Escolar Documentos
Profissional Documentos
Cultura Documentos
www.nature.com/clinicalpractice/neph
august 2007 vol 3 no 8 SCHRIER ET AL. nature clinical practice NEPHROLOGY 429
70 Normotensive
of retinopathy (P<0.001), neuropathy (P<0.001)
P = 0.005
63 and cardiovascular disease (P<0.001), accor
Proportion of patients with complication (%)
60
Hypertensive ding to 2 analysis.11 Furthermore, Cohen et al.
P = 0.001
54 detected a relationship in the ABCD trial
P = 0.05a
P = 0.005 between diabetic autonomic insufficiency and
50 48 49
47 peripheral neuropathy, with the duration of
45
diabetes and the presence of retinopathy.12
40 37 Deletion polymorphism of the ACE gene was
associated with nephropathy13 and increased
30 left ventricular mass (LVM) in patients with
diabetes enrolled in the ABCD trial.14 Smoking
20 19 was also shown to be a risk factor for nephro
pathy in these individuals.15 Blood homo
10 cysteine levels were highly correlated with
diabetic nephropathy16 and autonomic neuro
0 pathy;17 the cause and effect of this relation-
Renal Retinopathy CVD Neuropathy ship is, however, unclear. Diminished exercise
Figure 1 Complications at baseline in patients enrolled in the ABCD capacity, as assessed by peak oxygen consump-
randomized clinical trial. There were significantly more complications in tion (peak VO2), was independently asso
hypertensive than in normotensive patients with type 2 diabetes. aFor systolic ciated with an increased incidence of diabetic
hypertension only. Abbreviation: CVD, cardiovascular disease. Permission nephropathy and retinopathy in patients with
obtained from Elsevier Mehler PS et al. (1997) Am J Hypertens 10: 152161.
diabetes without a history of coronary artery
disease.18 A provocative observation was that
patients treated with insulin were significantly
enalapril, would have equivalent effects on the more likely to have retinopathy, neuropathy or
prevention or delay of progression of these nephropathy than those treated with oral hypo-
complications in patients with type 2 diabetes.9 glycemic agents.19 This difference persisted
when patients who had had diabetes for the
Baseline Characteristics of ABCD same amount of time were compared. The effect
trial Enrollees on vascular permeability of insulin, as well as
Baseline data from the ABCD trial yielded its mitogenic, atherogenic and thrombogenic
a number of interesting findings that have actions, were proposed as potential explanations
improved our understanding of the relation- for these findings.
ships between various patient characteristics The ABCD trial also revealed that the pres-
and diabetic complications. At enrollment, ence of certain diabetic complications at base-
nephropathy, retinopathy, cardiovascular disease linenamely, overt albuminuria and autonomic
and neuropathy were significantly more preva- neuropathywas a strong predictor of future
lent among hypertensive patients with type 2 cardiovascular events over 5years of follow-up.
diabetes (diastolic blood pressure >90mmHg) Overt albuminuria (>300mg/24h) in patients
than among those with normotensive diastolic with type 2 diabetes was a highly significant
blood pressure (8090mmHg; Figure 1).10 The predictor of future heart failure,20 and auto-
results of the 5-year interventional phase of nomic neuropathy was associated with an
the ABCD trial were, therefore, analyzed separa increased incidence of stroke.21
tely for the hypertensive and normotensive
cohorts. There were no significant differ- Intervention phase of the ABCD
ences in age, duration of diabetes, glycosylated trial: hypertensive cohort
hemoglobin level or BMI between the patients The randomization protocol for the hypertensive
randomly allocated to intensive or moderate anti ABCD study is shown in Figure 2. The following
hypertensive therapy in either the hypertensive baseline demographics of the intensive (n=237)
or the normotensive substudies. and moderate (n=233) blood pressure therapy
Among the 950 patients with type 2 diabetes groups were comparable: age (58years for both
enrolled in the ABCD trial, there was a highly groups); gender (58% male for both groups);
significant relationship between the rate of duration of diabetes (11.9 vs 11.5years);
urinary albumin excretion and the presence glycosylated hemoglobin (11.6 vs 11.5%); BMI
ncpneph_2007_065f1.eps
430 nature clinical practice NEPHROLOGY SCHRIER ET AL. august 2007 vol 3 no 8
40
Hypertensive patients Enalapril 2: P = 0.003
(DBP >89 mmHg) 35
n = 470 35 Nisoldipine
2: P = 0.002
30
2: P = 0.007 27
Number of events
Intensive Moderate 25 24
blood pressure control blood pressure control
DBP 75 mmHg DBP 8090 mmHg
n = 237 n = 233 20
24
15
5
Figure 2 Randomization protocol for the
hypertensive ABCD study. Abbreviation: DBP,
0
diastolic blood pressure. Nonfatal All MI MI plus CV death
Table 1 Effect of intensive versus moderate blood pressure control on the (>300mg/24h; albuminuria) at baseline,
renal function of hypertensive and normotensive patients with overt diabetic neither moderate nor intensive blood pressure
nephropathy in the ABCD trial.30 control stabilized renal function, regardless of
Degree of blood Mean creatinine clearance P value the initial antihypertensive agent used (Table1).
pressure control (ml/min/1.73m2SE) Hypertensive patients with diabetes with overt
Baseline 5years nephropathy lost kidney function at a rate of
Hypertensive patients
approximately 5ml/min/year of creatinine
clearance.31 Although this rate of loss is clearly
Intensive 75.04.4 56.95.8 0.035
better than the loss of kidney function of 10
Moderate 77.55.5 52.65.8 0.006 12ml/min/year in patients with type 2 diabetes
Normotensive patients whose hypertension is untreated,32 it indicates
Intensive 84.57.2 57.79.2 0.032 that prevention of diabetic nephropathyin
contrast to slowing its progressionrequires
Moderate 76.06.3 52.99.7 0.042
early intervention at the normoalbuminuric or
microalbuminuric stage.
All-cause mortality over the 5years of the
hypertensive ABCD study was significantly
lower in the intensive than in the moderate
Obesity
blood pressure control group (5.5% vs 10.7%;
P<0.037).31 It is important to emphasize that
Insulin resistance this beneficial effect on mortality of intensive
(mean 133/78mmHg) versus moderate (mean
139/86mmHg) blood pressure control was
Smooth muscle Hyperinsulinemia Kidney noted in the absence of any differences between
cell proliferation treatment groups in blood glucose concentra-
tion, lipid levels or smoking prevalence. During
SNS activity Na+ the ABCD study, blood pressure control was
reabsorption
managed by nurse practitioners under physician
Vessels Heart supervision, whereas blood glucose and treat-
ment of lipid abnormalities remained under
the management of the patients primary care
Vasoconstriction Cardiac output
physician. The potential mechanisms by which
obesity and insulin resistance might increase
? Blood pressure blood pressure in patients with type 2 diabetes
are illustrated in Figure 4.
Figure 4 Interactions by which obesity and insulin resistance might lead to
hypertension in patients with type 2 diabetes. Abbreviations: Na+, sodium;
Intervention phase of the ABCD
SNS, sympathetic nervous system.
trial: normotensive cohort
The randomization protocol for the normo-
tensive ABCD study is shown in Figure 5. The
control groups. Although these patients with following baseline demographics of the inten-
diabetes were in their 60s, their mean renal sive (n=237) and moderate (n=243) blood
function after 5years (as assessed by 24h creati- pressure therapy groups were comparable: age
nine clearance) remained stable for those with (58.5 vs 59.6years); gender (53 vs 56% male);
either normoalbuminuria (<30mg/24h) or duration of diabetes (8.8 vs 9.2years); glycosyl-
microalbuminuria (30300mg/24h) at base- ated hemoglobin (11.5 vs 11.6%); BMI (11.5
line.31 This effect occurred in both the moderate vs 11.6kg/m2); total cholesterol (5.6 [216] vs
and intensive blood pressure control groups, 5.5mmol/l [214mg/dl]); blood pressure (136/84
and was independent of initial therapy (i.e. vs 137/84mmHg); and creatinine clearance (84
either nisoldipine or enalapril). This finding [1.4] vs 83ml/min [1.4ml/s]). The goal of inten-
indicates that reported declines in renal function sive intervention was to reduce diastolic blood
with increasing age might be due to inadequate pressure by 10mmHg using either nisoldipine or
blood pressure control in elderly patients. In enalapril; the moderate blood pressure control
patients with overt diabetic nephropathy group received placebo.
432 nature clinical practice NEPHROLOGY SCHRIER ET AL. august 2007 vol 3 no 8
Normotensive patients Table 2 Effect of intensive versus moderate blood pressure control on
DBP 8089 mmHg the progression of complications in patients with type 2 diabetes in the
n = 480 normotensive ABCD study.
Disease state Blood pressure control (% of patients P value
who progressed)
Microalbuminuria (n = 86)
Patient survival (%)
170
SBP DBP
154
150 144 144 141 140
Mean blood pressure (mmHg)
138 137
132
130 128
90 87 85 86
82 83 81 81
78 75
70
50
UKPDS UKPDS HOT goal HOT goal HOT goal Hypertensive Normotensive Hypertensive Normotensive
Less-strict Strict <90 DBP <85 DPB <80 DPB ABCD ABCD ABCD ABCD
blood blood Moderate Moderate Intensive Intensive
pressure pressure blood blood blood blood
control control pressure pressure pressure pressure
control control control control
Figure 8 Mean blood pressure achieved in diabetic patients in the UKPDS, HOT and ABCD trials. Only the intensive blood
pressure control groups in the hypertensive and normotensive ABCD studies reached the consensus JNC goal of <130/80mmHg.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
10.0
august 2007 vol 3 no 8 SCHRIER ET AL. nature clinical practice NEPHROLOGY 435
Type 2 diabetes
PAI-1
Plasmin
Extracellular matrix
synthesis
Fibrinolysis Proteolysis
Figure 10 Potential effects of increased levels of plasminogen activator inhibitor in type 2 diabetes on
cardiovascular and renal mortality. In individuals with type 2 diabetes, insulin, glucose, angiotensin II,
obesity, and hyperlipidemia all increase levels of plasminogen activator inhibitor. Abbreviations: APC,
activated protein C; PAI-1, plasminogen activator inhibitor-1; TGF-, transforming growth factor ;
tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; VLDL, very LDL. Permission
obtained from Nature Publishing Group Kamgar M et al. (2006) Kidney Int 69: 18991903.
130/80mmHg in type 2 diabetes. Results of clearance between the groups was detected.
a more-recent investigation, the ABCD-2 There was, however, a significant decrease in
Valsartan trial, provide some support for a urinary albumin excretion rate, a harbinger of
blood pressure goal of 120/80mmHg.41 During renal and cardiovascular complications, in the
this study, 129 normotensive patients with valsartan group (P<0.007).
type 2 diabetes with a mean baseline blood
pressure of 128mmHg were randomly assigned Conclusions
to receive either placebo or the angiotensin- A diabetes epidemic has emerged during the
receptor blocker valsartan. The blood pres- latter part of the 20th century and continues
sure goals were less than 120/80mmHg in the unchecked in the 21st century. Efforts to
valsartan group and less than 140/90mmHg prevent the formidable microvascular and
in the placebo group. After a mean of approxi macrovascular complications of diabetes are
mately 2years, those who had received urgently needed. Data from the ABCD studies
placebo had a mean (SE) blood pressure of give credence to the importance of aggressive
12411/806.5mmHg. The blood pressure blood pressure control, in both hypertensive
of patients in the valsartan group was signifi- and normotensive patients, as one effective
cantly lower, at 11811/756 (P<0.001). means of lessening the burden of complications
During follow-up, no difference in creatinine caused by type 2 diabetes mellitus.
ncpneph_2007_065f10.eps
436 nature clinical practice NEPHROLOGY SCHRIER ET AL. august 2007 vol 3 no 8
august 2007 vol 3 no 8 SCHRIER ET AL. nature clinical practice NEPHROLOGY 437
Acknowledgments 24 Schrier RW et al. (2002) Cardiac and renal effects 32 Parving HH et al. (1983) Early aggressive
The ABCD trial was of standard versus rigorous blood pressure control antihypertensive treatment reduces the rate of decline
supported by Bayer and in autosomal-dominant polycystic kidney disease: in kidney function in diabetic nephropathy. Lancet 1:
the National Institute of results of a seven-year prospective randomized 11751179
Diabetes, Digestive, and study. J Am Soc Nephrol 13: 17331739 33 Schrier RW et al. (2002) Effects of aggressive blood
Kidney Diseases (DK50298- 25 Tatti P et al. (1998) Outcome results of the Fosinopril pressure control in normotensive type 2 diabetic
02). The valsartan study Versus Amlodipine Cardiovascular Events Randomized patients on albuminuria, retinopathy and strokes.
was supported by Novartis Trial (FACET) in patients with hypertension and NIDDM. Kidney Int 61: 10861097
Pharmaceutical Company. Diabetes Care 21: 597603 34 Gall MA et al. (1995) Albuminuria and poor glycemic
We sincerely thank Jan 26 Hansson L et al. (1999) Effect of angiotensin- control predict mortality in NIDDM. Diabetes 44:
Darling for her excellent converting-enzyme inhibition compared with 13031309
support in the preparation conventional therapy on cardiovascular morbidity and 35 Turner R et al. for the UK Prospective Diabetes Study
of the manuscript. Dsire mortality in hypertension: the Captopril Prevention Group (1998) Tight blood pressure control and risk of
Lie, University of California, Project (CAPPP) randomised trial. Lancet 353: macrovascular and microvascular complications in
Irvine, CA, is the author of
611616 type 2 diabetes: UKPDS 38. BMJ 317: 703713
and is solely responsible for
27 The Heart Outcomes Prevention Evaluation Study 36 Hansson L et al. for the HOT Study Group (1998)
the content of the learning
Investigators (2000) Effects of an angiotensin- Effects of intensive blood pressure lowering and low-
objectives, questions and
answers of the Medscape- converting-enzyme inhibitor, ramipril, on cardiovascular dose aspirin in patients with hypertension: principal
accredited continuing events in high risk patients. N Engl J Med 342: 145153 results of the Hypertension Optimal Treatment (HOT)
medical education activity 28 Heart Outcomes Prevention Evaluation (HOPE) randomized trial. Lancet 351: 17551762
associated with this article. Study Investigators (2000) Effects of ramipril on 37 Mehler PS et al. (2003) Intensive blood pressure control
cardiovascular and microvascular outcomes in people reduces the risk of cardiovascular events in patients
with diabetes mellitus: results of the HOPE study and with peripheral arterial disease and type 2 diabetes.
Competing interests MICRO-HOPE substudy. Lancet 355: 253259 Circulation 107: 753756
RW Schrier has declared
29 ALLHAT Collaborative Research Group (2002) 38 Nobakhthaghighi N et al. (2006) Relationship between
associations with the
Major outcomes in high-risk hypertensive patients urinary albumin excretion and left ventricular mass with
following companies:
Amgen, Astellas Pharma
randomized to angiotensin-converting enzyme mortality in patients with type 2 diabetes. Clin J Am
and Otsuka America inhibitor or calcium channel blocker vs diuretic: the Soc Nephrol 1: 11871190
Pharmaceuticals. See the Antihypertensive and Lipid-Lowering Treatment to 39 Seyoum B et al. (2006) Exercise capacity is a predictor
article online for full details Prevent Heart Attack Trial (ALLHAT). JAMA 288: of cardiovascular events in patients with type 2
of the relationship. The 29812997 diabetes mellitus. Diab Vasc Dis Res 3: 197201
other authors declared no 30 Wright JT Jr et al. (2005) Outcomes in hypertensive 40 Kamgar M et al. (2006) Impaired fibrinolytic activity
competing interests. black and nonblack patients treated with in type II diabetes: correlation with urinary albumin
chlorthalidone, amlodipine, and lisinopril. JAMA 293: excretion and progression of renal disease. Kidney Int
15951608 69: 18991903
31 Estacio RO et al. (2000) Effect of blood pressure control 41 Estacio RO et al. (2006) Effect of intensive blood
on diabetic microvascular complications in patients pressure control with valsartan on urinary albumin
with hypertension and type 2 diabetes. Diabetes Care excretion in normotensive patients with type 2
23 (Suppl 2): SB54SB64 diabetes. Am J Hypertens 19: 12411248
438 nature clinical practice NEPHROLOGY SCHRIER ET AL. august 2007 vol 3 no 8