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DEMA-CVNGII THIU

C C CNG TR NH NGHIN CUKHOA H C T I H I NGH TIM M CHMI N TRUNG V TY NGUYN M

R NG L N TH VI T I C LCTH NG 8/2011

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Hypertension in diabetic patientsUpdate and Pratical Clinical Applications

CANADA-CHEP 2010, AHA 2010ADA 2011 & WISCONSIN DMECG 2011

Prof. Nguyen Hai Thuy. MD,PhDHue College of Medicine and Pharmacy

Hue City-VietNam

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I.INTRODUCTION

Hypertension (HTN) a common comorbidity of diabetes,affecting the majority of patients, with prevalencedepending on type of diabetes, age, obesity, and ethynicity

The prevalence of HTN in adults with DM is 20 60%, which i

1.5 3 times higher than that in age-matched individualswithout DM. Nguyen hai Thuy, Huynh Van Minh (2000-2002, Hue City ) :

(490 diabetic in- outpatients, BP140/90 mmHg): HTN :29.91%

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HTN in T1DM There is a relationship between the prevalence of HTN and

increasing albuminuria (study of 981 type 1 diabetic patientsfor five or more years)

HTN was present in 19 % of patients with normoalbuminuria, 30 % with microalbuminuria, and 65 % with macroalbuminuria. 75 to 85 % with progressive diabetic nephropathy The incidence of HTN rises from 5% at 10 years, to 33 % at 20

years, and 70 % at 40 years ..

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HTN in T2DMHTN co-exists with type II in 40% at age 45 and 60% at ag

A series of over 3500 newly diagnosed type 2 diabeticpatients 39% were already hypertensive . In approximately one-half of these patients, the elevation in

BP occurred before the onset of microalbuminuria . HTN was strongly associated with obesity and, not

surprisingly, the hypertensive patients were at increased riskfor CV morbidity and mortality.

70% of type II patients die from cardio-vascular disease.DEMA-CVN.COM

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II. PATHOPHYSIOLOGY OF HYPERTENSIOIN THE DIABETES MELLITUS

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Glycemic

Variability

Diabetes: A New Paradigm?

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Epidemiologic studies provide evidence for co-existencof HTN and DM and possibly point towards a commongenetic and environmental factor promoting both DMand HTN.

Similarly, clustering of HTN , insulin resistance or frank

type 2 DM, hyperlipidaemia and central obesity havebeen documented in several populations.

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Inhibition of glucose oxidation by FA utilization

insulin receptor substrate (IRS) , protein kinase-B (PKB). pyruvate dehydrogenase (PDH),Phosphofructokinase-1 (PFK1), DEMA-CVN.COM

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FATTY ACIDS AND INSULIN RESISTANC

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Cardiovascular targets and actions of insulin.

Muniyappa R et al. Endocrine Reviews 2007;28:463-491 2007 by Endocrine Society

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Pathway-selective insulin resistance in PI3K signaling creates imbalance between

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Pathway selective insulin resistance in PI3K signaling creates imbalance betweenprohypertensive and antihypertensive vascular actions of insulin exacerbated by

compensatory hyperinsulinemia.

Muniyappa R et al. Endocrine Reviews 2007;28:463-491

2007 by Endocrine SocietyDEMA-CVN.COM

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Alternative pathways whereby compensatory hyperinsulinemia contributes to myocytehypertrophy through the sympathetic nervous system activation and MAP kinase/ERKpathways at a time when insulin receptor mediated Akt-1 activation is impaired.DEMA-CVN.COM

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HepaticInsulinClearance

PortalFFA

PlasmaInsulin

Renal Na+

Reabsorption

Hypertension

VisceralFat Stores

Fat Cell Products and Hypertension

Vascular Constriction

Angiotensin I

Angiotensin IIAngiotensinogen

Bray GA. Contemp Diagn Obes. 1998. DEMA-CVN.COM

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Insulin resistance, increased tissue inflammation andreactive oxygen species (ROS) production resulting in

Endothelial dysfunction , Increased tissue renin angiotensin aldosterone system

(RAAS) and Increased sympathetic nervous system (SNS) activity

have all been implicated in this complex pathophysiologyof DM and HTN.

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Unique aspects of HTN in diabetic patients

Salt sensitivity and volume expansion Isolated systolic HTN Loss of nocturnal decline of BP Microalbumine Orthostatic hypotension

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III.Screening and diagnosisHypertension in diabetic patients

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III.Screening of hypertension Measurement of BP in the office should be done

a trained individual and should follow theguidelines established for nondiabetic individuals: Home BP self-monitoring 24-h ambulatory BP monitoring may provide

additional evidence of white coat and maskedHTN and other discrepancies between office andtrue BP.

DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011

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"White coat hypertension"

Puig JG (1995) : WCH : 51% (43 diabetic pamean age, 57 years)Nielsen F (1997) : WCH 23% ( 30 diabeticpatients, mean age, 61 years)

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Recommendations: Hypertension/Blood Pressure

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Recommendations: Hypertension/Blood PressureControl

Screening and diagnosis

Measure blood pressure at every routine diabetes visit If patients have systolic blood pressure

130 mmHg or diastolic blood pressure 80 mmHg Confirm blood pressure on a separate day Repeat systolic blood pressure 130 mmHg or diastolic blood

pressure 80 confirms a diagnosis of hypertension (C)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27

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Blood Pressure and

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Current evidence suggeststhat:

Blood Pressure andTarget Organ Damage (TOD)

24-h blood pressure correlates most closely with TOD(compared to clinic or casual BP)

Higher incidence of cardiovascular events when bloodpressure remains elevated at night (non-dippers)

Blood pressure variability is an independent determinantof TOD

Highest incidence of cardiovascular events occurs in AM

Adapted from: Sokolow, et al. 1966; Devereux, et al. 1983; Devereux, et al. 1987;Parati, et al. 1987; Mancia. 1990.

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Elderly Diabetic Patients Blood pressure must be measured in older patients with

special care as some older persons havepseudohypertension (falsely high sphygmomanometerreadings) due to excessive vascular stiffness as determined

for example by using pulse wave pressure.

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Medial vascular calcification in diabetes mellitus

Arterial stiffnessIncreased central aortic pressure and left ventricular afterload and

lowered central diastolic and coronary perfusion pressures, leadingto subendocardial ischaemia and interstitial fibrosis.DEMA-CVN.COM

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Doppler Measurements Ultrasound Doppler

The flow velocity is obtained frothe spectral estimation of thereceived Doppler signal

In order to know where along the beamthe blood flow data is colledted, a pulsedDoppler must be used DEMA-CVN.COM

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Ankle-brachial Index (ABI)

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Ankle brachial Index (ABI)

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IV Classification of hypertension in diabetes

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IV.Classification of hypertension in diabetes There are 3 categories of HTN in diabetic patients

1.Primary, or essential, HTN is the most common type of HTN in persons with DM. Its cause is unknown . 2.Secondary HTN, which includes HTN associated with

diabetic renal disease as well as HTN from other disea

contributes to 5% to 10% of the cases. 3.Other problematic manifestations of BP control may be

associated with both primary and secondary HTN.Examples are isolated systolic HTN and orthostatic

hypotension...DEMA-CVN.COM

E l i f d f HTN if
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Evaluation for secondary causes of HTN if : BP resistant to three or more antihypertensive agents worsening control in previously well-controlled patient, severe HTN (>180/110 mmHg), significant hypertensive target organ damage, onset in

adults 50 years of age,

lack of family history, findings on exam or laboratory results that suggest

secondary cause.

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Identifiable causes of hypertension

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Identifiable causes of hypertension Chronic kidney disease Coarctation of the Aorta Cushings Syndrome Drug induced Obstructive uropathy Pheochromocytoma Primary aldosteronism and other mineralocorticoid excess

states Renovascular HTN stenosis and fibromuscular dysplasia Sleep Apnea

Thyroid (either HYPER or HYPO) or parathyroid diseaseDEMA-CVN.COM

RENAL ARTERY STENOSIS CAPTOPRILS

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RENAL ARTERY STENOSIS CAPTOPRIL S

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Doppler sonography in renal artery stenosis

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Color Doppler image demonstrating

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Color Doppler image demonstratingnormal intrarenal vasculature

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V. CVD risk factors associated

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with HTN in diabetic patients Central obesity Family history Male sex or postmenopause state Cigarette smoking

Physical inactivity Insulin resistance/hyperinsulinemia Microalbuminuria Dyslipidemia :TG,HDL.C, non -HDL.C

CRP Endothelial dysfunction fibrinogen PAI -1 homocystein noctural dipping of B

and heart rate Salt sensitivity

Left ventricular hypertrDEMA-CVN.COM

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Pathways to Cardiovascular Morbid Events

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y

Devereux and Alderman: Circulation 1993;88:1444-1455.

LV Dysfunction

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Pathways to Cardiovascular Events in Diabetes:L f h S H S d

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Lessons from the Strong Heart Study

LV Dysfunction CV Events

CV Death{Adapted from Devereux and Alderman: Circulation 1993;88:1444-1455.

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Noninvasively Measurable Manifestations

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of Preclinical Cardiovascular Disease

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Atherosclerotic carotid artery in hypertensive diabetic patient

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Nguyen hai Thuy, Pham Gia Khai, Le Huy Lieu (1994-1996)

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FMD (Fl M di t d

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FMD (Flow MediatedDilation)

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2 Left ventricular hypertrophy (LVH)

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2. Left ventricular hypertrophy (LVH)

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Cornell voltage x QRS duration: (RaVL+SV3 [+ 6 mm in women]) x QRS

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Okin PM et al . JACC 1995;25:417-23.

duration. LVH > 2,440 mm*msec.

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LEFT VENTRICULAR HYPERTROPHY

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ANATOMY and ECHO

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LVMI in type 2 diabetic patients

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yp pTran Thi Van Anh,Nguyen Hai Thuy, Nguyen Anh Vu (2006-2007)

Prevalence of LVH with LVMI( male >125g/m2 and female > 110 g/m2) was 40%

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Diastolic dysfunction

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Normal

Screening the diabeticcardiomyopathy byevaluating diastolic

function

Echocardiography study of 48hypertensive type 2 diabetic patien(Nguy en Hai Thu y, Nguy en QuViet- 200 3) Prevalence of diastoldysfunction : 81,25% in which f

degree was 70,83%DEMA-CVN.COM

Normal diastolic function and diastolic dysfunction( b i ) b i d l h h

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(obesity) by tissue doppler echography

Raev D.C. (1994) : diastolic dysfunction more frequent and early than systolicdysfunction in type 1 diabetic patientsPoirier P and al (2001) : study of diastolic dysfunction in diabetic patients without

HTN showed that diabetic cardiopathy is special cardiomypathy, independent withCAD and HTN.DEMA-CVN.COM

3. SYSTOLIC DYSFUNCTION

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Definition of Abnormal Albuminuria inDi b M lli

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Diabetes MellitusMicroalbuminuria Macroalbuminuria

(Nephropathy)

Detected by dipstick No Yes

Urine Albumin / Cr 30 - 299 mg Alb / g Cr > 300 mg Alb / g Cr

Renal Risk Marker of future nephropathy

in some

Marker progressive ren

disease

Cardiovascular Risk Increased Increased

* Random (Spot) urine preferably A.M. recommended

2005. American College of Physicians. All Rights Reserved.

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Management of hypertesionin diabetic patients

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Management

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In patients with DM, the Joint National Committee onthe Detection, Evaluation, and Treatment of High BloodPressure (JNC 7), and ADA 2011 recommends a target BPof

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Goals A goal systolic blood pressure

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Treatment (1) Patients with a systolic blood pressure 130 139

mmHg or a diastolic blood pressure 80 89 mmHg May be given lifestyle therapy alone for a

maximum of 3 months If targets are not achieved, patients should be

treated with the addition of pharmacologicalagents (E)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(supplDEMA-CVN.COM


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Treatment (2) Patients with more severe hypertension (systolic

blood pressure 140 mmHg or diastolic bloodpressure 90 mmHg) at diagnosis or follow -up

Should receive pharmacologic therapy in addition

to lifestyle therapy (A)



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Treatment (3) Lifestyle therapy for hypertension

Weight loss if overweight DASH-style dietary pattern including reducing

sodium, increasing potassium intake Moderation of alcohol intake Increased physical activity (B)


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Table 3. Lifestyle Modifications to Manage Hypertension*

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Impact of a 5 mmHg Reduction

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p gOverall Reduction

Stroke 14%

Coronary Heart Disease 9%

All Cause Mortality 7%

Hypertension 2003;289:2560-2DEMA-CVN.COM

PharmacotherapyI l di b i i i h HTN d

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In general, diabetic patients with HTN need morethan one type of medication.

The choice of antihypertensive drug should bedetermined by the drugs capacity to

(1) lower blood pressure, (2) protect the diabetic patients kidneys from

ongoing injury, and (3) avoid side effects.

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Angiotensin Converting Enzyme Inhibitors ( ACE-

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improve insulin sensitivity, retard the progression of diabetes and even prevent the development of diabetes in

hypertensive patients by inhibiting RAAS.

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Angiotensin Receptor Blockers ( ARBd h f d b d

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Reducing the progression of diabetes and carryother cardiovascular and renal benefits noticed inACE-I, by virtue of its RAAS blockade.

Have beneficial effects on glucose metabolism thatare likely independent of bradykinin-mediated

mechanisms. LIFE study, losartan reduced the relative risk of

developing type 2 diabetes by 25% whencompared with the beta-blocker atenolol.

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Angiotensin Receptor Blockers ( ARBR d ti i th l ti i k f d l i g di b t

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Reduction in the relative risk of developing diabeteswas noted in the Candesartan in Heart failure:

Assessment of Reduction in Mortality and morbidity(CHARM) studies. The Valsartan Antihypertensive Long-term Use

Evaluation (VALUE) trial demonstrated the

advantage of an ARB, valsartan, over a calciumchannel blocker (CCB), amlodipine, in reducing therelative risk of new onset diabetes by 23% inpatients with HTN aged 50 years or older.

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B e t a - b l o c k e r sC dil l h b h t i d dil t ti d

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Carvedilol has been shown to induce vasodilatation andimprove insulin sensitivity

produces less aggravation of hyperglycemia andhyperlipidemia.

Recommendations for persons with DM who are takingbeta-blockers include testing blood glucose often andtreating hypoglycemia when blood glucose is 70 mg/dL orlower, regardless of symptoms or lack of symptoms .

Monitoring serum potassium level, lipid profile, andhemoglobin A1c are also recommended.

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Diuretics Thiazides have been shown to cause electrolyte
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Thiazides have been shown to cause electrolyteimbalances, metabolic changes and volume contraction.

ALLHAT, which compared a thiazide (chlorthalidone) withcalcium channel blocker (CCB) (amlodipine) or an ACE-I(lisinopril), found that the thiazide was less expensive superior to the ACE-I or CCB in lowering the incidence of CVD in hypertensive populations.

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Adrenergic (Alpha-1) Blockers
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The use of adrener gic (a lpha-1) bl ockers (such asprazosin , terazosin , and doxazosin ) in diabetic patientswith HTN has been controversial.

The adrenergic (alpha-1) portion of the ALLHAT studywas discontinued because of a high rate of complications.

These drugs are still considered appropriate to use as anadjunct to therapy in difficult-to-control cases. The alpha-blockers, such as prazosin , do not have

adverse effects on glucose or lipid levels.

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Metabolic modulators

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FFAs are mobilized from adiposetissue to inhibit the uptake of glucoby muscle (including heart muscle)

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The result is hyperglycemia and

increased insulin resistance.Elevated FFAs also act onmitochondria (mito) to cause excessoxygen wastage with formation ofROS. The consequences includemitochondrial and cellulardysfunction (ionic changes,increased cell calciumand sodium).

Metabolic interventions decreaseinsulin resistance, hyperglycemia,DEMA-CVN.COM

Table 1. Clinical Trials of BP Medications in Patients With DiabetesStudy n Follow-

Upi d

BP (mmHg) DrugsTested

Impact onOutcomes

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Period(years)

UKPDS 5,102 20 Tight goal150/85versus lessstringent

goal

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UpPeriod

(years)

Tested

HOPE,MICRO-HOPE

9,297(3,577withdiabetes)

3.5 (4.5) Mean BP forboth groups139/79 atbaseline

Ramiprilversusplacebo

Ramipril group (136/76 mmHgdecreased MI, stroke,cardiovascular death, and all-cause mortality; decreasednephropathy

ALLHAT 42,418,(13,101withdiabetes)

4.9 Mean BP146/83 atbaseline

Amlodipineversuslisinoprilversuschlorthalidone

Chlorthalidone group: lowersystolic BP than amlodipine orlisinopril; no difference forfatal/nonfatal MI; increased heafailure with amlodipine andlisinopril versus chlorthalidone

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Table 1. Clinical Trials of BP Medications in Patients With DiabetesStudy n Follow-

Up PeriodBP (mmHg) Drugs

TestedImpact on Outcomes

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Up Period(years)

Tested

ABCD 470 5 Diastolicgoal:intensive < 75versusmoderate 1.36

Patients with more Severe Microvascular Dysfunctionare at Increased Risk of Death and/or Heart Failure

Neglia et al., Circulation 2002

Dip MBF< 1.36 ml/min/g

Increased relativerisk of 3.5 times

in 5 yrs

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Natural History of Diabetic Nephropathy

Hypertension

Albuminuria Cardiovascular

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Declining GFR

Time

G F R

ESRD

B P

TimeGlomerular Basement Membrane

PodocytesFoot process

DamagedEndothelium

Albumin-rich filtrate

AlbuminLeak

GFR

Death Risk

C

V R

i s k ( f o

l d

)

20

15

10

5

10 20 40 60 80

2005. American College of Physicians. All Rights Reserved.DEMA-CVN.COM

Progression of Diabetic NephropathyChronology Pathology

Diagnosisand Screening

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Present at diagnosis ofdiabetes

Increased kidney andglomerular size Mean arterial BP normal

Within first 5 yearsBasement membrane

thickeningNormal BP or slight

elevation (1 mm Hg/year

After 6-15 years(~35% patients)

Further basementmembrane thickening,mesangial expansion

UAE = 20-200 g/dayBP >3 mm Hg/year

After 15-25 years(~35% of patients)

Clear, pronouncedabnormalities

proteinuria

GFR decline~ 10 mL/min/year

BP >5 mm Hg/year

ESRD after 25-30 years Glomerular closure,advanced glomerulopathyGFR 5 mm Hg/year

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

UAE = Urinary albumin excretion

Mogensen CE. Diabetologia . 1999;42:263-285.

gy gy and Screening

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Diabetic Nephropathy Management

Parameter Target

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Parameter

Lower BP Block RAAS Improve glycemia . Lower LDL cholesterol.. Anemia management ... Endothelial protection Smoking..

Target

< 130/80 mmHgACEi or ARB to max toleratedA1c < 6.5% (Insulin/TZD)

< 100 (70) mg/dl statin + other

Hb 11-12 g/dl (Epo + iron)Aspirin dailyCessation


Diabetic Nephropathy: What about proteinuria?

Lower BP to goal with max dose ACEi or ARB

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Lower BP to goal with max dose ACEi or ARB Consider Adding: ACEi to ARB, mineralocorticoid

receptor antagonist to ACEi or ARB Calcium Channel Blockers

Non-dihydropyridine Dihydropyridine


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George L. Bakris, James R. Sowers. ASH Position Paper: Treatment of Hypertension in Patients WithDiabetes An Update THE JOURNAL OF CLINICAL HYPERTENSIONVOL. 10 NO. 9 SEPTEMBER 2008

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CONCLUSIONS

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Adapted from Devereux and Alderman: Circulation 1993;88:1444-1455.

LV Dysfunction CV Events

CV Death

{Optimal control of glycemia, BP, lipids, regimensoptimized to reverse LVH, dysfunction & plaque

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Thank you for your attention

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