Hypertensive Dyslipidaemics

Therapy of hypertensives with dyslipidaemia Unlearning towards better learning

The agenda for today
Hypertension – the background
Current status of dyslipidaemia
The case studies
The clinical trials & the observations
The learnings
The summary

Hypertension The background

Hypertension
What we record as B.P.
It is only a marker of the bigger problem
The Truth is
Hypertension is a multi-organ systemic disease
The Problem is
Hypertension is asymptomatic in 85% of cases

Hypertension – Be wise
It is wrong
To consider Hypertension as an isolated disease
The Truth is
Hypertension, DM, Dyslipidemia, Obesity coexist
They are the 4 pallbearers to the grave of CHD/CVD
For all of them
Primary & secondary prevention by TLC = answer
Afflicted with one, must be screened for all other thieves

Hypertension – Therapy goal
Goal BP
To Keep B.P. < 140/90 mm Hg in each patient
This may be revised to 120/80 may be ? 110/70
MRFIT’s cut off values are 115/75 mm Hg
The Truth is
It is essential to keep the B.P at or below the goal
But, It also matters how the goal B.P. is achieved !

Current status Hypertension and dyslipidaemia

Rule of halves in hypertension
What is this rule of halves in HT ?
JNC 7. May 2003; Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
For every 800 adults in the community
400 are HT (either ↑ SBP or ↑ DBP or both)
Of them only 200 are diagnosed HT
Of them only 100 are started on treatment
Of them only 50 are on correct drug
Of them in only 25 the goal B.P. is attained
Means 25 ÷ 400 = 6% only have goal BP
And we have yet to look at HT with other conditions

People with concomitant hypertension & dyslipidemia 90 million with dyslipidemia JNC 7. May 2003; Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III. 27 million with concomitant hypertension, dyslipidemia 50 million with hypertension

People with concomitant hypertension & dyslipidemia 9 million diagnosed (33%) 18 million undiagnosed (67%) Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.

People with concomitant hypertension & dyslipidemia Source: Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES-III), CDC 1994; data from 1999.

People with concomitant hypertension & dyslipidemia 10% Treated For Hypertension & Dyslipidemia Source: Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES-III), CDC 1994; data from 1999. 3% at Goal

Co-prevalence of dyslipidemia & hypertension in India The prevalence of coexistence of dyslipidemia and hypertension in patients surveyed at Apollo Hospitals (n=501) Indian Heart Journal 1996: 48(4): 371-374 0 10 20 30 40 50 Percent 60 70 80 90 100 0 TC>200 mg/dl (n=501) LDL>130 mg/dl (n=486) HDL<35 mg/dl (n=501) TG>200 mg/dl (n=496) TC/HDL ratio>4.5 (n=500)

MRFIT - Hypertension and Dyslipidemia and CAD Risk Adapted from Neaton JD, et al. Arch Intern Med . 1992;152:56-64. Age-adjusted CAD death rates

The approach
Global risks assessment and reduction is the best way to reduce CV events.
Hypertension and Hyperlipidemia are 2 most common risks found in our population.
New antihypertensive drugs are beneficial in BP control and prevention of CV events.
Multi-drug combinations should be used to modify risk factors and/or metabolic disturbances but is usually associated with poor compliance.

Whom to Screen for Dyslipidemia?
Influenced by cardiac risk factors:
By age alone:
Men over age 40
Women over age 50 (or post-menopausal)
Other risk factors (at any age):
DM, HTN, Smoking, Abdominal Obesity
Family history of early cardiovascular disease
Physical signs of hyperlipidemia (at any age):
Xanthomata, xanthelasmas, arcus corneae, etc
Evidence of existing atherosclerosis (any age)

Factors Influencing Risk Assessment
Metabolic Syndrome
Abdominal Obesity
Apolipoprotein B (apoB)
Lipoprotein(a)
Homocysteine
C-Reactive Protein (CRP)
Genetic Risk
Hormone Replacement Therapy (HRT)

Presence of the Metabolic Syndrome
A clustering of cardiovascular risk factors, including abdominal obesity, insulin resistance, and hypertension, as well as lipid abnormalities (↑TGs and ↓HDL)
Presence of Abdominal Obesity
with waist circumference as a useful estimate

Apolipoprotein B (apoB)
There is 1 molecule of apoB in each atherogenic lipid particle (VLDL, IDL, LDL, lp(a))’
↑apoB (for the same lipid levels) = smaller, denser, more atherogenic LDL particles
Better estimate than LDL of cardiovascular risk
ApoB levels correlate better than LDL levels to clinical outcomes in statin trials
For ‘high risk’ patients, target apoB <0.9g/L
Sample does not need to be fasting

Lipoprotein(a) (lp(a))
Appears to be an independent risk factor for premature atherosclerosis and CAD
Its atherogenicity seems to depend on the presence of other factors, and its utility as a risk factor seems to disappear if the LDL is markedly lowered
Monogenic and not responsive to diet
Lp(a) >30mg/dL in patients with TC/HDL ratio >5.5 or other major risk factors may indicate need for earlier and more intensive LDL-lowering therapy

Homocysteine
↑homocysteine levels predict adverse outcomes in patients with CAD
Fixed-dose folate & B12 trials looking at cardiovascular endpoints are ongoing
No ‘treat-to-target’ trial (to homocysteine <9μmol/L)
No evidence yet to screen for homocysteine

↑CRP may add prognostic information to Framingham Study data
↑CRP associated with abdominal obesity and the metabolic syndrome
May be clinically useful in identifying people who are at higher risk than their Global Risk Assessment would indicate (especially for people with a calculated 10-year risk of 11-19%, so calculated to be at ‘moderate risk’)

Do not measure during an acute illness or in patients with chronic inflammatory disease
Measure 2x, two weeks apart, and use the lower value
Low risk <1 mg/ml & high risk 3-10mg/ml
If >10mg/ml, look for infection/inflammation

Hypertensive patient with Dyslipidaemia Case study

Patient # 1
A 57-year old man, who staying in a small town, comes to see his son in the big city and the son gets him to you for opinion.
Approximately a year back, he suffered a myocardial infarction, but has since been asymptomatic. He does not have any other significant past medical history.
His current medications include aspirin 81 mg daily and a beta-blocker.
His sitting blood pressure is 155/95 mmHg, heart rate 58 beats/min.
Pertinent laboratory values: glucose 86 mg/dl; total cholesterol 228 mg/dl; HDL-C 37 mg/dl; LDL-C 128 mg/dl.
An echocardiogram shows concentric LVH and preserved left ventricular systolic function (ejection fraction 56%).

Question # 1
A statin (to reduce LDL-C to ≤ 100 mg/dl), a calcium channel blocker, and a diuretic.
An angiotensin-receptor blocker and a statin (to reduce LDL-C to ≤ 70 mg/dl).
An ACE inhibitor and a statin (to reduce LDL-C to ≤ 120 mg/dl).
Oral nitrates, hydralazyne, and a statin (to reduce LDL-C to ≤ 70 mg/dl).
Niacin, a calcium channel blocker, and a diuretic.
Which of the following should be done?
An ACE inhibitor and a statin (to reduce LDL-C to ≤ 120 mg/dl).

MRFIT - Effect of Systolic & Diastolic BP on CHD Mortality *Men aged 35-57 years followed for a mean of 12 years. <120 120-139 140-159 160+ CHD Death Rate per 10,000 Person-Years 48.3 37.4 34.7 43.8 38.1 80.6 31.0 25.5 24.6 25.3 25.2 24.9 Systolic BP (mm Hg) Diastolic BP (mm Hg) Neaton et al. Arch Intern Med . 1992;152:56-64. 100+ 80-89 70-74 <70 75-79 90-99 23.8 16.9 13.9 12.8 12.6 11.8 20.6 10.3 11.8 8.8 8.5 9.2 Patient in Question # 1

Treatment of hypertensive patients with Dyslipidaemia The learning from different studies

Selected major trials
PROVE IT – TIMI 22
MRC/BHF Heart Protection Study
ASCOT- LLA
ALLHAT

Lower is better
statin therapy provides benefits even with lower LDL-C
Adapted from Kastelein JJP. Atherosclerosis . 1999;143(suppl 1):S17-S21., Sever PS, et al. Lancet . 2003;361:1149-1158., Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016 0 210 Patients with CHD Event (%) Mean LDL-C Level at Follow-up (mg/dL) Secondary prevention Primary prevention Atorvastatin 90 110 130 150 170 190 5 10 15 20 25 AFCAPS-S WOSCOPS-S WOSCOPS-P CARE-S LIPID-P 4S-P LIPID-S CARE-P 4S-S AFCAPS-P ASCOT-S ASCOT-P Simvastatin Pravastatin Lovastatin HPS-S HPS-S HPS-P HPS-P S=statin treated P=placebo treated

PROVE IT – TIMI 22: moderate vs intensive statin therapy in pts. with ACS Cannon CP, et al. N Engl J Med. 2004;350:1-10. No. at Risk Pravastatin Atorvastatin 2063 2099 1688 1736 1536 1591 1423 1485 810 842 138 133 106 106 95 62 0 20 40 60 80 100 120 Pravastatin 40 mg/day (n=2063) Atorvastatin 80 mg/day (n=2099) Median LDL-C (mg/dL) Baseline Final (Mean, 24 mo) P <0.001

PROVE IT: Intensive Statin Therapy ↓ All-Cause Mortality and Risk of MACE No. at Risk Pravastatin Atorvastatin 2063 2099 1688 1736 1536 1591 1423 1485 810 842 138 133 Cannon CP, et al. N Engl J Med. 2004;350:1-10. Months of Follow-up

MRC/BHF Heart Protection Study
HPS: Lancet 360(9326):7-22, 6 July 2002
20,556 men & women aged 40-80 with TC >3.5
All at ‘high risk’ of CAD
Known CAD/MI/PVD/CVS
DM, HTN, or both
RCT: Simvastatin 40mg vs. placebo
Decreased death rate by 13%
Decreased combined cardiovascular end points by 24%
Benefits in all subgroups, including baseline LDL <2.6
Very compelling, well done trial
Ultimate LDL target still unclear, other studies now looking at LDL targets of <1.8

ASCOT – LLA - Rationale
Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm
Premise
High prevalence of dyslipidemia in hypertensive patients
Most CV disease events occur in patients with BP and lipid concentrations deemed normal
Hypothesis
Lipid lowering will benefit hypertensive patients, not conventionally deemed dyslipidemic

ASCOT – LLA - Findings
In patients with hypertension and additional CV risk factors, addition of atorvastatin
Had significant effects on nonfatal CVD and fatal MI
Benefits even in absence of traditional dyslipidaemia
Identification of the at-risk patient with hypertension and other CV risk factors enables appropriate treatment for CV event prevention
Study was stopped after 3 years because of significant benefit in the treatment group

Diet control & dyslipidaemia reduction

Time course of Statin effects * Time course established Days Years LDL-C lowered* Inflammation reduced Vulnerableplaques stabilized Endothelial function restored Ischemic episodes reduced Cardiac events reduced*

Therapy
In ‘high risk’ patients:
Start drug treatment immediately, concurrently with diet and lifestyle modification
Priority is to get LDL <2.5 and TC/HDL <4
Given HPS data, treat with Simvastatin 40mg or equivalent statin for LDL target.
If can’t reach LDL target:
Bile acid sequestrants (cholestyramine, colestipol), or
Ezetimibe - better tolerated
Either can decrease LDL by another 10-20% compared with statin alone

Treatment of hypertensive patients with Dyslipidaemia Different antihypertensive perspectives

Elevated SBP in Type 2 Diabetes Increases Cardiovascular Risk Stamler J et al. Diabetes Care . 1993;16:434-444. Elevated SBP increases risk of CV death almost twofold in diabetic vs nondiabetic patients 20 Cardiovascular Mortality Rate per 10,000 Patient-Years SBP (mm Hg) Nondiabetic patients Diabetic patients 250 200 150 100 50 0 <120 120–139 140–159 160–179 180–199  200 MRFIT

Hypertension Optimal Treatment (HOT) Study Lancet 1998; 351: 1755–62 p=0.005 (DM) 0 5 10 15 20 25 Events/1000 pt-years <90 <85 <80 Target diastolic BP DM non-DM Reduction in CV events

Questions on antihypertensives
Antihypertensives are very effective in reducing clinical outcomes. But the adverse metabolic effects of these agents significantly reduce their benefit, in comorbid hypertension especially in hypertension with dyslipidaemia and in Syndrome-X cases.
Is the “how to” of hypertension control as important as the “how well” of hypertension control in patients requiring more than one anti-hypertensive agent?

Questions on antihypertensives
Is there synergy between certain anti-hypertensive medication combinations that outweigh benefits of the individual medications?
The adverse effects of thiazide-type diuretics on blood cholesterol, glucose, potassium, uric acid have been known for more than 40 years

Approaches to hypertension therapy

Lifestyle Modification approach in hypertension therapy 5–20 mm/10 kg wt loss Weight reduction All put together reduce BP by 20 to 55 mmHg 2–4 mmHg Abstinence from alcohol 4–9 mmHg Physical activity 2–8 mmHg Dietary sodium reduction 8–14 mmHg Adopt DASH [Dietary Approaches to Stop Hypertension] eating plan Approximate BP reduction [range] Modification

ALLHAT
ALLHAT is the first study to report on the effect of antihypertensive regimens on clinical outcomes in hypertensives with the MetS.
ALLHAT was designed to evaluate the effect of diuretics on clinical outcomes compared to agents without these adverse metabolic effects
ALLHAT

ALLHAT - Definition of MetS (DS) participants
Any 3 or more of the following:
Hypertension (present in all as a condition of enrollment into ALLHAT)
Fasting glucose >100 mg/dl or 100-125 mg/dl in non-diabetics with MetS
BMI ≥ 30 kg/m2
Fasting triglycerides ≥ 150 mg/dL
HDL cholesterol <40 mg/dl in men, <50 mg/dl in women
ALLHAT

ALLHAT
How large is the difference in metabolic effects, esp the effect on glucose?
Does the effect associate with an increase in adverse clinical outcomes compared to drugs with a more favorable metabolic profile?
Are patients at higher risk (e.g. patients with diabetes or the metabolic syndrome) more vulnerable to the adverse effects of available antihypertensive agents?
ALLHAT

Hypertension Trial 42,418 high-risk hypertensive patients 90% previously treated, 10% untreated STEP 1 AGENTS Chlorthalidone 12.5-25 mg Amlodipine 2.5-10 mg Lisinopril 10-40 mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 STEP 2 AND 3 AGENTS (5 years)* Atenolol 28.0% Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9% * Of participants with data available for determination. ALLHAT

Outcomes in ALLHAT participants with the metabolic syndrome
Patients with metabolic syndrome (MetS) are at very high risk for complications of hypertension
Use of agents with favorable metabolic effects esp recommended in hypertensives with MetS
Alpha-blockers and RAS inhibitors demonstrate the most favorable effect on blood glucose and lipids,
CCBs are intermediate, followed by THZ-diuretics.
ALLHAT

Summary & conclusions
Despite a more favorable metabolic profile, antihypertensive therapy initiated with an  - blocker, an ACEI, or a CCB was NOT superior to one initiated with a thiazide-type diuretic, including in those with MetS.
ALLHAT fails to support an increase in CVD risk associated with diuretic-induced glucose elevation or incident diabetes in hypertensive patients.
ALLHAT

Summary & conclusions
ALLHAT provides further evidence against the consideration of intermediate outcomes in the selection of antihypertensive agents.
Findings apply equally to Black and non-Black populations
ALLHAT

Effect of various antihypertensives on coexisting disorders

Effect of various antihypertensives on coexisting disorders Parameter Diuretic ACEi, ARB β blocker Ca + Blocker Ischemia No effect Improves Improves Negative LVH, LVF Improves Improves Improves* Negative CV Mortality Improves Improves Improves Increases Heart rate No effect No effect Bradycardia Tachycardia Use in DM Negative Excellent Negative Negative Lipid effects Negative Excellent Negative Neutral Fluid & Na Enhances No effect Vasoconstr. Vasodilatory K ex / bronchi Enhances No effect Bronchospa No effect UA / Conduct. ↑ Uric acid No effect ↓ conduction No effect

Treatment of hypertensive patients with Dyslipidaemia Learning on alpha blockade

Effect of various drugs on CHD risk Drugs 1995 14%  – 25%  Atenolol 19%  Captopril 18%  Enalapril 15-45%  Doxazosin Effect on CHD risk Drug

Change in Lipid Levels with Doxazosin Treatment: HALT Study Total-C LDL-C Triglycerides HDL-C Change in Lipid Levels (mg/dl) Am Heart J 1996;131: 966-973

Changes in Lipid Parameters after 24 weeks Total Chol. HDL Chol. HDL Total Chol. Triglyc Am J Card 1987;59:103G Average ( + S.E.)

How does doxazosin reduce lipids
Upregulation of LDL receptors
Decreased cholesterol synthesis
Decreased absorption of cholesterol from GIT
Decrease in lipoprotein lipase activity
Inhibition of VLDL synthesis

Doxazosin and CHD risk reduction
Beneficial effect on lipids
Beneficial effect on insulin resistance
Improved fibrinolytic activity
Reduces left ventricular hypertrophy
All these should effectively reduce the risk of CHD

Summary for all studies
Lower pill burden was associated with better Adherence to AHT [antihypertensive treatment] and LLT [lipid lowering treatment]
Patients who initiated AHT and LLT concurrently were significantly more likely to be adherent to both regimens
Single-pill regimens were associated with significantly better persistence to ACE inhibitors, diuretics, and antidiabetic agents

Concomitant Hypertension/Dyslipidemia: Key Management Principles
Individualize 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

Concomitant Hypertension/Dyslipidemia: Key Management Principles
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

Recording Chart

Treatment of hypertensive patients with Syndrome X The approach

Remember
The deadly trio to manage, whenever you see any one-
Hypertension
Dyslipdeamia
Insulin resistance
Why is this so?
FFAs

Elevated FFAP: contribute to hypertension, dyslipidemia, and insulin resistance Eckel RH et al. Lancet. 2005;365:1415-28. VLDL = very low density lipoproteins Hypertension Triglyceride (intramuscular droplet) Sympathetic nervous system Glycogen Insulin FFA FFA Glucose VLDL  HDL-C  Small dense LDL FFA Insulin Triglyceride C-II C-III B-100 and CO 2

The cardiovascular dysmetabolic syndrome Am. J. Med., 1998; 105(1A): 1S-3S Hypertension Obesity Hyperinsulinaemia Diabetes Hypertriglyceridaemia Small, dense LDL Low HDL Hypercoagulability Insulin resistance Atherosclerosis Endothelial dysfunction

Participants with Diabetes in ANTI-HYPERTENSIVE drug trials
ALLHAT
15,297
ASCOT
5,145
VALUE
4,891
HOPE
3,577 (43.6% hypertensive)
CONVINCE
3,266
HOT
1,501
LIFE
1,195
UKPDS
1,148
SHEP
583
Syst-Eur
492
ABCD
470
ANBP-2
426

Treatment of hypertensive patients with Dyslipidaemia Summary of Learning

Key Challenges Overview: Summary
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

Paradigm shift in anti-hypertensive therapy
It is not just ↓B.P., but today we must strive to
Alter the modifiable risk factors
Keep the SBP < 140 and DBP < 90
Prevent or halt or reduce Target Organ Damage –
LVH, CHD, CHF, CVA, CRF, PVD & Retina.
Prevent or control DM (as HT + DM is hazardous)
Prevent or control Dyslipidemia (Endothelial Dysf.)
Reduce morbidity and mortality
Improve QUALY – Quality Adjusted Life Years

What is the essential approach in hypertension treatment?

What is MOST essential in hypertension treatment?
Not that ‘my drug is superior to yours’
Not that ‘this trial is better than that’
Nor ‘this combination is better than that’
But to get AS MANY PEOPLE as we can to goal SBP < 140 & DBP < 90
And prevent or halt TOD.
Of course, tailor the treatment as per individual patient’s co-morbidities.

What is new in hypertension treatment?
HT is a multi-organ disease, and so not to consider in isolation but to look for ‘Co-Thieves’
Today’s goal BP is 140/90 – It will sure be less tomorrow
It matters to attain goal; matters more how it is attained. Monotherapy is gone; Combined Rx replaces
In DM, CKD, IHD the cut off values are 10 mm less

What is new in hypertension treatment?
↑ SBP is more important than ↑ DBP; Often ignored!
Wide pulse pressure (SBP-DBP) signifies arterial damage
Target organ damage (TOD) must be investigated and treated.
LVH = single imp. predictor of mortality and morbidity
ABI, MAU, ABPM, PWV etc., identify high risk cases early

Hypertensive Dyslipidaemics

by BALASUBRAMANIAM IYER

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