Diabetes and Hypertension

Reviews/Commentaries/Position Statements PERSPECTIVES ON THE NEWS

ZACHARY T. BLOOMGARDEN, MD diastolic BP goals at 5 years in 235 patients in each group, there were 25 myocardial infarctions with nisoldipine patients vs. 5 with enalapril patients; his article covers presentations and nal and eye disease, macrovascular end stroke occurred in 11 vs. 7 patients, and symposia dealing with the relation points, and congestive heart failure CVD death occurred in 10 vs. 5 patients, T between diabetes and hypertension (CHF), which may in part reflect diabetic respectively, suggesting an increase in that were given at the 16th Scientific cardiomyopathy. The Hypertension Op- risk with the calcium channel blocker Meeting of the American Society of Hy- timal Therapy (HOT) trial of 18,790 pa- (CCB) (4). In the Fosinopril vs. Amlodi- pertension, San Francisco, CA, 15–19 tients, of whom 8% had diabetes and were pine Cardiovascular Events Trial (FAC- May 2001. treated with felodipine followed by ACEI ET) of 380 patients, 38% of the patients At a symposium at the 16th Scientific and then followed by additional agents, were treated with amlodipine, 34% were Meeting of the American Society of Hy- showed a clear relation of BP to cardiovas- treated with fosinopril, and 28% were pertension (ASH), San Francisco, CA, cular disease (CVD) events in the diabetes treated with combination. “The bottom 15–19 May 2001, Willa Hsueh, Los An- subgroup when comparing patients ti- line of that trial” was that myocardial in- geles, CA, discussed clinical trials in hy- trated to diastolic BP Ͻ90, Ͻ85, and Ͻ80 farction, stroke, and hospitalization an- pertension. The Sixth Report of the Joint mmHg, with lowest risk at BP Ͻ138/83 gina occurred more frequently with the National Committee on Prevention, De- mmHg (1). This was less evident without CCB alone, with rates of stroke, myocar- tection, Evaluation and Treatment of diabetes. At enrollment, most patients dial infarction, or hospitalized angina oc- High Blood Pressure (JNC-VI, 1997, were treated with a single drug, but by the curring 5.0, 2.6, and 1.1 times per 100 available at http://www.nhlbi.nih.gov/ time the study was over, two-thirds re- person-years in the respective groups, guidelines/hypertension/jnc6.pdf) de- quired multiple drug treatment. Whether suggesting “that the combination fared fined essential hypertension as a blood the post hoc diabetic subgroup analysis better” (5). In the Heart Outcomes Pre- pressure (BP) Ͼ140/90 mmHg, but was positive because of the increased vention Evaluation (HOPE) trial of pa- Hsueh noted that only 25% of patients event rate among individuals with diabe- tients at high risk for CVD treated with with hypertension have no complications tes, leading to greater statistical power, or ramipril vs. placebo, 38% had diabetes, such as renal disease, cardiac disease, because of a real difference between pa- with myocardial infarction, stroke, CVD obesity, diabetes, and hyperlipidemia. BP tients with and without diabetes is not death, and total mortality all significantly goals are lower for patients with such known. In the Sysotlic Hypertension in reduced with ramipril administration (6). complications. In the JNC-VI, patients Europe Trial (Syst-Eur), even more im- Furthermore, there was less need for re- with diabetes were noted to be at high risk pact was seen in diabetic versus nondia- vascularization, less hospitalization for and were given a BP goal of Ͻ130/85 betic patients, again suggesting the need heart failure, and a 32% decrease in new- mmHg, whereas for individuals with Ͼ1 to aggressively treat BP in patients with onset diabetes among those not known to g proteinuria, the goal to lessen target or- diabetes (2). have diabetes at onset. Although BP was 3 gan damage was set at 125/75 mmHg. In Which class of BP treatment should mmHg lower in the ramipril group, these the U.K. Prospective Diabetes Study (UK- be used? The Captopril Prevention data offer the “tantalizing suggestion” that PDS) patients were treated with either an Project (CAPPP) trial showed that pa- angiotensin 2 (A2) is a “real culprit” in ACE inhibitor (ACEI) or ␤-blocker (BB) tients with diabetes had decreased cardio- diabetes and that treatment directed at A2 and achieved levels of 144/82 vs. 154/87 vascular events, stroke, and other end is particularly beneficial. George Bakris, mmHg over 8 years. However, at a ques- points with captopril, and again the non- Chicago, IL, who spoke later, noted that tion-and-answer session after the lecture, diabetic group showed a less definitive more than half of patients with diabetes in it was noted that captopril was given only difference (3.) In the Appropriate Blood the HOPE trial were hypertensive accord- once or twice daily and therefore may not Pressure Control in Diabetes (ABCD) ing to the 130/85 mmHg definition, so have had optimal benefit. Both treatments trial, which compared nisoldipine with that, in a sense, the study shows the use- reduced microvascular end points of re- enalapril and 75 mmHg with Ͻ90 mmHg fulness of the stricter JNC-VI BP goals. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● Why does A2 have such a strong ef- Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with fect on CVD? A2 is both a direct vasocon- the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. strictor and stimulates endothelin-1 (ET- Abbreviations: A2, angiotensin 2; ABCD, Appropriate Blood Pressure Control in Diabetes; ACEI, ACE 1), another potent vasoconstrictor. A2 is inhibitor; ANP, atrial natriuretic peptide; ARB, angiotensin receptor blocker; ASH, American Society of Hypertension; AT-1, A2 type 1; BB, ␤-blocker; BP, blood pressure; CCB, calcium channel blocker; CHD, proinflammatory, stimulates adhesion coronary heart disease; CHF, congestive heart failure; CVD, cardiovascular disease; ESRD, end-stage renal molecule expression by the endothelial disease; ET-1, endothelin-1; GFR, glomerular filtration rate; HCTZ, hydrochlorothiazide; HOPE, Heart surface, stimulates the prothrombotic Outcomes Prevention Evaluation; HOT, Hypertension Optimal Therapy; JNV-VI, Sixth Report of the Joint substance plasminogen-activator inhibi- National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; NO, nitric oxide; PAI-1, plasminogen-activator inhibitor-1; RAS, renin-angiotensin system; RBF, renal blood flow; tor-1 (PAI-1), decreases nitric oxide (NO) TGF-␤, transforming growth factor-␤; TNF, tumor necrosis factor; UKPDS, U.K. Prospective Diabetes Study; activity and has pro-oxidant action in VA, Veterans Administration. converting NO to superoxide radical, and

DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001 1679 Perspectives on the News acts as a growth factor that leads to tissue group, and, indeed, for patients with glo- (ARBs). A requirement for more than one remodeling, which may be enhanced in merular filtration rate (GFR) between 20 agent is almost invariable in patients with diabetes. Hsueh noted that PAI-1 also in- and 65 mg/day and with Ͼ300 mg/day BP Ͼ15/10 mmHg above the goal of hibits tissue matrix metaloproteinases, proteinuria, use of ramipril as primary 130/85 mmHg. He stressed the need to with less degradation of interstitial matrix treatment led to a 36% lower rate of de- reduce morbidity and mortality “by the increasing fibrosis. In the kidney, ne- cline in GFR and to a 48% lesser chance of least intrusive means possible.” phropathy is controlled by hyperglyce- GFR Ͻ25 mg/day, ESRD, or death, as Arya Sharma, Berlin, Germany, dis- mia, hyperinsulinemia, A2, and stretch, compared with amlodipine treatment, de- cussed the related topic of the choice of all of which affect transforming growth spite slightly better BP control in the latter BP treatment in obese individuals. “Obe- factor-␤ (TGF-␤), which stimulates extra- group (systolic BP 132 vs. 133 mmHg sity,” he said, “is not only the most impor- cellular matrix and thereby promotes the with ramipril) (7). Bakris stated that to tant, but it is also the most widespread” sclerotic changes in the kidney. As seen in achieve this degree of benefit, “You need risk factor. Thus, weight loss is crucial. a mouse failing to express the LDL recep- meaningful doses” (ramipril 10–20 mg, Sodium retention accompanies weight tor and atherosclerosis evident at age 2 enalapril or lisinopril 40–80 mg, etc). It gain, driven by both increased sympa- months, BP is increased with A2 infusion, appeared likely that patients with lesser thetic activity and an increase in the activ- with further “dramatic changes” involving degrees of proteinuria also showed better ity of the RAS. Obesity is associated with fibrosis, inflammation, and atherosclero- outcome with the ACEI. increased cardiac output, increased sis. A2 binds to receptors in cardiac fibro- With microalbuminuria, Bakris em- plasma volume, and, initially, decreased blasts of mice, rats, and humans, phasized the need to “forget the kidney, peripheral resistance. In his studies of promoting growth and stimulating think heart, think vasculature.” In large BMI-matched hypertensive and normo- TGF-␤, increasing extracellular matrix epidemiologic trials, microalbuminuria is tensive individuals, plasma norepineph- with increased fibronectin and collagen I a major risk factor for CVD, even in pa- rine levels were increased. Leptin may and III in the heart, affecting local PAI-1, tients without hypertension, as defined by play a role in obesity-hypertension by and stimulating adhesion receptors, systolic BP Ͼ140 mmHg. In a recent Dan- driving sympathetic activity, increasing thereby increasing “the ability of these fi- ish study, nondiabetic, nonobese, normo- heart rate, and causing volume retention broblasts to stick to their extracellular ma- tensive individuals with albuminuria had and ultimately leading to increased BP. trix” via mediators such as osteopontin. slightly higher systolic BP and showed a Interestingly, there is a correlation be- There is prominent cardiac interstitial fi- smaller vasodilatory response to nitro- tween leptin and plasma angiotensino- brosis with A2 infusion in animal models glycerin, suggesting that albuminuria it- gen. All of the RAS is expressed by of diabetic cardiomyopathy. self may be an important treatment goal adipose tissue, including renin, angio- Bakris stressed that diabetes is now (8). He pointed out that the CCB group of tensinogen, ACE, and the A2 type 1 the main cause of end-stage renal disease the ABCD study, which had more CVD (AT-1) receptor. In hypertensive verus (ESRD) in both the U.S. and Europe. He events, did not show the reduction in mi- normotensive subjects, renin is increased noted that in the third National Health croalbuminuria seen with the ACEI. Al- and the AT-1 receptor downregulates. and Nutrition Examination Survey, only though it is uncertain whether this is “One wonders what is happening,” 11% of patients with diabetes had BP important at systolic BP Ͻ115–120 Sharma said, “to all the angiotensinogen Ͻ130/85 mmHg, and stated, “If you’re mmHg, at higher levels, inhibition of the that’s coming out of the adipose tissue” in not at goal, [the treatment is] not suffi- renin-angiotensin system (RAS) is re- overweight individuals. Fasting is associ- cient.” More recently than JNC-VI, lower- quired. Also, referring to a study in which ated with diuresis, related to action of ing the diastolic goal to 80 mmHg, with verapamil showed similar decrease in atrial natriuretic peptide (ANP). Obese ACEI as initial treatment, has been sug- proteinuria to that seen with ACEI (9), patients have low ANP and show poor re- gested. By comparing a variety of trials of Bakris pointed out that there are two sponse to exogenous ANP. This is caused BP treatment of patients with renal dis- classes of CCB and that nondihydropyri- in part by the high adipocyte expression ease and with and without diabetes, it has dines may protect the kidney. He con- of the ANP “clearing receptor.” Diet been shown that systolic BP between 130 cluded that one should start with an downregulates the clearing receptor, a and 140 mmHg, compared with levels be- ACEI, then use a thiazide or a nondihy- major mechanism of the diuresis of fast- tween 140 and 150 mmHg, leads to pa- dropyridine CCB, with BB treatment for ing. Thus, adipose tissue as a paracrine tients “do[ing] a lot better.” Indeed, Bakris patients with rapid pulse or post– organ mediates the relationship between noted, a patient with a creatinine level of 2 myocardial infarction. He noted that for BMI and BP. But “the story is far more mg/dl whose systolic BP decreases from patients under age 50 years, he used dia- exciting,” with a variety of cardiovascular 160 to 130 will “save 5 years” of ESRD, stolic Ͻ80 mmHg, and for patients over genes, including ET-1 and tumor necrosis with the degree of decrease in proteinuria age 50 years, he used systolic Ͻ130 factor (TNF)-␣ expressed by adipose tis- being an important marker of future ben- mmHg as the main BP targets. When sue. “There is a lot of scope for research efit. Bakris pointed out, “The sicker you asked about the use of high-dose ACEI here,” Sharma said, that will assist in our are, the more impact you’re going to versus somewhat lower-dose ACEI in understanding of the relation between ad- have.” In addition, lowering BP will “save combination with other agents, Bakris re- ipose tissue and BP. the taxpayer $250,000.” plied that there are as yet no data; he also How then should we manage our The African American Study of Kid- noted that combinations of ACEI with di- obese hypertensive patients? Before ad- ney Disease trial showed that the ACEI uretics or CCB may be as useful as those dressing pharmacologic treatment, ramipril was quite effective in this ethnic with angiotensin receptor blockers weight loss—the highest priority—must

1680 DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001 Bloomgarden be achieved. Although weight loss can de- tients],” suggesting that investigators 25–100 mg daily, captopril 12.5–50 mg crease hypertension, after several years should perform such post hoc analyses of twice daily, clonidine 0.1–0.3 mg twice “these patients are back where they start- existing trials and should pay more atten- daily, diltiazem SR 60–180 mg twice ed,” so this clearly is not a clinically effec- tion to the pharmacologic treatment of daily, or prazosin 2–10 mg twice daily, tive approach. Sharma noted that the obesity. When asked whether tying “the titrated to a diastolic BP goal of Ͻ90 guidelines “tell us nothing” in terms of leptin theory with angiotensinogen mmHg, and then placed on a 1-year pharmacology. We have much informa- would support the argument for using an maintenance phase. Clonidine and prazo- tion pertaining to hypertension treatment ACE inhibitor,” Sharma answered in the cin were associated with more side effects in minorities and for patients with diabe- affirmative, pointing out that, in addition and drug withdrawals. tes or dyslipidemia. Obesity starts with a to ethnic differences in response to drugs, Age and race were the major variables BMI of 30 kg/m2, but in most recent stud- there may be equally important differ- explaining differences in response to the ies, with the exception of the UPKDS and ences based on body weight. Another au- various agents. Obese patients were the ABCD trial, these patients were ex- dience member asked about clonidine, younger, with lower systolic and similar cluded; consequently, data are limited. As which Sharma suggested has good blood diastolic BP. Only the 1-year success with far as pharmacokinetics, it is uncertain pressure–lowering effects but “practically atenolol was affected by obesity, with pa- what happens to lipophilic drugs with abolishes postprandial thermogenesis,” tients whose BMI exceeded 30 kg/m2 be- this “enormous reservoir.” Body fat pre- which may explain the frequency of ing 2.5 times more likely to have BP dicts response to vasodilators, while there weight gain. In addition, Sharma encour- successfully controlled than those with is an inverse relationship between body aged frequent measurement of BP and the BMI Ͻ27 kg/m2. For hypertensive men fat and the BP response to nifedipine. A use of large cuff size, noting that one can with similar levels of untreated BP, there study comparing efficacy in obese and also use a wrist BP measurement. Obese was no other difference in response to the lean patients with hypertension suggests patients, he stated, often require a greater antihypertensive medications based on that CCBs are more effective than BBs for number of medicines, and “obese patients presence or absence of obesity. Pulse lean subjects, whereas the BB response is are usually managed very poorly. Doctors pressure showed the greatest response to better in obese subjects. In the Treatment often have a very negativistic approach to the diuretic and ␣-blocker; there was no in Obese Patients With Hypertension these patients.” In regard to central versus significant difference between the weight (TROPHY) study, 232 obese patients peripheral obesity, the relation of the RAS groups. Weight increased 1.7 lb with pra- were treated with lisinopril or hydrochlo- and of 11-␤ hydroxysteroid dehydroge- zosin, with evidence of fluid retention rothiazide (HCTZ). Of these patients, nase to central versus peripheral fat, and rather than increased adipose mass, and 60% responded to lisinopril 40 mg, but the potential impact of drugs on fat distri- decreased 2.1 lb with HCTZ and capto- only 43% responded to HCTZ, only at an bution, Sharma agreed that hypertension pril. Patients treated with atenolol showed a excessive dose of 50 mg daily (10). How- risk is related more to fat distribution. nonsignificant “upward trend” in weight. ever, Sharma noted that BBs promote Moreover, study of gene expression by Naftali Stern, Tel Aviv, Israel, noted weight gain, as seen in the UKPDS, in Peter Arner showed that ␤-adrenergic ex- that “the large trials have achieved systolic which the degree of weight gain was twice pression differed in subcutaneous and levels significantly higher than the current as great with atenolol than with captopril. visceral fat (11). Drug studies of antihy- targets. The feasibility of achieving sys- Weight gain from BBs is seen within 6 pertensive agents may show that BBs pro- tolic [BP] Ͻ130 and the implication of months, in association with decreased mote development of visceral adipose such treatment for the diastolic BP are un- metabolic rate, with decreased postpran- tissue, which might be significant. known.” He studied “the practicality of dial thermogenesis, and with increased li- William Cushman, Memphis, TN, re- intensive blood pressure lowering to pogenesis. This may explain several ported analysis of data from the Veterans Ͻ130/85” in 257 type 2 diabetic hyper- metabolic side effects, such as the 30% Administration (VA) Cooperative Study tensive patients over a 22-month period. increased risk of type 2 diabetes with BBs. Group on Antihypertensive Agents, who Treatment was individualized, with ACEI In contrast, the HOPE and CAPPP studies assessed whether obesity influences the whenever possible, and with BB for pa- show decreased risk of type 2 diabetes response to antihypertensive agents and tients with a history of prior coronary with ACEI treatment. Thus, the treatment examined the effects of BP drugs on heart disease (CHD). The final BP was de- of hypertension in obese individuals is weight over time. He noted that some fined by either a stable level of Ͻ130/85 preferentially an ACEI or perhaps an ARB, drugs, particularly BBs, may promote mmHg, a diastolic BP Ͻ50 mmHg, or “a in combination with a diuretic, or per- weight gain and that in the UKPDS, there stable BP that the treating physician haps with a nondihydropyridine CCB. He was a 3.4-kg weight gain in the group thought was not amenable to further in- noted that an additional pharmacologic treated with atenolol compared with the tervention.” The diastolic target was approach is that of treatment of obesity group treated with captopril, although it achieved in Ͼ90% of the patients, but the per se, as with orlistat, which can cause was uncertain whether this was a benefi- systolic goal was achieved in only 32% of and maintain weight loss; hypertensive cial effect of captopril or an adverse effect the patients, with an achieved mean sys- patients on this agent showed the ex- of atenolol. A total of 1,292 men from 15 tolic BP of 133 mmHg. Upon entry, pa- pected fall in BP proportional to the de- U.S. VA centers with untreated diastolic tients used a mean of 1.2 antihypertensive gree of weight loss. hypertension (95–109 mmHg), exclud- agents, and at study end, close to three In conclusion, Sharma mentioned ing patients with diabetes on treatment or drugs were used per patient. The final di- that “there are currently no hard end with recent cardiac events, were random- astolic BP was Յ70 mmHg in 57% of the point studies in obese hypertensive [pa- ized to HCTZ 12.5–50 mg daily, atenolol patients, with levels Ͻ70 mmHg occur-

DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001 1681 Perspectives on the News ring particularly in older patients, whose individuals to raise glucose to 8–9 patient reluctance. The final problem is prevalence of CHD was 52%. Those with mmol/l. When captopril is administered, that hypertension is complex, and in higher final diastolic levels, however, had RBF increases further. Lansang et al. (12) many patients it cannot be controlled a 28% prevalence of CHD. Stern stated, reported a similar finding of glucose- with a single drug. In the 1980s, a dia- “Once the diastolic reaches 50, I tend not induced RAS activation in a rat model, stolic BP of 95 mmHg was shown to be to push the systolic further, particularly in with glucose infusion increasing the RBF achieved with monotherapy only in ap- light of the high prevalence of coronary response to the ARB candesartan. Obesity proximately half of patients; with more disease.” He concluded, “Attempting to further activates the system, perhaps be- aggressive goals, this figure is less likely to lower the systolic to Ͻ130 leads to exces- cause of either increased hepatic or be reached. Physicians favor mono- sive diastolic lowering in a significant increased adipocyte production of angio- therapy because of cost, although Neutel fraction,” and wondered “whether or not tensinogen. pointed out that combination drugs are the benefits of attempted tight lowering of Hollenberg discussed the question of often available. Another reason often systolic pressure in type 2 diabetes out- non-ACE pathways to A2 generation. If given is the difficulty in distinguishing the weigh the risk of excessive reduction of ACE is the only pathway, “it shouldn’t cause of side effects with multiple agents diastolic pressure,” although there was no matter whether you block” at the level of (although this appears to be an incorrect definite evidence of adverse effect in his renin, at ACE, or with an angiotensin an- objection as it is usually clear which agent study. tagonist. However, renin inhibitors have is causing which side effects). He sug- At a symposium on the role of ARBs in greater effects than ACEI, suggesting that gested that giving a maximal dosage of the management of hypertension in pa- there may be non-ACE pathways of A2 any agent may increase side effects, again tients with type 2 diabetes, Norman Hol- generation. Similarly, A2 antagonists ap- suggesting the benefit of low-dose fixed lenberg, Boston, MA, noted that clinical pear to have greater effects than captopril, combination treatments, such as those trials have shown the greater importance suggesting that ARB may have greater with low-dose thiazides, which may par- of systolic BP over diastolic BP, with pro- clinical efficacy than ACEI. Hollenberg ticularly improve the benefit of ARBs. An gressive downward recommendations for concluded with a reference to Albert Ein- addendum mentioned after a subsequent BP goals and the benefit of blocking the stein, who said, “Everything should be talk is that loop diuretics do not reduce BP RAS in preventing adverse outcome. made as simple as possible but not sim- other than with volume overload, while Many years ago, data from the Joslin pler,” stressing that blocking the renin thiazides have vasodilatory actions and Clinic showed the prevalence of diabetic system is particularly effective in patients may play a role even with serum creati- retinopathy to increase over time, with al- with diabetes because of their multiple re- nine as high as 2 mg/dl. most all patients eventually showing evi- nin-related abnormalities, including ge- Neutel presented an analysis of 50 pa- dence of disease, whereas nephropathy netic factors, obesity, ethnicity, and tients treated with a combination of ACEI showed a delay in onset, reflecting the in- hyperglycemia, converging at the AT-1 and ARB. Administering irbesartan 150 sensitivity of the early measurements of receptor. mg, lisinopril 10 mg, or the combination proteinuria and a subsequent plateau in Joel M. Neutel, Orange, CA, dis- and then a doubled dose showed signifi- frequency, suggesting that some patients cussed the role of combination therapy in cant improvement in BP with both the are and others are not at risk. This dis- the management of high-risk hyperten- low- and high-dose combinations over crepancy, presumably, is not only related sive patients, pointing out that the 10/5- the medicines given individually. Thus, to glycemia, but is also related to heredi- mmHg systolic/diastolic BP difference in these agents are complementary in BP ef- tary factors. The first report of the latter the UKPDS led to improvement in CVD, fect, and other data show complementary showed that indeed a polymorphism of as did the 4-mmHg diastolic BP difference renal effect, although we do not have data the ACE gene predisposes to nephropa- between the high and low BP arms of the on cardiovascular end points. Combina- thy. The patient with type 2 diabetes HOT study. “This,” he said, “is where we tions of CCB and ACEI show benefit, as shows low renin, as compared with the have the great disconnect,” as data from compared with single agents, probably normal to high renin state found in type 1 many studies show “that we are not get- because of the lower BPs achieved. An im- diabetes. In studies with the ARB irbesar- ting even close.” Only ϳ25% of patients portant lesson shown in the HOT study is tan, patients with type 2 diabetes and ne- in the U.S. have BP Ͻ140/90 mmHg, and that the reduction of BP in the lowest goal phropathy showed greater activation of in Canada this figure is 16%, in the U.K. it group could only be achieved with mono- the RAS than nondiabetic subjects, de- is 6%, and in the developing world it is therapy in 25% of patients. Neutel sug- spite their suppression of renin. Hollen- zero. “If we really want to get CVD down, gested that physicians should begin to use berg pointed out that the low basal renin we have to get back to the basics.” In the combination therapy as a first-line ap- activity with paradoxically enhanced re- U.S., $12 billion per year is spent on BP proach, particularly with initial BP Ͼ160/ sponse to irbesartan suggests increased treatment. A problem is that compliance 100 mmHg. tissue renin response. Indeed, analysis of is important, influenced by the side ef- Thomas Giles, New Orleans, LA, dis- the response of renin activity to progres- fects of the drugs and their convenience of cussed the relation between endothelial sively higher doses of irbesartan shows dosing; a drug that must be taken twice function and the RAS. The normal endo- that the low plasma renin in type 2 diabe- daily will show lower compliance than a thelium resists thrombi and allows pene- tes “masks a highly active system.” There daily treatment agent. Another barrier to tration of complexes such as the LDL is a marked increase in renal blood flow BP control is the clinical practice of doc- particle. The endothelium plays a role in (RBF) with hyperglycemia, which can be tors to not titrate drugs because of con- the regulation of vascular tone and shown with glucose infusion in normal cern about side effects or because of smooth muscle function. Endothelial dys-

1682 DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001 Bloomgarden function may be considered a difference domains, creating a specific binding subjects, we should aim for “presyncope.” in response to agonists from that seen pocket. The activated AT-1 receptor cou- There are, of course, both neuroendo- with normal endothelium. In states of hy- ples with members of a G-protein nucle- crine benefits of RAS in providing BP reg- pertension, the effect of A2 on vascular otide family and triggers phospholipase C ulation and injury and repair autocrine hypertrophy and remodeling shows this and subsequently diacyl-glycerol, with and paracrine effects of the RAS, which, dysfunctional quality. Individuals with vasoconstrictor and mitogenic effects. “when they occur in a repetitive fashion hypertension and those with a family his- The “sartan” ARBs neutralize these effects, lead to [. . . ] maladaptive problems.” tory of hypertension whose blood pres- with differences in affinity and duration of Lowering BP with a RAS blocker can in sure is in the normal range show effect between various agents. A2 triggers concert lower systemic and glomerular increased vasoconstriction with a lesser vascular oxidases that increase oxidative pressures, reduce proteinuria, and pro- fall in vascular resistance and increase in stress. These overpower the antioxidant vide nonhemodynamic benefits. The is- forearm blood flow in response to a vari- systems, activating chemokines and cyto- sue still to be addressed, Weir suggested, ety of mediators. Hypertension is associ- kines, leading monocytes to penetrate the is what the difference between ACEI and ated with endothelial thickening, with vascular endothelium and form foam ARB means clinically. alteration in cell size and shape and in- cells. In a study of a nonhuman primate In a related report at the ASH meet- creased expression of leukocyte adhesion model of atherosclerosis, losartan in a ing, Wheeldon et al. (14) discussed the molecules, thereby increasing atheroscle- dose insufficient to lower blood pressure results of the Micro-Albuminuria Reduc- rosis. The blood vessel undergoes patho- and without difference in lipids showed tion with Valsartan (MARVAL) trial, logic changes that may be related to profound deactivation of monocytes and which compared 332 patients with type 2 differences in endothelial function, with an anti-atherosclerotic effect. diabetes treated with valsartan 80–160 concentric remodeling, leading to in- A study of individuals in their 40s mg or amlodipine 5–10 mg daily with ad- creased vascular smooth muscle and wall with coronary disease and with increased dition of bendrofluazide and doxazosin thickening without change in the lumen. adhesion molecule release and oxidative and aimed for a target BP of 135/85 In atherosclerosis, the wall remodels out- stress showed that 75–150 mg irbesartan mmHg. Urine albumin decreased from 58 ward until injury with infection, such as decreased inflammatory mediator release, to 32 and from 55 to 51 mg/min in the chlamydia, or until glucotoxicity super- adhesion molecule production, and su- two groups, with 30 vs. 15% becoming venes, leading to fracture of the cap, peroxide anion production. In the Cande- normoalbuminuric and BP decreasing which caused thrombosis if sudden or sartan and Lisinopril Microalbuminuria 11.2/6.2 vs. 11.6/5.8 mmHg, respec- ischemia if gradual. (CALM) trial, 199 patients with type 2 tively. Patel et al. (15) presented analysis ACE is an endothelial cell protein that diabetes, followed for 24 weeks, demon- of the relation between BP and progres- only enters the circulation after specific strated a greater fall in BP and albumin- sion from background retinopathy to enzymatic cleavage, but its most impor- uria with combination than with either maculopathy or proliferative retinopathy tant activity occurs in the tissues. Thus, agent alone (13). A number of clinical tri- requiring photocoagulation. The retinal Giles stated, all effective ACEIs are “tissue als are in progress to further explore the perfusion pressure, the difference be- ACEIs.” He noted that the preferred sub- efficacy of the combination. tween two-thirds of the mean arterial strate of ACE is bradykinin, and there are Matthew Weir, Baltimore, MD, re- pressure and the intraocular pressure, many other substrates of ACE. Thus, viewed the processes of renal autoregula- and the pulse pressure, the difference be- ACEIs have a variety of effects, including tion designed to maintain pressure of 50 tween systolic and diastolic pressures, decreased action of A2 at the AT-1 recep- mmHg within the glomerulus by modu- were more strongly associated with the tor, causing suppression of renin and in- lating the vasoconstrictive states of two need for photocoagulation than the sys- creased thirst, and blockage of local arteriolar systems, the afferent and the ef- tolic pressure alone. Patel et al. (15) sug- effects of A2, including inotropy, arrhyth- ferent systems. In disease, there is damage gested the use of these measures as mogenicity, thrombogenicity via PAI-1 to the afferent arteriole, leading to de- specific goals of treatment. Swislocki et al. stimulation, neuroexitation (both periph- creased autoregulation, with more pres- (16) reviewed outcome of BP treatment erally and centrally), and, finally, stimu- sure transmitted to the glomeruli, even at among the 5,225 patients with diabetes in lation of ET-1 production. A2, if arterial normal BP. From the perspective the VA Northern California Health Care dysregulated, particularly with decreased of the glomerulus, then, the state we de- System. Systolic BP was Ͻ130 mmHg in NO, can stimulate an NADH-NADPH ox- scribe as “hypertension” has no meaning, 32% of the patients and Ͼ140 mmHg in idase, leading to oxidant effects and to up- as dysregulation of the afferent arteriole 46% of the patients; diastolic BP was Ͻ85 regulation of converting enzyme, a may damage the glomeruli at normal sys- mmHg in 83% of the patients and Ͼ90 potential vicious cycle. ACEI and AT-1 temic BP. With diabetes, increasing mean mmHg in 9% of the patients, further sug- receptor blockers, separately and to- BP within the normal range leads to loss of gesting the much greater ease of treating gether, are then rational treatment ap- kidney function. In patients with poorly the latter. proaches. Other vasodilatory natriuretic treated hypertension, the rate of loss of Brook et al. (17), noting that earlier Ϫ Ϫ hormones may be important future ther- GFR is 12 ml ⅐ min 1 ⅐ year 1, with a studies have shown abnormal endothelial apeutic targets. blood pressure of 140/90 mmHg, while function with obesity and that this pre- David Gomolin, Boston, MA, discuss- the rate of loss is halved, and with lower dicts adverse prognosis, studied 32 adults ing ARB in clinical practice, described the blood pressures, one can further decrease with BMI 27–40 kg/m2 and with normal molecular structure of the AT-1 receptor, the rate of loss in half again. How low is levels of traditional CVD risk factors. Bra- which has seven cell membrane–based desirable? Weir suggested that, in diabetic chial artery flow–mediated dilatation

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