ABSTRACT. Hypertension, impaired renal function, and proteinuriaare commonly associated to the presence of diabetes. They playa major role in the development of cardiovascular and renaldamage. Effective antihypertensive treatment reduces the progressionof diabetic nephropathy and improves cardiovascular prognosis.Accordingly, tight BP control (<130/80 mmHg) is currentlyrecommended in diabetic patients. Achieving BP targets representsthe most important determinant of cardiovascular and renal protection.However, it has been suggested that specific classes of antihypertensivedrugs may exert additional organ protection beyond their BPcontrol. The pharmacologic blockade of the renin-angiotensin-aldosteronesystem has been shown to convey greater renal and cardiovascularprotection compared with other classes of drugs. In particular,studies focusing on renal end point suggest that angiotensin-convertingenzyme inhibitors (ACEI) are the first-choice drugs in type1 diabetes. Both ACEI and angiotensin II receptor blockers preventthe progression from microalbuminuria to clinical proteinuriain type 2 diabetes, but angiotensin blockers provide betterrenoprotection in patients with overt nephropathy. Regardingcardiovascular protection, several studies (but not all) haveshown that ACEI exert a protective effect on diabetic patients.Recently, interesting results in favor of angiotensin receptorblockers have been reported in the IDNT, RENAAL, and LIFE studies.It should be noted that to achieve maximal renal and cardiovascularprotection, most diabetic patients require integrated therapeuticintervention, including not only several antihypertensive drugs,but statins and antiplatelet therapy as well.
Diabetes, hypertension, impaired renal function, and proteinuriaare commonly associated conditions that act as a guilty company.They are, in fact, responsible for an increase in the risk ofdevelopment and/or progression of cardiovascular disease, nephropathy,and retinopathy.
Arterial BP plays a very important role in the development ofrenal damage and presents a complex relationship with diabeticnephropathy, with nephropathy raising BP, and with BP acceleratingthe course of nephropathy (1). Furthermore, as shown by epidemiologicstudies, hypertension is responsible for increased cardiovascularmorbidity and mortality associated with diabetes mellitus (1).Effective antihypertensive treatment reduces the risk of developmentand progression of nephropathy and, as is especially evidentwith angiotensin-converting enzyme (ACE) inhibitors (ACEI) andangiotensin receptor blockers (ARB), it lowers cardiovascularmorbidity and mortality (2,3). Accordingly, current consensusgroups have recommended tight BP control (<130/80 mmHg) indiabetic patients (2,4–7).
Proteinuria is considered a predictor of renal disease progression.Proteinuria acts on tubular cells by inducing inflammation andconsequently interstitial fibrosis. In addition, proteinuriafavors dyslipidemia, which aggravates renal damage and increasescardiovascular risk. A direct correlation exists between thedegree of proteinuria and the progression rate to end-stagerenal disease (ESRD) in diabetic nephropathy as well as in otherglomerular diseases. Lastly, proteinuria also predicts cardiovascularmorbidity and mortality in both diabetic and nondiabetic patients(8).
Overactivity of the renin-angiotensin system (RAS) has beendescribed in diabetic nephropathy (9). Angiotensin II (AngII)acts in synergy with hyperglycemia, contributing to glomerularhypertension and co-stimulating the synthesis of extracellularmatrix proteins by means of transforming growth factor–(TGF-) induction, which consequently causes renal hypertrophy.A rationale for the RAS blockade therefore exists. ACEI andARB improve glomerular hypertension and partially prevent renalhypertrophy in diabetes. ACEI suppress the RAS but do not blockthe production of non–ACE-mediated AngII. On the otherhand, ARB provide a more complete blockade of AngII effectsby selectively binding to the AT1 receptors and offering bettertolerance. Furthermore, by stimulating AT2 receptors, the ARBmay help prevent hypertrophic effects and could provide organprotection.
Retinopathy is a common and potentially devastating complicationin diabetic patients. Yet ophthalmologic evaluation has shownthat about 30% of type 2 diabetic patients who have biopsy-provendiabetic nephropathy do not have diabetic retinopathy (10).In these patients, the presence of retinopathy is associatedwith an increased risk of progressive renal disease as wellas of cardiovascular events and death. Therefore, retinopathyalso represents a predictor of renal and cardiovascular outcomesin diabetic patients (11).
Hypertension is an important determinant of the progressionof diabetic renal disease from microalbuminuria to overt nephropathy(12). Several studies performed on normotensive, microalbuminuricpatients with either type 1 or type 2 diabetes have shown thatACEI are very effective in reducing the incidence of overt proteinuria(secondary prevention) regardless of the BP levels (approximaterisk reduction ratio [aRRR], 70% to 100%) (13–16). TheMicroHOPE Study (17), which was performed on a large population,as well as two other smaller studies (18,19) confirm the efficacyof ACEI compared with other types of treatment in hypertensive,microalbuminuric, type 2 diabetic patients, in secondary prevention(aRRR, 23 to 68%). However, the same effect was not observedin two other studies (20,21). ACEI, therefore, seem to be moreeffective on microalbuminuric, normotensive patients than onhypertensive ones. The IRMA study, a multicentric, randomized,double-blind, placebo-controlled trial that evaluated the effectof irbesartan in secondary prevention, conferred an importantrenoprotective role to ARB in type 2 hypertensive diabetic patients(22). In this trial, 590 patients were followed up for 2 yrafter being randomized to receive 150 mg of irbesartan, or 300mg of irbesartan, or placebo, together with additional antihypertensiveagents (excluding ACEI, ARB, and dihydropyridine calcium channelblockers [CCB]), to achieve the goal BP of less than 135/85mmHg. The primary end point of the study was the onset of overtnephropathy. The mean achieved BP was 143/83 in the 150-mg group,141/83 in the 300-mg group, and 144/83 in the placebo group.With respect to the primary end point, treatment with 150 mgof irbesartan or 300 mg of irbesartan appeared to be much moreeffective than conventional therapy (CT) (aRRR, 44% and 68%versus CT). Furthermore patients treated with the higher doseof irbesartan more frequently regressed to normoalbuminuria(17/100 in the 300-mg group, 12/100 in the 150-mg group, and10.5/100 patients per year in the control group).
Hypertension is the main factor leading to the decline in renalfunction and the consequent progression to end-stage renal disease(ESRD) in patients with overt nephropathy. Our meta-analysisof nine longitudinal studies that used various antihypertensivedrugs in proteinuric patients with type 1 diabetes shows thatachieved BP values play an overwhelming role in determiningthe decline in GFR. The curve shows that there is a fourfoldreduction in the decline of GFR when the mean arterial pressurevalues are below 100 mmHg. Various types of treatment providedsimilar efficacy in slowing the progression of nephropathy,regardless of the drug that was used (23). The results of theIrbesartan Diabetic Nephropathy Trial (IDNT) were analyzed todetermine the optimal level of achieved BP that is requiredto slow the nephropathy progression rate in type 2 diabetes.It was found that the level of systolic BP is strongly correlatedto the risk of progressing to a renal event. After adjustingfor systolic BP, diastolic BP did not appear to be a predictorof renal outcome in this analysis (24). Both analyses show thattight BP control is therefore an essential part of managingpatients with overt nephropathy to prevent renal complications.
The renoprotective role of ACEI, beyond what can be attributedto BP reduction, has been shown in only 2 of 5 studies thatcompared these drugs to either CT or to CCB (25–29) intype 1 diabetic patients with overt nephropathy. In type 2 diabeticpatients who also have overt nephropathy, 4 of 5 small trialsthat evaluated the effects of various classes of drugs failedto demonstrate that ACEI play any specific renoprotective role(20,30–33).
Recently, two large randomized, blinded clinical trials showedthat ARB are very effective in protecting against the progressionof nephropathy caused by type 2 diabetes (34,35). The designof these two trials was similar, although the baseline characteristicsof the study populations were somewhat different (baseline BPvalues, degree of proteinuria, and prevalence of white, Europeansubjects were all slightly higher in the IDNT study than inthe RENAAL study). In the IDNT trial, the 1715 patients whowere randomized to irbesartan, amlodipine, or placebo, togetherwith CT (excluding ACEI, ARB, or CCB) were followed up for approximately2.6 yr. The achieved BP in the irbesartan group was similarto what was observed in the amlodipine group, but it was slightlyhigher in the CT group (140/77, 141/77, and 144/80 mmHg, respectively).The risk of primary composite end point (doubling of serum creatinine,ESRD, or death) in subjects treated with irbesartan was significantlylower compared with subjects who received placebo (aRRR, 19%)and those who received amlodipine (aRRR, 24%). The risk of doublingserum creatinine was lower in the irbesartan group than in boththe placebo group (aRRR, 29%) and the amlodipine group (aRRR,39%) (34). In the RENAAL study, 1513 patients were followed-upfor approximately 3.4 yr after being randomized to either losartanor placebo, along with non-ACEI or non-ARB therapy. The BP valuesachieved at the end of the study were 140/74 and 142/74 mmHgin the losartan and in the CT groups, respectively. Treatmentwith losartan resulted in a reduction (aRRR, 15%) in the riskof the primary composite end point (doubling of serum creatinine,ESRD, or death). Lastly, the risk of doubling serum creatininein the losartan group was 25% lower than in the placebo group(35). In both studies, the benefits of ARB clearly exceededwhat might be attributable to changes in BP alone. Finally,by analyzing the IDNT study results to examine the factors associatedwith progressive renal disease in type 2 diabetes, we can seethat proteinuria predicts poor renal outcome in these patientsand that treatment with irbesartan is associated with a greaterreduction in proteinuria than treatment with amlodipine or placebo(36). Thus, ARB are currently considered the treatment of choicein hypertensive, type 2 diabetic patients for the tertiary preventionof ESRD.
Some interest in the use of other antihypertensive therapeuticstrategies to prevent poor renal outcome in diabetic patientshas now emerged. Short studies, aimed at assessing the efficacyof the combined treatment of ACEI plus ARB in patients withdiabetic or nondiabetic renal disease, have shown promisingresults regarding both the anti-proteinuric effects and theantihypertensive efficacy of these combinations (37,38). Ina recent trial that was followed-up for 2.9 yr, 263 nondiabeticpatients were randomly assigned to receive 100 mg/d losartan,3 mg/d trandolapril, or a combination of both drugs at equivalentdose. The risk of primary composite end point (doubling of serumcreatinine or ESRD) was significantly lower in the combinationtherapy group than in the monotherapy groups (RR = 0.52) (39).At present further studies on diabetic patients are needed.
A recent study reported that aldosterone escape is observedin 40% of the type 2 diabetes patients with early nephropathy,despite the use of ACEI (40). In this trial, administering spironolactone(25 mg-d) together with an ACEI (trandolapril, 1.5 mg/d) topatients with aldosterone escape led to a significant decreasein urinary albumin excretion and left ventricular mass index,with no changes in either BP or serum potassium levels at theend of a 24-wk study period. This study suggests that the aldosteroneblockade may represent the optimal therapy for diabetic patientswith microalbuminuria or overt proteinuria who show aldosteroneescape during ACEI treatment and who no longer benefit fromthe maximal antiproteinuric effects of ACE inhibition
Retinal Protection
The UKPDS (41) and the normotensive-Appropriate Blood PressureControl in Diabetes (ABCD) trial (42) showed that a reductionin BP (144/82 versus 154/87 in the former study, and 128/75versus 137/81 in the latter) in patients with type 2 diabetesresults in a risk reduction for the progression of diabeticretinopathy (UKPDS, RR = 34%; normotensive-ABCD, RR = 26%).However, the same result was not found in the hypertensive-ABCDtrial (20).
Cardiovascular Protection
The presence of arterial hypertension increases the risk ofcardiovascular disease associated with diabetes mellitus byat least two times compared with subjects with either diabetesor hypertension alone (1).
Evidence from two placebo-controlled trials, i.e. the SystolicHypertension in the Elderly Program and the Systolic Hypertensionin Europe Trial (43,44) showed that active treatment of arterialhypertension prevented major clinical complications in patientswith type 2 diabetes. Indeed, a 9 and 10 mmHg decrease in meansystolic BP was associated with a 34% and 62% reduction, respectively,in the relative risk of cardiovascular events.
Furthermore, randomized clinical trials have demonstrated thatintensive BP control is more effective in reducing cardiovascularcomplications compared with moderate BP control (20,41,45,46).Data from the UKPDS showed that a 10 mmHg decrease in systolicBP was associated with a 29% reduction in relative risk of cardiovascularevents. Moreover, considering that no threshold for arterialpressure was identified in this study, we may conclude thatwith regards to this subset of patients, the lower the systolicBP, the lower the risk of complications. In the HOT study, significantreductions in major cardiovascular events were observed despiterelatively small differences in the achieved BP (RRR in cardiovascularevents of 24% and 51% for differences in systolic BP of 3 and4 mmHg, respectively). The ABCD trial, which included cardiovascularevents only as a secondary end point, demonstrated that theintensive BP control in hypertensive patients was associatedwith a significantly lower incidence of cardiovascular complicationscompared with moderate BP control, whereas no differences wereobserved in the normotensive group (20,42,46). Thus, currentguidelines for treating hypertensive patients with diabetesrecommend a target BP below 130/85, or even below 130/80 mmHg(2,4–7).
The additional cardiovascular protection conferred by ACEI,beyond their BP effect, is currently controversial (Table 1).Some recent trials, indeed, have shown that ACEI-based antihypertensiveregimens are more effective in reducing the risk of cardiovascularcomplications in hypertensive type 2 diabetic patients thanCT (17,47,48) or CCB (20,46,49). By contrast, other comparativetrials have failed to show any clear-cut superiority of ACEIin reducing cardiovascular morbidity and mortality in hypertensiveor normotensive diabetics over CT (50,51) or CCB (42,51). Lastly,the recent ALLHAT trial did not demonstrate any differencesin cardiovascular outcomes in a large cohort of type 2 diabeticpatients randomized to a diuretic, a CCB, or an ACEI (52).
Table 1. The effect of various drugs on cardiovascular events in diabetes
As far as the use of CCB is concerned, some trials have demonstratedthat the effects of this class of drugs are similar to thoseobserved with CT (51,53,54). Since it was believed that CCBare responsible for a greater percentage of cardiovascular events,these findings could allow us to rule out this hypothesis withregards to hypertensive patients with type 2 diabetes. Recentstudies demonstrated a significant reduction in cardiovascularmorbidity and mortality when losartan, an angiotensin II receptorantagonist, was compared with CT in a large cohort of diabeticpatients with hypertension and left ventricular hypertrophy,with an average follow-up of 5 yr (4). Moreover, results fromthe IDNT and RENAAL trials showed that treatment with both irbesartanand losartan resulted in a significant reduction in hospitalizationfor heart failure compared with the placebo-treated group intype 2 diabetic patients with overt nephropathy. By contrast,no significant differences were detected in either study betweenthe ARB-treated group and the controls with regard to the aggregateend point of death from cardiovascular causes, nonfatal myocardialinfarction, stroke, or heart failure resulting in hospitalization.This possibly reflects the higher risk for diabetic patientswith clinical proteinuria (34,35).
Lastly, an integrated therapeutic intervention, not only withantihypertensive medication, but also with statins, antiplatelettherapy, and optimal glycemic control, has been shown to reducemacrovascular complications in diabetic subjects (55).
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Abstract
Introduction
(TGF-
