Hypertension and DyslipidemiaHypertension and Dyslipidemia

An ominous—and common—An ominous—and common—combinationcombination

NED FERGUSON, M.D.NED FERGUSON, M.D.

March 2004March 2004

NCEP ATP IIINCEP ATP IIIMetabolic Syndrome CriteriaMetabolic Syndrome Criteria

Risk Factor* Defining Level Abdominal obesity† (waist circumference) Men ‡ >40 in Women >35 in TG >150 mg/dL HDL-C Men <40 mg/dL Women <50 mg/dL BP >130/>85 mmHg FBG 110 mg/dL**Diagnosis is established when Diagnosis is established when >> 3 of these risk factors are present 3 of these risk factors are present††Abdominal obesity is more highly correlated with metabolic risk factors Abdominal obesity is more highly correlated with metabolic risk factors than is than is BMIBMI‡‡Some men develop metabolic risk factors when circumference is only Some men develop metabolic risk factors when circumference is only marginally increasedmarginally increased

Expert Panel on Detection, Evaluation, and Treatment of High Blood Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Cholesterol in Adults. JAMAJAMA. 2001;285:2486-2497.. 2001;285:2486-2497.

Key Challenges Overview: Key Challenges Overview: SummarySummary

Obesity is significant risk factor for several interrelated conditions– Hypertension– Dyslipidemia– Diabetes– Atherosclerosis

Even relatively low levels of elevated blood pressure and lipids impart significant increased CVD risk

Hypertension and dyslipidemia often occur concomitantly

Concomitant hypertension and dyslipidemia increase CVD risk exponentially

Statement of NeedStatement of NeedThe scope: Concomitant hypertension and dyslipidemia occurs more

commonly than would be expected in the general population 1 in 4 American adults have hypertension ~40% of US adults have total serum cholesterol levels > 200 mg/dL Framingham data showed ~50% of men and women who presented

with treatable hypertension also had an abnormal lipid profile

The problem: ~27 million Americans have both hypertension and dyslipidemia Only ~9 million have been diagnosed with both Only ~3 million are being treated for both

The need: When 1 condition is diagnosed, check for the other If both are detected, treat maximally to decrease CVD risk and

events

A Growing NeedA Growing Need

More Americans than ever before could benefit from treatment of hypertension and dyslipidemia

– The graying of the population

– More-aggressive guidelines JNC 7 and NCEP ATP III

– The weight of the evidence

– The evidence of the weight

national epidemic of obesity

JNC 7JNC 7More-Aggressive GuidelinesMore-Aggressive Guidelines

BP

Classification

Systolic BP, mmHg*

Diastolic BP, mmHg*

Normal <120 And <80Prehypertension 120-139 Or 80-89Stage 1 hypertension

140-159 Or 90-99

Stage 2 hypertension

>160 Or >100

Goal of TherapyUncomplicated hypertension <140/90Heart failure or target organ damage

<130/85

Diabetes and/or chronic renal disease

<130/80

Chronic renal disease with proteinuria

<125/75

OVERCOMING CLINICAL INERTIA OVERCOMING CLINICAL INERTIA TO CONTROL HYPERTENSIONTO CONTROL HYPERTENSION

Importance of systolic BP-explain seriousness and urgency for treatment to patients

Need for multiple drugs is common-due to progression of disease, not failure of care

“Mild” elevation of BP is not “mild”-patients will suffer if this is not treated

ATP IIIATP IIIMore-Aggressive GuidelinesMore-Aggressive Guidelines

Risk Category LDL Goal (mg/dL)

LDL Level at

Which to

Initiate TLC (mg/dL)

LDL Level at Which

to Consider

Drug Therapy (mg/dL)

CHD or CHD Risk Equivalents

(10-year risk >20%)

<100 >100 >130

(100-129: drug optional)

2+ Risk Factors

(10-year risk <20%)

<130 >130 10-year risk 10%-20%: >130

10-year risk <10%: >160

0-1 Risk Factor <160 >160

>190

(160-189: LDL-lowering

drug optional)

NCEP ATP III. NCEP ATP III. JAMAJAMA. 2001;285:2486.. 2001;285:2486.

Six Stages of Medication Six Stages of Medication AdherenceAdherence

Stage 4: “You are ill. Take this medicine until you feel well, and continue for a lifetime of therapy, even if you never again feel ill.”

Stage 5: “You are well. Take this medicine every day for the rest of your life to prevent illness.”

Courtesy: Ockene IS.

Six Stages of Medication Six Stages of Medication AdherenceAdherence

Stage 6: “You are well. Take this medicine, which may make you feel sick, will be expensive, and will constantly remind you that you have a ‘problem,’ every day for the rest of your life to prevent an illness that is unlikely to occur for many years, and that may never occur even if you don’t take the medication.”

Courtesy: Ockene IS.

Adherence to Antihypertensive Adherence to Antihypertensive and Lipid-Lowering Therapy Over and Lipid-Lowering Therapy Over TimeTime Only about 1 in 3 patients was classified as adherent

to concomitant antihypertensive and lipid-lowering therapy over time.

– Another third was not adherent with either therapy in each interval.

– Remainder of the population (25%-30%) was adherent with one medication (usually antihypertensive therapy) but not the other.

Adherence was better when therapies were initiated on or about the same date (within 0-30 days of each other).

Chapman RH, et al. Chapman RH, et al. American Heart Association.American Heart Association. 2003. 2003.

Nonadherence to Therapy: Nonadherence to Therapy: A Major ChallengeA Major Challenge

Nonadherence (aka noncompliance, nonpersistance, etc.) is a major problem

Within 1 year, ~50% of patients overall discontinue use of drugs

An additional ~35% discontinue treatment within 2 years

National Council on Patient Information and Education, 1997.National Council on Patient Information and Education, 1997.

Consequences of Consequences of Nonadherence Nonadherence

Because of improper use, 30%-50% of prescriptions fail to produce desired therapeutic results

Nonadherence causes unnecessary hospital admissions costing $25 billion annually in the US

National Council on Patient Information and Education.

Berg JS, et al. Ann Pharmacother. 1993;27:S1-24.

Physician Adherence Physician Adherence ManagementManagement

“How do you remember to take your medicine?” “As is the case with many patients, do you ever miss or

forget a dose?” “How do you remember to take your medication on

weekends or while traveling?” “What do you think you could do to avoid missing

doses?” “Might any future events interfere with taking your

medication?”

Clinician uses problem-solving approach based on questioning the patient in a nonjudgemental manner

Insull W. Insull W. J Intern Med. 1997;241:317.J Intern Med. 1997;241:317.

Concomitant Concomitant Hypertension/Dyslipidemia: Key Hypertension/Dyslipidemia: Key Management PrinciplesManagement Principles Individualize care based on specific needs, but avoid unduly

prioritizing treatment of 1 condition over the other Educate patients about CVD risk reduction

– Simultaneous blood pressure control and lipid-lowering through TLC

Employ treatment approaches that facilitate long-term adherence by considering real-world issues– Drug cost– Dosing schedules– Number of pills taken per day– Adverse effects

Regularly update patients on current numbers and goals for both blood pressure and lipids– Explain significance of numbers– Record goal in chart to prompt follow-up at each visit

JNC 7JNC 7Thorough Hypertension EvaluationThorough Hypertension Evaluation

Physical examination– Appropriate measurement of BP, verified in contralateral

arm– Optic fundi examination– BMI calculation– Auscultation for carotid, abdominal, femoral bruits– Thorough examination of heart and lungs– Examination of abdomen for enlarged kidneys, masses,

abnormal aortic pulsation– Palpation of lower extremities for edema, pulses– Neurological assessment

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

JNC 7JNC 7Lifestyle ModificationsLifestyle Modifications

Healthy lifestyle is critical for hypertension management– Reduces BP– Enhances antihypertensive drug efficacy– Decreases CVD risk

DASH diet (1600 mg sodium/d) may be as efficacious as single-drug therapy

Combinations of > 2 modifications can achieve even better results

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

DASH StudyDASH StudyEffects of Diet onEffects of Diet onSystolic and Diastolic Blood Systolic and Diastolic Blood PressurePressure Dietary Approaches to Stop Hypertension 459 adults with mild hypertension or high-normal

blood pressure (<160/80-95) randomized for 8 weeks to:– Control diet or– High fruit/vegetable diet or– DASH combination diet (high fruit/vegetable, low

saturated fat and cholesterol, high calcium, high potassium)

Sodium intake and body weight remained constantAppel LJ, et al. Appel LJ, et al. N Engl J Med.N Engl J Med. 1997;336:1117-1124. 1997;336:1117-1124.

JNC 7JNC 7Combination TherapyCombination Therapy

Most patients require > 2 drugs to achieve goals If blood pressure > 20/10 mmHg above goal, consider

initiating treatment with 2 drugs– Separate prescriptions, or fixed-dose combinations– Using lower-than standard doses of > 2 drugs may improve

efficacy and reduce adverse effects

Use caution in patients at risk for orthostatic hypotension– Diabetes– Autonomic dysfunction– Older patients

Chobanian AV, et al. Chobanian AV, et al. JAMA.JAMA. 2003;289:2560-2572. 2003;289:2560-2572.Law MR, et al. Law MR, et al. BMJ.BMJ. 2003;326:1427-1434. 2003;326:1427-1434.

How Low Should LDL-Cholesterol How Low Should LDL-Cholesterol Be? New Guidelines are NeededBe? New Guidelines are Needed

BRITISH HEART PROTECTION STUDY: Simvastatin 40 mg reduces risk of CV events by 30% even in patients with initial untreated LDL-C < 100 mg/dL

ARBITER: Regression of carotid atherosclerosis as measured by carotid artery intima-media thickness is directly related to the absolute LDL-C level obtained on statin therapy. The greatest regression occurred with an LDL-C < 70 mg/dL.

REVERSAL: The effect of 18 months of intensive LDL-C lowering therapy with atorvastatin (46% reduction from baseline) was compared with more moderate therapy with pravastatin (25% from baseline), in CHD patients.

The intensive LDL-C lowering regimen halted the progression of atherosclerosis as measured by total plaque volume using intravascular ultrasound (IVUS).

ASCOT: In treated hypotensive patients, at moderate risk for CV events and with average baseline LDL-C of 130 mg/dL, 10 mg atorvastatin reduced all CV events and stroke by 21-36% compared with placebo. This effect emerged early and led to early termination of the lipid-lowering arm of the study. Final LDL-C on therapy was 84 mg/dL.

Events Events ** in the Major Prevention in the Major Prevention TrialsTrials

Trial N

# of Events Placeb

o

# of Events Statin

RR Reductio

n

% Events

Not Avoided

4S 4444 622 431 34 66WOS 6595 248 174 31 69CARE 4159 274 212 24 76AFCAPS/TexCAPS

6605 183 116 37† 63

LIPID 9014 715 557 24 76Lancet 1994;344:1383-1389.

N Engl J Med. 1995;333:1301-1307.

N Engl J Med. 1996;335:1001-1009.

N Engl J Med. 1998;339:1329-1357.

JAMA. 1998;279:1615-1622.

*Nonfatal MI/CHD death

†Includes unstable angina

Low HDL Low HDL CholesterolCholesterol

Postprandial Postprandial HyperlipidemiaHyperlipidemia

Small, Small, Dense LDLDense LDL

HYPERTRIGLYCERIDEMIAHYPERTRIGLYCERIDEMIA

Procoagulant StateProcoagulant StateInsulin ResistanceInsulin Resistance Triglyceride-RichTriglyceride-RichLipoproteinLipoproteinRemnantsRemnants

Figure 2. Association of elevated serum trigylceride levels and Figure 2. Association of elevated serum trigylceride levels and atherogenic risk factors. Modified from Brewer HB Jr. atherogenic risk factors. Modified from Brewer HB Jr. Hypertriglyceridemia: changes in the plasma lipoproteins associated Hypertriglyceridemia: changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease. Am J Cardiol with an increased risk of cardiovascular disease. Am J Cardiol 1999;83:3F-12F, with permission from Excerpta Medica Inc.1999;83:3F-12F, with permission from Excerpta Medica Inc.

Lowering LDL-C Is Not EnoughLowering LDL-C Is Not Enough

Despite significant lowering of LDL-C in the Despite significant lowering of LDL-C in the statin trials, over 65% of treated patients statin trials, over 65% of treated patients continue to have, or die from, CV events.continue to have, or die from, CV events.

Most patients with atherosclerotic disease Most patients with atherosclerotic disease have a mixed dyslipidemia with elevated have a mixed dyslipidemia with elevated LDL-C, but as importantly, elevated LDL-C, but as importantly, elevated triglycerides and low levels of HDL-C.triglycerides and low levels of HDL-C.

This atherogenic lipid profile is characterized by This atherogenic lipid profile is characterized by small, dense LDL lipoprotein particles and low small, dense LDL lipoprotein particles and low levels of large, protective HDL particles.levels of large, protective HDL particles.

It appears that “ideal lipid goals” for high risk It appears that “ideal lipid goals” for high risk patients need to be lower than published patients need to be lower than published guidelines and prudent and safe recommendations guidelines and prudent and safe recommendations are:are:

TC

TG

HDL

LDL

<150 mg/dL

<100 mg/dL

>50 mg/dL

>70-80 mg/dL