Transcript Expression of the epithelial Na+ channel and other

Both Amiloride and Nebivolol Have a
More Favourable Effect on Glucose
Tolerance Than Hydrochlorothiazide in
the Treatment of Essential Hypertension
Stears AJ, Woods SH, Watts MM, Graggaber J,
Burton TJ, Brown MJ
Department of Clinical Pharmacology,
Addenbrookes’ Hospital, Cambridge
Disclosures
• This study is an investigator-led study
supported by an unrestricted grant from
Menarini
Evidence to support thiazide use
• Thiazide and thiazide-like diuretics have been used for
treatment of essential hypertension since the 1950’s
• Evidence for their inclusion in clinical guidelines is based
on 4 decades of cardiovascular outcome trials
• ALLHAT1,2 - 42,418 subjects comparing chlorthalidone
with lisinopril, amlodipine and doxazosin
• Chlorthalidone was as beneficial as the comparator
drugs in lowering blood pressure and preventing
cardiovascular and renal outcomes
• Chlorthalidone was superior in preventing heart failure
1ALLHAT
Investigators. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;283;1967–1975.
2ALLHAT
Investigators. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel
blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–2997.
Thiazides and new onset diabetes
• ALLHAT1,2
9.3% chlorthalidone
7.2% amlodipine
5.6% lisinopril
• ASCOT3
11.4% atenolol ± thiazide
8.0% amlodipine ±
perindopril
• INSIGHT4
5.6% co-amilozide
4.3% nifedipine
3Bjorn
New onset diabetes in ASCOT
Dahlof et al; Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding
bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), Lancet 2005; 366: 895–
906
4Morris J Brown et al; Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the
International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT), Lancet • Vol 356 • July 29, 2000
Mechanism: thiazides and diabetes
• Mechanism underlying the association of
thiazides with diabetes is not understood
• Not known if the principal defect is
impaired insulin secretion or increased
insulin resistance5
• Changes in plasma potassium
concentration may affect glucose
tolerance6
5Barry
L. Carter et al; Thiazide-Induced Dysglycemia , Call for Research From a Working Group From the National Heart,
Lung, and Blood Institute, Hypertension 2008;52;30-36
6Zillich AJ; Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006;48:219 –224.
Potassium sparing diuretics
• Few studies of
glucose metabolism7
• BP lowering efficacy
of amiloride similar to
thiazide in SALT8,9
• Cardiovascular
outcome studies not
available
7Boquist
L. Effects of amiloride on insulin release, serum glucose and insulin, and glucose tolerance of mice. Med Biol. 1980 Apr; 58(2):109-11.
J. Hood and Morris J. Brown ;The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) Double-Blind Crossover Trial in Patients With
Low-Renin Hypertension and Elevated Aldosterone-Renin Ratio,Circulation 2007;116;268-275
9JP Thomas: Comparison of thiazides and amiloride in treatment of moderate hypertension, BMJ 286, 25 June 1983
8Susan
.
β1-selective beta blockade
• Studies investigating metabolic effects of newer
β1-selective selective β-blockers have found
them to be neutral or beneficial10
• Outcome studies showing metabolic effects of
atenolol used relatively high mean doses
• Our previous study showed no change in 2-hour
glucose from baseline during an oral glucose
tolerance test (OGTT) after 4 weeks treatment
with atenolol11
10Basile
JN; One size does not fit all: the role of vasodilating beta-blockers in controlling hypertension as a means of reducing
cardiovascular and stroke risk. Am J Med.123(7 Suppl 1):S9-15.
11Stears
2008
AJ et al; Early Metabolic Changes with Thiazide or Beta Blocker Therapy for Essential Hypertension;, Poster Presentation BHS
Study objectives
• Primary objective
– What are the changes from baseline in an
OGTT after 4 weeks treatment with
hydrocholorothiazide (HCTZ) compared with
amiloride and nebivolol monotherapy and
combination therapy with HCTZ/nebivolol?
• Secondary objective
– What is the effect of each drug/drug
combination on blood pressure?
Inclusion/exclusion criteria
Inclusion criteria
• 18-75 years
• BP untreated
>140/90 and
<170/110mmHg
• BP treated with drugs
other than beta blockers
or diuretics and
BP>140/85mmHg
Exclusion criteria
• Previous intolerance of
study drugs
• Diabetes
• Gout, asthma
• Heart failure, liver failure,
renal failure, terminal
illness
• Women of child bearing
potential
• Inability to give informed
consent
Study design
Phase 1
HCTZ
25mg
0
Phase 2
HCTZ
Placebo
50mg
washout
Neb
5mg
Phase 3
Phase 4
HCTZ HCTZ
Neb
25mg+ 50mg +
Amil
Placebo
Placebo
10mg
Neb
Neb
10mg
washout
washout
5mg
10mg
2
4
8
10
12
16
18
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
20
24
26
Phase 5
Amil
Placebo Placebo Placebo
20mg
washout
28
32
34
36
Weeks
Visit 1
Visit 9 Visit 10 Visit 11 Visit 12 Visit 13 Visit 14 Visit 15
Randomised, double blind, placebo
controlled,cross-over study
BP, 75g OGTT, and electrolytes
measured at 0, 2 and 4 weeks for
each phase of study
HCTZ - hydrochlorothiazide
Neb - nebivolol
Amil - amiloride
Baseline characteristics
Male/Female
Age (years)
BMI (kg/m2)
Baseline SBP (mmHg)
Baseline DBP (mmHg)
17/20
65 (41-75)
28.6 (4.2)
144.3 (13.7)
85.4 (9.9)
Results are mean (sd), except for age which is median (range)
OGTT at baseline and 4 weeks
Amiloride vs HCTZ
Plasma glucose (mmol/L)
11
Baseline
4 weeks
10
9
8
7
6
5
p=0.006
p <0.0001
4
0
30
60
120
0
30
60
Time (mins)
Time (mins)
Amiloride
HCTZ
120
Mean 2-hour glucose 6.70 mmol/l on amiloride vs 7.49 mmol/l on HCTZ
OGTT at baseline and 4 weeks
11
Plasma glucose (mmol/L)
10
9
8
7
Amiloride
Nebivolol
Combination
HCTZ
Placebo
6
5
4
0
30
60
Time (mins)
120
0
30
60
120
Time (mins)
Baseline
4 weeks
Mean 2-hour glucose 6.77 mmol/l on nebivolol vs 7.49 mmol/l on HCTZ
BP at baseline, 2 and 4 weeks
Systolic BP
Diastolic BP
150
92
90
88
86
140
Diastolic BP (mmHg)
Systolic BP (mmHg)
145
135
130
125
120
Amiloride
Nebivolol
Combination
HCTZ
Placebo
82
80
78
76
74
72
70
115
0
84
2
Weeks
4
68
0
2
Weeks
4
Insulin and potassium at baseline
and 4 weeks
Amiloride
30 min
insulin
(units)
K+
(mmol/l)
Nebivolol
HCTZ
Combination
0 wks
4 wks
0 wks
4 wks
0 wks
4 wks
0 wks
391.2
(297.4)
467.8†
(267.6)
373.3
(250.6)
395.8
(257.8)
381.2
(223.6)
383.2
(253.5)
389.8
(221.4)
4.1
(0.3)
4.5†
(0.3)
4.2
(0.3)
4.3
(0.3)
4.2
(0.3)
3.7†
(0.4)
4.1
(0.3)
*p<0.05, †p<0.001
4 wks
Placebo
0 wks
4 wks
420.8
(322.8)
385.2
(220.1)
387.6
(225.8)
3.7†
(0.3)
4.2
(0.4)
4.1*
(0.3)
Negative correlation between change in 2-hour
glucose and change in potassium between
baseline and 4 weeks
r = -0.28, p<0.0001
Results summary
• Glucose tolerance significantly impaired with
HCTZ compared with amiloride or nebivolol
• Similar BP lowering with HCTZ, nebivolol and
amiloride
• Combination therapy with HCTZ/nebivolol has
better BP lowering efficacy
• Combination therapy has similar metabolic
effects to HCTZ monotherapy
• Negative correlation between change in 2-hour
glucose and change in plasma potassium
Conclusions
• Should amiloride or an amiloride/thiazide
combination replace thiazides as the
diuretic of choice?
– BHF funded ‘Pathway 3’ study - Does a
combination of HCTZ/amiloride have a
metabolic advantage over HCTZ alone?
• β1-selective beta blockers appear to lack
the deleterious effect on glucose tolerance
previously reported for atenolol
Acknowledgments
•
•
•
•
•
•
•
•
•
Study volunteers
Prof MJ Brown
Sarah Woods
Michaela Watts
Dr Johann Graggaber
Dr Swe Myint
Dr Fraz Mir
Dr Tim Burton
Staff on Clinical Investigation Ward
Questions?
Result (mean±sd)
Amiloride
Nebivolol
HCTZ
Combination
0 wks
4 wks
0 wks
4 wks
0 wks
4 wks
0 wks
Fasting
glucose
(mmol/l)
5.19
(0.47)
5.23
(0.55)
5.23
(0.52)
5.24
(0.59)
5.16
(0.52)
5.45†
(0.55)
5.25
(0.63)
2-hour
glucose
(mmol/l)
7.07
(2.17)
6.70
(1.88)
7.21
(2.09)
6.79
(2.21)
7.00
(2.36)
7.55*
(2.24)
Fasting
insulin
(units)
66.4
(46.6)
65.5
(31.5)
61.5
(38.1)
66.9
(44.6)
67.1
(38.3)
30 min
insulin
(units)
391.2
(297.4)
467.8†
(267.6)
373.3
(250.6)
395.8
(257.8)
4.1
(0.3)
4.5†
(0.3)
4.2
(0.3)
SBP
(mmHg)
139.1
(12.9)
132.3†
(15.0)
DBP
(mmHg)
82.8
(8.4)
81.2
(7.8)
K+
(mmol/l)
4 wks
Placebo
0 wks
4 wks
5.47*
(0.64)
5.30
(0.71)
5.19
(0.52)
7.39
(2.44)
7.65
(2.13)
7.38
(2.38)
6.65*
(2.08)
71.8
(39.7)
64.2
(47.2)
75.6*
(48.4)
68.0
(43.0)
61.1
(34.9)
381.2
(223.6)
383.2
(253.5)
389.8
(221.4)
420.8
(322.8)
385.2
(220.1)
387.6
(225.8)
4.3
(0.3)
4.2
(0.3)
3.7†
(0.4)
4.1
(0.3)
3.7†
(0.3)
4.2
(0.4)
4.1*
(0.3)
142.3
(14.7)
131.2†
(16.2)
140.6
(12.0)
129.8†
(13.7)
140.6
(16.0)
121.6†
(12.2)
141.0
(11.4)
137.0*
(11.8)
84.4
(11.5)
77.4†
(10.4)
84.1
(8.7)
80.7*
(9.8)
83.8
(10.0)
74.7†
(9.8)
85.6
(8.1)
83.1*
(8.6)
Management of hypertension in adults in primary care
NICE guideline 34, June 2006
Clinical management of hypertension in adults
NICE clinical guideline 127, August 2011
Oral glucose tolerance test
Fasting
glucose
(mmol/l)
Normal
< 6.0
2 hour
glucose
(mmol/l)
< 7.8
Impaired
6.1 - 7.0
7.8 - 11.1
Diabetes
> 7.0
> 11.1
Diuretics for hypertension
• Diuretics inhibit sodium
reabsorption from
different parts of the
nephron
• Thiazides - early distal
tubule, inhibit sodiumchloride co-transporter
(NCT)
• Amiloride - late distal
tubule, inhibits epithelial
sodium channel (ENaC)
Study Design
• Double-blind, placebo controlled, cross-over
study
• Inclusion criteria: essential hypertension, BP
>140/85mmHg, <170/110mmHg, no diabetes
• 5 active treatment phases, each phase
separated by a 4-week placebo washout
• Patients supplied with home blood pressure
monitor for duration of study