diabetes and hypertension: blood pressure control and consequences

Diabetes and Hypertension: Blood PressureControl and ConsequencesMatthew R. Weir

Diabetes and hypertension are the leading causesof end-stage renal disease in the Western world.Inadequate control of both systemic andglomerular capillary pressure in diabetics results inincreasing hydraulic force and mechanical stretchon the glomeruli, with a subsequent increase inproteinuria and ultimately glomerulosclerosis.Therapeutic strategies that combine systemic andglomerular capillary pressure reduction result inreduced proteinuria and are ideal for preventingrenal injury. Both experimental and clinical studieshave demonstrated the importance of intensivecontrol of blood pressure, preferably to systolicblood pressure (SBP) < 130 mm Hg to delay

progression of renal disease. In particular, drugsthat block the renin-angiotensin system (RAS)offer the advantage of consistently reducingglomerular capillary pressure and proteinuriarelative to changes in systemic blood pressure.This combination of events is ideal for delayingprogression of renal disease. However, the use ofdrugs that block the RAS is not a surrogate formaintaining tight control of blood pressure. Am JHypertens 1999;12:170S–178S © 1999 AmericanJournal of Hypertension, Ltd.

KEY WORDS: Diabetes, hypertension, angiotensin II,RAS, renal disease.

Hypertension and diabetes are the mostcommon causes of end-stage renal dis-ease in the United States.1,2 Moreover,they contribute even more substantially

in the development of cardiovascular disease (CVD).In 1997, more than 35% of patients entering dialysishad been diagnosed with diabetes and hypertension.2

The prognosis for patients with diabetic renal diseasehas improved considerably due to more aggressivetherapy to reduce blood pressure and proteinuria.3,4

Diabetic patients without proteinuria tend to havelower systemic blood pressure than proteinuric pa-tients. Clinical studies have demonstrated that theonset of microalbuminuria often coincides with a clin-ically apparent increase in blood pressure.5–7 In fact,

systemic blood pressure correlates more with changesin urinary microalbumin excretion than with many ofthe variables in diabetic patients including glycemiccontrol, age, duration of diabetes, gender, and bodymass index.8 Blood pressure tends to increase moreconsistently in patients with microalbuminuria than indiabetic patients without it. Even modest increases inblood pressure within the so-called “normal” range(110/70 to 130/80 mm Hg) can be indicative of pro-gressive nephropathy.9 Therefore, it makes sense tointervene as soon as possible to prevent blood pres-sure elevation to greater than 110–120/70–80 mm Hgto prevent increased risk of renal disease.

The benefits of reducing blood pressure on renalfunction in diabetic patients were first demonstratedin the late 1970s by Mogensen, who discovered thattighter control of blood pressure to a level belownormotensive (,130/80 mm Hg) reduced renaldisease progression rates.10 This was subsequentlyconfirmed by long-term studies by Parving et al.11

Parving et al employed standard antihypertensive

From the Division of Nephrology, Department of Medicine, Uni-versity of Maryland School of Medicine, Baltimore, Maryland.

Address correspondence to Dr. M.R. Weir, Division of Nephrol-ogy, Department of Medicine, University of Maryland School ofMedicine, 22 S. Greene St., Baltimore, Maryland 21201.

AJH 1999;12:170S–178S

© 1999 by the American Journal of Hypertension, Ltd. 0895-7061/99/$20.00Published by Elsevier Science, Inc. PII S0895-7061(99)00219-8

therapies (diuretics, b-blockers, and vasodilators) todemonstrate that reducing blood pressure to 129/84mm Hg was associated with a reduction in albumin-uria and a 50% decrease in the rate of renal diseaseprogression.11

In this review, I will discuss the implications ofrenal autoregulation and intensive blood pressurecontrol, and how these factors have an impact on ourdecisions about blood pressure treatment and choiceof therapy. The mechanistic effects of renin-angioten-sin system (RAS) blockade and its benefits on bloodpressure and renal function will be discussed in lightof both experimental and clinical trials. A review ofthe antagonistic effects of dietary salt on the effects ofdrugs that block the RAS will be reviewed, with em-phasis on clinical relevance. Mechanistic differencesbetween angiotensin-converting enzyme (ACE) inhib-itors and angiotensin type-1 receptor blockers (ARB)will also be reviewed, with a discussion on the impactthey have on blood pressure, proteinuria, and therate of progression of renal disease. An argument willbe made for tighter control of blood pressure, prefer-ably to systolic blood pressure (SBP) , 130 mm Hg.This lower blood pressure should be the goal regard-less of whether or not drugs that block the RAS areused. Drugs that block the RAS, such as ACE inhibi-tors or ARB, are beneficial for renal function andshould be routinely employed to control blood pres-sure and proteinuria in diabetic hypertensives. How-ever, they should not be used in lieu of proper bloodpressure control.

RENAL AUTOREGULATION: HOW LOWSHOULD YOU REDUCE SYSTEMIC BLOOD

PRESSURE?

Glomerular capillary pressure is carefully regulateddue to the unique vascular anatomy of the glomeru-lus. The glomerulus is arranged in series between tworesistance vessels—the afferent and efferent arterioles.These arterioles respond to a variety of stimuli, allow-ing the independent regulation of glomerular capil-lary pressure. In general, an increase or decrease insystemic blood pressure causes directionally similarchanges in glomerular capillary pressure. An increasein afferent vessel tone is associated with a reduction inglomerular capillary pressure. Conversely, glomerularcapillary pressure may increase in response to eleva-tion in efferent vessel tone. Healthy vessels will re-spond almost instantly to changes in systemic bloodpressure so that glomerular capillary pressure remainsrelatively constant over a wide range of perfusionpressures.12 The ability of the glomerulus to regulatepressure may be impaired by renal disease or by dif-ferent medications. As systemic blood pressure rises,the kidney increases afferent glomerular arteriolartone so as to limit too much pressure from entering the

glomerulus. However, at SBP $ 150 mm Hg, this pro-tective mechanism may be limited and the resultantglomerular capillary hypertension may cause injury.13

In patients with diabetic renal disease, disease of theafferent arteriole may further impair its ability to limitsystemic blood pressure from entering the glomeru-lus. In addition, increased efferent glomerular arterio-lar tone is often present in diabetics, possibly due tothe excessive vascular responsiveness to angiotensinII. This combination of events results in elevated glo-merular capillary pressure.14 Consequently, a thera-peutic strategy that reduces systemic blood pressure(Figure 1)15 and efferent glomerular arteriolar tone isideal for limiting glomerular injury in diabetics.16

Angiotensin II is a powerful vasoconstrictor in thekidney. It vasoconstricts both the afferent and efferentglomerular arterioles. However, the efferent arteriolesmay be more sensitive than the afferent arterioles tothe vasoconstrictive effects of angiotensin II. There-fore, drugs that block the RAS subsequently lowerglomerular capillary pressure as they lower systemicblood pressure. In contradistinction, other drug classesthat do not attenuate the RAS do not consistentlylower glomerular capillary pressure in concert withreducing systemic blood pressure. Although the pre-cise relation between systemic and glomerular capil-lary pressure cannot always be assumed to be exact, itis safe to say that the lower the systemic blood pressure,the greater the likelihood of lower glomerular capillarypressure. Drugs such as calcium channel blockers (CCB)or direct acting vasodilators preferentially dilate the af-ferent glomerular arterioles. Thus, if blood pressure isnot reduced sufficiently, a paradoxical increase in glo-merular capillary pressure could occur.

FIGURE 1. Cross-section of the glomerulus exposed to essen-tial hypertension. As mean arterial pressure (MAP) rises, it in-duces preglomerular vasoconstriction with an increase in afferentglomerular arteriolar resistance (RA) and a resultant fall in renalplasma flow (RPF). There is no overall change in glomerularcapillary pressure (PGC) because of an increase in efferent glomer-ular resistance (RE) due to activation of the intrarenal reninangiotensin system. There is a decline in glomerular ultrafiltrationcoefficient (KF). Reprinted with permission from Reference 15.

AJH–DECEMBER 1999–VOL. 12, NO. 12, PART 2 DIABETES AND HYPERTENSION 171S

These understandings about glomerular hemody-namics and renal autoregulation suggest more inten-sive and sustained control of blood pressure will con-trol glomerular capillary pressure and reduce thelikelihood of renal injury. In addition, drugs that blockthe RAS provide additional advantages in that theyconsistently reduce systemic and glomerular capillarypressures.

BENEFITS OF RAS BLOCKADE

Experimental and clinical studies have demonstratedthe benefits of drugs that block the RAS on delayingprogression of diabetic16 and nondiabetic renal dis-ease.17 These results are summarized in Table 1.

The hemodynamic benefits of RAS blockade aremore important than the nonhemodynamic benefits.Constant reduction of blood pressure has been dem-onstrated to be the most important benefit of ACEinhibitors in both experimental and clinical studiesof progressive renal disease.3–6,14,16–21 Nonhemody-namic benefits such as the stimulation of extracellularmatrix degradation or inhibition of macrophage/monocyte infiltration into glomerular vascular beds22

are beneficial but less important than intensive sys-temic and glomerular capillary pressure control.

The reduction of proteinuria is independent ofchanges in systemic blood pressure, perhaps due tothe improvement of glomerular permselectivity ofproteins. Reducing proteinuria is beneficial for thekidney because it reduces the phagocytic uptake ofglycosylated proteins within the mesangial beds of theglomeruli and the renal tubules. Consequently, thisreduces cytokine production and elaboration of solu-ble mediators of fibrosis and growth.23 It is likely thatwith more intensive control of blood pressure, thenonhemodynamic effects of RAS blockade becomeless important, whereas at higher levels of bloodpressure these properties may be of greater magni-tude. There is experimental data that supports theconcept that RAS blockade drugs have beneficialeffects on kidney structure independent of bloodpressure.14,16,17,22 However, these benefits have notbeen proved in human clinical studies, as patientswho derived renoprotective benefit from ACE inhibi-

tors have almost always had lower systemic bloodpressures.

EXPERIMENTAL STUDIES: BENEFITS OFBLOOD PRESSURE REDUCTION

The best experimental studies assessing the relation-ship between systemic blood pressure, glomerular in-jury, and the impact of antihypertensive therapy haveemployed radiotelemetric monitoring to accurately as-sess average systemic blood pressure.20,21 This tech-nology offers consistent blood pressure measurement,as opposed to intermittent measurement with tail-cuffmonitoring. Griffen et al discovered a strong correla-tion between systemic blood pressure and glomerularinjury in rats with remnant kidneys.20 They found thatthe autoregulation of renal blood flow was impairedin rats with renal disease, and their glomerular capil-lary pressure varied directly with changes in systemicblood pressure. This has important implications whenone evaluates the impact of antihypertensive therapy.Lowering blood pressure is always important. Buthow the drugs affect glomerular hemodynamics andthe autoregulation of blood flow to the kidney is ofconsiderable significance.

Drugs that block the RAS consistently reduced bothsystemic and glomerular capillary pressure.14,16,17 Themagnitude of pressure reduction correlates directlywith the development of glomerulosclerosis. Calciumchannel blockers impair autoregulation because theypreferentially dilate the afferent arteriole as they lowerblood pressure. The slope of the relationship betweenblood pressure and renal injury is steep in experimen-tal studies when using CCB, indicating that there is amarked dependency of blood pressure reduction inprotecting against glomerulosclerosis.20 Regardless ofthe antihypertensive therapy employed in experimen-tal studies, the likelihood of renal injury decreaseswith the reduction of blood pressure (Figure 2).

The experimental studies using the more sophisti-cated radiotelemetric blood pressure monitoring dis-cussed previously reveal the important relationshipbetween blood pressure reduction and attenuation ofrenal injury regardless of therapy. These observationsare in contrast to studies using the tail-cuff method formeasuring blood pressure, which have demonstratedthat drugs that block the RAS are more renoprotective.However, this inconsistency in data between the tail-cuff method and the radiotelemetric methods may berelated to the inherent variability of the intermittenttail-cuff measurement and its inaccuracy in evaluatinghypertensive vascular load in the kidney. However,the studies using both tail-cuff and radiotelemetricmethods of measuring blood pressure consistentlyshow that lowering blood pressure retards diabeticand nondiabetic glomerulosclerosis.

TABLE 1. BENEFITS OF RAS BLOCKADE FORRENAL PROTECTION

Hemodynamic effectsReduction in systemic blood pressureReduction in glomerular capillary pressure? Reduction in proteinuria

Nonhemodynamic effects? Stimulation of extracellular matrix degradation? Inhibition of macrophage/monocyte infiltration

AJH–DECEMBER 1999–VOL. 12, NO. 12, PART 2172S WEIR

CLINICAL STUDIES

Epidemiologic evidence strongly supports the conceptthat the risk of developing progressive nephropathyincreases proportionately with systemic blood pres-sure, particularly SBP.24 Findings from the MultipleRisk Factor Intervention Trial (MRFIT) established theassociation of high SBP and the increased risk of de-veloping renal injury. This association suggests that itmay be necessary to reduce blood pressure to levelseven lower than the traditional target of 140/90 mmHg to protect kidney function.24,25

Clinical trials assessing the rate of progression ofrenal disease have always focused on the mean arte-rial pressure (MAP), which is defined as the diastolicblood pressure (DBP) plus one-third of the differencebetween the SBP and DBP. Unfortunately, this meansthat the MAP is heavily weighted on DBP and maynot reflect absolute risk. For example, using the tradi-tional MAP of 92 mm Hg as the goal blood pressurefor patients in renal disease clinical trials, patientswith blood pressures of 125/75 or 156/60 mm Hgwould have the same MAP, yet have a dramatic dif-ference in SBP and pulse pressure. The latter group(156/60 mm Hg) might be more likely to developrenal disease, thus confounding our assessment of theimpact of treated MAP on the rate of progression ofrenal disease.

Despite the lack of a precise risk equation usingDBP, SBP, or pulse pressure measurements, clinicalstudies have consistently demonstrated the benefits ofreducing blood pressure (either the SBP or DBP) todelay progression of renal disease, particularly in pa-tients with diabetes and evidence of nephropa-thy.3,4,11,18 The first clinical trials demonstrating thesebenefits are more than 20 years old. These early stud-

ies demonstrated that regardless of the class of anti-hypertensive therapy, tight blood pressure controlwas associated with a reduction in the progression ofrenal disease. However, many of these studies dem-onstrated that ACE inhibitors consistently reducedboth systemic blood pressure and proteinuria in hy-pertensive diabetics, which resulted in delayed renaldisease progression.3 As we will discuss, the problemwith many of these clinical trials comparing ACE in-hibitors with other therapies is that blood pressurereduction is more consistent in the ACE inhibitor-treated groups than in the control groups. This con-founds the analysis, as it cannot be determinedwhether the benefit is related to blood pressure reduc-tion or an independent factor.

In a large metaanalysis of clinical trials, Kasiske etal3 noted that regardless of the type of antihyperten-sive used, there was an increase of 3.7 mL/min inglomerular filtration rate (GFR) for each 10 mm Hgreduction in MAP. Although ACE inhibitors are moreconsistent in reducing blood pressure, proteinuria,and renal disease progression, statistically the choiceof drug class was not as important as the overallbenefit of blood pressure reduction.

Other large clinical studies suggest that the benefitof blood pressure reduction on diabetic kidney diseaseis not apparent unless blood pressure is reduced to# 130/70 mm Hg.26 In patients with type 1 diabetes,two clinical trials have helped us learn more about theimportance of blood pressure control on the progres-sion of renal disease. Viberti et al27 studied 92 patientswith type 1 and type 2 diabetes and persistent mi-croalbuminuria without hypertension (mean bloodpressure was 124/77 mm Hg). Patients were random-ized to receive either the ACE inhibitor captopril or aplacebo. After a 2-year follow-up, the mean bloodpressure in the captopril group was 122/74 mm Hgcompared with 126/76 mm Hg in the placebo group.This 4/2 mm Hg difference was statistically significant(P , .05) and was associated with the prevention ofurinary albumin excretion and progression to clinicalproteinuria (Figure 3). This indicates that treatment ofnormotensive microalbuminuric diabetics can be ben-eficial in delaying the likelihood of overt nephropathy.However, it does not answer the question whether itwas a specific benefit of the ACE inhibitor or bloodpressure reduction.

The other important clinical trial of hypertensivetype 1 diabetes subjects was conducted by the Collab-orative Study Group.4 In this study, 409 patients withrates of urinary protein excretion . 500 mg/day andserum creatinine , 2.5 mg/dL were randomized toreceive either an ACE inhibitor or other medication(not an ACE inhibitor, ARB, or CCB) to reduce bloodpressure to , 140/90 mm Hg. The results of the studyfound that the patients receiving the ACE inhibitor

FIGURE 2. Correlation of glomerular injury score and overallaveraged systolic blood pressure as determined with radioteleme-tric monitoring in rats with partial nephrectomy. Rats receivedeither no treatment (open squares), enalapril (closed squares),triple therapy (open triangles), or high-dose triple therapy (closedtriangles) (r 5 0.84). Reprinted with permission from Reference 20.


had a slower decline in renal function and displayeda 50% reduction in the risk of death, dialysis, andtransplantation. However, the MAP during all fol-low-up visits was 96 mm Hg in the ACE inhibitorgroup and 100 mm Hg in the placebo group (P , .05).The decrease in blood pressure in patients with pre-existing hypertension (defined as . 140/90 mm Hg)was 2 mm Hg greater in the captopril group than inthe placebo group (P , .16). The decrease in bloodpressure in patients without hypertension was 5 mmHg greater in the captopril group compared to theplacebo group (P , .001). Despite the dramatic differ-ences in outcome between the ACE inhibitor groupand the placebo group, the question remains whetherthe benefit is due to reduced blood pressure as op-posed to an independent factor.

Clinical trials involving patients with type 2 diabe-tes have yielded similar results as studies of patientswith type 1 diabetes. Ravid et al evaluated the im-pact of an ACE inhibitor versus placebo therapy in156 patients with type 2 diabetes and a MAP . 107mm Hg (140/90 mm Hg) and urine albumin excretionrates # 30 mg/24 h.28 Subjects received either placeboor 10 mg a day of enalapril, and were followed for 5years. At the end of the study, there was a consistentdecline in renal function associated with the reductionin albuminuria from the ACE inhibitor therapy (Fig-

ure 4). However, MAP increased from 96.1 to 102 mmHg in patients receiving the placebo, whereas it onlyincreased from 98.2 to 100 mm Hg in patients receiv-ing the ACE inhibitor. This study illustrates the im-portance of treating “normotensive” normoalbumin-uric patients to delay the risk for developingprogressive albuminuria. The United Kingdom Pro-spective Diabetes Study (UKPDS) comprised 1148 pa-tients with type 2 diabetes and hypertension.29 Partic-ipants were randomized to one of two levels of bloodpressure reduction groups: less tightly controlled (,180/105 mm Hg) or more tightly controlled (, 150/85mm Hg). Subjects were administered either captoprilor a b-blocker as the primary therapy and mean fol-low-up was 8.4 years. The patients in the tightly con-trolled blood pressure group achieved a mean bloodpressure of 144/82 mm Hg, which was 10/5 mm Hglower than subjects in the less tightly controlledgroup. This group demonstrated a dramatic reductionin the risk of both macro- and microvascular events(Figure 5). However, between the captopril and ateno-lol groups, there was no difference in the number ofpatients progressing to proteinuria or doubling serumcreatinine (Table 2). Most of the patients in this clinicaltrial were titrated taking multiple medications, whichmay explain the lack of difference between the twoprimary therapies on the rate of progression of renaldisease. Additionally, it has been argued that theshort-acting ACE inhibitor captopril was ineffectively

FIGURE 3. Change in albumin excretion rate, fractional albu-min excretion, mean arterial pressure, and glomerular filtrationrate in type 1 and type 2 normotensive diabetics receiving capto-pril 50 mg (solid line) or placebo (dashed line). Values are mean 6SEM. Asterisk 5 P # .01 for captopril v placebo for change frombaseline. Reprinted with permission from Reference 27.

FIGURE 4. Change in creatinine clearance, albumin excretion,and mean blood pressure in normotensive patients with type 2diabetes and no evidence of proteinuria. Each value represents theannual group mean based on 2–3 measurements per patient. Thedecrease in creatinine clearance was more pronounced in theplacebo group (P , .05 for the fifth year and P , .04 for the sixthyear). Patients who received enalapril had a lesser degree of albu-minuria (P 5 .001). Reprinted with permission from Reference 28.


administered as it was only dosed 25 to 50 mg twice aday. Despite these arguments, it is important to notethat lower blood pressure remains the critical factor indelaying renal disease progression.

Increasing dietary salt offsets both the antihyperten-sive and antiproteinuric effects of most antihyperten-sive drugs, especially ACE inhibitors.30,31 This effectmay be disastrous for the diabetic hypertensive asreducing blood pressure and proteinuria has clearlybeen shown to delay progression of renal disease.Consequently, there should be a concerted effort toevaluate dietary salt consumption in diabetic hyper-tensives and develop clinical strategies to modify saltintake.

ACE INHIBITORS VERSUS ARB: EFFECTS ONBLOOD PRESSURE AND PROTEINURIA

Angiotensin-converting enzyme inhibitors and ARBare pharmacokinetically different (Figures 6,7).32,33 AnACE inhibitor inhibits the conversion of angiotensin Ito angiotensin II and interferes with the degradationof bradykinin. It is unknown which of these effects isthe most important in lowering both systemic bloodpressure and glomerular capillary pressure. Clinicalstudies have demonstrated that although plasma an-giotensin II levels return to baseline with chronic ACEinhibitor therapy, blood pressure remains reduced.34

This finding raises two interesting questions: whydoes plasma blood pressure remain reduced, andwhere is the angiotensin II being formed if not in theplasma? The former question on the mechanism of

FIGURE 5. Comparative percent reduction in cardiovascularendpoints in the tight glucose control (open bars) and tight bloodpressure control (solid bars) groups in the United Kingdom Pro-spective Diabetes Study. Note the important effects of the greaterreduction in blood pressure in the tight blood pressure controlgroup as compared with the tight glucose control group (210/5mm Hg) in reducing cardiovascular and diabetic endpoints (sud-den death, death from hyperglycemia or hypoglycemia, fatal andnonfatal myocardial infarction, angina, heart failure, renal failure,amputation, vitreous hemorrhage, retinal photocoagulation, blind-ness, or cataract extraction). Reprinted with permission fromReference 29.

FIGURE 6. The mechanism of action of ACE inhibitors, whichare designed to interfere with the conversion of angiotensin I toangiotensin II, and which also interfere with the degradation ofbradykinin. Note that alternate pathways for angiotensin produc-tion are not effected nor is there any specific blockade of angioten-sin receptor binding sites in vascular beds.

FIGURE 7. The mechanism of action of angiotensin type 1receptor blockers, which have no effect on the synthesis of angio-tensin 1. These agents specifically antagonize the binding of an-giotensin II to its type 1 receptor in tissue. Binding of angiotensinII to other sites such as the type 2 receptor may result in vasodi-lation and other opposing effects to those controlled by the type 1receptor.

TABLE 2. UNITED KINGDOM PROSPECTIVEDIABETES STUDY RENAL DISEASE RESULTS

(9 YEARS)*

Captopril AtenololP

Value

Proportion of patientsprogressing to aurinary albuminconcentration $ 50mg/L 31% (48/153) 26% (38/146) .31

Proportion of patientsprogressing to aclinical proteinuria. 300 mg/L 5% (7/153) 10% (14/146) .09

* There was no difference in serum creatinine or in the proportion ofpatients who had a twofold increase in creatinine over a 9-year period.


blood pressure reduction may be related to the ACEinhibitor-induced increase in bradykinin and subse-quent stimulation of prostaglandins and nitric oxide.The latter question is more difficult to answer, butmay reflect ongoing angiotensin II synthesis withinvascular beds, which is unaffected by the ACEinhibitor.

Angiotensin type 1 receptor blockers have no effecton angiotensin II synthesis whether via the ACE orother known enzymatic pathways that exist in vascu-lar beds.32,33 These compounds block the angiotensintype 1 binding site in vascular tissue, which is respon-sible for the vasoconstrictive, growth-promoting, andsalt-retentive actions of angiotensin II. In fact, the onlysimilarity between the mechanisms of action of ACEinhibitors and ARB is that they both increase reninactivity. This effect reflects a dampening of the activityof the RAS or a reduction of systemic blood pressure.

Both drug classes are similarly capable of reducingblood pressure and proteinuria in human subjects.35

There are some differences in renal blood flow re-sponses that are evident with both low- and high-saltdiets (Figure 8).36 Angiotensin type 1 receptor blockershave a more robust ability to maintain renal bloodflow in the presence of a high-salt diet compared withACE inhibitors, which may prove to be important incontrolling blood pressure, particularly in the low-renin hypertensive. The greater renal blood flow re-sponses with the ARB compared with ACE inhibitorsmay reflect the renal vascular contribution of angio-

tensin II production, which may be an important partof the biology of the intrarenal RAS.

There are two large international clinical trials as-sessing the ability of ARB to delay the progression ofrenal disease in hypertensive diabetics. One studycompares losartan and a traditional non–ACE inhibi-tor/non–CCB therapy, whereas the other study com-pares irbesartan, amlodipine, and placebo as the pri-mary antihypertensive therapy. In both clinical trials,additional medications can be added to facilitate re-duction of SBP to , 140 mm Hg and , 135 mm Hg,respectively. The latter study will provide an interest-ing comparison between the mechanistic effects of anARB (which dilates an efferent glomerular arteriolelike an ACE inhibitor) and a CCB (which dilates anafferent glomerular arteriole) on blood pressure, pro-teinuria, and renal disease progression. An interimanalysis of this data does show divergent responses ofthese two different drug classes on proteinuria. De-spite almost identical reductions in blood pressure, theARB reduced proteinuria whereas the CCB increasedit.37 However, the long-term effects of these primarytherapies (taking the additional medications and theultimate achievement of goal blood pressure into con-sideration) will soon show whether or not ARB man-ifest unique kidney function protective properties asopposed to traditional therapies (diuretics, b-blockers,vasodilators) or CCB (amlodipine). Hopefully, thesestudies will provide some important answers as towhether drugs that block the RAS have unique prop-erties that protect kidney function even at lower levelsof blood pressure, unlike other antihypertensive drugclasses.

It is unlikely that there will be clinical trials com-paring the effects of ACE inhibitors and ARB on therate of renal disease progression, as both have beenseen to protect kidney function in experimental stud-ies, as well as lower blood pressure and proteinuria inhuman clinical trials. Of interest is a recent clinicaltrial that suggested these two drug classes might haveadditional beneficial antiproteinuric effects in humansubjects with glomerulonephritis and macroprotein-uria.38 In a clinical trial of a dozen normotensive pa-tients with IgA nephropathy, an ARB was added to anACE inhibitor. This study is of interest for two rea-sons: it demonstrates that the drugs may reduce pro-teinuria independent of blood pressure reduction, andthat their mechanisms of action are sufficiently dissim-ilar that they are complementary in their effects inreducing proteinuria. These observations obviouslyhave substantial clinical importance with regard tostrategies for reducing both blood pressure and pro-teinuria in human diabetic subjects.

FIGURE 8. Renal blood flow responses to different types ofrenin-angiotensin system inhibition in humans on a low-salt diet.Note that there is a net increase in renal plasma flow with all threetherapeutic classes. The increased renal blood flow responses withthe angiotensin type 1 receptor blockers may indicate the ability ofthis drug class to block the renal vascular contribution to angio-tensin II production. Reprinted with permission from Reference 36.


CONCLUSIONS

The Sixth Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment ofHigh Blood Pressure provides an important consensusopinion that blood pressure in diabetic hyperten-sives—particularly those with proteinuria—should bereduced to , 130/85 mm Hg, with optimal bloodpressure , 120/80 mm Hg.39 This recommendationresults from both experimental and human studies ofdiabetic renal disease, which have shown that reduc-ing blood pressure may delay progression of renaldisease. Lower blood pressure, regardless of thechoice of drug, will help to preserve renal function. Asdiscussed, even treating diabetics with normo- or mi-croalbuminuria with a blood pressure of 120/70 mmHg will delay the development of nephropathy.27

There is no evidence in clinical studies, even in pa-tients with substantially compromised renal function,that more intensive control of blood pressure willresult in adverse cardiovascular sequelae.40 Thus,there is no J-curve for health care professionals to beconcerned about.

Drugs that block the RAS remain the drugs of choiceto protect against progressive renal injury largely be-cause of their ability to consistently reduce both sys-temic and glomerular capillary pressure.3,18 Conse-quently, they are also more able to consistently reduceproteinuria. Whether drugs that block the RAS haveunique blood pressure effects is largely speculative;evidence from clinical trials has demonstrated thatthey consistently reduce blood pressure in nondiabeticnephropathy.19 A large metaanalysis of diabetic pa-tients revealed lower blood pressure to be the mostsignificant variable in slowing the rate of progressionof renal disease.3 Angiotensin type 1 receptor blockerswill likely be found to possess similar renal protectiveeffects as ACE inhibitors. This is due to their ability toreduce both systemic blood pressure and proteinuriain human subjects as well as retard histologic evidenceof glomerulosclerosis in experimental models.41 Al-though mechanistically different, these drugs providesimilar overall clinical effects and are perhaps bestused in combination to take full advantage of theirunique antihypertensive and antiproteinuric effects.

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diabetes and hypertension: blood pressure control and consequences

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