Diabetes and Hypertension
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Reviews/Commentaries/Position Statements PERSPECTIVES ON THE NEWS Diabetes and Hypertension ZACHARY T. BLOOMGARDEN, MD diastolic BP goals at 5 years in 235 pa- tients in each group, there were 25 myo- cardial 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.