Title: Treatment Of Hypertensive Patients With Dyslipidemia And The Metabolic Syndrome: Update from the ALL
1Treatment 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
2Presenter 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
3BACKGROUND
- 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
4PRESENTATION 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?
5Elevated 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
6Hypertension 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.
7Biochemical Results
plt.05 compared to chlorthalidone Ann Intern
Med. 1999130461-470.
8Biochemical Results Doxazosin vs. Chlorthalidone
plt.05 compared to chlorthalidone
9Biochemical Results Fasting Glucose mg/dL
plt.05 compared to chlorthalidone
10Biochemical Results Fasting Glucose mg/dL
Doxazosin vs. Chlorthalidone
plt.05 compared to chlorthalidone
11Participants with DM in AHT Drug Trials
12Outcomes 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
13Outcomes in the Blood Pressure Component of ALLHAT
Favors
Favors Amlodipine
Chlorthalidone
Favors Favors Lisinopril
Chlorthalidone
Whelton PK et al. Arch Intern Med 20051651401
14New 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.
15Effect of Incident Diabetes on ALLHAT
Endpoints(Cox Regressions Beginning at 2 Years)
Barzilay J et al Arch Intern Med. 20061662191
16Effect of Change in Fasting Glucose on ALLHAT
Endpoints(Cox Regressions Beginning at 2 Years)
Barzilay J et al Arch Intern Med. 20061662191
17Effect of Change in Fasting Glucose on ALLHAT
Endpoints(Cox Regressions Beginning at 2 Years)
18Effect of Incident Diabetes on CHD Heart
Failure by Treatment Group(Cox Regressions
Beginning at 2 Years)
19Effect of Incident Diabetes on Total Mortality by
Treatment Group(Cox Regressions Beginning at 2
Years)
Barzilay J et al Arch Intern Med. 20061662191
20Cardiovascular 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
21OUTCOMES 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.
22Definition 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
23Baseline Characteristics - Participants With
and Without DS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt.05
24Baseline Characteristics - Participants With
and Without DS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt.05
25Blood Pressure at 5 Yearsby Baseline DS Status
26Amlodipine/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
27Lisinopril/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
28Blood Pressure at 5 Yearsby Baseline MetS Status
29Baseline Characteristics - Participants With
and Without MetS
30Blood Pressure at 5 Yearsby Baseline MetS Status
31Lisinopril/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
32Lisinopril/Chlorthalidone Relative Risk and 95
Confidence Intervals 6-year Rate per 100
Black
Black
33Biochemistries at 4 Yearsby Baseline MetS Status
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36Baseline Characteristics - Non-Diabetic
Participants With and Without MS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt0.05
37Baseline Characteristics - Non-Diabetic
Participants With and Without MS
Randomized to chlorthalidone, amlodipine, or
lisinopril. plt0.05
38Blood Pressure at 5 Yearsby Baseline MS Status
(Non-Diabetics)
39Metabolic 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
40SUMMARY 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
41The End