapy in order to preserve glomerular filtration rate and ultimately to reduce mortality.
The routine measurement of microalbuminuria allows early identification of the subgroup of patients at increased risk of developing clinical nephropathy.
Microalbuminuric Type 1 diabetic patients show a number of characteristic pathological abnormalities. In addition to elevated BP and abnormal circadian rhythm, there are also associated abnormalities of vagal function, lipid profile and endothelial function, as well as an increased prevalence of retinopathy.
The first section of this two-part review focusses on the early changes associated with renal involvement in Type 1 diabetes. It addresses the associations between urinary albumin excretion, glycaemic control, smoking, BP, circadian BP variation, QT interval abnormalities and autonomic function in three groups of patients; those with normoalbuminuria, those progressing towards microalbuminuria and those with established low-grade microalbuminuria.

JRAAS 2002;3:222-242.

POPULAR
TOPICEDITORIAL REVIEWThe renin-angiotensin-aldosterone system and the eye in diabetes
W David Strain, Nish Chaturvedi

Diabetic retinopathy is the leading cause of blindness in the under 65s, and with the burden of disease case load expected to exceed 200 million worldwide within 10 years, much effort is being spent on prophylactic interventions. Early work focused on improving glycaemic control; however, with the publication of EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) and United Kingdom Prospective Diabetes Study (UKPDS), the focus has recently moved to control of blood pressure and specifically the renin-angiotensin system (RAS). There is a large body of evidence for a local RAS within the eye that is activated in diabetes. This appears to be directly responsible, as well as indirectly through other mediators, for an increase in concentration of vascular endothelial growth factor (VEGF), a selective angiogenic and vasopermeability factor that is implicated in the pathogenesis of diabetic retinopathy. Inhibition of angiotensin-converting enzyme appears to reduce concentrations of VEGF, with a concurrent anti-proliferative effect independent of systemic VEGF levels or blood pressure. Angiotensin II (Ang II) Type 1 (AT₁) receptor blockade has been shown to reduce neovascularisation independent of VEGF levels in animal models. This may be due to antagonism of activation of mitogen-activated protein kinase, which is a potent cellular proliferation stimulator, by Ang II, although this needs further evaluation.

JRAAS 2002;3:243-246.

POPULAR
TOPICEDITORIAL REVIEWThe pharmacokinetics and pharmacodynamics of angiotensin-receptor blockers in end-stage renal disease
Domenic A Sica, Todd WB Gehr

Angiotensin-converting enzyme (ACE) inhibitors and more recently angiotensin-receptor blockers (ARBs) have become popular therapies in the end-stage renal disease (ESRD) patient. The ability of either of these drug classes to reduce blood pressure in the ESRD patient is well accepted; however, there is considerably less information available to guide the clinician in the safe and effective use of these drugs in the ESRD patient with congestive heart failure and/or coronary artery disease. Head-to-head studies in the ESRD patient are lacking for both drug classes. Several pharmacokinetic factors can influence the selection of these drugs, including dialysability and the propensity for systemic accumulation. ACE inhibitors (ACE-Is) and ARBs are recognised as having a range of nonpressor effects that are pertinent to patients with ESRD. Such effects include their ability to decrease both thirst drive and erythropoiesis. These drug classes, though, are distinguishable by the unique adverse effect profile for ACE-Is. As is the case in patients without renal failure, ESRD patients can experience cough and, less frequently, angioneurotic oedema with ACE-Is. In the ESRD population, so-called anaphylactoid dialyser reactions can occur in conjunction with ACE-I use. The use of a drug from within the ARB class carries both less risk and permits a compound with a preferred pharmacokinetic profile – limited dialysability and minimal systemic accumulation – to be administered. These attributes would favour the increased use of ARBs in this population.

JRAAS 2002;3:247-254.