8/4/2019 TMMT 5.8. 20111
1/118
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
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
2/118
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
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
3/118
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%
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
4/118
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 ..
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
5/118
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
8/4/2019 TMMT 5.8. 20111
6/118
II. PATHOPHYSIOLOGY OF HYPERTENSIOIN THE DIABETES MELLITUS
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
7/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
8/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
9/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
10/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
11/118
Glycemic
Variability
Diabetes: A New Paradigm?
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
12/118
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.
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
13/118
Inhibition of glucose oxidation by FA utilization
insulin receptor substrate (IRS) , protein kinase-B (PKB). pyruvate dehydrogenase (PDH),Phosphofructokinase-1 (PFK1), DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
14/118
FATTY ACIDS AND INSULIN RESISTANC
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
15/118
Cardiovascular targets and actions of insulin.
Muniyappa R et al. Endocrine Reviews 2007;28:463-491 2007 by Endocrine Society
DEMA-CVN.COM
Pathway-selective insulin resistance in PI3K signaling creates imbalance between
8/4/2019 TMMT 5.8. 20111
16/118
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
8/4/2019 TMMT 5.8. 20111
17/118
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
8/4/2019 TMMT 5.8. 20111
18/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
19/118
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
8/4/2019 TMMT 5.8. 20111
20/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
21/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
22/118
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.
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
23/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
24/118
Unique aspects of HTN in diabetic patients
Salt sensitivity and volume expansion Isolated systolic HTN Loss of nocturnal decline of BP Microalbumine Orthostatic hypotension
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
25/118
III.Screening and diagnosisHypertension in diabetic patients
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
26/118
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
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
27/118
"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)
DEMA-CVN.COM
Recommendations: Hypertension/Blood Pressure
8/4/2019 TMMT 5.8. 20111
28/118
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
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
29/118
DEMA-CVN.COM
Blood Pressure and
8/4/2019 TMMT 5.8. 20111
30/118
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.
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
31/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
32/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
33/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
34/118
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.
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
35/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
36/118
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
8/4/2019 TMMT 5.8. 20111
37/118
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
8/4/2019 TMMT 5.8. 20111
38/118
Ankle-brachial Index (ABI)
8/4/2019 TMMT 5.8. 20111
39/118
Ankle brachial Index (ABI)
DEMA-CVN.COM
IV Classification of hypertension in diabetes
8/4/2019 TMMT 5.8. 20111
40/118
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
http://hypertension-highbloodpressure.com/index.php/the-diseasehttp://hypertension-highbloodpressure.com/index.php/the-diseasehttp://hypertension-highbloodpressure.com/index.php/the-diseasehttp://hypertension-highbloodpressure.com/index.php/the-disease8/4/2019 TMMT 5.8. 20111
41/118
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.
DEMA-CVN.COM
Identifiable causes of hypertension
8/4/2019 TMMT 5.8. 20111
42/118
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
8/4/2019 TMMT 5.8. 20111
43/118
RENAL ARTERY STENOSIS CAPTOPRIL S
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
44/118
Doppler sonography in renal artery stenosis
DEMA-CVN.COM
Color Doppler image demonstrating
8/4/2019 TMMT 5.8. 20111
45/118
Color Doppler image demonstratingnormal intrarenal vasculature
DEMA-CVN.COM
V. CVD risk factors associated
8/4/2019 TMMT 5.8. 20111
46/118
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
8/4/2019 TMMT 5.8. 20111
47/118
DEMA-CVN.COM
Pathways to Cardiovascular Morbid Events
8/4/2019 TMMT 5.8. 20111
48/118
y
Devereux and Alderman: Circulation 1993;88:1444-1455.
LV Dysfunction
Devereux and Alderman: Circulation 1993;88:1444-14DEMA-CVN.COM
Pathways to Cardiovascular Events in Diabetes:L f h S H S d
8/4/2019 TMMT 5.8. 20111
49/118
Lessons from the Strong Heart Study
LV Dysfunction CV Events
CV Death{Adapted from Devereux and Alderman: Circulation 1993;88:1444-1455.
DEMA-CVN.COM
Noninvasively Measurable Manifestations
8/4/2019 TMMT 5.8. 20111
50/118
of Preclinical Cardiovascular Disease
Devereux and Alderman: Circulation 1993;88:1444-1455.DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
51/118
DEMA-CVN.COM
Atherosclerotic carotid artery in hypertensive diabetic patient
8/4/2019 TMMT 5.8. 20111
52/118
Nguyen hai Thuy, Pham Gia Khai, Le Huy Lieu (1994-1996)
DEMA-CVN.COM
FMD (Fl M di t d
8/4/2019 TMMT 5.8. 20111
53/118
FMD (Flow MediatedDilation)
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
54/118
DEMA-CVN.COM
2 Left ventricular hypertrophy (LVH)
8/4/2019 TMMT 5.8. 20111
55/118
2. Left ventricular hypertrophy (LVH)
DEMA-CVN.COM
Cornell voltage x QRS duration: (RaVL+SV3 [+ 6 mm in women]) x QRS
8/4/2019 TMMT 5.8. 20111
56/118
Okin PM et al . JACC 1995;25:417-23.
duration. LVH > 2,440 mm*msec.
(10 mm + 19 mm + [6 mm for woman]) x 100 msec = 3500 mm*msecDEMA-CVN.COM
LEFT VENTRICULAR HYPERTROPHY
8/4/2019 TMMT 5.8. 20111
57/118
ANATOMY and ECHO
DEMA-CVN.COM
LVMI in type 2 diabetic patients
8/4/2019 TMMT 5.8. 20111
58/118
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%
DEMA-CVN.COM
Diastolic dysfunction
8/4/2019 TMMT 5.8. 20111
59/118
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
8/4/2019 TMMT 5.8. 20111
60/118
(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
8/4/2019 TMMT 5.8. 20111
61/118
DEMA-CVN.COM
Definition of Abnormal Albuminuria inDi b M lli
8/4/2019 TMMT 5.8. 20111
62/118
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.
8/4/2019 TMMT 5.8. 20111
63/118
Management of hypertesionin diabetic patients
DEMA-CVN.COM
Management
8/4/2019 TMMT 5.8. 20111
64/118
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
8/4/2019 TMMT 5.8. 20111
65/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
66/118
DEMA-CVN.COM
Recommendations: Hypertension/Blood PressureControl
8/4/2019 TMMT 5.8. 20111
67/118
Goals A goal systolic blood pressure
8/4/2019 TMMT 5.8. 20111
68/118
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
Recommendations: Hypertension/Blood PressureControl
8/4/2019 TMMT 5.8. 20111
69/118
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)
ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(supplDEMA-CVN.COM
Recommendations: Hypertension/Blood PressureControl
8/4/2019 TMMT 5.8. 20111
70/118
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)
ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(supplDEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
71/118
Table 3. Lifestyle Modifications to Manage Hypertension*
DEMA-CVN.COM
Impact of a 5 mmHg Reduction
8/4/2019 TMMT 5.8. 20111
72/118
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
8/4/2019 TMMT 5.8. 20111
73/118
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.
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
74/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
75/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
76/118
Angiotensin Converting Enzyme Inhibitors ( ACE-
8/4/2019 TMMT 5.8. 20111
77/118
improve insulin sensitivity, retard the progression of diabetes and even prevent the development of diabetes in
hypertensive patients by inhibiting RAAS.
DEMA-CVN.COM
Angiotensin Receptor Blockers ( ARBd h f d b d
8/4/2019 TMMT 5.8. 20111
78/118
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.
DEMA-CVN.COM
Angiotensin Receptor Blockers ( ARBR d ti i th l ti i k f d l i g di b t
8/4/2019 TMMT 5.8. 20111
79/118
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.
DEMA-CVN.COM
B e t a - b l o c k e r sC dil l h b h t i d dil t ti d
8/4/2019 TMMT 5.8. 20111
80/118
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.
DEMA-CVN.COM
Diuretics Thiazides have been shown to cause electrolyte
http://hypertension-highbloodpressure.com/index.php/antihypertensive-drugs/diureticshttp://hypertension-highbloodpressure.com/index.php/antihypertensive-drugs/diuretics8/4/2019 TMMT 5.8. 20111
81/118
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.
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
82/118
8/4/2019 TMMT 5.8. 20111
83/118
8/4/2019 TMMT 5.8. 20111
84/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
85/118
DEMA-CVN.COM
Adrenergic (Alpha-1) Blockers
http://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/prazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/terazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/doxazosin-mesilate8/4/2019 TMMT 5.8. 20111
86/118
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.
DEMA-CVN.COM
http://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/prazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/terazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/doxazosin-mesilatehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/prazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/terazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/doxazosin-mesilatehttp://hypertension-highbloodpressure.com/index.php/high-blood-pressure-drugshttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/prazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/prazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/high-blood-pressure-drugshttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/doxazosin-mesilatehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/terazosin-hydrochloridehttp://hypertension-highbloodpressure.com/index.php/blood-pressure-drugs/prazosin-hydrochloride8/4/2019 TMMT 5.8. 20111
87/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
88/118
DEMA-CVN.COM
Metabolic modulators
8/4/2019 TMMT 5.8. 20111
89/118
DEMA-CVN.COM
FFAs are mobilized from adiposetissue to inhibit the uptake of glucoby muscle (including heart muscle)
8/4/2019 TMMT 5.8. 20111
90/118
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
8/4/2019 TMMT 5.8. 20111
91/118
Period(years)
UKPDS 5,102 20 Tight goal150/85versus lessstringent
goal
8/4/2019 TMMT 5.8. 20111
92/118
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
DEMA-CVN.COM
Table 1. Clinical Trials of BP Medications in Patients With DiabetesStudy n Follow-
Up PeriodBP (mmHg) Drugs
TestedImpact on Outcomes
8/4/2019 TMMT 5.8. 20111
93/118
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
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
109/118
DEMA-CVN.COM
Natural History of Diabetic Nephropathy
Hypertension
Albuminuria Cardiovascular
8/4/2019 TMMT 5.8. 20111
110/118
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
8/4/2019 TMMT 5.8. 20111
111/118
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
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
112/118
DEMA-CVN.COM
Diabetic Nephropathy Management
Parameter Target
8/4/2019 TMMT 5.8. 20111
113/118
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
2005. American College of Physicians. All Rights Reserved.DEMA-CVN.COM
Diabetic Nephropathy: What about proteinuria?
Lower BP to goal with max dose ACEi or ARB
8/4/2019 TMMT 5.8. 20111
114/118
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
2005. American College of Physicians. All Rights Reserved.DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
115/118
DEMA-CVN.COM
8/4/2019 TMMT 5.8. 20111
116/118
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
DEMA-CVN.COM
CONCLUSIONS
8/4/2019 TMMT 5.8. 20111
117/118
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
DEMA-CVN.COM
Thank you for your attention
8/4/2019 TMMT 5.8. 20111
118/118
DEMA-CVN.COM