Dharmeizar

Divisi Ginjal Hipertensi, Departemen Ilmu Penyakit Dalam Fakultas Kedokteran, Universitas Indonesia RSUPN Dr. Cipto Mangunkusumo, Jakarta

The prevalence of diabetes mellitus in adults in Asian-Pacific nations.

Type 2 Diabetes, Practical Target and Treatment, 4th ed

UKPDS. BMJ 2000;321:405-412

Hypertension in patients with DM

Is a common problem in type 1 and type 2 DM Among those with type 1 DM. the incidence of hypertension rises from 5% at 10 years, to 33% at 20 years, and 70% at 40 years There is a close relation between the prevalence of hypertension and increasing albuminuria In type 2 DM : 39% were already hypertensive in newly diagnosed patients, hypertension was strongly associated with obesity, and patients were at increased risk for CV morbidity and mortality

The Classifications of Blood Pressure

JNC 6 Category SBP/DBP Optimal Normal Borderline Hypertension Stage 1 Stage 2 Stage 3 Isolated St. 1 Isolated St. 2 < 120/80 120-129/80-84 130-139/85-89 140/90 140-159/90-99 150-179/100-109 180/110
Stage 2

JNC 7 Category Normal

Prehypertension

ESH
SBP (mmHg) DBP (mmHg) < 120 < 130 130-139
(High Normal)

< 80 < 85 85-89

Hypertension Stage 1 140-159 160-179 180 140-159 160 90-99 100-109 110 < 90 < 90

Kaplans Clinical Hypertension, 2010

90

Percent of Population

80
69,6

76,4 64,7 53,7 55,8 64,1

70 60 50 40 30 20 10 0 20-34 35-44 45-44 Men 55-64 Women

13,4 6,2 23,2 16,5 36,2 35,9

65-74

75+

Prevalence of HBP in adults more than 20 years by age and sex (NHANES: 2005 to 2006). Adapted from NCHS and NHLBI. Hypertension is defines as SBP 140 mmHg or DBP 90 mmHg, taking antihypertensive medication, or being told twice by a physician or other professional that one has hypertension. (From Lloyd-Jones D, Adam R. Carnethon M, et al. Heart disease and stroke statistics-2009 update: A report from the American Heart Association statistics committee and stroke statistics subcommittee. Circulation 2009; 119:e21-e181, with permission) Kaplans Clinical Hypertension, 2010

Complications of Hypertension: End-Organ Damage

Hypertension

Hemorrhage, Stroke

LVH, CHD, CHF

Retinopathy
CHD = coronary heart disease CHF = congestive heart failure LVH = left ventricular hypertrophy

Peripheral Vascular Disease

Renal Failure, Proteinuria

Slide Source Hypertension Online www.hypertensiononline.org

Chobanian AV, et al. JAMA. 2003;289:2560-2572.

Guidelines for the management of arterial Hypertension. European Heart Journal (2007) 28, 14621536

* Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the BP. Drug abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; Aldo ANT, aldosterone antagonist; BB, beta-blocker; CCB, calcium channel blocker. Conditions for which clinical trials demonstrate benefit of specific classes of antihypertensive drugs. JNC VII

Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg Increment in Systolic/Diastolic BP*
Cardiovascular mortality risk 8
8X risk

6
4 2
1X risk

4X risk 2X risk

115/75

135/85

155/95

175/105

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 4069 years Lewington et al. Lancet 2002;360:190313

Economic Burden of Cardiovascular Disease in the US Estimated for 2005

400 393.5

Billions of Dollars

300

254.8

200 142.1 100 56.8 59.7 27.9 0 Heart disease Coronary heart disease Stroke Hypertensive Congestive disease heart failure Total CVD*

American Heart Association. Heart Disease and Stroke Statistics2005 Update.

Antihypertensive Treatment Can Reduce Cardiovascular Events in Diabetic Patients Hypertension Optimal Treatment Study
Target DBP
(mm Hg)

Achieved SBP*
(mm Hg)

Achieved DBP*
(mm Hg)

Events Per 1000 Patient-Years

Patients with Diabetes

30 25 20 15 10 5 0

P = 0.005

90 85 80
*Mean

143.7 141.4 139.7

85.2 83.2 81.1

501 501 499

of all blood pressures for all study patients in the blood pressure subgroups from 6 months of follow-up to the end of the study.

DBP = diastolic blood pressure SBP = systolic blood pressure Events include all myocardial infarctions, all strokes, and all other cardiovascular deaths. Hansson L, et al. Lancet. 1998;351:17551762.

Slide Source Hypertension Online www.hypertensiononline.org

Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes
Recommended Drugs
Compelling Indication Diuretic BB ACEI ARB CCB Aldo ANT

Heart failure Post-myocardial infarction High coronary disease risk

Diabetes
Chronic kidney disease Recurrent stroke prevention

JNC VII, 2003

Canadian Recommendation for the Management of Hypertension, 2009

Guidelines for the management of arterial Hypertension. European Heart Journal (2007) 28, 14621536

Management issues in hypertensive diabetics. S Afr Fam Pract 2011; 53: 144-148

Angiotensinogen
Renin

Angiotensin I
ACE Inhibitors Angiotensin Converting Enzyme (ACE)

Angiotensin Receptor blockers

Angiotensin II AT2 receptor

AT1 receptor
Vasoconstriction Sympathetic activation Cell proliferation Aldosterone release Renal sodium resorption

Vasodilation Inhibition of cell growth apoptosis

Atherosclerosis, hypertension

Fig. 7-4. The renin-angiotensin system with the major effects of stimulation at AT1 and AT2 receptors and the sites of action of ACEIs and ARBs. (Modified from Nickenig G. Should angiotensin II receptor blockers and statins be combined? Circulation 2004; 110:1013-1020)
Kaplans Clinical Hypertension, 2010

Proteinuria Apoptosis Glomerular hemodynamics Tubular transport Growth of glomerular and tubular cells

Induction of reactive oxigen species

Angiotensin II

Inhibition of NO synthesis Metabolic effects

Induction of chemokines
Upregulation of Tolllike % receptors Stimullation of extracellular matrix sythesis, inhibition of extracellular matrix turnover

Increase in tubular HDL and Albumin uptake

Figure 3. Ang II is a cytokine with many effects on the kidney, clearly beyond the classical function as a hemodynamic mediator. J Am Soc Nephrol 17: 2985-2991, 2006

Kidney Angiotensinogen Renin Alternative pathway (Chymase) Inactive Prorenin

Bradykinin

Ang I
ACE Ang II
Inactive fragments

Active Prorenin

AT1R
CNS Vascular Edothelium

Adrenal cortex

Prorenin receptor Aldosterone Fibrosis

Sympathetic activation

Smooth muscle

Cardiac (myocrdial) cells

Kidney
Endhotelial dysfuntion

Sodium retention

Inflammation

Individual cell growth

Fig. 3-22 The renin-angiotensin-aldosterone system. Ang I, angiotensin 1; Ang II, angiotensin II, ACE, angiotensin converting enzyme; AT1R, type 1 angiotensin receptor Kaplans Clinical Hypertension, 2010

Angiotensin II
TGF-1

Afferant glomerular arteriole resistance

Impaired auto regulation

Suppresses nephrin transcription and decreases the synthesis of negatively charged proteoglycans

Downregulation of prolyl hydroxylase 3

Degradation of hypoxiainducible factor 1

Transcapillary pressure

Podocyte apopthosis VEGF

Enhances capillary filtration pressure

Synthesis of the 3 chain of collagen type IV

PROTEINURIA

Ruster C, J Am Soc Nephrol 2006 Remuzzi G, J Clin Invest 2006 Sharma K, Am J Renal Physiol 2005 Brinkkoetter PT, J Am Soc Nephrol 2004 Wolf G, Am J Nephrol 2004

Angiotensin II
The Rho kinase pathway

Activates transcription factor NF-B

Stimulates factor Ets

Upregulates mesangial cells Toll-like 4 receptors

Upregulation of VCAM-1, Integrins, MCP-1, RANTES IL-6, IL-18, TNF-

Enhances NF-B activation

Macrophages, monocytes, and lymphocytes infiltration

Ruster C, J Am Soc Nephrol 2006 Wolf G, Kidney Int 2002 Zhan Y, J Clin Invest 2005 Wolf G, J Am Soc Nephrol 2006

Angiotensin II TGF-
Procollagen type I Stimulates synthesis of collagen type 1 & 3
Extracellular matrix AT1

Fibroblast and fibronectin

Connective tissue growth factor (CTGF)

Angiotensin IV
Induces PAI-1 & TIMP-1

Inhibit metalloproteinases

FIBROSIS
Wolf G, Miner Electrolyte Metab 1998 Rodriguez-Vita J, Circulation 2005 Abrahamsen CT, Pharmacology 2002 Ruster C, J Am Soc Nephrol 2006

Inhibits matrix turnover

Extracellular matrix

Angiotensin II
Renal Activity of preganglionic symphatiche neurons

Vasoconstriction
Renin

Damage on: DNA carbonyl compounds advanced oxidation protein products oxidized LDL

MAP and HR
Pro-inflammatory effects (IL-1, IL-6, TNF )
Attracting and activating leucocytes Damage endothelial cells

Growth-promoting effect on the wall intra renal vessels

ROS production

Pro-apoptotic cascade in proximal tubules

Angiotensin II

TGF-

Cell and extracellular matrix proliferation

Glomerularsclerosis

Tubular atrophy

Interstitial fibrosis

Wolf G, Am J Physiol 1990 Ruster C, J Am Soc Nephrol 2006

RAAS: beneficial effects of inhibition on the CVS and kidney

Cardiovascular system (CVS) Elevated BP Vascular smooth muscle cell growth LVH Prevents LV remodeling after MI Prevents HF after MI Sympathetic NS activity Stabilization of atherosclerotic plaque Normalization of endothelial function Fibrinolytic system Kidney Sodium and water reabsorption Proteinuria Glomerular and tubulointerstitial fibrosis Stabilization of renal function in CKD

LVH=left ventricular hypertrophy; NS=nervous system Cowie MR. In Cardiovascular Medicine. Eds: Willerson JT, et al. 2007.

No. 1

Penelitian HOPE study (2000)

Jumlah Pasien 3577

Obat yang dipakai Ramipril, Plasebo

Lama Penelitian 4,5 tahun

Target TD (mmHg) < 140/90

Hasil Ramipril: MCI turun 22%; Stroke turun 33%; CV death turun 37%, total mortality turun 24%, nefropati turun 24% Losartan: insidens doubling creatinine turun 25%, ESRD turun 28%, perawatan pertama untuk CHF turun 32%, proteinuria turun 35% Irbesartan menurunkan doubling creatinine, risiko relatif ESRD, on set mulai dialisis Amlodipin group: fatal dan non fatal stroke turun 23%, total CV events turun 16%, all caused mortality turun 11% Indopamid + perindopril: fatal atau non fatal stroke turun 30%, risiko kematian stroke turun 39%, risiko kematian akibat penyakit jantung turun 23%, risiko CHF turun 64%

RENAAL study (2001)

1513

Losartan, Plasebo

3,4 tahun

< 140/90

IDNT (2001)

1715

Irbesartan, Amlodipine, Plasebo Amlodipine + Perindopril; Atenolol + Thiaside Indopamid, atau ditambah Perindopril

2,6 tahun

< 135/85

ASCOT BPLA study (2005) HYVET (2008)

19257

5,5 tahun

< 140/90 < 130/80 (DM)

3845

1,8 tahun

< 150/80

No. 6

Penelitian ASCOTBPLA (2005)

Jumlah Pasien 19257

Obat yang dipakai Amlodipine + perindropil, atenolol + bendroflumet iazide

Lama Penelitian 5.5 tahun

Target TD (mmHg) 140/90 (non diabetik), 130/80 (diabetik)

Hasil Amlodipe+perindropil menurunkan kejadian non fatal MI dan kejadian koroner fatal, menurunkan fatal dan non fatal stroke, menurunkan kejadian kardiovaskuler & prosedurnya, menurunkan seluruh penyebab mortalitas Rata-rata TD yang lebih rendah didapatkan pada telmisartan atau kombinasi telmisartan dan ramiipril, Efek samping lebih sering ditemukan pada ramipril. Hipotensi dan disfungsi ginjal lebih sering ditemukan pada telmisartan

ONTARGE T (2008)

25620

Telmisartan dan atau ramipril

56 bulan

Schematic comparison of a normal nephron, a nephron in diabetic nephropathy (DN), and a nephron in DN after administration of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB)

Guidelines for the management of arterial Hypertension. European Heart Journal (2007) 28, 14621536

Suggested Approach to Achieve BP Goal in Patients with Diabetes

ASH Position Paper: Treatment of Hypertension in Patients With Diabetes-An Update. J Clin Hypertens (Greenwich, 2008;10:707-713

Majority of Hypertensive Patients Need Multiple Medications for Effective Management

More Than 1 Agent Is Usually Required to Get to BP Goal
IDNT (135/85 mm Hg) UKPDS 83 (< 85 mm Hgdiastolic)

3.80 2.70 2.75 3.70 3.25 2.00 0 1 2 3 Number of Agents 4

ABCD (<75 mm Hgdiastolic) MDRD (<92 mm Hgmean arterial pressure) HOT (<80 mm Hgdiastolic)
ALLHAT (<140/90 mm Hg)

Multiple medications can increase the complexity of treatment

Bakris et al. Am J Kidney Dis. 2000;36:646-661; Brenner et al. N Engl J Med. 2001;345: 861-869; Lewis et al. N Engl J Med. 2001;345:851-860; Cushman et al. J Clin Hypertens. 2002;4:393-404. 32

Summary of treatment

The blood pressure goal is 130/80 mmHg. Multiple drugs are best to achieve target blood pressure. ACE inhibitors or ARBs should be part of the regimen. In type 1 diabetes mellitus with any degree of albuminuria, an ACE inhibitor/ ARB is necessary In type 2 diabetes mellitus with any degree of albuminuria, an ACE inhibitor/ARB is necessary, especially with renal insufficiency Start with ACE inhibitors or ARBs. If systolic blood pressure is > 20 mmHg higher than the goal of 130 mmHg, add a diuretic or calcium-channel blocker. If still uncontrolled, add an ACE-I or ARB, plus diuretic, plus calcium channel blocker. If still uncontrolled, add an aldosterone-receptor blocker. Add statin to reduce macrovascular risk.
Management issues in hypertensive diabetics. S Afr Fam Pract 2011; 53: 144-148

 Lifestyle therapy for hypertension consists of: weight loss, if overweight; Dietary Approaches to Stop Hypertension (DASH)style dietary pattern including reducing sodium and increasing potassium intake; moderation of alcohol intake; and increased physical activity. (B) Pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. If needed to achieve blood pressure targets, a thiazide diuretic should be added to those with an estimated GFR (eGFR) (see below) 30 ml/min/1.73 m2 and a loop diuretic for those with an eGFR < 30 ml/min/1.73 m2. (C) Multiple drug therapy (two or more agents at maximal doses) is generally required to achieve blood pressure targets. (B)
ADA, Standards of Medicalcare in Diabetes. Diabetes Care 2011;34 (Suppl 1):S11-S61

Summary

Major guidelines suggested that the goal BP in patients with DM is less than 130/80 mmHg An ACEI or ARB is clearly preferred as initial therapy in any hypertensive diabetic patient. Other antihypertensive drugs can be added if the BP goal is still not achieved: CCB, diuretics, BB, alpha-blocker