© 2005 solvay pharmaceuticals gmbh ® registered trademark date of preparation: december 2005...
TRANSCRIPT
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© 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: December 2005Material Code: 201 0241
MOXONIDINE
A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity
®
®
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Please seeSummary of Product Characteristics
before prescribing moxonidine
References cited in this slide set are numbered to correspond with those in the companion moxonidine e-monograph
Details of formulations and dosage recommendations may vary between countries
Trade names include: Physiotens®, Cynt®, Fisiotens®, Moxon®, Norcynt® and Normatens®
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Metabolic syndrome
1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14
• Elevated blood pressure is often associated with obesity, insulin resistance and dyslipidaemia
• Clustering of these symptoms has given rise to the concept of the ‘metabolic syndrome’ (with high risk of diabetes and CVD)
They may all reflect varying degrees of sympathetic overactivity1
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Sympathetic overactivity
Sympathetic overactivity may be a central feature linking hypertension with other components of the metabolic syndrome
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2. Mancia G et al. J Hum Hypertens 1997;11(suppl 1):S3-S8., 3. Goldstein DS. Hypertension 1981;3:48-52., 4. Julius S, Valentini M. Blood Press 1998;7(suppl 3):5-13
• In animal models, sympathetic overactivity can initiate and maintain elevated blood pressure2
• In humans, plasma norepinephrine levels in hypertensive patients are significantly higher than in normotensive controls (p<0.05)3
• Sympathetic activation is seen in early phases of hypertension and may precede blood pressure elevation in some patients4
Link with hypertension
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1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14
• Sympathetic activity can be high in young subjects with borderline hypertension
• This suggests that increased sympathetic activity is the cause, rather than the consequence, of blood pressure elevation1
Link with hypertension
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5. Scherrer U et al. Circulation 1994;89:2634-2640., 6. Landsberg L. Cardiovasc Risk Factors 1993;3:153-158
• Raised BMI is associated with an increased rate of sympathetic nerve discharge in skeletal muscle5
• There is a correlation between BMI, body fat distribution and urinary norepinephrine excretion6
Link with obesity
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7. Jamerson KA et al. Hypertension 1993;21:618-623., 8. Huggett RJ et al. Circulation 2003;108:3097-3101.,9. Valensi P et al. ESC 2004 (www.solvaycardio.com)
• Sympathetic activation is a major component of insulin resistance in clinical experiments7 and in humans with type 2 diabetes8
• Cardiac autonomic dysfunction occurs in:
- 30-50% of patients with diabetes
- 40% of obese patients without diabetes9
Link with insulin resistance and diabetes
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10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19., 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65., 12. Lanfranchi A et al. Blood Press 1998;7(suppl 3):40-45
• Sympathetic overactivity is also implicated in:
- renal disease10
- left ventricular hypertrophy11
- congestive heart failure12
Link with other risk factors
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Incidence of metabolic syndrome13
13. Isomaa B et al. Diabetes Care 2001;24:683-689
In a study of 4,483 subjects aged 35-70 years, metabolic syndrome was present in:
• 10-15% with normal fasting blood glucose
• 42-64% with impaired glucose tolerance/ impaired fasting glucose
• 78-84% with type 2 diabetes
Metabolic syndrome was defined as the presence of at least two of: obesity, hypertension, dyslipidaemia, microalbuminuria
Risk of CHD, stroke and CV mortality was higher in people with metabolic syndrome (p<0.001)
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Origin of cardiovascular symptoms9
9. Valensi P et al. Presented at a satellite symposium at the ESC Congress 2004, Munich, Germany.
Lifestyle
Adiposityinflammation
INSULIN RESISTANCE /METABOLIC SYNDROME
Arterial rigidity hypertension
Cardiovascular complications
Atherothrombosis ArrhythmiasLVH
- free fatty acids- oxidative stress
Endothelial dysfunction
Relative sympathetic overactivity
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Treatment strategy
14. Hansson L. Blood Press 1998;7(suppl 3):20-22
Autonomic dysfunction appears to have an important role in many
patients with metabolic syndrome
Treatment of patients with hypertension should take account of associated metabolic conditions14
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Rationale for moxonidine
15. Hamilton CA. In: van Zwieten PA et al (eds). The I1 Imidazoline Receptor Agonist Moxonidine. 2nd Ed, London: Roy Soc Med,1996:7-30., 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10
Moxonidine binds selectively and with high affinity to I1-receptors in the RVLM16
thus reducing peripheral sympathetic activity
• Sympathetic tone is regulated centrally in the rostral ventrolateral medulla (RVLM)15
• This region contains imidazoline I1-receptors and 2-adrenoceptors which regulate sympathetic activity
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Overview of moxonidine - 1
16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10., 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:967-972., 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620
• Lowers peripheral arterial resistance without significant effects on cardiac output17
• Relatively little affinity for 2-receptors in the brainstem16 (adverse events such as sedation and dry mouth are infrequently reported during prolonged therapy)28
• Low potential for drug interactions
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Overview of moxonidine - 2
The above studies are described in later slides
• Effective when used as monotherapy
• An effective adjunct to other first-line therapies such as diuretics and ACE-inhibitors
• Linear dose-response effect allows dose titration
• Improves glucose metabolism / insulin resistance
• Neutral effect on the lipid profile
• Renal protective effect
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Efficacy studies reviewed in this slide set
• Monotherapy versus active comparators
• Dose response
• Long-term efficacy
• Combination with other antihypertensives
• Diabetic / prediabetic hypertensive patients
• Obese hypertensive patients
• Postmenopausal hypertensive women
• Hypertensive patients with LVH
• Role in renal protection
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Moxonidine versus active comparators
Moxonidine has been found to be similarly effective to other first-line antihypertensive agents in reducing blood pressure including:
• Diuretics (hydrochlorothiazide - HCTZ)
• Beta-blockers (atenolol)
• ACE inhibitors (captopril and enalapril)
• Calcium-channel blockers (nifedipine)
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Moxonidine versus hydrochlorothiazide19
• Double-blind, placebo-controlled parallel group, randomised study in general practice (n=160)
• Moxonidine (0.4mg/day) compared with HCTZ (25mg /day) in mild-to-moderate hypertension
• After 8 weeks of monotherapy, moxonidine and HCTZ both gave significant reductions in BP compared with placebo (p<0.05)
• No significant differences between the drugs
19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28
Results using the two active agents in combination are described on a later slide
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Response after 8 weeks of moxonidine or atenolol in a randomised, double-blind study in mild-moderate hypertension
Moxonidine versus atenolol20
20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49
% responders
moxonidine0.2-0.4mg/day
atenolol50-100mg/day
71%(20/28)
68%(17/25)
100 -
80 -
60 -
40 -
20 -
0 -
N.S.
Response was defined as DBP <90 mmHg
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Mean sitSBP and sitDBP during 4 weeks of treatment with moxonidine (0.2-0.4mg/day) or captopril (25-50mg/day) in a randomised, double-blind study
Moxonidine versus captopril21
21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):429-432
Mean blood
pressure (mmHg)
200 -
160 -
120 -
80 -
week 1 week 2 week 3 week 4
captopril (n=25)
moxonidine (n=25)
0
systolic
diastolic
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Moxonidine versus captopril22
• A randomised, double-blind, 4-week study compared moxonidine (0.2mg bd) versus captopril (25mg bd)
• 26 patients with mild-to-moderate hypertension (over 80% also had evidence of endocrine or metabolic diseases)
• Both drugs reduced BP by similar amounts
• No evidence of rebound hypertension with moxonidine on withdrawal of therapy
22. Kraft K, Vetter H. J Cardiovasc Pharmacol 1994;24(suppl 1):S29-S33
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Moxonidine versus enalapril23
• 8-week, double-blind, placebo-controlled study of moxonidine (0.2-0.4mg/day, n=47) versus enalapril (5-10mg/day, n=47) in outpatients with mild-to-moderate hypertension
• Both drugs were significantly superior to placebo at week 8 for sitBP (p<0.001), 24hr SBP (p=0.002) and 24hr DBP (p<0.001)
• Response rates were comparable between moxonidine and enalapril (66% vs 60%)
23. Küppers HE et al. J Hypertens 1997;15:93-97 Response was defined asDBP <90 mmHg or >10 mmHg reduction
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Change in DBP at week 8 with moxonidine (n=51) and enalapril (n=53) in a randomised, double-blind, placebo-controlled study in mild-to-moderate hypertension
Moxonidine versus enalapril24 – high dose
24. Prichard BNC et al. Blood Press 2002;11:166-172
p<0.001
moxonidine0.6mg/day
enalapril20mg/day
p<0.001
Mean change in DBP from
baseline (mmHg)
-11.9
- 0 -
- 4 -
- 8 -
- 12 -
- 16 -
placebo
- 2.3
- 13.2
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Moxonidine versus enalapril25 – low dose
• 8-week, double-blind, randomised, placebo-controlled study in mild-to-moderate hypertension
• Moxonidine 0.2mg/day (n=54) versus enalapril 5mg/day (n=59)
• Both gave significant reductions in DBP versus placebo (p<0.001)
• No significant difference between moxonidine and enalapril in their effects on blood pressure
25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51
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Mean SBP and DBP after 0.2-4mg/day moxonidine (n=116) and 20-40mg/day nifedipine (n=113) in a double-blind study
Moxonidine versus nifedipine26
26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44
Mean blood
pressure (mmHg)
180 -
160 -
140 -
120 -
100 -
80 -
4 8 12 19
nifedipine
moxonidine
0 week 26
systolic
diastolic
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Moxonidine versus nifedipine27
• 4-week, randomised, double-blind study in 60 patients aged 45-71 years
• Compared moxonidine (0.2-0.4mg/day) versus
sustained-release nifedipine (20-40mg/day)
• Mean BP reductions after 4 weeks:
- moxonidine ... from 167/100 to 132/83 mmHg
- nifedipine ... from 167/99 to 134/83 mmHg
27. Mangiameli S et al. Z Allg Med 1992;68:862 866
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Percentage of patients requiring a moxonidine dose increase from 0.2mg to 0.4mg daily after two weeks of treatment in four clinical trials 20,21,26,27
Dose-response with moxonidine
20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49., 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):429-432., 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44., 27. Mangiameli S et al. Z Allg Med 1992;68:862-866
Prichard 1992
42%(49/116)28%
(8/29)
100 -
80 -
60 -
40 -
20 -
0 -
% patients
requiring dose
doubling
56%(14/25)
10%(3/30)
Lotti 1993
Wolf 1992
Mangiameli 1992
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Dose-response of moxonidine in reducing office sitDBP at trough from three double-blind, placebo-controlled trials
Linear dose-response25
25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51
0.2mg
15 -
10 -
5 -
0 -
Mean placebo-adjusted
reduction in sitDBP
(mmHg)
0.4mg 0.6mg
moxonidine dosage (mg/day)
4.65
7.01
10.5
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Change in mean sitSBP and sitDBP during up to two years of treatment with moxonidine (week 3 = end of dose titration)
Long-term efficacy of moxonidine28
28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620., 44. Prichard BNC. In: van Zwieten PA et al, editors. The I1
Imidazoline Receptor Agonist Moxonidine. 2nd Edition. London: Roy Soc Med, 1996:49-75
Change in mean
blood pressure (mmHg)
180 -
160 -
140 -
120 -
100 -
80 -
2 years (n=49)
1 year (n=141)
26 52 78 1040
systolic
diastolic
weeks of moxonidine treatment
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• Open, multicentre study of 223 outpatients with mean sitBP >160/95 to <240/114 mmHg
• Moxonidine (0.2-0.6mg/day) was given for 12 months, with a supplementary diuretic if required
• Mean sitBP was reduced by 25/15 mmHg at week 12 and by 27/16 mmHg at week 52
• Response was 82% at week 12 and 85% at week 52
29. Trieb G et al. Eur J Clin Res 1995;7:227-240 Response defined as DBP <90 mmHg or a reduction of >10 mmHg
Long-term efficacy of moxonidine29
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Mean reduction in sitDBP after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study
Moxonidine in combination with HCTZ19
19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28
Mean reduction
in diastolic blood
pressure from
baseline (mmHg)
13mmHg(n=40)
*16mmHg
(n=42)***p<0.05 vs placebo
**p<0.05 vs placebo and monotherapies
- 0 -
- 10 -
- 20 -
placebomoxonidine(0.4mg/day)
HCTZ25mg/day
moxonidine+ HCTZ
(0.4/25mg/day)
12mmHgn=37
*
9mmHg(n=41)
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Percentage response for all patients after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study
100 -
80 -
60 -
40 -
20 -
0 -
% patients with
response
moxonidine+ HCTZ
(0.4/25mg/day)
HCTZ(25mg/day)
moxonidine(0.4mg/day)
placebo
44%(n=41)
70%(n=37)
70%(n=40)
88%(n=42)
Intent-to-treat analysis. Response defined as DBP <90 mmHg or >10 mmHg decrease
Moxonidine in combination with HCTZ19
19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28
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Mean change in SBP and DBP after 4 weeks of combination therapy in patients who had not responded to previous moxonidine monotherapy
Combination therapy – TOPIC study30
30. Waters J et al. J Clin Basic Cardiol 1999;2:219-224
0 -
- 4 -
- 8 -
- 12 -
- 16 -
- 20 -
Change in mean BP from baseline (mmHg) -10.7
*
-7.3*
-7.9
-5.5 -3.2-4.4
* p<0.05 versus the other combinations
-4.8
moxonidine 0.4mg+ amlodipine 5mg
(n=81)
moxonidine 0.4mg+ enalapril 10mg
(n=82)
moxonidine 0.4mg+ HCTZ 12.5mg
(n=90)
sitDBPsitSBP
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• Prediabetic conditions include insulin resistance, hyperinsulinaemia and hyperglycaemia
• Long-term benefits of antihypertensive therapy may be compromised if the drugs chosen have adverse effects on insulin sensitivity
• In hypertensive patients, moxonidine has been shown to reduce plasma glucose levels and increase insulin sensitivity
Diabetic/prediabetic hypertensive patients
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Effects of moxonidine (0.4mg/day for 8 weeks) in hypertensive patients with reduced insulin sensitivity in a double-blind, placebo-controlled, randomised, parallel group study
31. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35
% change
from baseline
GLUCOSE INFUSION RATE
INSULIN SENSITIVITY INDEX
25 -
20 -
15 -
10 -
5 -
0 -
- 5 -
-10 -
- 6.0%
p=0.004
N.S.
p=0.026
21%
- 6.0%
p=0.027
21%
p=0.056
N.S.
placebo (n=13)
moxonidine (n=25)
Effects on insulin resistance31
Insulin sensitivity evaluated by hyperinsulinaemic euglycaemic clamp test. Insulin sensitivity index = glucose infusion rate/mean insulin concentration at steady-state
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• 30 patients with mild-to-moderate hypertension and normal glucose tolerance
• Insulin sensitivity was studied after 6 months of treatment with moxonidine (0.2-0.6mg/day)
• Following oral GTT, the 2-hour plasma insulin level was statistically significantly reduced by moxonidine compared with pretreatment (18% reduction, p<0.05)
32. Almazov VA et al. J Hypertens 2000;18(suppl 2):12
Patients with normal glucose tolerance32
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• Open, randomised study of 202 mildly hypertensive, insulin-resistant, overweight patients
• Moxonidine (0.2mg bd) or metformin (500mg bd) for 16 weeks
• Insulin AUC after OGTT was 14.7% lower with moxonidine than metformin (p=0.052)
• Difference in AUC between treatments was 23.8% in patients with high sympathetic activity at baseline (p<0.05)
33. Betteridge J. ESC 2004 (www.solvaycardio.com)
Insulin-resistant hypertensive patients33
High sympathetic activity was defined as heart rate of >80 beats per minute
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• 12-week study in hypertensive patients with type 2 diabetes
• Moxonidine (0.2-0.6mg/day as an adjunct to stable antihypertensive therapy) versus metoprolol
• Moxonidine significantly improved fasting plasma glucose levels compared with metoprolol
• No significant differences between treatments in the change in insulin sensitivity from baseline
34. Jacob S et al. Exp Clin Endocrinol Diabetes 2004;112(6):315-322
Hypertensive diabetic patients34
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• Hypertension in obese patients may be related to activation of renal sympathetic nerves and stimulation of the renin-angiotensin system45,46
• Urinary norepinephrine levels increase with rising BMI49
• Most obese subjects and obese hypertensive patients have high circulatory levels of the hormone leptin50,51
45. Hall JE. Am J Hypertens 1997;10: S49-S55., 46. Tuck ML et al. N Engl J Med 1981;304:930-933., 49. Landsberg L. J Cardiovasc Pharmacol 1994;23(suppl 1):S1-S8., 50. Barroso SG et al. Trace Elem Electrolytes 2003;20:134-139., 51. Masuo K et al. Am J Hypertens 2001;14:530-538
Obesity and hypertension
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Effects of moxonidine 0.2-0.4mg/day and amlodipine 5mg/day on office sitDBP after 12 and 24 weeks in an open study of 40 obese patients with mild-to-moderate hypertension
Moxonidine in obese hypertensives37
37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25
Change in sitDBP
from baseline (mmHg)
*p<0.05 vs baseline (no significant difference between active treatments)
- 0 -
- 10 -
- 20 -
week 12 week 24 week 12 week 24
-10.2
*
moxonidine amlodipine
-12.7
*-14.7
*
-15.9
*
BP was controlled in 58% patients on moxonidine and 52% on amlodipine
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Effect of 24 weeks of moxonidine 0.2-0.4mg/day. Subgroup analysis according to blood pressure response (response was defined as achieving office BP <140/90mmHg)
Metabolic effects in obese hypertensives37
37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25
non-responders
responders
reduction of standing norepinephrine (pg/ml)
100 -
50 -
0 -
90.7
57.3
reduction of plasma leptin (pg/ml)
5.54.3
reduction of fasting insulin (U/ml)
9.6
4.7
6 -
3 -
0 -
10 -
5 -
0 -
** p<0.003 responders vs non-responders* p<0.05 responders vs non-responders
** * *
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• Moxonidine (0.4mg/day) was added to the current antihypertensive treatment of 112 obese patients with uncontrolled hypertension
• Open, multicentre study in primary care, which included 25 patients with type 2 diabetes
• After 6 months of treatment, there were mean decreases in SBP and DBP of 23.0 and 12.9 mmHg, respectively
• Overall, SBP and DBP were controlled in 63% and 86% of patients, respectively
38. Abellán J et al. Kidney Int 2005;67(suppl 93):S20-S24
Moxonidine in obese hypertensives38
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• SBP tends to increase in women after the menopause
• The prevalence of hypertension in women after the menopause is similar to that in men52
• ‘Menopausal metabolic syndrome’ describes comorbidities such as hypertension, abdominal obesity, insulin resistance, type 2 diabetes, and changes in the lipid profile53,54
Postmenopausal hypertension
52. Burt VL et al. Hypertension 1995;25:305-313., 53. Tong PL et al. Atherosclerosis 2002;161(2):409-415., 54. Mercuro G et al. Ital Heart J 2001; 2(10):719-727
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Menopausal metabolic syndrome55
55. Sjoberg L et al. Int J Clin Pract 2004;suppl 139:4-12
MENOPAUSE
Regional fat metabolism
Estrogen deficiency
Central adiposity
Insulin resistance Hypertension and endothelial dysfunction
Metabolic syndrome
Vascular inflammationImpaired glucose tolerance
Type 2 diabetes Atherosclerosis
Energy expenditure
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Change from baseline in plasma glucose during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women
Moxonidine in postmenopausal women35
35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32
Plasma glucose
(mmol/L)
0hr 1hr 2hr
AUCHours after oral glucose tolerance test
0.2 -0 -
- 0.2 -- 0.4 -- 0.6 -- 0.8 -- 1.0 -
atenololmoxonidine *p<0.01 versus pretreatment
* *
*
Intention to treat analysis
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35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32
Plasma insulin (mU/L)
0hr 1hr 2hrAUCHours after oral glucose tolerance test
6 -4 -2 -0 -
- 2 -- 4 -- 6 -
atenololmoxonidine
Change from baseline in plasma insulin during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women
Moxonidine in postmenopausal women35
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• LVH in hypertensive patients is an adaptation response to try and overcome increased peripheral vascular resistance
• LVH is a major independent risk factor for cardiovascular morbidity and mortality62,63
• Sympathetic overstimulation may play an important role in the development of myocardial hypertrophy64
LVH and hypertension
62. Levy D et al. N Engl J Med 1990;322:1561-1566., 63. Koren MJ et al. Ann Intern Med 1991;114:345-352., 64. Trimarco B et al. Circulation 1985;72:38-46
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Interventricular septum end-diastolic diameter at baseline and after 3, 6 and 9 months of moxonidine monotherapy (0.2-0.6mg/day) in 20 hypertensive patients with LVF
Moxonidine in LVH11
11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65
baseline
1.8 -
1.6 -
1.4 -
1.2 -
1.0 -
Interventricular septum
end-diastolic diameter (cm)
3 6 9
p<0.05
p<0.05
p<0.05
months
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Left ventricular mass at baseline and after 3, 6 and 9 months of moxonidine monotherapy (0.2-0.6mg/day) in 20 hypertensive patients with LVF
11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65
400 -
350 -
300 -
250 -
200 -
150 -
Left ventricular
mass (g)
p<0.05p<0.05
monthsbaseline 3 6 9
Moxonidine in LVH11
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• Increased sympathetic activity leads to renal vasoconstriction, stimulation of renin release, and stimulation of sodium reabsorption10
• Moxonidine may be renoprotective by:
- reducing sympathetic output centrally
- direct renal effects (independent of blood pressure lowering) via imidazoline binding
sites in the kidney
Renal protection in hypertension
10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19
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Mean muscle sympathetic nerve activity (MSNA) in nine hypertensive patients with chronic renal failure given eprosartan alone or with moxonidine. Controls were healthy age-matched persons (n=22)
Renal protective effects39
50 -
40 -
30 -
20 -
10 -
0 -
Mean MSNA
(burst/min)
healthy controls
eprosartan +
moxonidine
39. Neumann J et al. J Am Soc Nephrol 2004;15:2902-2907
eprosartanbaseline
p<0.05 p<0.05
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• Predictors of allograft survival were evaluated in 601 renal transplant patients
• A number of factors increased the relative risk of allograft loss, the most important being renal vascular resistance
• Another risk factor was high heart rate (pulse>80 beats/min) which suggests increased sympathetic activity
• The use of moxonidine was associated with an approximately 70% reduction of allograft failure
Improved allograft survival40
40. Radermacher J et al. New Engl J Med 2003;349:115-124
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• Microalbuminuria is predictive of retinopathy, LVH, CV events and all-cause mortality
• 12.8% of people with metabolic syndrome are estimated to have microalbuminuria52
• Moxonidine reduces urine albumin excretion in:
- non-obese hypertensive patients with microalbuminuria (p<0.001 vs baseline)41
- normotensive patients with well controlled type 1 diabetes (p<0.006 vs placebo)42
Effect on microalbuminuria
41. Krespi PG et al. Cardiovasc Drugs Ther 1998;12:463-467., 42. Strojek K et al. 36th Ann Meeting of the EASD (2000), Jerusalem, Israel, 17-21 September., 52. Burt VL et al. Hypertension 1995;25:305-313
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Effect of moxonidine (0.3mg/day, n=89) and nitrendipine (20mg/day, n=82) on serum creatinine in patients with advanced renal failure
Effect on serum creatinine43
43. Vonend O et al. J Hypertens 2003;21:1709-1717
serum creatinine
(µmol/L)
500 -
400 -
300 -
200 -
100 -
0 - 1 2 3 4
nitrendipinemoxonidine
65 0months
p<0.05
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Treatment-emergent adverse events affecting > 4% patients after monotherapy with moxonidine 0.6mg/day, enalapril 20mg/day, or placebo in an 8-week randomised, double-blind trial
Moxonidine - adverse events24
24. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51
dry m
outh
diarrh
oea
headac
he
bronch
itis
% patients
reporting adverse
events
enalapril(n=53)
placebo(n=50)
nause
a
back
pain
gastro
-
ente
ritis
moxonidine(n=51)
dizzin
ess
20 -
10 -
0 -
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Tolerability in a 52-week study28
28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620
13%
week3
% patients
reporting adverse
events
20 -
15 -
10 -
5 -
0 -
DRY MOUTH TIREDNESS
3% 2%
week12
week52
5%
week3
0% 0%
week12
week52
Treatment-emergent adverse events affecting >2% of patients in a long-term, open-label study of moxonidine
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Moxonidine - contraindications
* Please see National Prescribing Information or SmPC, as licence details may vary between countries
• Known hypersensitivity to any of the components of the product
• Sick sinus syndrome
• Bradycardia (resting heart rate <50bpm)
The following are listed on the Master SmPC for moxonidine:*
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The coloured area identifies the imidazoline part of the structure
Chemical structure of moxonidine
H3C
Cl
NH
OCH3
N
NHN
N
71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21
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Mode of action of moxonidine
16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10
• The autonomic nervous system is regulated by cardiovascular control centres in the rostral ventrolateral medulla (RVLM) in the brain stem
• Sympathetic response is mediated through imidazoline binding sites in the RVLM
• Moxonidine has a highly selective agonist effect on imidazoline I1-receptors in the RVLM16
• This causes inhibition of sympathetic activity and reduced peripheral resistance
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Acts within the RVLM
72. Haxhiu MA et al. J Cardiovasc Pharmacol 1992; 20 (suppl 4):S11 S15
• Microinjection of moxonidine into the RVLM of spontaneously hypertensive rats produces rapid, dose-dependent reductions of arterial blood pressure72
• There is no effect on blood pressure if moxonidine is injected into adjacent (non-RVLM) areas of the medulla
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Selective for I1 receptors
16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10., 73. Haxhiu MA et al. Cardiovasc Drugs Ther 1993;7(suppl 2):155(Abstr 155)
• The blood pressure-lowering effect of moxonidine is reversed by injection of efaroxan (an I1-receptor antagonist) into the RVLM73
• In vitro, moxonidine has an approximately 70-fold greater affinity for I1-receptors compared with 2-receptors16
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Selectivity of moxonidine for imidazoline (I1) and 2-receptors (Ki = affinity constant).
Moxonidine is highly selective16
-5 -4 -3 -2 -1 0 1 2 3
2 > I1
16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10
I1 > 2
moxonidine
rilmenidine
clonidine
norepinephrine
epinephrine
guanabenz
Affinity for I1 versus 2-receptors (log Ki at I1 receptors divided by Ki at 2-receptors)
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Actions of centrally-acting agents71
2 - adrenoceptor
Dry mouth Lowering of blood pressure
I1 - imidazoline receptor
71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21
-methyldopa
Salivary glands
Nucleus coeruleus
Nucleus tractus solitarii
MOXONIDINEclonidineselective
Rostral ventrolateral medulla (RVLM)
Inhibition of sympathetic nerve activity
Inhibition of norepinephrine release
Peripheral vasodilation
(non-selective)
Sedation
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Effects on catecholamine levels
37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25., 74. Kirch W et al. J Clin Pharmacol 1990;30:1088-1095
• Single oral doses of moxonidine reduce plasma norepinephrine levels in patients with hypertension74
• The fall in plasma norepinephrine correlates with the reduction in SBP (p=0.05) and DBP (p=0.02)
• Reductions in plasma catecholamine levels reported in clinical studies with moxonidine37
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Effect of moxonidine on cardiac output and systemic vascular resistance
Haemodynamic effects of moxonidine17
17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:967-972
dyn.sec/cm5
2000 -
1800 -
1600 -
1400 -
1200 - 1 2 3 40
cardiac output
systemic vascular resistance
- 8
- 6
- 4
- 2
- 0
Hours post-administration
L/min
*
* *
* p<0.01
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Neutral effect on lipid profile
70. Data on file, Solvay Pharmaceuticals GmbH., 75. Elisaf MS et al. J Hum Hypertens 1999;13:781-785
• In a study of 20 hypertensive patients, moxonidine produced no statistically significant changes in HDL, LDL or total cholesterol, or triglycerides75
• There were no significant changes in these lipid parameters in an analysis of pooled results from several placebo-controlled trials70
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Pharmacokinetics of moxonidine78
ParameterSingle dose*
Multiple dose
Time to peak plasma concentration (hr) 0.74 0.67
Peak plasma concentration (ng/ml) 1.29 1.33
Area under the curve (0-infinity) (ng.hr/ml) 4.18 4.02
Terminal half-life (hr) 2.12 1.97
Total clearance (ml/min) 830 863
Renal clearance (ml/min) 530 522
78. Weimann H-J, Rudolph M. J Cardiovasc Pharmacol 1992;20(suppl 4):S37-S41 * oral dose 0.2mg bd (n=12)
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Pharmacokinetics of moxonidine76,77
76. Theodor R et al. Eur J Drug Metab Pharmacokinet 1991;16(2):153-159. 77. Trenk D et al. J Clin Pharmacol 1987;27:988-993
• 80-90% of an oral dose is absorbed
• Bioavailability = 88%
• Protein binding = 7%
• About 10% is metabolised (metabolites have low antihypertensive potency)
• Peak plasma concentrations reached within 60 min; mean plasma half-life is about 2 hours
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Pharmacokinetics of moxonidine - 2
77. Trenk D et al. J Clin Pharmacol 1987;27:988-993., 78. Weimann H-J, Rudolph M. J Cardiovasc Pharmacol 1992;20 (suppl 4):S37-S41., 79. Kirch Wet al. Clin Pharmacokinet 1988;15:245-253
• Does not accumulate in plasma with repeated dosing77,78
• Pharmacokinetics are not significantly affected by food78
• No dose adjustment needed in older patients whose renal function is normal for age
• No evidence of moxonidine accumulation after multiple dosing in older subjects78
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Plasma concentration-time profile of moxonidine after an oral single dose (0.2mg) and after giving 0.2mg bd for 5 days (n=12)
Plasma profile of moxonidine77
77. Trenk D et al. J Clin Pharmacol 1987;27:988-993
Plasma concentration
mcg/L
2000 -
1 2 3 40
single dose
multiple dose
Time after administration (hours)
100 -
1000 -
600 -
300 -
6 7 85
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Plasma concentration-time profile of moxonidine (0.3mg once-daily for 7 days) in patients with and without renal impairment (n=8 per group)
Plasma profile in renal impairment79
79. Kirch W et al. Clin Pharmacokinet 1988;15:245-253
Log plasma concentration
mcg/L
4.0 -
3 6 9 120
Time after administration (hours)
0.01 -
0.4 -
0.1 -
0.04 -
18 21 2415
1.0 -GFR <30ml/min
GFR 30-60ml/min
GFR >90ml/min
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Low likelihood of drug interactions
• Only 7% protein binding - interaction with highly protein bound drugs is unlikely
• No substantial pharmacokinetic interaction with digoxin, HCTZ or glibenclamide
• Has been co-administered with hypolipidaemic agents
• Effect of sedatives/hypnotics may be intensified
• Avoid use with alcohol or tricyclic antidepressants
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• 0.2mg, 0.3mg, 0.4mg tablets
• 0.2mg usual starting dose
• Can be increased to 0.4mg daily after 2-3 weeks
• Can be increased to 0.6mg daily after a further 2-3 weeks
Dosage of moxonidine
Appearance of pack varies between countries
Usual maintenance dose is 0.4mg per day
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• May be taken with or without food
• Stop treatment gradually over two weeks
• If stopping a combined moxonidine/beta-blocker regimen, stop the beta-blocker a few days before moxonidine is gradually stopped
• No dose adjustment required in the elderly
• Starting dose of 0.2mg/day in patients with moderate to severe renal impairment - if necessary and well tolerated the dose can be increased to 0.4mg/day
Administration
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• Many patients with hypertension have metabolic syndrome - with one or more conditions such as insulin resistance, impaired glucose tolerance, obesity and altered lipid profile
• When treating these patients it would be appropriate to select an antihypertensive agent with a beneficial or neutral effect on the other components of the metabolic syndrome
Summary - 1
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• Moxonidine acts centrally to reduce sympathetic stimulation
• It is as effective as other classes of antihypertensive agents in reducing SBP and DBP
• It may be used as monotherapy, but is a good option for adjunctive therapy in patients with the metabolic syndrome
Summary - 2
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• diabetics
• impaired glucose tolerance / insulin resistance
• obese
• postmenopausal metabolic syndrome
Summary - 3
Moxonidine lowers blood pressure and improves the metabolic profile in several types of hypertensive patients:
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• Beneficial effects have been seen with moxonidine in hypertensive patients with LVH
• Moxonidine has been shown to have renoprotective properties
• Moxonidine is well tolerated
• A low level of drug interactions, once-daily dosing, and linear dose-response are advantageous when using moxonidine in combination regimens
Summary - 4
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Cynt ®
Physiotens ®
Solvay Pharmaceuticals
December 2005