Treatment Of Hypertensive Patients With Dyslipidemia And The Metabolic Syndrome: Update from the ALL - PowerPoint PPT Presentation

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Treatment Of Hypertensive Patients With Dyslipidemia And The Metabolic Syndrome: Update from the ALL

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Title: Treatment Of Hypertensive Patients With Dyslipidemia And The Metabolic Syndrome: Update from the ALL


1
Treatment Of Hypertensive Patients With
Dyslipidemia And The Metabolic SyndromeUpdate
from the ALLHAT
  • Jackson T. Wright, Jr. MD, PhD
  • Professor of Medicine
  • Case Western Reserve University
  • Program Director, WT Dahms Clinical Research Unit
  • CWRU CTSA
  • Director, Clinical Hypertension Program
  • University Hospitals Case Medical Center and
  • the Louis Stokes Cleveland VAMC

2
Presenter Disclosure Information
Jackson T. Wright, Jr, MD, PhD
FINANCIAL DISCLOSURE Research support Glaxo
Smith Kline, Novartis, NIH Consulting Novartis,
MSD, Sanofi, Pfizer, NIH Honoraria Novartis,
Sanofi, Pfizer I RECEIVE NEITHER TRAVEL,
HONORARIA, NOR DINNERS FROM MANUFACTURERS
PROMOTING THIAZIDE-TYPE DIURETICS
UNLABELED / UNAPPROVED USES DISCLOSURE None
3
BACKGROUND
  • The adverse effects of thiazide-type diuretics on
    blood cholesterol, glucose, potassium, uric acid
    have been known for more than 40 years
  • While shown to be very effective in reducing
    clinical outcomes, some have suggested that the
    adverse metabolic effects of these agents
    significantly reduce their benefit
  • ALLHAT was designed to evaluate the effect of
    diuretics on clinical outcomes compared to agents
    without these adverse metabolic effects

4
PRESENTATION OUTLINE
  • 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?

5
Elevated SBP in Type 2 Diabetes Increases
Cardiovascular Risk
Elevated SBP increases risk of CV death almost
twofold in diabetic vs nondiabetic patients
Stamler J et al. Diabetes Care. 199316434-444.
20
6
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
N9,061
N9,054
N9,048
N15,255
STEP 2 AND 3 AGENTS (5 years)
Hydralazine 10.9
Atenolol 28.0
Clonidine 10.6
Reserpine 4.3
Of participants with data available for
determination.
7
Biochemical Results
plt.05 compared to chlorthalidone Ann Intern
Med. 1999130461-470.
8
Biochemical Results Doxazosin vs. Chlorthalidone
plt.05 compared to chlorthalidone
9
Biochemical Results Fasting Glucose mg/dL
plt.05 compared to chlorthalidone
10
Biochemical Results Fasting Glucose mg/dL
Doxazosin vs. Chlorthalidone
plt.05 compared to chlorthalidone
11
Participants with DM in AHT Drug Trials
12
Outcomes in the Blood Pressure Component of ALLHAT
DIABETIC GROUP
Favors Favors Amlodipine
Chlorthalidone
Favors Favors Lisinopril
Chlorthalidone
Whelton PK et al. Arch Intern Med 20051651401
13
Outcomes in the Blood Pressure Component of ALLHAT

Favors
Favors Amlodipine
Chlorthalidone
Favors Favors Lisinopril
Chlorthalidone
Whelton PK et al. Arch Intern Med 20051651401
14
New diabetes and CVD risk Verdecchia 2004
  • 795 treated HTs, median FU 6 yrs.
  • Diuretic rx (low-mod dose HCTZ or CLTD)
    independently predictive of new diabetes.
  • Adjusted RR (95 CI) of CVD-renal event (n63)
  • --BL DM, 3.57 (1.65, 7.73)
  • --New DM, 2.92 (1.33, 6.41)
  • Results for specific regimens not given, only
    11 on diuretic/ß blocker alone.

Verdecchia et al. Hypertension 200443963-69.
age, 24h SBP, LVH.
15
Effect of Incident Diabetes on ALLHAT
Endpoints(Cox Regressions Beginning at 2 Years)
Barzilay J et al Arch Intern Med. 20061662191
16
Effect of Change in Fasting Glucose on ALLHAT
Endpoints(Cox Regressions Beginning at 2 Years)
Barzilay J et al Arch Intern Med. 20061662191
17
Effect of Change in Fasting Glucose on ALLHAT
Endpoints(Cox Regressions Beginning at 2 Years)
18
Effect of Incident Diabetes on CHD Heart
Failure by Treatment Group(Cox Regressions
Beginning at 2 Years)
19
Effect of Incident Diabetes on Total Mortality by
Treatment Group(Cox Regressions Beginning at 2
Years)
Barzilay J et al Arch Intern Med. 20061662191
20
Cardiovascular Death () 14.3 yrs Follow up
SHEP-X Systolic Hypertension in the Elderly
Program extended follow-up. Kostis, et al. Am
J Cardiol. 20059529-35
plt 0.05 vs no diabetes
21
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 HTNives with MetS
  • However, no clinical outcome data are available
    to justify this recommendation
  • Alpha-blockers and RAS inhibitors demonstrate the
    most favorable effect on blood glucose and
    lipids, CCBs are intermediate, followed by
    THZ-diuretics.
  • ALLHAT is the first study to report on the effect
    of antihypertensive regimens on clinical outcomes
    in hypertensives with the MetS.

22
Definition of MetS (DS) ALLHAT Participants
  • Any 3 or more of the following
  • Hypertension (present in all as a condition of
    enrollment into ALLHAT)
  • Fasting glucose gt100 mg/dl or 100-125 mg/dl in
    non-diabetics with MetS
  • BMI 30 kg/m2
  • Fasting triglycerides 150 mg/dL
  • HDL cholesterol lt40 mg/dl in men, lt50 mg/dl in
    women

23
Baseline Characteristics - Participants With
and Without DS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt.05
24
Baseline Characteristics - Participants With
and Without DS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt.05
25
Blood Pressure at 5 Yearsby Baseline DS Status
26
Amlodipine/Chlorthalidone Relative Risk and 95
Confidence Intervals
With Dysmetabolic Syndrome
Without Dysmetabolic Syndrome
0.95 (0.84 - 1.07)
1.05 (0.90 - 1.22)
0.97 (0.88 - 1.06)
0.93 (0.83 - 1.04)
0.87 (0.74 - 1.04)
1.04 (0.83 - 1.29)
1.32 (1.15 - 1.51)
1.45 (1.20 - 1.75)
1.05 (0.98 - 1.12)
1.05 (0.96 - 1.15)
0.81 (0.51 - 1.26)
1.27 (0.96 - 1.68)
0.50
1
2
0.50
1
2
Favors Chlorthalidone
Favors Amlodipine
Favors Chlorthalidone
Favors Amlodipine
27
Lisinopril/Chlorthalidone Relative Risk and 95
Confidence Intervals
With Dysmetabolic Syndrome
Without Dysmetabolic Syndrome
1.01 (0.90 - 1.13)
1.02 (0.88 - 1.20)
1.01 (0.93 - 1.12)
1.02 (0.91 - 1.14)
1.09 (0.93 - 1.28)
1.20 (0.97 - 1.48)
1.28 (1.12 - 1.47)
1.02 (0.83 - 1.25)
1.14 (1.06 - 1.21)
1.07 (0.98 - 1.17)
1.22 (0.92 - 1.63)
0.76 (0.48 - 1.21)
0.50
1
2
0.50
1
2
Favors Chlorthalidone
Favors Lisinopril
Favors Chlorthalidone
Favors Lisinopril
28
Blood Pressure at 5 Yearsby Baseline MetS Status
29
Baseline Characteristics - Participants With
and Without MetS
30
Blood Pressure at 5 Yearsby Baseline MetS Status
31
Lisinopril/Chlorthalidone Relative Risk and 95
Confidence Intervals 6-year Rate per 100
non-Black
non-Black
Without Metabolic Syndrome
1.00 (0.82 - 1.21)
1.02 (0.88 - 1.18)
1.13 (0.85 - 1.49)

0.98 (0.76 - 1.27)
1.05 (0.94 - 1.18)
0.78 (0.39 - 1.55)
0.50
1
2
Favors Lisinopril
Favors Chlorthalidone
32
Lisinopril/Chlorthalidone Relative Risk and 95
Confidence Intervals 6-year Rate per 100
Black
Black

33
Biochemistries at 4 Yearsby Baseline MetS Status
34
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35
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36
Baseline Characteristics - Non-Diabetic
Participants With and Without MS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt0.05
37
Baseline Characteristics - Non-Diabetic
Participants With and Without MS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt0.05
38
Blood Pressure at 5 Yearsby Baseline MS Status
(Non-Diabetics)
39
Metabolic Syndrome by Definition with and without
Diabetes Mellitus (History and Glucose ?
125)Relative Risk and 95 Confidence Intervals
  • Amlodipine/Chlorthalidone Lis
    inopril/Chlorthalidone
  • Without DM With DM Without DM
    With DM
  • CHD 0.96 (0.79 - 1.16) 0.95 (0.84
    1.07) 1.09 (0.91 - 1.30) 1.01 (0.90 1.13)
  • All-cause mortality 0.98 (0.83 - 1.15) 0.97
    (0.88 1.06) 1.04 (0.89 - 1.22) 1.02 (0.93
    1.12)
  • Stroke 0.84 (0.62 - 1.13) 0.87 (0.74
    1.04) 1.22 (0.94 - 1.58) 1.09 (0.93 1.28)
  • Heart Failure 1.09 (0.85 - 1.38) 1.32 (1.15
    1.51) 1.31 (1.04 - 1.64) 1.28 (1.12 1.47)
  • Combined CVD 1.03 (0.92 - 1.14) 1.05 (0.98
    1.12) 1.19 (1.07 - 1.32) 1.14 (1.06 1.21)
  • ESRD 0.69 (0.36 - 1.36) 1.27 (0.96
    1.68) 1.08 (0.61 - 1.91) 1.22 (0.92 1.62)
  • plt 0.05

40
SUMMARY AND 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 provides further evidence against the
    consideration of intermediate outcomes in the
    selection of antihypertensive agents.
  • Findings apply equally to Black and non-Black
    populations

41
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