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Home , Moxonidine, Rilmenidine

AJH 2001; 14:322S–324S

Update on : Clinical Benefits

John L. Reid

Rilmenidine is an imidazoline derivative that appears to consistent with a reduction in long-term cardiovascular lower (BP) by an interaction with imida- risk, as would recently described actions on the zoline (I1) receptors in the brainstem (and kidneys). Ril- (reducing left ventricular hypertrophy) and the menidine is as effective in monotherapy as all other first- (reducing microalbuminuria). Although no data are yet Downloaded from https://academic.oup.com/ajh/article/14/S7/322S/137317 by guest on 28 September 2021 line classes of drugs, including diuretics, ␤-blockers, available from prospective long-term outcome studies, angiotensin converting enzyme (ACE) inhibitors, and cal- rilmenidine could represent an important new develop- cium antagonists. It is well tolerated and can be taken in ment in antihypertensive therapy and the prevention of combination for greater efficacy. Sedation and dry mouth cardiovascular disease. Am J Hypertens 2001;14:322SÐ324S are not prominent side effects and withdrawal hyperten- © 2001 American Journal of , Ltd. sion is not seen when treatment is stopped abruptly. Recently, in addition to a reduction in BP, this agent Key Words: Blood pressure, rilmenidine, imidazoline, insu- has been shown to improve tolerance, lipid risk lin resistance, metabolic syndrome, microalbuminuria, ventricu- factors, and insulin sensitivity. These changes would be lar hypertrophy, end-organ damage.

n spite of major developments during the past 50 included in the treatment choice of several key outcome years, there is still no single ideal antihypertensive trials (Veterans Administration [VA] trials and European I drug. The benefits of blood pressure (BP) reduction Working Party on Hypertension in the Elderly [EWPHE]). (systolic and diastolic) in a wide range of populations is These drugs have never been used as the primary treat- well established, as is the safety of more aggressive tar- ment choice in large enough numbers to draw firm con- gets.1 This strategy, however, will require multiple drugs clusions about their influences on cardiovascular outcome. to be used in most patients to achieve these goals. Several In recent years, centrally acting drugs have been used classes of drugs can lower BP to a similar extent in both much less frequently because of limitations of adverse the short and medium term; it is less clear whether all effects (sedation, dry mouth, and depression) and the avail- classes have similar long-term effects on cardiovascular ability of better tolerated alternative agents in other morbidity and mortality. The evidence from randomized classes. There is, however, evidence that the centrally controlled trials available to date supports the long-term induced increase in sympathetic nervous activity contrib- benefit of drugs such as diuretics and ␤-blockers.2 There is utes to the increase in BP in some, if not all, patients with increasing evidence of the benefit of angiotensin convert- .7 There is thus a sound rationale in ing enzyme (ACE) inhibitors and calcium channel block- the treatment of hypertension with agents that can act on ers. Controversy remains as to whether they are as good, the central nervous system to reduce efferent sympathetic better, or less good than older classes.3,4 Prospective co- tone. hort studies and other nonrandomized trials support the In recent years, there has been a strong case made that view that outcome may be different depending on the class some imidazoline derivatives may lower central sympa- of drug used.5 There is some evidence from randomized thetic tone and BP by a different mechanism compared controlled trials supporting differences in cardiovascular with and . Instead of acting as ago- ␣ outcome, which may be independent of BP. The Antihy- nists at 2 receptors, imidazoline agents are bound to pertensive and Lipid Lowering treatment to prevent Heart specific imidazoline (I1) receptors or binding sites reduc- ␣ ␣ Attack Trial (ALLHAT) suggested that a peripheral 1 ing BP without the range or intensity of other 2-receptorÐ antagonist may be less effective than a diuretic in essential mediated central effects, such as sedation and dry mouth.8 6 hypertensives. The I1 receptors have been located in the brainstem and Centrally acting drugs, such as , methyldopa, also in renal tubules. Both sites could contribute to the and clonidine, were widely used in the treatment of hy- antihypertensive and natriuretic actions of imidazolines. pertension from the mid-1960s onward. Methyldopa was The experimental evidence for a central antihyperten-

Received July 10, 2001. Accepted July 24, 2001. Address correspondence and reprint requests to Prof. J. L. Reid, From the Department of Medicine and Therapeutics, University of Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Glasgow, Glasgow, Scotland. G11 6NT, Scotland, UK.

0895-7061/01/$20.00 © 2001 by the American Journal of Hypertension, Ltd. PII S0895-7061(01)02239-7 Published by Elsevier Science Inc. AJH–November 2001–VOL. 14, NO. 11, PART 2 UPDATE ON RILMENIDINE 323S sive action of imidazolines has been extended by studies Rilmenidine: exploring the identity of I1 receptors and the signal trans- Metabolic Consequences duction pathways.8 In clinical practice, the imidazoline agents have been developed and marketed in many coun- As noted above, BP reducing efficacy is only one of the tries as a new potential first-line antihypertensive treat- goals of modern antihypertensive therapy. A further con- sideration is whether the treatment itself modifies benefi- ment. Rilmenidine was the first application of the I1 imi- dazoline receptor discovery, and the arrival of cially or adversely other cardiovascular risk factors. Early has confirmed the interest of this new antihypertensive studies in trials with small numbers observed no changes therapeutic class. How do these imidazoline drugs com- in plasma levels of glucose, insulin, or lipids with short- pare with older centrally acting drugs in terms of tolera- term (8 to 12 weeks) treatment with rilmenidine or mox- bility? How do they compare with alternative classes act- onidine. More recent studies confirm lipid neutrality, but ing by other mechanisms in terms of efficacy and suggest that insulin sensitivity and glucose tolerance may Downloaded from https://academic.oup.com/ajh/article/14/S7/322S/137317 by guest on 28 September 2021 tolerability? What is the evidence that imidazoline agents be improved in obese subjects or those with insulin resis- may modify the progression of atherosclerosis and its tance. In a 6-month, double-blind, controlled study in cardiac, renal, and cerebrovascular sequelae? This short hypertensive patients with metabolic syndrome X, rilmeni- review provides answers to the first two of these questions dine significantly lowered plasma fasting and 2-h glucose and an update on the third. levels and insulin concentration after an oral glucose tol- erance test.11 The clinical benefit of rilmenidine on confirmed the previous experimental results that Rilmenidine: have been obtained by imidazoline I1 agents. Indeed, using Efficacy and Tolerability a hyperinsulemic, euglycemic clamp, an 8-week period of Rilmenidine has been extensively studied in a large num- treatment with moxonidine improved insulin resistance as ber of randomized, double-blind trials in which treatment indicated by an increase in the glucose infusion rate and 12 has not only been compared with placebo, but also with the insulin sensitivity index. In view of the associations the other commonly used classes of antihypertensive between hypertension, obesity, and insulin resistance, and drugs. These studies, which have been previously re- the possible underlying contribution of increased sympa- viewed,9 showed no significant differences in the effects of thetic activity of these conditions, imidazoline agents may rilmenidine on systolic or diastolic pressure compared have a particular role in the management of these patients. with , , captopril, or amlodip- ine. The side effects reported and numbers of withdrawals Rilmenidine and from therapy were no more common on rilmenidine than on comparable drugs. This excellent tolerability contrasted Target Organ Damage with the findings in trials comparing rilmenidine with A further therapeutic objective “beyond BP” of antihyper- methyldopa or clonidine where similar decreases in BP tensive therapy is an improvement in preexisting target were accompanied by much higher levels of symptom side organ damage and protection from cardiac, renal, and effects, principally sedation and dry mouth on methyldopa cerebrovascular disease. Small, early, open studies sug- and clonidine. Of particular note were studies where treat- gested that rilmenidine would reduce left ventricular ment was abruptly interrupted. In one trial, treatment with mass.9 Further trials suggested the improvement was sim- either atenolol or rilmenidine was interrupted and BP ilar to other classes of antihypertensive drugs such as recovery followed over 7 days. There was a slow return of nifedipine.13 Recently in a large open study, but with BP over 3 to 5 days, without any overshoot, symptoms, or blinded echo analysis, the effects of rilmenidine on reduc- evidence of sympathetic overactivity with both rilmeni- tion of left ventricular mass have been confirmed.14 The dine and atenolol. In contrast, in a further trial when improvement was directly related to the baseline left ven- clonidine was interrupted, the BP effect reversed rapidly tricular mass, but not directly to the BP decrease. As far as within 10 to 12 h, whereas after cessation of the other effects on the kidney are concerned, early studies on imidazoline, moxonidine, there was a gradual reversal of insulin-dependent diabetics showed no change in protein- antihypertensive effect over several days. Experience in uria. controlled trials and extended open studies suggest that In a recent pilot report in nonÐinsulin-dependent dia- rilmenidine can be used together with other antihyperten- betic patients with microalbuminuria, rilmenidine was as sive classes, with useful increases in efficacy and no par- effective as captopril, both in lowering BP and also in ticular adverse interactions.9 reducing microalbuminuria.15 Although there have been Acceptability and tolerability of rilmenidine was also no reports of effects on cerebrovascular disease in humans, studied in a very large open postmarketing study in some it has been claimed that rilmenidine reduced the size of 18,000 patients.10 Rilmenidine was well tolerated with few experimental cerebral infarcts in the rat and appeared to do side effects and, in a substantial majority of patients, was so independently of any BP decrease.16 These potential effective as monotherapy in achieving target levels of BP, neuroprotective effects of rilmenidine warrant further eval- even when follow-up was extended to 1 year and beyond. uation. 324S UPDATE ON RILMENIDINE AJH–November 2001–VOL. 14, NO. 11, PART 2

Imidazolines and 2. Collins R, Peto R, MacMahon S, Herbert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH: Blood Long-Term Outcome pressure, stroke and coronary heart disease, part 2. Short-term Imidazoline I agents, and particularly rilmenidine10,17 reductions in blood pressure: overview of randomised drug trials in 1 their epidemiological context. Lancet 1990;335:827Ð838. have been assessed in 1- to 2-year pragmatic open studies. 3. Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson The decrease in BP was maintained throughout the 2-year JD, Cavazzini C, Furberg CD: Health outcomes associated with period. Double-blind controlled studies could confirm this calcium antagonists compared with other first-line antihypertensive long-term antihypertensive efficacy. Beyond the antihy- therapies: a meta-analysis of randomised controlled-trials. Lancet 2000;356:1949Ð1954. pertensive indication of imidazoline I1 agents, moxonidine has been evaluated in congestive in a large 4. Blood Pressure Lowering Treatment Trialists’ Collaboration: Ef- fects of ACE inhibitors, calcium antagonists, and other blood- controlled morbidity and mortality outcome trial (MOX- pressure-lowering drugs: results of prospectively designed over-

CON). This study was terminated prematurely because of views of randomised trials. Lancet 2000;356:1955Ð1964. Downloaded from https://academic.oup.com/ajh/article/14/S7/322S/137317 by guest on 28 September 2021 increased events in the moxonidine-treated group. The 5. Lever AF, Hole DJ, Gillis CR, McCallum IC, McInnes GT, Mc- results of this study have not yet been fully published. Kinnon PL, Meredith PA, Murray LS, Reid JL, Robertson JWK: Do There are remaining doubts as to whether the outcome was ACE inhibitors protect against cancer?. Lancet 1998;352:179Ð184. related to the study itself, the patient group treated, or the 6. The ALLHAT Officers and Coordinators for the ALLHAT Collab- orative Research Group: Major cardiovascular events in hyperten- use of high doses (five times the usual antihypertensive sive patients randomized to vs chlorthalidone. JAMA dose) of a new long-acting formulation of moxonidine 2000;283:1967Ð1975. (0.75 mg). At the present time, the lack of outcome data in 7. Esler M: The sympathetic system and hypertension. Am J Hypertens hypertensive patients limits the evidence base justifying 2000;13:99SÐ105S. 8. Bousquet P: Identification and characterization of I imidazoline the wider use of these drugs. 1 receptors: their role in blood pressure regulation. Am J Hypertens 2000;13:84SÐ88S. Conclusions 9. Reid JL: Rilmenidine: a clinical overview. Am J Hypertens 2000; 13:106SÐ111S. Imidazoline derivatives such a rilmenidine offer the po- 10. Luccioni R: Evaluation pharmaco-e«pide«miologique de la rilme«ni- tential to lower BP by a central action without the draw- dine chez 18335 hypertendus. Presse Med 1995;24:1857Ð1864. backs of the side effects of earlier central agents. Rilmeni- 11. De Luca D, Izzo R, Fontana D, Lovino G, Argenziano L, Vecchione dine in controlled trials is as effective as other commonly C, Trimarco B: Haemodynamic and metabolic effects of rilmenidine used classes of drugs. It can be used safely in combina- in hypertensive patients with metabolic syndrome X. A double-blind parallel study versus amlodipine. J Hypertens 2000;18:1515Ð1522. tion with other classes if necessary. There is emerging 12. Haenni A, Lithell H: Moxonidine improves insulin sensitivity in evidence of favorable effects on metabolic risk factors, insulin-resistant hypertensives. J Hypertens 1999;17(suppl 3):S29Ð particularly glucose metabolism and insulin sensitivity. S35. Reports of reduction in left ventricular mass and mi- 13. Sadowski Z, Szwed H, Kuch-Wocial A, Kubasik A, Januszewicz W, croalbuminuria suggest target organ protection of the heart Krupa-Wojciechowska B, Polak G, Stejfa M, Dvorak I, Balazovjech and kidney. I, Dubai G, Simon K: Regression of left ventricular hypertrophy in hypertensive patients after 1 year of treatment with rilmenidine: a Rilmenidine warrants consideration as a new potential double-blind, randomized, controlled (versus nifedipine) study. first-line choice of alone or in com- J Hypertens 1998;16(suppl 3):S55ÐS62. bination. 14. Lengyel M, Borba«s S, Zora«ndi A: Regression of left ventricular hypertrophy in mild-moderate hypertension in one year of treatment with rilmenidine. Eur Heart J 2000;21:101. References 15. Bauduceau B, Mayaudon H, Dupuy O: Rilmenidine in the hyper- tensive type 2 diabetic: a controlled pilot study versus captopril. 1. Hansson L, Zanchetti A, Carruthers SG, Dahlo¬f B, Elmfeldt D, J Cardiovasc Risk 2000;7:57Ð61. Julius S, Me«nard J, Rahn KH, Wedel H, Westerling S, for the HOT 16. Maiese K, Pek L, Berger SB, Reis DJ: Reduction in focal cerebral Study Group: Effects of intensive blood-pressure lowering and low- ischemia by agents acting at imidazole receptors. J Cereb Blood dose aspirin in patients with hypertension: principal results of the Flow 1992;12:53Ð63. Hypertension Optimal Treatment (HOT) randomised trial. Lancet 17. Fillastre JP: Effets de la rilmenidine sur le syste`me nerveux central 1998;351:1755Ð1762. et sur le rein. Arch Mal CÏur 1989;82:19Ð23.