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GII THIU

CAC CNG TRINH NGHIN CU KHOA HOC TAI HI NGHI TIM MACH MIN TRUNG VA TY NGUYN M RNG LN TH VI TAI C LC THANG 8/2011

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Hypertension in diabetic patients

Update and Pratical Clinical Applications
CANADA-CHEP 2010, AHA 2010 ADA 2011 & WISCONSIN DMECG 2011

Prof. Nguyen Hai Thuy. MD,PhD Hue 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 prevalence depending on type of diabetes, age, obesity, and ethynicity The prevalence of HTN in adults with DM is 2060%, which is 1.53 times higher than that in age-matched individuals without 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 patients for 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 T2DM
HTN co-exists with type II in 40% at age 45 and 60% at age 75. A series of over 3500 newly diagnosed type 2 diabetic patients 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 risk for CV morbidity and mortality. 70% of type II patients die from cardio-vascular disease.
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II. PATHOPHYSIOLOGY OF HYPERTENSION IN THE DIABETES MELLITUS

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Diabetes: A New Paradigm?

Glycemic Variability

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 Epidemiologic studies provide evidence for co-existence of HTN and DM and possibly point towards a common genetic and environmental factor promoting both DM and HTN. Similarly, clustering of HTN, insulin resistance or frank type 2 DM, hyperlipidaemia and central obesity have been 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), DEMA-CVN.COM 13 Phosphofructokinase-1 (PFK1),

FATTY ACIDS AND INSULIN RESISTANCE

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Cardiovascular targets and actions of insulin.

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

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2007 by Endocrine Society

Pathway-selective insulin resistance in PI3K signaling creates imbalance between prohypertensive and antihypertensive vascular actions of insulin exacerbated by compensatory hyperinsulinemia.

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

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Alternative pathways whereby compensatory hyperinsulinemia contributes to myocyte hypertrophy through the sympathetic nervous system activation and MAP kinase/ERK DEMA-CVN.COM 17 pathways at a time when insulin receptor mediated Akt-1 activation is impaired.

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Fat Cell Products and Hypertension

Visceral Fat Stores
Portal Hepatic Plasma

FFA

Insulin Clearance Vascular Constriction

Insulin

Renal Na+

Reabsorption

Angiotensinogen

Angiotensin II Hypertension

Angiotensin I

Bray GA. Contemp Diagn Obes. 1998.

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Insulin resistance, increased tissue inflammation and reactive oxygen species (ROS) production resulting in Endothelial dysfunction, Increased tissue reninangiotensinaldosterone system (RAAS) and Increased sympathetic nervous system (SNS) activity have all been implicated in this complex pathophysiology of 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 diagnosis Hypertension in diabetic patients

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III.Screening of hypertension
Measurement of BP in the office should be done by a trained individual and should follow the guidelines established for nondiabetic individuals: Home BP self-monitoring 24-h ambulatory BP monitoring may provide additional evidence of white coat and masked HTN and other discrepancies between office and true BP.
DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011
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"White coat hypertension"

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

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Recommendations: Hypertension/Blood Pressure Control

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 Target Organ Damage (TOD)

24-h bloodevidence suggests closely with TOD Current pressure correlates most (compared to clinic or casual BP) that: Higher incidence of cardiovascular events when blood pressure remains elevated at night (non-dippers) Blood pressure variability is an independent determinant of 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 have pseudohypertension (falsely high sphygmomanometer readings) 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 stiffness Increased central aortic pressure and left ventricular afterload and lowered central diastolic and coronary perfusion pressures, leading to subendocardial ischaemia and interstitial fibrosis.
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Doppler Measurements Ultrasound Doppler

The flow velocity is obtained from In order to know where along the beam the spectral estimation of the the blood flow data is colledted, a pulsed DEMA-CVN.COM received Doppler signal 37 Doppler must be used

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Ankle-brachial Index (ABI)

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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 diseases, 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...
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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 <20 years or >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

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 disease
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RENAL ARTERY STENOSIS

CAPTOPRILS TEST

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Doppler sonography in renal artery stenosis

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Color Doppler image demonstrating normal intrarenal vasculature

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V. CVD risk factors associated 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
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CRP Endothelial dysfunction fibrinogen PAI-1 homocystein noctural dipping of BP and heart rate Salt sensitivity Left ventricular hypertrophy
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Pathways to Cardiovascular Morbid Events

LV Dysfunction

Devereux and Alderman: Circulation 1993;88:1444-1455 Devereux and Alderman: Circulation 1993;88:1444-1455.
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Pathways to Cardiovascular Events in Diabetes: 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 of Preclinical Cardiovascular Disease

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

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Atherosclerotic carotid artery in hypertensive diabetic patient Nguyen hai Thuy, Pham Gia Khai, Le Huy Lieu (1994-1996)

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FMD (Flow Mediated Dilation)

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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 duration. LVH > 2,440 mm*msec.

(10 mm + 19 mm + [6 mm for woman]) x 100 msec = 3500 mm*msec

Okin PM et al. JACC 1995;25:417-23.
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LEFT VENTRICULAR HYPERTROPHY ANATOMY and ECHO

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LVMI in type 2 diabetic patients

Tran 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 Screening the diabetic cardiomyopathy by evaluating diastolic function

Echocardiography study of 48 hypertensive type 2 diabetic patients (Nguyen Hai Thuy, Nguyen Quoc Viet-2003) Prevalence of diastolic dysfunction : 81,25% in which first degree was 70,83%

Normal

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Normal diastolic function and diastolic dysfunction (obesity) by tissue doppler echography

Raev D.C. (1994) : diastolic dysfunction more frequent and early than systolic dysfunction in type 1 diabetic patients Poirier P and al (2001) : study of diastolic dysfunction in diabetic patients without HTN showed that diabetic cardiopathy is special cardiomypathy, independent with CAD and HTN.
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3. SYSTOLIC DYSFUNCTION

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Definition of Abnormal Albuminuria in Diabetes Mellitus

Microalbuminuria Macroalbuminuria
(Nephropathy)

Detected by dipstick

No

Yes

Urine Albumin / Cr Renal Risk

30 - 299 mg Alb / g Cr Marker of future nephropathy

> 300 mg Alb / g Cr Marker progressive renal

in some
Cardiovascular Risk Increased

disease
Increased

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

2005. American College of Physicians. All Rights Reserved.

Management of hypertesion in diabetic patients

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Management
In patients with DM, the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), and ADA 2011 recommends a target BP of <130/80mmHg in order to prevent death and disability associated with high BP. < 125/75 mmHg in diabetic patient with 1g proteinuria and renal insufficiency Once HTN is detected both pharmacological and nonpharmacological interventions should be implemented.
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Recommendations: Hypertension/Blood Pressure Control

Goals A goal systolic blood pressure <130 mmHg is appropriate for most patients with diabetes (C) Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate (B) Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg (B)
ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27.

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Recommendations: Hypertension/Blood Pressure Control

Treatment (1) Patients with a systolic blood pressure 130139 mmHg or a diastolic blood pressure 8089 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 pharmacological agents (E)
DEMA-CVN.COM 68 ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27.

Recommendations: Hypertension/Blood Pressure Control

Treatment (2) Patients with more severe hypertension (systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg) at diagnosis or follow-up Should receive pharmacologic therapy in addition to lifestyle therapy (A)

DEMA-CVN.COM 69 ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27.

Recommendations: Hypertension/Blood Pressure Control

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)

DEMA-CVN.COM 70 ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27.

Table 3. Lifestyle Modifications to Manage Hypertension*

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Impact of a 5 mmHg Reduction

Overall Reduction

Stroke
Coronary Heart Disease All Cause Mortality

14%
9% 7%

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Hypertension 2003;289:2560-2572.

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Pharmacotherapy
In general, diabetic patients with HTN need more than one type of medication. The choice of antihypertensive drug should be determined 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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ACE inhibitors & ARBs

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Angiotensin Converting Enzyme Inhibitors ( ACE-I)

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 (ARBs)

Reducing the progression of diabetes and carry other cardiovascular and renal benefits noticed in ACE-I, by virtue of its RAAS blockade. Have beneficial effects on glucose metabolism that are likely independent of bradykinin-mediated mechanisms. LIFE study, losartan reduced the relative risk of developing type 2 diabetes by 25% when compared with the beta-blocker atenolol.
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 Reduction in the relative risk of developing diabetes was 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 calcium channel blocker (CCB), amlodipine, in reducing the relative risk of new onset diabetes by 23% in patients with HTN aged 50 years or older.
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Angiotensin Receptor Blockers (ARBs)

Beta-blockers
Carvedilol has been shown to induce vasodilatation and improve insulin sensitivity produces less aggravation of hyperglycemia and hyperlipidemia. Recommendations for persons with DM who are taking beta-blockers include testing blood glucose often and treating hypoglycemia when blood glucose is 70 mg/dL or lower, regardless of symptoms or lack of symptoms. Monitoring serum potassium level, lipid profile, and hemoglobin A1c are also recommended.
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Diuretics
Thiazides have been shown to cause electrolyte imbalances, metabolic changes and volume contraction. ALLHAT, which compared a thiazide (chlorthalidone) with a calcium channel blocker (CCB) (amlodipine) or an ACE-I (lisinopril), found that the thiazide was less expensive and superior to the ACE-I or CCB in lowering the incidence of CVD in hypertensive populations.

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Diuretics
Hydrochlorothiazide or chlorthalidone could be considered as a first-line therapy for many diabetic patients with HTN, despite the fact that they may adversely affect insulin resistance and potassium balance in some individuals. Treating volume expansion with thiazide diuretics can increase the activity of the RAAS. Thus, combining a diuretic with an ACE-I or an ARB can be an effective BP lowering combination. It has been shown that the unfavorable effects of thiazide diuretics on lipid and glucose metabolism are dose related and do not generally occur if low doses are used.
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Calcium Channel Blockers (CCBs)

A dihydropyridine CCB (amlodipine) was used in the ALLHAT trial. Nondihydropyridine CCBs (such as verapamil and diltiazem) may help to reduce albumin excretion and coronary events. The nondihydropyridine group, which also lowers heart rate, has been shown to give additional protection to the kidneys, when combined with ACE inhibitors. Some people experience more edema with CCBs, and the agents may be less appropriate for the elderly. Amlodipine and felodipine may assist with the control of isolated systolic HTN. CCBs do not have adverse effects on glucose or lipid levels. Their role as renoprotective agents in DM has not been demonstrated.
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Adrenergic (Alpha-1) Blockers

The use of adrenergic (alpha-1) blockers (such as prazosin, terazosin, and doxazosin) in diabetic patients with HTN has been controversial. The adrenergic (alpha-1) portion of the ALLHAT study was discontinued because of a high rate of complications. These drugs are still considered appropriate to use as an adjunct 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 adipose tissue to inhibit the uptake of glucose by muscle (including heart muscle). The result is hyperglycemia and increased insulin resistance. Elevated FFAs also act on mitochondria (mito) to cause excess oxygen wastage with formation of ROS. The consequences include mitochondrial and cellular dysfunction (ionic changes, increased cell calcium and sodium). Metabolic interventions decrease DEMA-CVN.COM 90 insulin resistance, hyperglycemia,

Table 1. Clinical Trials of BP Medications in Patients With Diabetes Study n Follow- BP (mmHg) Drugs Impact on Up Tested Outcomes Period (years) UKPDS 5,102 20 Tight goal Tight: Favors tight 150/85 captopril or control: decreased versus less atenolol death from stringent diabetes, stroke, goal < and microvascular 180/105 disease (retinopathy) HOT 18,79 3.8 Diastolic Calcium < 80 group: 0 goal 80 channel decreased major versus 90 blocker cardiovascular DEMA-CVN.COM 91 plus others events

Table 1. Clinical Trials of BP Medications in Patients With Diabetes Study

HOPE, MICROHOPE

9,297 (3,577 with diabetes)

FollowUp Period (years) 3.5 (4.5)

BP (mmHg)

Drugs Tested

Impact on Outcomes

Mean BP for both groups 139/79 at baseline Mean BP 146/83 at baseline

Ramipril versus placebo

ALLHAT 42,418, (13,101 with diabetes)

4.9

Ramipril group (136/76 mmHg): decreased MI, stroke, cardiovascular death, and allcause mortality; decreased nephropathy Amlodipine Chlorthalidone group: lower versus systolic BP than amlodipine or lisinopril lisinopril; no difference for versus fatal/nonfatal MI; increased heart chlorthalid failure with amlodipine and one lisinopril versus chlorthalidone
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Table 1. Clinical Trials of BP Medications in Patients With Diabetes Study n FollowBP (mmHg) Drugs Impact on Outcomes Up Period Tested (years) ABCD 470 5 Diastolic Nisoldipine Intensive: decreased goal: versus death; no difference intensive < 75 enalapril for retinopathy or versus neuropathy; increased moderate < MI with nisoldipine 8089 versus enalapril; renal function stabilized with both drugs ACCORD 4,73 4.7 Systolic goal Stepped No difference in BP 3 < 120 versus care to nonfatal MI, nonfatal < 140 reach goals stroke, or cardiovas-cular death DEMA-CVN.COM 93

Recommendations: Hypertension/Blood Pressure Control

Treatment (6) In pregnant patients with diabetes and chronic hypertension
Blood pressure target goals of 110129/6579 mmHg are suggested in interest of long-term maternal health and minimizing impaired fetal growth

ACE inhibitors, ARBs, contraindicated during pregnancy (E)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27. DEMA-CVN.COM 94

 During pregnancy, treatment with ACE inhibitors and ARBs is contraindicated, since they can cause fetal damage. Chronic diuretic use during pregnancy has been associated with restricted maternal plasma volume, which might reduce uteroplacental perfusion. Antihypertensive drugs known to be effective and safe in pregnancy include methyldopa, labetalol, diltiazem, clonidine, and prazosin.

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DIABETIC HEART DISEASE IN HYPERTENSIVE DIABETIC PATIENTS

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DIABETIC CARDIOMYOPATHY (DCM) and DIABETIC HEART DISEASE (DHD)

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Changes in Myocardial Structure

Myocellular and Interstitial Fibrosis
The extent and frequency of diastolic dysfunction is directly proportional to the HbA1c level

Fibrosis

(Devereux et al. Circulation 2000)

HYPERGLICEMIA Accumulation of AGEs Disturbed Ca++ handling Cross linking of collagen FIBROSIS DIASTOLIC DYSFUNCTION

Hypertrophy
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Hypertensive heart disease

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Hypertensive heart disease

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Potential factors to influence coronary reserve in hypertensive heart disease.

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Primary mechanism 1.Increased myocardial mass 2.Myocardial and periarteriolar fibrosis 3.Decrease in capillary density per cardiomyocyte unit area (rare- faction of the vascular bed) 4.Vascular medial hypertrophy with lumen encroachment

Functional consequences Increased basal O2 consumption Reduced coronary reserve Increased extravascular force and reduced vascular lumen Increased coronary resistance Increased coronary resistance Reduced coronary reserve Increased diffusion distance Reduced supply of nutrients to myocytes

Decreased vascular lumen Increased coronary resistance Reduced coronary reserve 5.Endothelial or vascular muscle Increased coronary vasomotor tone and resistance dysfunction Reduced coronary autoregulation and coronary reserve
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Positron Emission Tomography

Technology of choise to assess microvascular function
Quantitative Imaging of Microvascular Function (Myocardial Blood Flow MBF)

MBF (ml/min/g)
, Bellina et al., J Nucl Med 1990
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Microvascular Dysfunction in Idiopathic DC

75% of pts with microvascular dysfunction
Patients with more Severe Microvascular Dysfunction are at Increased Risk of Death and/or Heart Failure Increased relative risk of 3.5 times in 5 yrs Dip MBF < 1.36 ml/min/g

MBF > 1.36 P = 0.0012 MBF < 1.36

Neglia et al., Circulation 2002

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Natural History of Diabetic Nephropathy

Albuminuria
Albumin-rich filtrate
Podocytes Foot process

Hypertension

Cardiovascular Death Risk

20

BP

CV Risk (fold )

15 10 5 1

Glomerular Basement Membrane

Damaged Endothelium

Time Declining GFR

Albumin Leak

GFR

0 20 40 60 80 100

GFR
ESRD

Time
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Progression of Diabetic Nephropathy

Chronology
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
Present at diagnosis of diabetes Within first 5 years After 6-15 years (~35% patients) After 15-25 years (~35% of patients) ESRD after 25-30 years
UAE = Urinary albumin excretion
Mogensen CE. Diabetologia. 1999;42:263-285. DEMA-CVN.COM

Pathology
Increased kidney and glomerular size Basement membrane thickening Further basement membrane thickening, mesangial expansion Clear, pronounced abnormalities proteinuria

Diagnosis and Screening

Mean arterial BP normal Normal BP or slight elevation (1 mm Hg/year) UAE = 20-200 g/day BP >3 mm Hg/year GFR decline ~10 mL/min/year BP >5 mm Hg/year

Glomerular closure, advanced glomerulopathy

GFR <10 mL/min BP >5 mm Hg/year

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Diabetic Nephropathy Management

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

Target < 130/80 mmHg ACEi or ARB to max tolerated A1c < 6.5% (Insulin/TZD) < 100 (70) mg/dl statin + other Hb 11-12 g/dl (Epo + iron) Aspirin daily Cessation
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Diabetic Nephropathy: What about proteinuria?

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 With DiabetesAn Update THE JOURNAL OF CLINICAL HYPERTENSIONVOL. 10 NO. 9 SEPTEMBER 2008
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CONCLUSIONS

LV Dysfunction

CV Events CV Death

Optimal control of glycemia, BP, lipids, regimens optimized to reverse LVH, dysfunction & plaque

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

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Thank you for your attention

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