Dr Mohamed Al-Ameen Nephrology& Transplantation Specialist KAAH&OC.

Dr Mohamed Al-AmeenNephrology& Transplantation Specialist

KAAH&OC

• HTN is the leading cause of morbidity and mortality worldwide.

• Affecting 20–60% of diabetics.

• HTN is common in Diabetics vs in Non diabetics 1.5 to 3 times.

Management of Hypertension in Diabetics

HTN in DM:HTN in DM: FactsFacts

• Hypertensive Diabetics vs Hypertensive non diabetics Twice the risk of CVD

• 1 in every 4 individuals in US has HTN. ADA 2005

• The greatest reduction in cardiovascular mortality occurs at achieving a diastolic blood pressure of ~80 mmHg and systolic blood pressure to <130 mmHg


HTN in DM:HTN in DM: FactsFacts

IHD Mortality Rate in each age dacade vs HTNIHD Mortality Rate in each age dacade vs HTN

HTN in DM:HTN in DM: FactsFacts Management of Hypertension in Diabetics

WHOWHO Fact Fact

SheetSheet

WorldWorld KSAKSA

20002000 20302030 20002000 20302030

DMDM 171,000,000171,000,000 366,000,000366,000,000 890,000890,000 2,523,0002,523,000

USA: o ~ 60% of Diabetics are HTN.o14% of Af. Am. have HTN& DM

ADA 2005

1,513,8001,513,800543,000543,000219,600,000219,600,000102,600.000102,600.000

EstimatedEstimated

DM+HTNDM+HTN 1,513,8001,513,800543,000543,000219,600,000219,600,000102,600.000102,600.000

EstimatedEstimated

DM+HTNDM+HTN

Germany: o 50% of 1ry care pts have HTN.o 12% of all pts have HTN& DM.

Lehnert H et al. 2005Lehnert H et al. 2005

133,800,000 801,880NOW


HTN in DM:HTN in DM: PrevalencePrevalence

WHOWHO Fact Fact

SheetSheet

WorldWorld KSAKSA

20002000 20302030 20002000 20302030

DMDM 171,000,000171,000,000 366,000,000366,000,000 890,000890,000 2,523,0002,523,000

USA: o One in every four has HTN.o ~ 60% of Diabetics are HTN.

ADA 2005

Germany: o 50% of 1ry care pts have HTN.o 12% of all pts have HTN&DM.

Lehnert H et al. 2005Lehnert H et al. 2005


HTN in DM:HTN in DM: PrevalencePrevalence

133,800,000 801,880NOW

Only 25 percent of patients with hypertension have adequate control of their blood pressure

The Third National Health and Nutrition Evaluation Survey The Third National Health and Nutrition Evaluation Survey (NHANES III) (NHANES III)

• 29% of diabetic individuals with hypertension were unaware 29% of diabetic individuals with hypertension were unaware of the diagnosis.of the diagnosis.

• 43% of diabetic individuals with hypertension were untreated.43% of diabetic individuals with hypertension were untreated.

• 55% of diabetic individuals on treatment had a blood pressure 55% of diabetic individuals on treatment had a blood pressure ≥140/90.≥140/90.

• 12% of diabetic individuals on treatment had a blood pressure 12% of diabetic individuals on treatment had a blood pressure <130/85.<130/85.

Am J Prev Med 22:42–48, 2002

NEJM 2000; 342:905 Diabetes Care 2005; 28:310 Am J Kid Dis 2007; 49 (Suppl 2):S74

HypertensiveHypertensivePopulationsPopulations

95%95%-- MacroalbuminuriaMacroalbuminuria

80%80%-- MicroalbuminuriaMicroalbuminuria

50%50%-- At At DxDx

•• Type 2 DMType 2 DM



30%30%-- NormoalbuminuriaNormoalbuminuria


60% 60% Diabetic U.S. adultsDiabetic U.S. adults

30%30%All U.S. adultsAll U.S. adults

HypertensiveHypertensivePopulationsPopulations



50%50%-- At At DxDx




30%30%-- NormoalbuminuriaNormoalbuminuria


60% 60% Diabetic U.S. adultsDiabetic U.S. adults

30%30%All U.S. adultsAll U.S. adultsType 1Type 1

(¼ are Htn)(¼ are Htn)

At Diagnosis: 20-40%At Diagnosis: 20-40%

With Microalbuminuria: 30-50%With Microalbuminuria: 30-50%

With Macroalbuminuria: 65-88%With Macroalbuminuria: 65-88%

Type 2Type 2

(½ are Htn)(½ are Htn)

At Diagnosis: 50%At Diagnosis: 50%

With Microalbuminuria: 80%With Microalbuminuria: 80%

With Macroalbuminuria: >90%With Macroalbuminuria: >90%

HTN in DM:HTN in DM: PrevalencePrevalence Management of Hypertension in Diabetics

DiabetesDiabetes HypertensionHypertension

HTN in DM:HTN in DM: PARTNERS IN CRIMEPARTNERS IN CRIME Management of Hypertension in Diabetics

HTN vs No HTN DM vs No DM

2.4x ↑ in DM 2.0x ↑ 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-2

DM-1 DM-1




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 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

AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 66, NUMBER 7 / OCTOBER 1, 2002

Diabetes and Diabetes and HTN HTN vsvs Diabetes Diabetes

Relative Risk Relative Risk of of ComplicationsComplications

CHDCHD X 3.0X 3.0

StrokeStroke X 4.0X 4.0

RetinopathyRetinopathy X 2.0X 2.0

NephropathyNephropathy X 2.0X 2.0

NeuropathyNeuropathy X 1.6X 1.6

MortalityMortality X 2.0X 2.0

75% die from CVD75% die from CVD

NEJM 2005; 352:341


Association between refractory hypertension and cardiometabolic risk

The HIPERFRE study, 2008

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

The HIPERFRE study, 2008

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


HTN in DM:HTN in DM: PARTNERS IN CRIMEPARTNERS IN CRIME

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


HTN in DM:HTN in DM: PARTNERS IN CRIMEPARTNERS IN CRIME

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

Redu

ctio

n in

Risk

(%)

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

-20 -

-10 -

Tight BP Control vs. Tight Glucose ControlTight BP Control vs. Tight Glucose Control

HTN in DM:HTN in DM: Effect of BP ControlEffect of BP Control

Tight BP Control vs. Tight Glucose ControlTight BP Control vs. Tight Glucose Control

HTN in DM:HTN in DM: Effect of BP ControlEffect of BP Control

Tight BP Control Tight Glucose Control

1. Measure BP properly.2. Define Hypertensive Patients.3. Evaluate hypertensive Patients.4. Therapy

HTN in DM:HTN in DM: Practical StrategyPractical Strategy

HTN in DM:HTN in DM: 1- Measure BP Properly 1- Measure BP Properly The measurement of BP is likely the clinical procedure of greatest importance that is performed in the sloppiest manner.” (Norman Kaplan, M.D.) Lancet 2007; 370:591

Health care professionals should take particular care to ensure that they are using accurate techniques to measure BP in all their patients.” (International Working Group, 2008) J Hum Hypertens 2008; 22:63

∆ BP (mm Hg) if not done

Rest ≥ 5min, quite ↑ 12/6

Seated, back supported ↑ 6/8

Cuff medsternal level ↑ ↓ 2/inch

Correct cuff size ↑ 6-18/3-14

Bladder center over artery

↑ 3-5/2-3

Deflate 2 mm Hg/ sec ↑ SBP/↓ DBP Can J Card 2007; 23:529

HTN in DM:HTN in DM: 1- Measure BP Properly 1- Measure BP Properly Joint National CommiteeJoint National Commitee

Caffeine, exercise, and smoking should be avoided for at least 30 minutes prior to measurement. JNC-7

The patient should be seated for at least 5 minutes, relaxed and not moving or speaking.The arm must be supported at the level of the heart. Ensure no tight clothing constricts the arm.Place the cuff on neatly with the centre of the bladder over thebrachial artery. The bladder should encircle at least 80% of the arm (but not more than 100%).The column of mercury must be vertical, and at the observers eyelevel.Estimate the systolic beforehand:

a) Palpate the brachial arteryb) b) Inflate cuff until pulsation disappearsc) Deflate cuffd) Estimate systolic pressure

Then inflate to 30 mmHg above the estimated systolic level needed to occlude the pulse.Place the stethoscope diaphragm over the brachial artery and deflate at a rate of 2-3mm/sec until you hear regular tapping sounds.Measure systolic (first sound) and diastolic (disappearance) to nearest 2mmHg.

HTN in DM:HTN in DM: 1- Measure BP Properly 1- Measure BP Properly Indications of Ambulatory BP monitoringIndications of Ambulatory BP monitoring

JNC-7


High Normal BP and CVD Risk

HTN in DM:HTN in DM: 2 2- - Define Hypertensive PatientsDefine Hypertensive Patients Joint National Committee 7 (JNC-7)Joint National Committee 7 (JNC-7)


HTN in DM:HTN in DM: 2- 2- Define Hypertensive PatientsDefine Hypertensive Patients Systolic or Diastolic Hypertension???????Systolic or Diastolic Hypertension???????

250

200

150

100

50

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

Systolic BP (mm Hg)Systolic BP (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

CV Mortality Risk Doubles WithCV Mortality Risk Doubles WithEach 20/10 mm Hg BP Increment*Each 20/10 mm Hg BP Increment*

• Stronger predictor of risk than diastolic BP:– Cardiovascular disease– Diabetic Nephropathy

• 65% of DM hypertensives have isolated systolic hypertension.

• Systolic hypertension more difficult to control Lancet 2002; 360:1903 Hypertension 2003; 42:1206

National Kidney Foundation: Guideline 8. Am J Kidney Dis 43 (Suppl. 1):S142 –S159, 2004. Sowers JR et al. Hypertension 37:1053 –1059, 2001.

• Diastolic hypertension predominates before age 50, either alone or in combination with SBP elevation.

• Systolic hypertension increases with age, and above 50 years of age, systolic hypertension represents the most common form of hypertension.

• DBP is a more potent cardiovascular risk factor than SBP until age 50; thereafter, SBP is more important.

• DBP control rates exceeded 90 percent, but SBP control rates were considerably less (60–70 percent)

J Clin Hypertens 2002;4:393-404. Hypertension 2001;37:12-8.


HTN in DM:HTN in DM: 2- 2- Define Hypertensive PatientsDefine Hypertensive Patients

Three-fourths of 1ry care physicians failed to initiate therapy if SBP 140-159.Three-fourths of 1ry care physicians failed to initiate therapy if SBP 140-159. Most physicians have been taught that the diastolic pressure is more important Most physicians have been taught that the diastolic pressure is more important than SBP and thus treat accordingly. than SBP and thus treat accordingly. Most primary care physicians did not pursue control to <140 mmHg.Most primary care physicians did not pursue control to <140 mmHg. J Clin Hypertens. 2000;2:324-30.J Clin Hypertens. 2000;2:324-30.

Systolic or Diastolic Hypertension???????Systolic or Diastolic Hypertension???????


HTN in DM:HTN in DM: 2- 2- Define Hypertensive PatientsDefine Hypertensive Patients Systolic or Diastolic Hypertension???????Systolic or Diastolic Hypertension???????


HTN in DM:HTN in DM: 2- 2- Define Hypertensive PatientsDefine Hypertensive Patients

Normal < 120/<80

Prehypertension 120-139/ 80-89

Stage 1 140-159/ 90-99

Stage 2 ≥ 160/ ≥100

Follow up BP Measurements Follow up BP Measurements

• Estimate CV Risk Factors.• Diagnose Target Organ Damage.• Exclude Identifiable Causes of HTN.• Routine Laboratory work up with ECG, lipid

profile and urinary albumin.


HTN in DM:HTN in DM: 3- Evaluate3- Evaluate Hypertensive Pts. Hypertensive Pts.

• HTN*• Age:

• Older than 55 years for men• Older than 65 years for women

• DM*• Abnormal Lipid Profile*:

• Elevated LDL (or total) cholesterol• Low HDL cholesterol*

• Estimated GFR <60 mL/min• Family history of premature CVD:

• men <55 years of age• women <65 years of age

• Microalbuminuria• Obesity* (BMI >30 kg/m2)• Physical inactivity

• Tobacco usage, particularly cigarettes


HTN in DM:HTN in DM: 3- Evaluate3- Evaluate Hypertensive Pts. Hypertensive Pts. Cardiovascular Risk FactorsCardiovascular Risk Factors

(140-age) x weight x 1.23 x (0.85 if female)(140-age) x weight x 1.23 x (0.85 if female) S Creatinine (micromol/l) S Creatinine (micromol/l)

(140-age) x Weight (Kg) x (0.85 if female)(140-age) x Weight (Kg) x (0.85 if female)

72 x S Creatinine (mg/dl)72 x S Creatinine (mg/dl)

Normoalbuminuria < 30 mg/dayMicroalbuminuria 30 - 300 mg /dMacroalbuminuria > 300 mg / day

BMI= Weight (Kg) / (Height in meter)2

• Heart• LVH• Angina/prior MI• Prior coronary revascularization• Heart failure

• Brain• Stroke or transient ischemic attack• Dementia

• CKD• Peripheral arterial disease• Retinopathy


HTN in DM:HTN in DM: 3- Evaluate3- Evaluate Hypertensive Pts. Hypertensive Pts. Target Organ DamageTarget Organ Damage

• ABCD diagnosis of 2ry HTN

A: Accuracy, Apnea, Aldosteronism

B: Bruit, Bad Kidney

C: Catecholamines, Coarctation, Cushing's S.

D: Drugs, Diet


HTN in DM:HTN in DM: 3- Evaluate3- Evaluate Hypertensive Pts. Hypertensive Pts. Identifiable Causes of HTNIdentifiable Causes of HTN

1. Blood Pressure Goal2. Life Style Modification3. Phamacological Therapy


HTN in DM:HTN in DM: 4- Therapy4- Therapy

• 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:HTN in DM: 4- Therapy4- Therapy Goal Blood PressureGoal Blood Pressure

Less Than 130/80

• 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:HTN in DM: 4- Therapy4- Therapy Goal Blood PressureGoal Blood Pressure Less Than 130/80

Can We Go to More Lower Target ?

IDNT JASN 2005;16(7):2170–2179

• Lowest Systolic Blood Pressure Is Associated with Stroke inStages 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:HTN in DM: 4- Therapy4- Therapy Goal Blood PressureGoal Blood Pressure Less Than 130/80

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

HTN in DM:HTN in DM: 4- Therapy4- Therapy Life Style ModificationsLife Style Modifications

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:HTN in DM: 4- Therapy4- Therapy Life Style ModificationsLife Style Modifications

HTN in DM:HTN in DM: 4- Therapy4- Therapy Life Style Modifications:Life Style Modifications: DietaryDietary

Dietary Sodium

Less than 2300mg / day(Most of the salt in food is hidden and comes from

processed food)

Dietary PotassiumIf required, daily dietary intake >80

mmol

Calcium supplementationNo conclusive studies for hypertension

Magnesium supplementationNo conclusive studies for hypertension

• High in fresh fruits• High in vegetables• High in low fat dairy

products•High in dietary and

soluble fibre•High in plant protein• Low in saturated fat

and cholesterol•Low in sodium

• Less than:– 2,300 mg sodium (Na) – 100 mmol sodium (Na)– 5,8 g of salt (NaCl)– 1 teaspoon of table salt

2,300 mg sodium = 1 level teaspoon of table salt

HTN in DM:HTN in DM: 4- Therapy4- Therapy Life Style Modifications:Life Style Modifications: Daily SodiumDaily Sodium

Exercise should be prescribed as adjunctive to pharmacological therapy

Should be prescribed to reduce blood pressure

Type cardiorespiratory activity- Walking, jogging- Cycling- Non-competitive swimming

Time - 30-60 minutes

Intensity - Moderate

Frequency - Four to seven days per weekFI

T

T

HTN in DM:HTN in DM: 4- Therapy4- Therapy Life Style Modifications:Life Style Modifications: Physical ActivityPhysical Activity

Hypertensive and all patientsBMI over 25 - Encourage weight reduction- Healthy BMI: 18.5-24.9 kg/m2

Waist Circumference Men Women- Europid, Sub-Saharan African, Middle Eastern <94 cm <80 cm- South Asian, Chinese <90 cm <80 cm- Japanese <85 cm <90 cm

For patients prescribed pharmacological therapy: weight loss has additional antihypertensive effects. Weight loss strategies should employ a multidisciplinary approach and include dietary education, increased physical activity and behavioural modification

HTN in DM:HTN in DM: 4- Therapy4- Therapy Life Style Modifications:Life Style Modifications: Weight LossWeight Loss

HTN in DM:HTN in DM: 4- Therapy4- Therapy Life Style ModificationsLife Style ModificationsIntervention Intervention AmountAmount SBP/DBPSBP/DBP

Reduce foods with Reduce foods with added sodium added sodium

- 1800 mg sodium- 1800 mg sodiumhypertensivehypertensive -5.1 / -2.7-5.1 / -2.7

Weight lossWeight loss per kg lostper kg lost -1.1 / -0.9-1.1 / -0.9

Alcohol intakeAlcohol intake - 3.6 drinks/day- 3.6 drinks/day -3.9 / -2.4-3.9 / -2.4

Aerobic exerciseAerobic exercise 120-150 min/week120-150 min/week -4.9 / -3.7-4.9 / -3.7

Dietary patternsDietary patternsDASH dietDASH diet

HypertensiveHypertensiveNormotensiveNormotensive

-11.4 / -5.5-11.4 / -5.5-3.6 / -1.8-3.6 / -1.8

• Use caution in initiating therapy with 2 drugs where agressive blood pressure lowering is more likely or more poorly tolerated (e.g. those with postural hypotension).

• ACE inhibitors and ARBs are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential.

• Diuretic-induced hypokalemia should be avoided through the use of potassium sparing agent if required.


HTN in DM:HTN in DM: 4- Therapy4- Therapy Important ConsiderationsImportant Considerations

• Monitor creatinine and potassium when combining K sparing diuretics, ACE inhibitors and/or ARBs.

• If Dihydropyridine CCB Chosen: Not to be used without ACEi or ARB agents.

• If a diuretic is not used as first or second line therapy, triple drug therapy should include a diuretic, when not contraindicated.

• Short-acting dihydropyridine calcium antagonists should not be used in IHD because of their potential to increase risk of mortality, particularly in the setting of acute myocardial infarction



• Beta Blockers– BBs less appealing as first-line agents for treatment of hypertension in patients

with either type 2 or type 1 diabetes mellitus (grade A).

– BBs, however, have proved effective in the management of the ischemic and congestive cardiomyopathies that are more common in patients with diabetes than in those without diabetes.

– Because the major adverse effects of BBs may be mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the new third-generation BBs (such as Nebivolol) or drugs that block both a and b receptors (such as Carvedilol) may prove to be particularly beneficial (grade A).

– These agents cause vasodilatation and an increase in insulin sensitivity. American Association of Clinical Endocrinologist, 2006– Beta adrenergic blockers are not recommended for patients age 60+ without

another compelling indication. CHEP 2008



• Beta Blockers (cont.)– Two drug combinations of beta blockers, ACE inhibitors and

ARBs have not been proven to have additive hypotensive effects.

– Therefore these potential two drug combinations should not be used unless there is a compelling (non blood pressure lowering) indication such as ischemic heart disease, post myocardial infarction, congestive heart failure or chronic kidney disease with proteinuria.

– It is not recommended to combine a non dihydropyridine CCB and a beta blocker to reduce the risk of bradycardia or heart block.



• If Diuretic Chosen: (Preferred if no other compelling indications): – Creatinine <1.8 mg/dL Thiazide Diuretic– Creatinine ≥1.8 mg/dL Loop Diuretic– Max. dose 25mg Hydrochlorothiazide or

equivalent)



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:HTN in DM: 4- Therapy4- Therapy Most Hypertensive Patients Need Multiple DrugsMost Hypertensive Patients Need Multiple Drugs


HTN in DM:HTN in DM: 4- Therapy4- Therapy Compelling IndicationsCompelling Indications


HTN in DM:HTN in DM: 4- Therapy4- Therapy ADA GuidelinesADA Guidelines

SystolicSystolic DiastolicDiastolicGoal (mmHg)Goal (mmHg) <130 <130 <80 <80

Behavioral therapy aloneBehavioral therapy alone 130–139 130–139 80– 80–8989(maximum 3 months) (maximum 3 months) then add pharmacologic then add pharmacologic treatmenttreatment

Behavioral therapy + Behavioral therapy + 140140 9090pharmacologic treatmentpharmacologic treatment Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.


HTN in DM:HTN in DM: 4- Therapy4- Therapy Practical ViewPractical View

1.1. Pts. At goal BP < 130 / 80.Pts. At goal BP < 130 / 80.

2.2. Pts. with BP 130-139 / 80-89. Pts. with BP 130-139 / 80-89.

3. 3. Pts. With BP ≥ 140 /90.Pts. With BP ≥ 140 /90.

1 32

WithoutCompellingIndications

WithCompellingIndications





- LSM- Recheck each visit

- LSM- Recheck each visit- Treat CI

-LSM 3 m-- if high BP drug Therapy

-LSM-Drug Th of HTN-Drug Th of CI

-LSM-Drug Th of HTN

-LSM- Drug combined-Drug of CI

ACE -ve or ARB (Or thiazide if no albuminuria or TOD)• Consider two-drug therapy if BPe ≥ 150/90 mmHg

≥ 140/90 Or albuminuria Or TOD

≥ 130/80 mmHg on two visits≤ 1 month apart

130–139/80–89 No albuminuria, No TODLSM for 3 months

≥ 130/80 mmHg after 1 m

Add thiazide (or BID loop diuretic if cr ≥ 1.8mg/dl or estimated GFR < ml/min/1.73m2)

Add nonDHP CCB (verapamil or diltiazem)

Substitute DHP CCB for nonDHP CCB• Add B-blockerAdd DHP CCB

Reassess for causes of resistant hypertension•Add α blocker, hydralazine, clonidine Consider consultation.




Algorithm for the Treatment of Hypertension in DMAlgorithm for the Treatment of Hypertension in DM

• In Type 2 patients: ACE-i or ARBs as a first line.• In Type 1 patients: ACE-I is recommended to

reduce protein excretion• Consider the use of verapamil or diltiazem in

patients with proteinuria unable to tolerate ACEi or ARBs.


HTN in DM:HTN in DM: 4- Therapy4- Therapy For Pts. With Microalbuminuria or ProteinuriaFor Pts. With Microalbuminuria or Proteinuria


HTN in DM:HTN in DM: 4- Therapy4- 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 RT

• 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

• • Increased HTN control• • Reduced hypokalemia• • Cardioprotective• • Available as a generic medication• • Increased adherence


HTN in DM:HTN in DM: 4- Therapy4- Therapy ACE-I + HCTZ: Excellent 1ACE-I + HCTZ: Excellent 1stst line agent line agent

• Consider continuing the ACE-I:• 38-55% Likelihood the cough will resolve. • Consider changing the time of administration or lowering the dose• Consider antitussives or lozenges while waiting for symptom to resolve.

• Consider switching to a 2nd ACE-I:• Effective for 1 in 10 patients

• Consider using a different drug class:• Diuretic, beta-blocker or calcium channel blocker• If an ACE-I is indicated because of comorbid conditions (e.g. DM,HF, CKD)

an ARB (i.e. LOSARTAN) can be used as an alternative


HTN in DM:HTN in DM: 4- Therapy4- Therapy ACE-I Cough ACE-I Cough

ACE-I or ARBs may cause Hyperkalemia:

1. Avoid other medications that cause hyperkalemia (K suppl, NSAIDs, Cox2 inhibitors, K sparing diuretics).

2. Evaluate causes of hyperkalemia.3. Treat hyperkalemia with diuretics.4. Continuo ACE-I or ARBs if K < 5.5 mmol/l.

Monitor GFR1. If GFR >30% within 4 weeks, evaluate.2. Continuo ACE-I or ARBs if GFR < 30% from

baseline over 4 months.


HTN in DM:HTN in DM: 4- Therapy4- Therapy ACE-I or ARBs and Hyperkalemia ACE-I or ARBs and Hyperkalemia


HTN in DM:HTN in DM: 4- Therapy4- Therapy Resistant HypertensionResistant Hypertension

ClassClass Drug (Trade Name)Drug (Trade Name) Usual Dose Range in MG/ Usual Dose Range in MG/ DAYDAY

Thiazide diureticsThiazide diuretics Chlorothiazed (Diuril)Chlorothiazed (Diuril)

Chlorthalidone (generic)Chlorthalidone (generic)

Hydroclorothiazide (Microzide, Hydroclorothiazide (Microzide, Hydro DIURIL)Hydro DIURIL)

Polythiazide (Renese)Polythiazide (Renese)

Indapamide (Lozol)Indapamide (Lozol)

Metalozol (Mykrox)Metalozol (Mykrox)

Metalazone (zaroxolyn)Metalazone (zaroxolyn)

125-500125-500

12.5-2512.5-25

12.5-5012.5-50

2-42-4

1.25-2.51.25-2.5

0.5-1.00.5-1.0

2.5-52.5-5

Loop diureticsLoop diuretics Bumetanide (bumex)Bumetanide (bumex)

Furosemide (Lasix)Furosemide (Lasix)

Torsemide (Demadex)Torsemide (Demadex)

0.5-20.5-2

20-8020-80

2.5-102.5-10

Potassium-sparing Potassium-sparing diureticsdiuretics

Amiloride (Midamor) Amiloride (Midamor)

Triamtrene (Dyrenium) Triamtrene (Dyrenium)

5-105-10

50-10050-100

Aldosterone receptor Aldosterone receptor blockersblockers

Eplernone ( Inspra)Eplernone ( Inspra)

Spironolactone (Aldactone)Spironolactone (Aldactone)

50-10050-100

25-5025-50

Anti Hypertensive Drugs

ACE InhibitorsACE Inhibitors Benazepril (Lotensin) captopril Benazepril (Lotensin) captopril (capoten)(capoten)

Enalapril (vasotec)Enalapril (vasotec)

Fosinopril (monopril)Fosinopril (monopril)

Lisinopril (prinivil, zestril)Lisinopril (prinivil, zestril)

Moexipril (Univasc)Moexipril (Univasc)

Perindopril (Accupril)Perindopril (Accupril)

Quinapril (Accupril)Quinapril (Accupril)

Ramipril (Altace)Ramipril (Altace)

Trandolapril(Mavik)Trandolapril(Mavik)

10-4010-40

25-10025-100

2.5-402.5-40

10-4010-40

10-4010-40

7.5-307.5-30

4-84-8

10-4010-40

2.5-202.5-20

1-41-4

Angiotensin II Angiotensin II

AntagonistsAntagonists

Candesartan (Atacand)Candesartan (Atacand)

Eprosartan (Teveltan)Eprosartan (Teveltan)

Irbesartan (Avapro)Irbesartan (Avapro)

Losartan (Cozaar)Losartan (Cozaar)

Olmesartan (Benicar)Olmesartan (Benicar)

Telmisartan (Micardis)Telmisartan (Micardis)

Valsartan (Diovan)Valsartan (Diovan)

8-328-32

400-800400-800

150-300150-300

25-10025-100

20-4020-40

20-8020-80

80-32080-320


Beta-BlockersBeta-Blockers Atenolol (Tenormin)Atenolol (Tenormin)

Betaxolol (Kerlone)Betaxolol (Kerlone)

Bisoprolol (zebeta)Bisoprolol (zebeta)

Metoprolol (lopressor)Metoprolol (lopressor)

Metoprolol extended release Metoprolol extended release (Toprol XL)(Toprol XL)

Nadolol (Corgard)Nadolol (Corgard)

Propranolol (Inderal)Propranolol (Inderal)

Propranolol long-acting Propranolol long-acting (Inderal LA)(Inderal LA)

Timolol (Blocadren)Timolol (Blocadren)

25-10025-100

5-205-20

2.5-102.5-10

50-10050-100

50-10050-100

40-12040-120

40-16040-160

60-18060-180

20-4020-40

Beta-Blockers with Beta-Blockers with intrinsic sypathomimetic intrinsic sypathomimetic

activityactivity

Acebutolol (Sectral)Acebutolol (Sectral)

Penbutolol (Levatol)Penbutolol (Levatol)

Pindolol (generic)Pindolol (generic)

200-800200-800

10-4010-40

10-4010-40

Combined Alpha– and Combined Alpha– and beta-blockersbeta-blockers

Carvedilol (Coreg)Carvedilol (Coreg)

Labetalol (Normodyne)Labetalol (Normodyne)

12.5-5012.5-50

200-800200-800


Calcium channel Calcium channel blockers- non blockers- non

DihydropyridinesDihydropyridines

Diltiazem extended releaseDiltiazem extended release

(cardizem CD, Dilacor XR, Tiazac) Diltiazem (cardizem CD, Dilacor XR, Tiazac) Diltiazem extended release (Cardizem LA)extended release (Cardizem LA)

Verapamil immediate release (calan, isoptin)Verapamil immediate release (calan, isoptin)

Verapamil long acting (calan SR,Verapamil long acting (calan SR,

Isoptin SR)Isoptin SR)

Verapamil – Coer (Covera HS, Verelan PM)Verapamil – Coer (Covera HS, Verelan PM)

180-420180-420

120-540120-540

80-32080-320

120-360120-360

120-360120-360

Calcium Channel Calcium Channel Blockers - Blockers -

DihydropyridinesDihydropyridines

Amlodipine ( Norvasc )Amlodipine ( Norvasc )

Felodipine (plendil)Felodipine (plendil)

Isradipine (Dynaciric CR)Isradipine (Dynaciric CR)

Nicardipine sustained release (Cardene SR)Nicardipine sustained release (Cardene SR)

Nifedipine long-acting (Adalat CC, procardia Nifedipine long-acting (Adalat CC, procardia XL)XL)

Nisoldipine (Sular)Nisoldipine (Sular)

2.5-102.5-10

2.5-202.5-20

2.5-102.5-10

60-12060-120

30-6030-60

10-4010-40


Alpha- BlockersAlpha- Blockers Doxazosin ( Cardura)Doxazosin ( Cardura)

Prazosin (minipress)Prazosin (minipress)

Terazosin (Hytrin)Terazosin (Hytrin)

1-161-16

2-202-20

1-201-20

Central alpha-agonists Central alpha-agonists and other centrally and other centrally

acting drugsacting drugs

Clonidine (Catapres)Clonidine (Catapres)

Clonidine patch (catapres-TTS)Clonidine patch (catapres-TTS)

Methyldopa (Aldomet)Methyldopa (Aldomet)

Resrpine (generic)Resrpine (generic)

Guanfacine (generic)Guanfacine (generic)

0.1-0.80.1-0.8

0.1-0.30.1-0.3

250-1000250-1000

0.05-0.250.05-0.25

0.5-20.5-2

Direct VasodilatorsDirect Vasodilators Hydralazine (Apresoline)Hydralazine (Apresoline)

Minoxidil (Loniten)Minoxidil (Loniten)

25-10025-100

2.5-802.5-80


Angiotensin II

AVP

Aldosterone

Vaso- constriction

Mesangial Contraction

Efferent Constriction

CNS Dypsogenia

Na+

Retention

IncreasedNorepinephrineRelease

Myocardial Hypertrophy

Vessel Hypertrophy

Deleterious Effects of Angiotensin IIDeleterious Effects of Angiotensin IIManagement of Hypertension in Diabetics

JNC-7Management of Hypertension in Diabetics

American Journal of Kidney Diseases, February 2007

NKF. American Journal of Kidney Diseases, February 2007


Dr Mohamed Al-Ameen Nephrology& Transplantation Specialist KAAH&OC.

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