MARRIAGE study - Diegori.it

Diabetes), FACET (Fosinopril versus AmlodipineCardiovascular Events Trial), and the CaptoprilPrevention Project (CAPPP) – suggested a substantialbenefit of ACE inhibitor therapy over other classes ofantihypertensives on several major outcomes, includingcardiovascular events in patients with hypertension plusDM 27 .CAPPP, which was the largest of these threestudies and in which the comparator medications toACE inhibitors were diuretics and/or beta-blockers,showed no difference in the primary outcome ofnon-fatal or fatal myocardial infarction (MI), or instroke or other cardiovascular deaths depite persistinghigher blood pressure in patients receiving the ACEinhibitor (there was a non-significant trend for fewercardiovascular deaths with captopril) 28 . Captopril wasmarkedly superior to conventional therapy in theprevention of several cardiovascular outcomes (notstroke) in patients with DM at baseline. The clinicalsuperiority of captopril in this subset of patients wasmost marked in those with evidence of poor glycaemiccontrol 29 .Separately, the results of UKPDS 39, a companionstudy to UKPDS 38, indicated that patients who usedcaptopril were significantly less likely to requireadditional hypoglycaemic agents and to have lowerlevels of glycosylated haemoglobin than patients whotook atenolol 30 . These were observations stronglysuggestive of better glycaemic control with the ACEinhibitor than with the beta-blocker. Average weightgain among atenolol-treated patients in UKPDS 39 wasalmost double that in the patients who receivedcaptopril, however, and may have contributed to theprofile of poor glycaemic control among the betablockercohort. This complicates analysis of thedifference between the two treatment regimens.Diuretic Therapy: Contentious Evidencefrom ALLHATConfounding influences also complicate analysis ofALLHAT 17 . This was not expressly a study inhypertensive patients with DM, but 36% of patientssatisfied that definition and the controversy that hasaccompanied the publication and interpretation of thisstudy is such that a discussion of its salient features iscalled for. On first encounter the results of this studyseem to contradict the evidence of trials such asCAPPP 28 by suggesting a superiority of diuretic(specifically chlorthalidone) therapy over an ACEinhibitor (lisinopril). In fact, this putative difference wasnot evident for the study primary endpoint and waslargely accounted for by non-fatal heart failure (the highincidence of which in the lisinopril group may well havebeen due to the abrupt withdrawal of pre-studydiuretics) and by stroke. This last endpoint is theoutcome most closely related to BP, making thesustained lower BPs in the chlorthalidone versuslisinopril groups a matter of more than academicimportance: during ALLHAT systolic BP in the lisinoprilgroup was 1.6–3.1 mmHg higher than in thechlorthalidone group. It should be recalled that inCAPPP also, ACE inhibitor therapy did not reduce theincidence of stroke more than other therapies.In connection with the BP differential in ALLHAT itshould be noted that much of the impression thatlisinopril was associated with worse outcomes thanchlorthalidone arose from the outcomes in blackAmericans, a group in which use of an ACE inhibitorunsupported by a diuretic would ordinarily bedeprecated 4 . Finally, it may be observed that amongpatients with DM at baseline chlorthalidone andlisinopril were closely equivalent for most endpointsincluding combined coronary and cardiovascular disease,a result that, bearing in mind the sustained inter-groupdifferences in BP, suggests other, non-haemodynamicmechanisms may have been in operation.Alpha-adrenoceptor Agents: Good inPrinciple, Less Good in PracticeALLHAT has also provided an important recentperspective on the use of peripherally acting alpha 1-blockers in hypertension. Doxazosin is probably themost widely used of these agents and has been reportedto exert favourable or neutral effects on glucose, insulinand lipids 31–33 . The decision to discontinue the doxazosinarm of the ALLHAT study because of excess heartfailure-related mortality relative to chlorthalidone 17 has,however, rightly eclipsed considerations of metabolicprofile and serves as a reminder that theoretical ancillarybenefits do not compensate for lack of core clinicaleffectiveness. Whether or not the particularcircumstances of the ALLHAT study contributed to thisunexpected outcome is hard to determine at present.Centrally acting alpha-agonists such as clonidine havelong been credited with a relatively favourable effect onmetabolic indices. The overall adverse effect profile ofthis drug is such, however, that it has largely passed outof routine use in the management of hypertension. Theavailability of a transdermal preparation appears not tohave materially affected this trend 34 .Effects of ARB Therapy: The LIFE StudyImportant clinical benefits of angiotensin-targetedtherapies emerged from the LIFE (LosartanIntervention For Endpoint reduction in hypertension)study 35 . This large trial (n > 9000) evaluated the impactof the angiotensin receptor blocker (ARB) losartan on© 2004 LIBRAPHARM LTD – Curr Med Res Opin 2004; 20(3) Moxonidine and ramipril: partners in a successful MARRIAGE? Rayner 361

Table 2. Comparison of the incidence of new-onset diabetes mellitus (DM) in controlled trials of antihypertensive drug therapiesStudy Drug(s) compared Duration (years) New-onset DM (rate, %)*ALLHAT ACEI vs. CCB vs. Diu 4.9 8.1 vs. 9.8 vs. 11.6ALPINE ARB (± CCB) vs. Diu (± BB) 1.0 0.5 vs. 4.1CAPPP ACEI vs. BB/Diu 6.1 6.5 vs. 7.3HOPE ACEI vs. placebo 4.5 3.6 vs. 5.4INSIGHT CCB vs. Diu 3.5 4.3 vs. 5.6LIFE** ARB vs. BB 4.8 6.0 vs. 8.0NORDIL CCB vs. BB/Diu 4.5 4.3 vs. 4.9SCOPE ARB vs. Diu 3.7 4.3 vs. 5.3ALLHAT = Antihypertensive and Lipid-Lowering Therapy to Prevent Heart Attack Trial 17 ; ALPINE =Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation 47 ; CAPPP =Captopril Prevention Project 28 ; HOPE = Heart Outcomes Protection Evaluation 40 ; INSIGHT =Intervention as a goal in hypertension treatment 43 ; LIFE = Losartan Intervention For Endpointreduction in hypertension 35 ; NORDIL = Nordic Diltiazem 44 ; SCOPE = Study on Cognition andPrognosis in the Elderly 45*p < 0.05 for all results except NORDIL and SCOPE (n.s.)**Diuretic used by > 80% patientsACEI = ACE inhibitor; ARB = angiotensin receptor blocker; BB = beta-blocker; CCB = calcium-channelblocker; Diu = diureticPrognostic impact ofmetabolic effectsThese observations on the differing metabolic effects ofvarious types of antihypertensives may have long-termclinical significance. As Julius et al. 48 have remarked,controlled trials to date have concentrated on patientswith established DM, which in effect is intervention at theend-stage of the disease process. The value of earlierintervention to prevent the development of overt DM orto moderate the risk associated with pre-diabetic statessuch as impaired insulin sensitivity is as yet unquantifiedbut, in view of the way in which DM and hypertensioninteract to inflate cardiovascular risk, it is plausible thatsuch an intervention might have great long-term benefits.The importance of this possibility is acknowledged in thelatest guidelines of the European Society of Hypertension,in which it is noted that, ‘Treatment-induced alterations ofmetabolic parameters, such as… induction or worsening ofthe metabolic syndrome or diabetes, although they canhardly be expected to increase cardiovascular eventincidence during the short term of a trial, may have animpact during the longer course of the patient’s life… 4 ’.The number of people with DM is projected to increase tomore than 220 million by 2010, and a substantialproportion of these people will also have hypertension 49–51 .Even a modest favourable impact of medication on theprogression to full-blown DM may therefore produce verylarge public health gains.Therapeutic potential of SIRAsFurther study of the influence of antihypertensivetherapies on insulin sensitivity in hypertension is clearlywarranted and desirable. Angiotensin-specific agents areobvious candidates for further evaluation, but recentresearch has indicated that moxonidine, an exemplar ofthe selective imidazoline receptor agonists (SIRAs),merits closer scrutiny. The drug is an effectiveantihypertensive 52–57 and appears to have encouragingmetabolic effects 58–65 . Moreover, pathophysiologicalconsiderations suggest that there may be opportunitiesfor synergy between SIRAs and drugs that act viaangiotensin, synergies that may be exploited to theadvantage of patients.Moxonidine Effects on Glycaemic Indices:Preclinical DataMoxonidine has been shown to partially restore glucosetolerance in fructose-fed rats subjected to a glucose loadand to normalize insulin levels in this model 58 . Similareffects have been reported in the Koletsky obesespontaneously hypertensive rat (SHROB) 59 . Laterstudies in this animal model of metabolic syndromeproduced evidence of increased sympathetic nervousactivity as a common denominator in both hypertensionand insulin resistance, and also provided evidence thatmoxonidine both lowered BP and improved glycaemiccontrol 60 . Similar observations have been reported inother animal models 61 .In addition to direct interaction between thesympathetic nervous system and the renin–angiotensinsystem, there is potential for the interplay of bothpathways with insulin 60,62 . The outlines of a possiblecomplementary effect of angiotensin-targeted therapiesand SIRAs on insulin sensitivity may be discerned inthese interactions. An instructive comparison may alsobe made between SIRAs and beta-blockers. Drugs ofboth classes are sympatholytic. However, beta-blockers© 2004 LIBRAPHARM LTD – Curr Med Res Opin 2004; 20(3) Moxonidine and ramipril: partners in a successful MARRIAGE? Rayner 363

act peripherally, with one of their effects being to bluntinsulin-mediated glucose transport into skeletal muscles(i.e. they impair insulin sensitivity). The centrally actingSIRAs reduce sympathetic outflow but not at theexpense of insulin sensitivity.Moxonidine Effects on Glycaemic Indices:Clinical DataHaenni and Lithell 63 conducted a placebo-controlleddouble-blind trial in insulin-resistant obese patientswith mild hypertension and reported an improvement inthe insulin sensitivity index following moxonidinetherapy (Figure 1), as well as an increase in the rate ofglucose infusion during a euglycaemic clamp test. Therewas also a reduction in fasting plasma glucose amongsubjects treated with moxonidine. Additional evidencefor effects of moxonidine on glucose and insulinmetabolism in humans emerged from work by Almazovet al. 64 , who described improvements in tissue insulinsensitivity and a reduction in the total area-under-thecurve(AUC) for insulin response to an oral glucose loadin hypertensive patients, and by Sanjuliani andcolleagues 65 , who demonstrated both a reduction inplasma insulin 2 h after an oral glucose tolerance test(OGTT) in non-diabetic hypertensive patients treatedwith moxonidine and a correlation between a reductionin insulin levels and a decline in plasma noradrenalinelevels.Parallel observations by Almazov and co-workers 64that metformin (administered to hypertensive patientswith impaired glucose tolerance) lowered BP inproportion to its effect on glycaemic status, togetherwith reports that the insulin-sensitizer rosiglitazonelowers BP 66 and, conversely, that various drugs enhanceinsulin sensitivity secondary to reducing BP, emphasizeChange (%)2520151050-5-10MM/IP = 0.026 P = 0.056n.s.P = 0.004 P = 0.027PlaceboFigure 1. Use of moxonidine (0.2mg b.i.d. for 8 weeks) wasassociated with significant increases in glucose infusion rate (M)and insulin sensitivity index (M/I) during an euglycaemicclamp test in patients (n = 38) with mild hypertension, reducedinsulin sensitivity (baseline M/I < 3.6) and body massindex > 27kg/m 2 . (Reproduced, with permission, from Ref. 63.)n.s.Moxonidinethe reciprocal nature of relations between BP andinsulin sensitivity. The sympathetic nervous system andthe renin–angiotensin system are probable mediators ofthis interconnection.The MARRIAGE studyA controlled clinical study of the impact of ACEinhibition and SIRA therapy on glycaemic control is nowunderway. The MARRIAGE study (Moxonidine AndRamipril Regarding Insulin And Glucose Evaluation) hasbeen designed to compare the effects of moxonidine andramipril on BP and glycaemic control in overweightpatients with mild–moderate hypertension and impairedfasting glycaemia. Inclusion criteria for this study aresummarized in Table 3.The primary endpoint of MARRIAGE is the responseof sitting diastolic BP (SiDBP) to monotherapy withmoxonidine (0.4 mg/day, the preferred maintenancedose) or ramipril (5 mg/day), or the combination of bothdrugs in those patients who require such therapy (Figure2). Patients are considered to have a satisfactoryresponse to therapy if SiDBP is reduced by at least 10%relative to baseline; normalization of SiDBP is defined asa reduction to less than 85 mmHg.Secondary endpoints of MARRIAGE include a rangeof indices of glucose homoeostasis: fasting glucose andinsulin levels; glucose and insulin levels after an OGTT(AUC and values at 0, 0.5, 1 and 2 h); and glycosylatedhaemoglobin. Response to therapy will be tested after12 and 24 weeks of treatment, with comparisons versusbaseline and between treatment groups.MARRIAGE will also provide an opportunity for thefurther evaluation of the safety and tolerability ofmoxonidine as part of combination therapy. Experienceto date has been favourable and the drug has been usedsuccessfully with exemplars of several other majorclasses of antihypertensives 68 . The acquisition of furtherdata is nevertheless desirable in an era when multidrugtherapy for hypertension is regarded as necessary for amajority of patients.Table 3. Inclusion criteria for the MARRIAGE study1. Standard office sitting diastolic blood pressure85–109 mmHg and/or systolic blood pressure140–179 mmHg.2. Impaired fasting glycaemia or diabetes mellitus(fasting plasma glucose 110 mg/dl to < 126 mg/dl[ 6.1 mmol/litre to < 7 mmol/litre])* or diabetesmellitus (fasting plasma glucose 26 mg/dl[ 7 mmol/litre]) treated with diet alone.3. Body mass index > 25.0 kg/m 2 to < 35.0 kg/m 2 .*Defined according to criteria published by the AmericanDiabetes Association 67364 Moxonidine and ramipril: partners in a successful MARRIAGE? © 2004 LIBRAPHARM LTD – Curr Med Res Opin 2004; 20(3)

12-week double-blind comparison: moxonidine vs. ramipril 12-week combination treatment: moxonidine + ramiprilPlacebo run-inWeek: -2 0 12 24PrescreeningScreening/randomizationMARRIAGE is being conducted at sites in France(Professor P. Valensi, CHU Jean Verdier, Paris) andGermany (Dr. J. Jordan, Berlin-Buch). Recruitment isexpected to be completed by the end of 2003, by whichtime it is anticipated that approximately 200 patientswill have been randomized. Results from this study willbe available in 2004 and may prove highly instructive inhelping to shape new treatment strategies for patientswho have hypertension and impaired insulin sensitivity.Comparison of the results of MARRIAGE with those ofDREAM (Diabetes Reduction Assessment withRamipril and Rosiglitazone) 49 may also provide usefulinsights into new treatment strategies for patients withhypertension and impaired insulin sensitivity. Inaddition, these studies may provide valuable additionalinformation about the relation between impairedglucose tolerance and frank DM.ConclusionsMoxonidine 0.4 mg ODRamipril 5 mg ODFigure 2. Outline protocol of the MARRIAGE studyThere are indications that certain types ofantihypertensives – notably those that target therenin–angiotensin system but possibly also the SIRAs –may have effects on glucose and insulin metabolism thatcan substantially improve the long-term clinicalprognosis of patients with metabolic syndrome orhypertension with DM. The MARRIAGE study is beingundertaken, to ascertain, among other things, whateffects the combination of a SIRA (moxonidine) with anACE inhibitor (ramipril) has on indices of glycaemiccontrol in hypertensive patients with impaired fastingglycaemia.AcknowledgmentCombination forNon-respondersPreparation of this manuscript was assisted by anunrestricted educational grant from SolvayPharmaceuticals GmbH, Hannover, Germany.References1. 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63. Haenni A, Lithell HO. Moxonidine improves insulin sensitivity ininsulin-resistant hypertensives. J Hypertens 1999;17(Suppl 3):S29-S3564. Almazov VA, Shlyatko EV, Blagosklonnaya YV, et al. Insulinresistance and arterial hypertension. The influence of moxonidineand metformin therapy. J Hypertens 2000;18(Suppl 2):[abstract 2B.6]65. Sanjuliani AF, Genelhu-Fagunde V, Barroso SG, et al. Effect of aimidazoline agonist on sympathetic activity and components ofthe insulin resistance syndrome in obese hypertensive Brazilianpatients. J Hypertens 2002;20:S206[abstract]66. Raji A, Seely EW, Bekins SA, et al. Rosiglitazone improves insulinsensitivity and lowers blood pressure in hypertensive patients.Diabetes Care 2003;26:172-867. American Diabetes Association. Screening for type 2 diabetes.Diabetes Care 2000;23(Suppl 1):S20-S2368. Waters J, Ashford J, Jäger B, Wonnacott S, Verboom C-Nfor the OPIC Investigators. Use of moxonidine as initialtherapy and in combination in the treatment of essentialhypertension – results of the TOPIC (Trial of Physiotens incombination) Study. J Clin Basic Cardiol 1999;2:219-24CrossRef links are available in the online published version of this paper:http://www.cmrojournal.comPaper CMRO-2477, Accepted for publication: 02 December 2003Published Online: 16 January 2004doi:10.1185/030079904125002991© 2004 LIBRAPHARM LTD – Curr Med Res Opin 2004; 20(3) Moxonidine and ramipril: partners in a successful MARRIAGE? Rayner 367