Strengthening the Global Risk

Management
 Hypertension is the number one risk factor
for global attributable mortality

World Health Organisation. Global atlas on cardiovascular disease prevention and control. 2011.
CVD = Cardiovascular Disease Available at: http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/index.html
 MRFIT trial:
Patients with hypertension and diabetes are at high risk of CV mortality
CV death rate per 10,000 person-years

300
Men with diabetes (n=5163) 242.6
250
Men without diabetes (n=342,815)

200
158.7 155.7
150 128.7
108.2
100 79.3
65.5 56.5
53.6
50 34.2
12.2 19.1

0
<120 120-139 140-159 160-179 180-199 ≥200

Systolic BP (mmHg)
BP = blood pressure;
MRFIT = Multiple Risk Factor Intervention Trial Stamler et al. Diabetes Care 1993;16:434–444
 Diabetes and hypertension increase the risk of
chronic kidney disease as well as CV disease

Chronic kidney disease CV disease

Kidney failure End Heart failure
stage

Decreased GFR Progression CV event

Albuminuria Initiation CAD, LVH

At increased risk

Risk factors: Diabetes, hypertension, age,

family history
CAD = coronary artery disease; CV = cardiovascular;
GFR = glomerular filtration rate; LVH = left ventricular hypertrophy
National Kidney Foundation. Am J Kidney Dis 2007;49(Suppl2):S1–S180
 Diabetes and hypertension are the leading causes of end-stage renal
disease (ESRD)

No. of US patients† (in thousands)1 Causes of ESRD

50
Diabetes
40
Hypertension
30

20

10
Glomerulonephritis
Cystic kidney
0
1980 1984 1988 1992 1996 2000 2004 2008
Year

In patients with diabetes and hypertension, the risk of developing ESRD is 5- to 6-times
greater than in individuals with hypertension alone2

†IncidentESRD patients; rates 1. USRDS 2009 Annual Data Report. NIH/NIDDKD, Bethesda, MD, 2009
adjusted for age, gender and race 2. Bakris et al. Am J Kidney Dis 2000;36:646–61
Absolute risk of CVD over 5 years by systolic blood
pressure at specified levels of other risk factors

Jackson et al. Lancet 365: 434, 2005

Anderson et al. Am Heart J 121: 293, 1991
Patients with co-morbid hypertension and diabetes have significantly
higher costs than patients with hypertension or diabetes alone

Eaddy MT et al. Curr Med Res Opin. 2008 Sep;24(9):2501-7

Burden of Hypertension in Developing Countries

31.7

Sharma et al. IHJ Feb 2006, Pakistan Med Research Council; Wolf‐Maier et al. JAMA 2003;289:2363 9
WHO bulletin; Gu et al. Hypertension 2002;40:920 7; Jo et al. J Hypertens 2001;19:1523 32; Riskedas Indonesia 2007
 More than 371 million people have diabetes.
Top 10 Countries/ Territories for People With Diabetes (20-79 years)

http://www.idf.org/sites/default/files/5E_IDFAtlasPoster_2012_EN.pdf
Prevalence of raised blood cholesterol in males*
(ages > 25 years old)

World Health Organisation. Global atlas on cardiovascular disease prevention and control. 2011.
Available at: http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/index.html
Crosslink CV - Metabolic diseases

Hypertension Diabetes

Lipid
abnormalities
Aldosterone and Angiotensin II inhibit insulin metabolic signaling in skeletal muscle

Progress in Cardiovascular Diseases 52 (2010) 401–409

Cardiometabolic Syndrome: Pathophysiology
RAS system interacts on Cardiometabolic Syndrome

AII—angiotensin II; ACE—

angiotensin-converting
enzyme; AGT—
angiotensinogen; CO—
cardiac output; FFA—free
fatty acid; NE—
norepinephrine;

NOS—nitric oxide
synthase; PI3-K—
phosphoinositide 3-kinase;
PKB—protein kinase B;
PRA—plasma renin
activity; PVR—peripheral
vascular resistance;
SNS—sympathetic
nervous system; TNF-α—
tumor necrosis factor-α.

Current Hypertension
Reports 2003, 5:393–401
CVD risk markers that contribute to global cardiometabolic risk

Can J Cardiol. 2011 Mar-Apr;27(2):e1-e33

CV Risks Scoring
 NCEP ATP III: Framingham Score
 Gender 10-year risk
 Age
• > 20% - CHD risk
 Total cholesterol equivalent
 Smoking • 10-20 %
 HDL • < 10%
 Systolic BP

 ESC/EAS 2011: SCORE

 Gender 10-year risk
 Age • > 10%: very high risk
 Total cholesterol • > 5%: high risk
 Smoking • > 1%: moderate risk
 Systolic BP • 1%: low risk
SCORE Chart

10-year risk of fatal

cardiovascular
disease (CVD) in
populations at high
CVD risk based on
the following risk
factors

European Heart Journal (2011) 32, 1769–1818

ESHESC and JNC 7 Guidelines Recommend Target BP Goals of <140/90 mmHg
for Uncomplicated Hypertension and <130/80 mmHg for Complicated Hypertension

Type of hypertension BP goal (mmHg)

Uncomplicated <140/90
Complicated
Diabetes mellitus <130/80
Kidney disease <130/80*
Other high risk (stroke, myocardial <130/80
infarction)
*Lower if proteinuria is >1 g/day

Non-diabetic chronic kidney disease — BP Target < 140/90 mmHg

2012
Task Force of ESH–ESC. J Hypertens 2007;25:110587
Chobanian et al. Hypertension 2003;42:1206–52
CHEP Guideline 2012
2011

Target goal

European Heart Journal (2011) 32, 1769–1818

TREATING GLOBAL RISKS
 Cardiovascular and metabolic abnormalities and treatment strategies
in the cardiometabolic syndrome

ACE—angiotensin-converting enzyme; ARB—angiotensin receptor blocker; ASA—acetylsalicylic acid; HMG-CoA—β-hydroxy-β-methylglutaryl coenzyme A;

IGF-1—insulin growth factor-1; LDL—low-density lipoprotein; RAAS—renin-angiotensin-aldosterone system; SBP—systolic blood pressure
Current Hypertension Reports 2003, 5:393–401
 Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS

Any Diabetic DM Microvascular

Stroke Endpoint Deaths Complications
0
5%
% Reduction In Relative Risk

10%
-10 12%

-20
24%

*
-30 32% 32%

* 37%
*P <0.05 compared to tight glucose control
-40 *
44%
Tight Glucose Control Tight BP Control
* (Goal <6.0 mmol/l or 108 mg/dL) (Average 144/82 mmHg)

-50

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661. Reprinted by permission, Harcourt Inc.
 The importance of controlling the RAAS in patients with
diabetes and hypertension

ESH/ESC guidelines for patients with hypertension and diabetes:1

‘A blocker of the renin-angiotensin system should be a regular

component of combination treatment and the one preferred when
monotherapy is sufficient’

ADA guidelines for patients with hypertension and diabetes:2

‘In people with diabetes, inhibitors of the renin-angiotensin system

(RAS) may have unique advantages for initial or early therapy of
hypertension’

JNC VII guidelines for patients with hypertension and diabetes:3

‘Combinations of 2 or more drugs are usually needed to achieve the target BP
goal of less than 130/80 mmHg’

ADA = American Diabetes Association 1. Mancia et al. J Hypertens 2007;25:1105–1187

ESH = European Society of Hypertension 2. ADA. Diabetes Care 2010;33(Suppl 1):S11–61
ESC = European Society of Cardiology 3. Chobanian et al. JNC VII Guideline
ESHESC Recommendations for Combining BP-lowering
Drugs and Availability as Single-pill Combinations
Diuretics

Angiotensin
b-blockers receptor blockers
(ARBs)

Calcium channel
a-blockers
blockers (CCBs)

Angiotensin-converting enzyme (ACE) inhibitors

Available as a single-pill combination

Less frequently used/combination used as necessary

Task Force for ESH–ESC. J Hypertens 2007;25:1105–87

Amlodipine/Valsartan Provides Effective BP Reduction Among
Patients at CV Risk

Schrader et al. ESH 2008 (poster presentation)

 Amlodipine/Valsartan: Up to 9 Out of 10 Patients Reach
BP Goal <140/90 mmHg

“Diabetic patients with BP <130/80 mmHg at Week 8 were

47.0% and 49.2% for 5/160 mg and 10/160 mg doses,
respectively”

5 of 10 hypertensive diabetic patients achieved BP goal

(<130/80 mmHg)

No hydrochlorothiazide add-on was permitted until after Week 8

Randomized, double-blind, multinational, parallel-group, 16-week study Allemann et al. J Clin Hypertens 2008;10:185–94
 Recommendations:
Diabetes - Dyslipidemia/Lipid Management
Treatment recommendations and goals
• Statin therapy should be added to lifestyle
therapy, regardless of baseline lipid levels,
for diabetic patients:
– with overt CVD (A)
– without CVD who are >40 years of age and have one or
more other CVD risk factors (A)

• For patients at lower risk (e.g., without

overt CVD and <40 years of age) (E)
– Statin therapy should be considered in addition to
lifestyle therapy if LDL cholesterol remains >100
mg/dl
– In those with multiple CVD risk factors
ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S29.
Comparable LDL and TG lowering of Fluvastatin XL with significant improvement of HDL
and small-dense LDL compared with Simvastatin 20 mg in Type 2 Diabetic

20
14 **
% change from baseline after 8 weeks

10
0.1
0
LDL Trigliserida HDL small-dense
LDL
-10
Fluvastatin 80 mg (n=48)
Simvastatin 20 mg (n=46)
-20
* p < 0.01 vs baseline
‡
-30 p not significant

-33 * **p < 0.01 vs Simvastatin

-40 -38 ***p < 0.05 vs Simvastatin
*‡
-45
-50 -48 * ***
-51
*‡
-55 *
-60
Bevilacqua M, et al. Adv Ther. 2005 Nov-Dec;22(6):527-42
Vasodilative effect of Incretins

Adapted from J Diabetes. 2012 Mar;4(1):22-

Vildagliptin: Mean Change in Blood Pressure in T2DM Patients with
SBP >140 mmHg and DBP >90 mmHg
Duration: 52 weeks
Vildagliptin vs metformin

DBP SBP
n= 89 53 150 84
BL= 94 94 149 150
0.0
Change from BL (mmHg)

-5.0 -4.2

-5.3

-7.5
*
-9.1
-10.0 Vildagliptin 50 mg twice daily
*
BL=baseline; DBP=diastolic blood pressure; SBP=systolic blood pressure; T2DM=type 2 diabetes mellitus.
Metformin 1000 mg twice daily
*P <0.05 vs metformin.
Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL. Abstract 521-P.

29
 Vildagliptin: Effect on Lipid Parameters Relative to Rosiglitazone

Duration: 24 weeks
Vildagliptin
vs rosiglitazone
14 TG TC LDL-C HDL-C

12
10
8
Change from Baseline (%)

6
4 **
2
0
−2
*
−4
** **
−6 Vildagliptin 50 mg twice daily (n=449)
Rosiglitazone 8 mg once daily (n=231)
−8
HDL=high-density lipoprotein; LDL-C=low-density lipoprotein cholesterol; TC=total cholesterol; TG=triglycerides.
Primary intention-to-treat population; n refers to the patient number in the TG test. *P=0.01; **P <0.003 vs rosiglitazone.
Rosenstock J, et al. Diabetes Care. 2007; 20: 217–223.
30
 SUMMARY

 Hypertension, high blood glucose and high cholesterol are still burden
for global mortality

 Comorbidities of these cardiometabolic disease increases mortality and

morbidity

 RAS blocker play important role on cardiometabolic disease

 Combination antihypertensive therapy are recommended to improve BP

lowering effect and achieve BP target on hypertensive diabetic or
hypertensive dyslipidemia patients

 Statin is recommended as first line therapy on dyslipidemic diabetic

patients, for its LDL lowering and pleitropic effects.

 DPP4-inhibitor has beneficial effects else than lowering HbA1c, also

improving BP and lipid profiles.