AJH 2001; 14:322S–324S Update on Rilmenidine: Clinical Benefits John L. Reid Rilmenidine is an imidazoline derivative that appears to consistent with a reduction in long-term cardiovascular lower blood pressure (BP) by an interaction with imida- risk, as would recently described actions on the heart zoline (I1) receptors in the brainstem (and kidneys). Ril- (reducing left ventricular hypertrophy) and the kidney 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;14:322S–324S are not prominent side effects and withdrawal hyperten- © 2001 American Journal of Hypertension, 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 glucose 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- essential hypertension.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 methyldopa and clonidine. 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-receptor– 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 reserpine, 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 moxonidine 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 insulin resistance 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 hydrochlorothiazide, atenolol, 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