hyper tension and diabetes the two terrorists together

HYPERTENSION AND DIABETES: THE TWO TERRORISTS TOGETHER

Kyaw Soe WinMBBS, MMedSc (Int Med), MRCPUK, FRCP (Edin), FAsCC, FAPSIC

Hot Topic in Cardiology 2014

Sedona Hotel23rd March 2014

The Two Terrorists in Cardiovascular World

The ENORMITY of the problem - compounded

How Common is this deadly Duo?

HTN is twice as common in DMHTN is twice as common in DM

New onset DM is 2.5 times in HTNNew onset DM is 2.5 times in HTN

20 to 40% of IGT pts have HTN20 to 40% of IGT pts have HTN

40 to 50% of Type 2 DM have HTN40 to 50% of Type 2 DM have HTN

Only 1/4 of HTN in DM is controlledOnly 1/4 of HTN in DM is controlled

DM + HTN – CV Risk 3 foldDM + HTN – CV Risk 3 fold

long-term survivors of diabetes tend to have lower BP

HTN in DM: Prevalence Hypertension in Type 1 and 2 Diabetes

Type 1

Develop after several years of DM

Ultimately affects ~30% of patients

With macroalbuminaemia-65-88%

Type 2

Mostly present at diagnosis

Ultimately affects at least 60% of patients

With macroalbuminaemia->90%

Percent Chance of Percent Chance of Cardiovascular Event in 5 YearsCardiovascular Event in 5 Years

No DiabetesNo Diabetes

>20%>20%15%15%--20%20%10%10%--15%15%5%5%--10%10%2.5%2.5%--5%5%<2.5%<2.5%

44 55 66 77 88 44 55 66 77 88 44 55 66 77 88 44 55 66 77 88

MenMenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

WomenWomenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

AgeAge7070

AgeAge6060

AgeAge5050

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

Percent Chance of Percent Chance of Cardiovascular Event in 5 YearsCardiovascular Event in 5 Years

DiabetesDiabetes

44 55 66 77 88 44 55 66 77 88 44 55 66 77 88 44 55 66 77 88

MenMenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

WomenWomenNonsmokerNonsmoker SmokerSmokerTotal Chol.:HDLTotal Chol.:HDL--Chol.Chol.

AgeAge7070

AgeAge6060

AgeAge5050

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

180/105180/105160/95160/95140/85140/85120/75120/75

>20%>20%15%15%--20%20%10%10%--15%15%5%5%--10%10%2.5%2.5%--5%5%<2.5%<2.5%

How and Why

DM + HT is dangerous?

The EVIDENCE BASE

SBP = systolic blood pressure; DBP = diastolic blood pressure.*Individuals aged 40-69 years, starting at blood pressure 115/75 mm Hg

Chobanian AV et al. JAMA. 2003;289:2560-2572.Lewington S et al. Lancet. 2002;360:1903-1913.

Cardiovascular Mortality Risk Doubles With Each 20/10 mm Hg BP Increment*

CardiovascularMortality

Risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

2x

4x

8x

Association of SBP and CV Mortalityin Men With Type 2 Diabetes

250

200

150

100

50

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

SBP (mm Hg)

CVmortality

rate/10,000

person-yr

NondiabeticDiabetic

CV, cardiovascular; SBP, systolic blood pressure.Stamler J et al. Diabetes Care. 1993;16:434-444.

≥200

End Point Hazard Ratios Associated With Increase in SBP

Hazard ratio

Adler A et al. BMJ. 2000;321:412–419.

Updated mean SBP (mm Hg)

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

110 120 130 140 150 160 170

Any end point related to diabetes (P<0.0001)

Death related to diabetes (P<0.0001)

All-cause mortality (P<0.0001)

HOT Study: Risk of Morbidity and Mortality inDiabetic Hypertensive Patients

Myocardial Infarction

Major CV Events

Stroke

CV Mortality

Total Mortality

90 mmHg80 mmHg

0 1 2 3 4

| | | |

Lancet 1998; 351: 1755–62

Each Perpetuates the Other

DiabetesDiabetes HypertensionHypertension

HTN in DM: PARTNERS IN CRIME

HTN vs No HTN DM vs No DM

2.4 x ↑ in DM 2.0 x ↑ in HTN

NEJM 2000; 342:905 Diabetes Care 2005; 28:310

Cause:Cause: Hypertension is usually Hypertension is usually renoparenchymalrenoparenchymal in origin in origin caused by Or pointing to underlying diabetic nephropathycaused by Or pointing to underlying diabetic nephropathy

Onset:Onset: Typically becomes manifest about the time that Typically becomes manifest about the time that patients develop patients develop microalbuminuriamicroalbuminuria. .

American Diabetic Association. American Diabetic Association. DiabDiab Care 2004Care 2004

Cause:Cause: Mainly due insulin resistance (as a facet of MS) Mainly due insulin resistance (as a facet of MS) But may be due to underlying DN or other causes.But may be due to underlying DN or other causes.

American Diabetic Association. Diab Care 2004

Onset: Onset: Usually precedes the onset of nephropathy and Usually precedes the onset of nephropathy and even the onset of type 2 diabetes by years or decade even the onset of type 2 diabetes by years or decade

Ritz et al. J Int Med. 2001 ; 249: 215Ritz et al. J Int Med. 2001 ; 249: 215--223223

DM-2

DM-1



Progression of DM - Nephropathy

Microalbuminuria as a Risk Factor for Death in Type 2 Diabetes

UAC, urinary albumin concentration.Adapted from Schmitz A et al. Diabetes Med. 1988;5:126-134.

Years after Diagnosis

Sur

viva

l

UAC ≤15 µg/mL

UAC 16-40 µg/mL

UAC 41-200 µg/mL

0.0

0.4

1.0

0.8

0.6

0.2

0 5 1021 3 4 76 8 9 11

Proteinuria & Risk of CV Mortality, Stroke, & CHD Events in Type 2 Diabetes

CHD, coronary heart disease; UPC, urinary protein concentration.CHD, coronary heart disease; UPC, urinary protein concentration.* Defined as CHD death or nonfatal MI.* Defined as CHD death or nonfatal MI. Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039.Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039.

A: UPC <150 mg/L B: UPC 150-300 mg/L C: UPC >300 mg/L

1.0

0.9

0.8

0.7

0.6

0.5

00 10 20 30 40 50 60 7080 90 Stroke CHD Events*

P<.001 for trends

Inci

denc

e (%

)

Red

uctio

n in

Sur

viva

l due

to

CV

Mor

talit

y

Months

A

B

C

P-values:Overall <.001A vs B =.013A vs C <.001B vs C <.001

0

10

20

30

40



The risk of diabetes associated with antihypertensive-drug therapy appears to be explained by the presence of hypertension.

Among the subjects who had hypertension, the risk among those not taking medication was similar to that among those taking one or more agents.

Among the subjects who were not taking any antihypertensive medication, the risk of diabetes was much higher among hypertensive Pts. than in non hypertensive.

0

5

10

15

Chlorthalidone Amlodipine Lisinopril

11.6%

9.8%8.1%

ALLHAT: Incidence of New-Onset Diabetes at 4 Years

JAMA 2002;288:2981-2997

Role of Antihypertensive Drugs



Taking a thiazide diuretic, ACE Taking a thiazide diuretic, ACE inhibitor, or CCB carry no inhibitor, or CCB carry no greater risk for the subsequent greater risk for the subsequent development of DM. development of DM.

DM was 28 percent more likely DM was 28 percent more likely to develop in subjects taking to develop in subjects taking BB than in those taking no BB than in those taking no medication.medication.

This adverse effect of BB must This adverse effect of BB must be weighed against the proven be weighed against the proven benefits of this drug in benefits of this drug in reducing the risk of reducing the risk of cardiovascular events cardiovascular events

Role of Antihypertensive Drugs

β-Blockers and the risk of new-onset diabetes mellitus

Prospective study of 12 550 patients w/o DM, aged 45-64, followed for 6 y. Multivariate analysis of 3804 who had HT at baseline.

1. Lancet 2002;359:995–1003. 2. N Engl J Med 2000;342:905–12.

Prospective study of 9193 hypertensives, aged 55-80, followed for 4.8 y. Analysis of 7998 w/o DM at baseline.

17.4

13.0

0

5

10

15

20

Atenolol Losartan

LIFE1

New

Cas

es P

er 1

000

Per

son

-Yea

rs (

%)

ARIC2

0

.5

1.0

1.5

Haz

ard

Rat

io

Atenolol RR 1.25 (1.12-1.37)

P<.001

25% Increased Riskβ-blocker RR 1.28 (1.04-1.57)

P<.05

28% Increased Risk

Thiazide

0.91

β-blocker

1.28

None

1.0

1.17

CCB

0.98

ACEI

Association between refractory hypertension and cardiometabolic risk

The HIPERFRE study, 2008

1,724 hypertensive patients, 35 physicians, 14 Primary Care Units

The HIPERFRE study, 2008The HIPERFRE study, 2008 1,724 hypertensive patients, 35 physicians, 14 Primary Care Units



Hypertensive patients without diabetes tend to be resistant to insulin and are hyperinsulinaemic compared with normotensive controls. Pollare T et al. Metabolism 1990, 39(2):167-174.

About 20% of patients with hypertension will develop type 2 diabetes in a three year period. Bosch J et al. N Engl J Med 2006, 355(15):1551-1562.

Fasting glucose levels increase in older adults with hypertension regardless of treatment type. BarzilayJ I et al. Arch Intern Med. 2006;166:2191-2201

The RAS itself plays imp. role in the development of diabetes.

Over activity of RAS appears to be linked to reduced insulin and glucose delivery to the peripheral skeletal muscle and impaired glucose transport and response to insulin signalling pathways, thus increasing insulin resistance.

Jandeleit-Dahm KA et al. J Hypertens 2005, 23(3):463-473.

Activation of a local pancreatic RAS, in particular within the islets, may represent an independent mechanism for the progression of islet cell damage in diabetes.

Ferrannini E et al. Diabetologia 2003, 46(9):1211-1219.


The Compound Jeopardy !!

2 x 4 x

Reilly MP et al – Circulation 2003; 108: 1546-1551

Plasma Glucose as Independent Risk Factor

Andersson, DK et al. Diabetes Care 18: 1534-1543

Effect of Hypertension on mortality in DM

Mortality vs systolic blood pressure

0

10

20

30

40

50

60

70

110 120 130 140 150 160

Systolic Blood pressure (mmHg)

Te

n Y

ea

r M

orta

lity

(p

er 1

000)

Non-diabetic

Diabetic

Effect of Cholesterol on Mortality in DM

Serum cholesterol vs Mortality

010203040506070

4 5 6 7

s-Cholesterol (mmol/L)

Ten

Yea

r M

ort

ality

(per

10

00) Non-diabetic

Diabetic

DEATH

LDL=low-density lipoprotein; HDL=high-density lipoprotein; MI=myocardial infarction; CHD=congestive heart failiure; HF=heart failure; ESRD=end-stage renal diseaseAdapted from Arch Intern Med. 2000; 160:1277-1283.

Insulin Resistance

Hyper-insulinemia

Triglycerides

LDLHDL

Visceral Fat

Angiotensin II

SympatheticActivity

+ Hypertension

Diabetes

CHD

Stroke

MI

HF

ESRD

Metabolic Syndrome Morbid States


Perpetuating Circus

CKD

Diabetes

BP

Lipids

CAD

ED

Diabetes promotes both the development and adverse impact of cardiovascular disease (CVD) risk factors (e.g. hypertension, dyslipidemia, renal dysfunction) and, as a consequence, accelerates cardiovascular age.

Persons with diabetes generally have a cardiovascular age 10 to 15 years in advance of their chronological age.

Advanced cardiovascular age substantially increases both the proximate and lifetime risk for CVD events, resulting in a reduced life expectancy of approximately 12 years.

2013 Canadian Diabetes Association guidelines

HTN in DM: Accelerates Vascular Age

HTN in DM: Facts

•Hypertension in diabetes :– it accelerates macrovascular disease– it accelerates microvascular disease

Glycemic control only is not enough

VASCULAR PROTECTION IS IMPORTANT

HypertensionDyslipidemia

Dysglycemia

Vascular Protection for CAD and CKD in DM

The EVIDENCE BASE

MANAGEMENT Guide

2 main sets of guidelines utilized in U.S. American Diabetes Association (ADA) American Association of Clinical Endocrinology (AACE)

(Lots of overlap, Evidence based, well accepted, clinically relevant and can be easily incorporated into clinical practice)

Canadian Diabetes Association 2013 Clinical Practice Guidelines (September 2013)

ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD ( August 2013 )

Diabetes Guideline Management

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association

The Essentials

Presentation by Dr. Tessa Laubscher Clinical Associate Professor, Family MedicineSaskatoon

Sept 2013

Canadian Diabetes Association 2013 Clinical Practice Guidelines

STANDARDS OF MEDICAL CARESTANDARDS OF MEDICAL CAREIN DIABETES—2014IN DIABETES—2014

1. Blood Pressure Goal

2. Life Style Modification

3. Phamacological Therapy

HTN in DM: Therapy

UKPDS Mean Blood Pressures

Less tight control 160/94 154/87

Tight control 161/94 144/82 Difference 1/0 10/5 P value n.s. <0.0001

Baseline(mm Hg)

Mean BP over 9 yrs(mm Hg)

UKPDS, United Kingdom Prospective Diabetes Study.UKPDS 38. BMJ. 1998;317:703-713.

Tight Glucose ControlTight Glucose Control

Tight BP ControlTight BP Control

**P < 0.05P < 0.05-50 -

-40 -

-30 -

0 - StrokeAny DM End Point DM Death

Microvascular Complications

Red

uctio

n in

Ris

k (%

)

UKPDS. BMJ. 1998:317;703-712.

-20 -

-10 -

Tight BP Control vs. Tight Glucose Control

Comparisons of More Intensive Blood Pressure Lowering Strategies With Less Intensive Strategies

0

5

10

15

20

25

Eve

nts

/10

00

pt-

year

s

<90 <85 <80

Target diastolic BP

DMnon-DM

Lancet 1998; 351: 1755–62

HOT Study(Diabetic Subgroup): Significant Benefit From Intensive Treatment in the DBP

HOT (Hypertension Optimal Treatment). ABCD-NT (Appropriate Blood Pressure Control in Diabetes) UKPDS (UK Prospective Diabetes Study) IDNT (Irbesartan in Diabetic Nephropathy Trial) INVEST (International Verapamil-Trandolapril) ADA (American Diabetic association) ISHIB (International Society of Hypertension in Blacks) CHEP (Canadian Hypertension Education Program) BHS (British Hypertension Society) JNC 7 (Joint National Committee 7)

HTN in DM: Therapy

Goal Blood PressureGoal Blood Pressure

Less Than 130/80

BP Targets in DM ( before 2013)

Ideal Blood Pressure

Without proteinuria < 130/80

With proteinuria < 125/75

Goal BP maximum for DM < 130/80

Almost all DM pts require > 1 drug for HTN

Identify the co-morbidity – CAD, CKD, CVD

National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3):646-661.

American Association of Clinical Endocrinologist, 2006 Target BP 125/75 If Proteinuria > 1gm

HTN in DM: Therapy

Goal Blood PressureGoal Blood Pressure Less Than 130/80

Can We Go to More Lower Target ?

IDNT JASN 2005;16(7):2170–2179

ACCORD trial , >4700 patients were assigned to intensive- ( achieved mean SBP 119mmHg) or standard treatment ( mean SBP 134mmHg) over a mean follow-up of 4.7 years.

The proportion of patients with serious side-effect- such as hypotension and declining renal function_ increased from 1.3 to 3.3% with aggressive treatment.

Since the risk-benefit ratio tipped towards harm, this study does not support a reduction of systolic BP below 130mmHg.

ACCORD trial

Lowest Systolic Blood Pressure Is Associated with Stroke in Stages 3 to 4 Chronic Kidney Disease

J Am Soc Nephrol 18: 960–966, 2007

HR of Stroke vs SBP

Can We Go to More Lower Target ?

HTN in DM: Therapy

Goal Blood PressureGoal Blood Pressure Less Than 130/80

20,358 individuals studied, 1549 (7.6%) had CKD

Bangalore et al. reported a meta-analysis of 13 RCTs with 37 736 patients with DM,IFG or IGT who, in the intensive group, had a systolic pressure ≤135 mm Hg and, in the standard group, ≤140 mmHg.

The more intensive control related to a 10% reduction in all-cause mortality (95% CI 0.83–0.98), a 17% reduction in stroke but a 20% increase in serious adverse events. Systolic BP ≤130 mmHg was related to a greater reduction in stroke but did not affect other cardiovascular events.

Can We Go to More Lower Target ?Less Than 130/80Goal Blood PressureGoal Blood Pressure

Rethinking Lower Blood Pressure Goals for Diabetic Patients with Coronary Artery Disease – Findings from the INternational VErapamil SR – Trandolapril STudy (INVEST)

Rhonda M. Cooper-DeHoff, Yan Gong, Eileen M. Handberg, Anthony A. Bavry, Scott J. Denardo, George L. Bakris and

Carl J. Pepine

on behalf of the INVEST Investigators

University of Florida

Gainesville, FL

Methods

Results: Outcome Rates

INVEST Follow Upn=6400

Tight Controln=2,255

Usual Control n=1,970

Not Controlled

n=2,175

p value

Outcome # of Events (Event Rate %)

Primary Outcome 286 (12.7) 249 (12.6) 431 (19.8) < 0.0001

Nonfatal MI 29 (1.3) 33 (1.7) 67 (3.1) 0.008

Nonfatal Stroke 22 (1.0) 26 (1.3) 52 (2.4) 0.001

Total MI 108 (4.8) 100 (5.0) 185 (8.5) < 0.0001

Total Stroke 34 (1.5) 33 (1.7) 70 (3.2) 0.0001

All Cause Mortality 248 (11.0) 201 (10.2) 334 (15.4) < 0.0001

Extended Follow Upn=4370

Tight Controln=1,389

Usual Control n=1,423

Not Controlled

n=1,558

p value

Outcome # of Events (Event Rate %)

All Cause Mortality 270 (19.4) 259 (18.2) 370 (23.7) 0.01

(n=2,255)

Reference

Results: Outcomes – Tight Control Group

Summary

Goals People with diabetes and hypertension

should be treated to a systolic blood pressure goal of <140 mmHg

Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden

Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg

Recommendations: Hypertension/Blood Pressure Control

ADA. VI. Prevention, Management of Complications. Diabetes Care 2014;37(suppl 1):S36

ADA 2014ADA 2014

Treatment Patients with blood pressure >120/80 mmHg

should be advised on lifestyle changes to reduce blood pressure

Patients with confirmed blood pressure higher than 140/80 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely subsequent titration of pharmacological therapy to achieve blood pressure goals

Recommendations: Hypertension/Blood Pressure Control


ADA 2014ADA 2014


Hypertension / BP control

• Screening and diagnosis– BP should be measured at every diabetes related visit and at least twice a

year.– Patients found to have elevated BP should have high BP confirmed on a

separate day.– Threshold for diagnosing hypertension in person with diabetes is BP ≥130/80

mmHg (may consider SBP up to 140 in elderly). – Target for treating BP is <130/80.

• Lifestyle therapy for elevated BP– Weight loss if overweight– DASH-style diet with reduced sodium and increased potassium intake– Moderation of alcohol intake– Increased physical activity

The EVIDENCE BASE FOR

Non- Pharmaco and

Pharmacotherapy

Intervention Intervention TargetTarget

Reduce foods with Reduce foods with added sodiumadded sodium < 2300 mg /day< 2300 mg /day

Weight lossWeight loss BMI <25 kg/mBMI <25 kg/m22

Alcohol restrictionAlcohol restriction Less or equal to 2 drinks/dayLess or equal to 2 drinks/day

Physical activityPhysical activity at least 30 minutes 4 times/weekat least 30 minutes 4 times/week

Dietary patternsDietary patterns DASH dietDASH diet

Smoking cessationSmoking cessation Smoke free environmentSmoke free environment

Waist CircumferenceWaist Circumference- Europid, Sub-Saharan - Europid, Sub-Saharan African, Middle EasternAfrican, Middle Eastern- South Asian, Chinese- South Asian, Chinese- Japanese- Japanese

Men WomenMen Women <94 cm <80 cm<94 cm <80 cm

<90 cm <80 cm<90 cm <80 cm <85 cm <90 cm<85 cm <90 cm

HTN in DM: Therapy

Life Style ModificationsLife Style Modifications

DASH Diet Plan

Type of Food Servings (1600 K cal)

Grains (whole grains) 6 per day

Vegetables 3 per day

Fruits (not tinned juices) 4 per day

Low fat milk 2 per day

Lean meat, poultry 3 per day

Nuts, seeds (dry roast, soak) 3 per week

Fats and oils 2 per day

Sweets and pastries 0 per day

Salt at table & salted foods None

HTN – Lifestyle modifications

Hypertension In Diabetes

Does choice of Antihepertensive

Drug matter?

Yes

Pathophysiology of hypertension in DM

Type 1 DM

Secondary to

nephropathy

Activation of the

RAAS

Type 2 DM

Hyperinsulinemia

Secondary to insulin resistance

Activation of the sympathetic nervous

system

Ideal anti HTN drug in DM

Must decrease blood pressure to ≤ 140/80 Must reduce the RAAS activity, improve ED Must prevent, improve or arrest proteinuria Must prevent and protect from CAD, CKD, CHF Must be favourable on glycemic control Must improve the dyslipidemia – not worsen it Must not worsen peripheral arterial disease Must improve ED and not cause impotence Must not decrease eGFR and serum creatinine Must not raise uric acid, serum potassium

Management Options

Diuretics

NDHP - CCBs

MNT

ExerciseNew BB

ACEi, ARB

ACEi or ARB – A must for VP

Antihypertensive, vasoprotective,

anti-thrombotic and anti-inflammatory Inevitable in DM more so in DM + HT/CVD Reduce CV events, Reduce atherosclerosis Reduce renal disease - a strong CV risk factor Metabolically ‘friendly’ drugs in DM They prevent new onset DM, Nephropathy Well-tolerated with few side effects

Vascular Protection ACE inhibitor Trials

Heart Outcomes Prevention Evaluation Study

A large, simple, randomized trial of Ramipril and vitamin E in patients at

high risk for cardiovascular events

0

0.05

0.1

0.15

0.2

0 500 1000 1500

Days of Follow-up

Kap

lan

-Mei

er R

ates

Ramipril Placebo

Primary Outcome - Ramipril vs Placebo

RR=0.78 (0.70-0.86) P=0.000002

Prespecified Subgroups – Ramipril vs Placebo

0.6 0.8 1.0 1.2RR (95% CI)

CVD+

CVD-

Diabetes

+

Diabetes

-

No. Of

Pts.

8160

1137

3578

5719

Placebo Rate

18.7

10.1

19.8

16.5

Conclusions: Ramipril vs Placebo

There is overwhelming evidence that Ramipril prevents: CV death, strokes and MI Heart Failure, Revascularization Development of diabetes Diabetic microvascular complications and

NephropathyThese benefits are consistently observed in a very broad

range of high risk patients and in addition to other effective therapies

The only adverse event is a 5% excess of cough

Study endpointsStudy endpoints

CV mortality + non fatal MI + cardiac arrestCV mortality + non fatal MI + cardiac arrest

Primary endpointPrimary endpoint

Secondary endpointsSecondary endpoints

Total mortality + non fatal MI + unstable angina +Total mortality + non fatal MI + unstable angina +

cardiac arrestcardiac arrest

Heart failureHeart failure

Revascularisation (PCI/CABG)Revascularisation (PCI/CABG)

StrokeStroke

PerindoprilPerindopril(%)(%)

PlaceboPlacebo (%)(%)

HypertensionHypertension 27.027.0 27.227.2

Diabetes mellitusDiabetes mellitus 11.811.8 12.812.8

HypercholesterolaemiaHypercholesterolaemia 63.363.3 63.363.3

Current smokerCurrent smoker 15.415.4 15.115.1

Risk factorsRisk factors

Primary endpointPrimary endpoint

% CV death, MI or cardiac arrest% CV death, MI or cardiac arrest

Placebo annual event rate: 2.4%Placebo annual event rate: 2.4%

Perindopril Perindopril

PlaceboPlacebop = 0.0003p = 0.0003RRR: RRR: 20%20%

YearsYears00

22

44

66

88

1010

1212

1414

00 11 22 33 44 55

Fatal and non fatal MIFatal and non fatal MI

PerindoprilPerindopril

PlaceboPlacebo

00

22

44

66

88

1010

00 11 22 33 44 55 YearsYears

(%)(%)

p < 0.001p < 0.001RRR: 24%RRR: 24%

Heart FailureHeart Failure

Perindopril Perindopril

PlaceboPlacebo

5500 11 22 33 44 YearsYears

p = 0.002p = 0.002RRR: 39%RRR: 39%

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0(%)(%)

Sub-groups analysisSub-groups analysis

0.50.5 1.01.0 2.02.0

HypertensionHypertension

RRR RRR (%)(%)PerindoprilPerindoprilbetterbetter

PlaceboPlacebobetterbetter

No hypertensionNo hypertension

Diabetes mellitusDiabetes mellitus

No diabetes mellitusNo diabetes mellitus

Stroke/TIAStroke/TIA

No stroke/TIANo stroke/TIA

18.618.6

19.919.9

18.918.9

19.019.0

15.815.8

19.919.9

The Prevention of Events with Angiotensin Converting

Enzyme Inhibit ion (PEACE) Trial

A double-blind, placebo-controlled, randomized trial

Sponsored by the National Heart, Lung, and Blood Institute

Study medication and additional support provided by Abbott Laboratories/Knoll

Marc Pfeffer, MD, Ph.D

Patient Flow

V i t a l s t a t u s u n k n o w nn = 2 5 ( 0 . 6 % )

L o s t t o f o l l o w - u pn = 6 6 ( 1 . 6 % )

T r a n d o l a p r i l( n = 4 1 5 8 )

V i t a l s t a t u s u n k n o w nn = 2 0 ( 0 . 5 % )

L o s t t o f o l l o w - u pn = 6 8 ( 1 . 6 % )

P l a c e b o( n = 4 1 3 2 )

R a n d o m i z e d( n = 8 2 9 0 )

Nov 1996 to June 2000

Median follow-up time = 4.8 years

Target dose 4 mg/day

Followed until December 31, 2003

Baseline Medical History

Characteristic, % Trandolapril Placebo

Documented MI 54 56

CABG or PCI 72 72

Diabetes 18 16

Hypertension 46 45

Stroke or TIA 7 6

Current cigarette use 14 15

1º Outcome and its

Components

Outcome Trandolapril n=4158

%

Placebo n=4132

%

Hazard Ratio (95% CI)

P-value

CV death, MI, CABG or PCI

21.9 22.5 0.96 (0.88-1.06) NS

CV death 3.5 3.7 0.95 (0.76-1.19) NS

Non-fatal MI 5.3 5.3 1.00 (0.83-1.20) NS

Revasc 17.8 18.0 0.98 (0.88-1.08) NS

Other Outcomes

Outcome Trandolapril n=4158

%

Placebo n=4132

%

Hazard Ratio (95% CI)

P-value

CHF hospitalization

2.5 3.2 0.77 (0.60-1.00) 0.048

CHF hospitalization or CHF death

2.8 3.7 0.75 (0.59-0.95) 0.018

Stroke 1.7 2.2 0.76 (0.56-1.04) 0.09

New diabetes 9.8 11.5 0.83 (0.72-0.96) 0.014

Death (any cause)

7.2 8.1 0.89 (0.76-1.04) 0.13

Onset of New Diabetes1

The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med 2004;351:2-58-68

†The analysis included 3432 patients in the trandolapril group and 3472 patients in the placebo group and excluded

patients with diabetes at baseline.

Pat

ien

ts (

%)

Placebo(absolute incidence 399/3472)

Trandolapril(absolute incidence 336/3432)

p=0.01

9.8%11.5%

12

10

8

6

4

2

0

Risk Reduction

17%

CHF as a primary cause ofhospitalization or death1

The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med 2004;351:2-58-68

p=0.02

Placebo(absolute incidence 1529/4132)

Trandolapril(absolute incidence 115/4158)

3.7%

2.8%

Pat

ien

ts (

%)

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Risk Reduction

25%

Role of ACE inhibitors in Vascular Health Management & PreventionRole of ACE inhibitors in Vascular Health Management & Prevention

IDNT & RENAAL: Study Design

SeCr, serum creatinine; ESRD, end-stage renal disease.SeCr, serum creatinine; ESRD, end-stage renal disease.† † Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.‡ ‡ Brenner BM et al. N Engl J Med. 2001;345:861-869.Brenner BM et al. N Engl J Med. 2001;345:861-869.

Patients:Patients: 1,715 HTN patients with type 2 1,715 HTN patients with type 2 1,513 HTN patients with 1,513 HTN patients with diabetes & nephropathydiabetes & nephropathy type 2 diabetes & type 2 diabetes &

nephropathynephropathy

Treatment arms:Treatment arms: irbesartan, amlodipine,irbesartan, amlodipine, losartan, placebolosartan, placebo

placeboplacebo

Target BP:Target BP: 135/85 mm Hg135/85 mm Hg 140/90 mm Hg140/90 mm Hg

Adjunctive therapy:Adjunctive therapy: Permitted except ARBs, Permitted except ARBs, Permitted including Permitted including ACE inhibitors, or CCBs ACE inhibitors, or CCBs CCBs, except ARBs or CCBs, except ARBs or

ACE inhibitorsACE inhibitors

Primary outcome:Primary outcome: Composite of doubling ofComposite of doubling of Composite of doubling of Composite of doubling of SeCr, ESRD, or deathSeCr, ESRD, or death SeCr, ESRD, or deathSeCr, ESRD, or death

Secondary outcomes: Secondary outcomes: CV events CV events CV eventsCV events

Mean Follow-up:Mean Follow-up: 2.6 years2.6 years 3.4 years3.4 years

RENAALRENAAL‡‡IDNTIDNT††

IDNT and RENAAL Trial Results

Doubling of Creat, 16 (P=0.02) 20 (P=0.02) 23 (P=0.006)- 4 (P=0.69) ESRD, or death

Doubling of Creat 25 (P=0.006) 33 (P=0.003) 37 (P<0.001)- 6 (P=0.60)

ESRD 28 (P=0.002) 23 (P=0.07) 23 (P=0.07) 0 (P=0.99)

Death -2 (P=0.88) 8 (P=0.57) -4 (P=0.8) 12 (P=0.4)

CV Morbidity 10 (P=0.26) 9 (P=0.4) -3 (P=0.79) 12(P=0.29) & Mortality

Losartan vs control

Irbesartan vs control

Irbesartan vs amlodipine

Amlodipine vs

control

RRR (%)

Comparison of Major Endpoints

RENAAL IDNT

Lewis EJ et al. N Engl J Med 2001;345:851-860.Brenner B et al. N Engl J Med 2001;345:861-869.

AASK MAP <92

Target BP (mm Hg)No. of antihypertensive agents

1

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

Trial 2 3 4

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Cushman WC et al. J Clin Hypertens. 2002;4:393-404.

IDNT SBP <135/DBP <85

ALLHAT SBP <140/DBP <90

HTN in DM: Therapy Most Hypertensive Patients Need Multiple Drugs

Other Effects of HTN Drugs

•Largest study in Type 2 diabetes patients

•The first study to evaluate everyday, real life diabetic patients over a broad range of BP: normotensive and hypertensive

•Very well treated patient with a lower rate of cardiovascular events compared to previous studies

How to differentiate ADVANCE : How to differentiate ADVANCE : Patients profi lePatients profi le

ADVANCE is different• From UKPDS: diabetic hypertensive patients with SBP at

study end > 145 mm Hg and HbA1C= 8.3• From Micro HOPE: higher r isk profi le, CAD, diabetes• From HOT and other hypertension studies: no BP target• From LIFE-diabetes: a subgroup with hypertension+LVH• From diabetes studies with ARBS in nephropathy: renal

endpoints

Blood pressure

Main results

Blood pressure reductionBlood pressure reduction

Δ 2.2 mmHg (95% CI 2.0-2.4); p<0.001

Δ 5.6 mmHg (95% CI 5.2-6.0); p<0.001

Diastolic

Systolic

PlaceboPerindopril-Indapamide

Mea

n B

loo

d P

ress

ure

(m

mH

g)

65

75

85

95

105

115

125

135

145

155

165

Follow-up (Months)

R 6 12 18 24 30 36 42 48 54 60

140.3 mmHg134.7 mmHg

Average BP during follow-up

77.0 mmHg74.8 mmHg

All-cause mortalityAll-cause mortality

Follow-up (months)

0

10

0 6 12 18 24 30 36 42 48 54 60

Placebo Perindopril-Indapamide

Cu

mu

lat i

ve i

nc

ide

nc

e (%

)

Relative risk reduction 14%: 95% CI 2-25%

p=0.025

5

DeathsDeaths

CardiovascularCardiovascular

Follow-up (months)

6 12 18 24 30 36 42 48 54 60

PlaceboPerindopril-indapamide

Non-cardiovascularNon-cardiovascular

Follow-up (months)

6 12 18 24 30 36 42 48 54 60

PlaceboPerindopril-indapamide

Relative risk reduction 18%; p=0.027

Relative risk reduction 8%; p=0.41

5% 5%

Cu

mu

lati

v e in

cid

ence

(%

)

Combined primary outcomesCombined primary outcomesMajor macro or microvascular Major macro or microvascular

eventevent

0

10

20

Follow-up (months)

0 6 12 18 24 30 36 42 48 54 60

PlaceboPerindopril-Indapamide

Relative risk reduction9%: 95% CI: 0 to 17%

p=0.041

Cu

mu

lat i

ve i

nc

ide

nc

e (%

)

Macrovascular 480 520 8% (-4 to 19)

Microvascular 439 477 9% (-4 to 20)

Combined macro+micro 861 938 9% (0 to 17)

Number of events

Per-Ind Placebo(n=5,569) (n=5,571)

Relative riskreduction (95% CI)

FavoursPer-Ind

FavoursPlacebo

Hazard ratio

0.5 1.0 2.0

*

*2P=0.04

Primary outcomesPrimary outcomesMajor macro or microvascular Major macro or microvascular

eventevent

Coronary eventsCoronary events

*2P=0.02

†Non-fatal MI or death from coronary heart disease

‡Unstable angina requiring hospitalization, coronary revascularization or silent MI

Major coronary heart disease† 265 294 11% (-6 to 24)

All coronary heart disease 468 535 14% (2 to 24)

Other coronary heart disease‡ 283 324 14% (-1 to 27)

*

Number of events



FavoursPer-Ind

FavoursPlacebo

Hazard ratio

0.5 1.0 2.0

Cerebrovascular eventsCerebrovascular events

Major cerebrovascular disease† 215 218 2% (-18 to 19)

All cerebrovascular disease 286 303 6% (-10 to 20)

Other cerebrovascular disease‡ 79 99 21% (-6 to 41)

2.0

*

*2P=0.40

†Non-fatal stroke or death from Cerebrovascular disease

‡Transient ischaemic attack or subarachnoid haemorrhage

Number of events



FavoursPer-Ind

FavoursPlacebo

Hazard ratio

0.5 1.0

Renal eventsRenal events

2.0

Hazard ratio

0.5 1.0

New or worsening nephropathy 181 216 18% (-1 to 32)

New microalbuminuria 1094 1317 21% (14 to 27)

Total renal events 1243 1500 21% (15 to 27)*

*2P=<0.01

Number of eventsPer-Ind Placebo

(n=5,569)(n=5,571)Relative risk

reduction (95% CI)FavoursPer-Ind

FavoursPlacebo

SummarySummary Routine treatment of type 2 diabetic patients

with Perindopril-indapamide resulted in:

• 14% reduction in total mortality• 18% reduction in cardiovascular death• 9% reduction in major vascular events• 14% reduction in total coronary events• 21% reduction in total renal events

Benefits appeared to be similar in all major subgroups. Treatment was very well tolerated, with few side effects

and adherence similar to that with placebo.

• Increased HTN control • Reduced hypokalemia • Cardioprotective • Increased adherence

HTN in DM: Therapy

ACE-I + Thiazide like Diuretics: Excellent 1st line agent

Which combination ? Which combination ? ADVANCE trial

HTN in DM: Therapy

Which combination ? Which combination ?

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial indicated that the calcium channel antagonist amlodipine is superior to hydrochlorothiazide in combination treatment with an ACE-I.

In 6946 patients with DM, the number of primary events was 307 in the group treated with amlodipine and 383 in the group treated with hydrochlorothiazide as the add-on to benazepril (P = 0.003), despite a similar reduction of blood pressure in both groups.

ACCOMPLISH trial

ACCOMPLISH trial

Cardiovascular mortalityCardiovascular mortality

Perindopril 4-8mgPerindopril 4-8mg

Total coronary end point Total coronary end point


Fatal and non fatal strokes Fatal and non fatal strokes


New onset of diabetesNew onset of diabetes


SBP and DBP over t ime SBP and DBP over t ime


HTN in DM: Therapy

ACE-I + ARBs: Limited UtilityACE-I + ARBs: Limited Utility Theoretically attractive: more complete RAAS blockade

Limited BP ↓ and ↓ CVD events vs ACE-I at max dose ONTARGET RCT: 25,620 with CVD ± Stroke ± DM Ramipril vs Telmisartan vs R ⊕ T

Minimal BP ↓: 2.4/1.4 mm Hg No ↓ CVD events More side effects

↓ Albuminuria 30-40% vs monoRx with ACE-I or ARB ? Effects on ESRD? NKF, 2007: consider if albumin/cr > 500 mg/g on monoRx

NEJM 2008; 358:1547 Am J Kid Dis 2007; 49(Suppl 2):S74

ONTARGET trial

HTN in DM: Therapy

Which combination ? Which combination ?

In the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, the addition of aliskiren to RAAS blockade in patients with T2DM at high risk for cardiovascular and renal events did not result in a decrease in cardiovascular events and may even have been harmful.

ALTITUDE trial

β -Blockers and their Effects

β1β1

β1β1

β1β2β1β2

β-Blockers and the risk of new-onset diabetes mellitus

Prospective study of 12 550 patients w/o DM, aged 45-64, followed for 6 y. Multivariate analysis of 3804 who had HT at baseline.

1. Lancet 2002;359:995–1003. 2. N Engl J Med 2000;342:905–12.

Prospective study of 9193 hypertensives, aged 55-80, followed for 4.8 y. Analysis of 7998 w/o DM at baseline.

17.4

13.0

0

5

10

15

20

Atenolol Losartan

LIFE1

New

Cas

es P

er 1

000

Per

son

-Yea

rs (

%)

ARIC2

0

.5

1.0

1.5

Haz

ard

Rat

io

Atenolol RR 1.25 (1.12-1.37)

P<.001

25% Increased Riskβ-blocker RR 1.28 (1.04-1.57)

P<.05

28% Increased Risk

Thiazide

0.91

β-blocker

1.28

None

1.0

1.17

CCB

0.98

ACEI

Name of β B Receptor ISA Comment

Acebutolol β 1 Yes Not Good

Penbutolol β 1, β 2 Yes Bad

Pindolol β 1, β 2 Yes Bad

Propranolol β 1, β 2 No No Good

Nadolol β 1, β 2 No No Good

Timolol β 1, β 2 No No Good

Atenolol β 1 No OK

Metoprolol β 1 No Very Good

Nebivolol β 1 No Excellent

Bisoprolol β 1 No Excellent

Labetalol α , β 1, β 2 No Emergency

Carvedilol α , β 1, β 2 No CHF, IHD

Advantages of Carvedilol

Neutral on glycemic control Improves insulin resistance, metabolic

syndrome and lipid neutral Add on to RAAS blockade in DM Improves MAU/ ACR and ED First β blockade approved for CHF

GEMINI trial and OPTIMIZE-HF Study

Treatment (3)• Pharmacological therapy for patients with

diabetes and hypertension C– A regimen that includes either an ACE inhibitor

or angiotensin II receptor blocker; if one class is not tolerated, substitute the other

• Multiple drug therapy (two or more agents at maximal doses) generally required to achieve blood pressure targets B

• Administer one or more antihypertensive medications at bedtime A

Recommendations: Recommendations: Hypertension/Blood Pressure ControlHypertension/Blood Pressure Control



Who Should Receive ACEi or ARB Therapy?

• Clinical Macrovascular disease [grade A, level A] or

• ≥55 years of age [grade A, level A for those with additional CVD risk

factors or end organ damage; grade D, consensus for all others] or • Microvascular disease [grade D, consensus]

At doses that have shown vascular protection [perindopril 8 mg daily (EUROPA), ramipril 10 mg daily

(HOPE), telmisartan 80 mg daily (ONTARGET)]

Among women with childbearing potential, ACEi or ARB should only be used in the presence of proper preconception

counseling & reliable contraception. Stop ACEi or ARB either prior to conception or immediately upon detection of pregnancy

2013

EUROPA Investigators, Lancet 2003;362(9386):782-788.HOPE study investigators. Lancet. 2000;355:253-59.

ONTARGET study investigators. NEJM. 2008:358:1547-59

HTN Rx. Algorithm in DM

BP > 140/80 (2 readings) No TOD / MAU

ACE/ARB + TLC 1 M

Goal BP ≤140/80Yes No

Add thiazide like Diuretic

Add Amlodipine

Verapamil/ Diltizem

Yes

Yes

No

TLC cont.

>140/90/MAU/TOD

1 Month

Add new βB /αB

No

No

No

Yes

Yes

1 Month

1 Month

1 Month ?

Thiazide like diuretic (low dose→Indapamide)

Long acting calcium channel blockers (amlodipine)

B blocker (cardioselective-e.g. Carvedilol, metoprolol)

1st potion ACEIs

Monotherapy

Drug therapy in

Hypertension with Diabetes

2nd option ARBsOR

+ Combination

Take home Message

HTN in DM is serious; So manage aggressively ( new Target <140/80mmHg)

TLC, Lipid control, Glycemic targets – VP is a must

drugs that act on the RAA axis are recommended for first-line use

ACE inhibitor should be considered first, but ARB should be substituted if ACE inhibitor not tolerated

MAU/ACR must for all DM – Predict CAD, CKD

Typically 2 or more drugs are needed for HTN Rx.

use a diuretic, and in a dosage, which has been shown effective in clinical endpoint trials

New β B, Carvedilol, CCBs are add-on drugs

Vascular Protection in DM

1. Atorvastatin (Lipid management)2. ASA (Acetyl Salicylic Acid) – (enteric coated)3. ACE inhibitors or ARBs for BP goal (140/80 as

well as Control of Nephropathy, Proteinuria (MAU)

4. A1c control 7%(Glycemic control)5. Cigarette smoking cessation6. Weight and waist management7. Physical Activity – at least 2 km/d x 5 d

Thank you

Strategy ComplicationReduction of Complication

Lipid control • Coronary heart disease mortality• Major coronary heart disease event• Any atherosclerotic event• Cerebrovascular disease event

↓36%¹

↓55%¹

↓37%¹

↓62%¹Blood Pressure Control

• Cardiovascular disease• Heart failure• Stroke• Diabetes-related deaths

↓51%²

↓56%³

↓44%³

↓32%³Blood Glucose Control • Heart Attack ↓37%³

1 The 4S Study2 Hypertension Optimal Treatment (HOT) Randomised Trial3 UKPDS

Highest Percentage Reduction of the Risk of Diabetic Complications in People with Type 2 Diabetes shown in Recent Studies

hyper tension and diabetes the two terrorists together

Health & Medicine

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