Contents

Summary

Practical Therapeutics

Drugs 38 (4): 621-633. 19890012-6667/89/00 I0-0621/$06.50/0© ADIS Press LimitedAll rights reserved.DRUG03 246

Hypertension in the Diabetic PatientSelection and Optimum ·Use of Antihypertensive Drugs

BernhardN. TrostMed izin ische Universitatspoliklinik, Inselspital , Bern , Switzerland

Summary 621I. Prevent ion and Non-Pharmacological T reatment 622

1.1 Prevention 6221.2 Non-Pharmacological Measures 622

2. Antih yperte nsive Drug Treatment in Diabetic Patients 6222.1 Genera l Considerations 622

2.1.1 Aims of Therapy 6222.1.2 Drug Effects 6232.1.3 Monito ring Adverse Effects 6232. 1.4 Overa ll Regimen 6232.1.5 Cost of T reatment 623

2.2 Specific Drug Groups 6232.2.1 Diuretics 6232.2.2 {J-Blockers 6252.2.3 Calcium Antagon ists 6262.2.4 ACE Inhibitors 6262.2.5 Drugs Affecting the Adrenergic System (Ot her than (J-Blockers) 6282.2.6 Direct Arteriolar Vasod ilation and Combination Thera py 630

3. Control of Therapy, and Outloo k 630

Understanding of the pathophysiology ofhypertension and diabetes mellitus and theirassociation is at present f ragmentary at best. Optimal antihypertensive drug therapy ofpatients with both disorders is therefore based on lim ited experimental data. practicalexperience and educated guesswork. and needs to be tailored to each (often mult imorbid)individual.

In most patients monotherapy would be preferred. and would begin with a calciumantagonist or a converting enzyme inhibitor at a low to moderate dosage. If this is noteffective an a[-adrenoceptor inhibitor. a cardioselective ;J-blocker or a diuretic. always ata low to moderate dosage, should be tried. If still unsuccessful, low dose combinations of2 of these drugs are next . The (long term) regimen should be as simple as possible. andits effects - desired and undesired - monitored as closely as the carbohydrate disorder.

622

Neither hypertension nor diabetes mellitus areclearcut homogeneous diseases. Rather, they aremultifaceted and dynamic expressions of patho­physiological dysequilibria in 2 areas which areclosely related and even intermingled by commonfactors, for example obesity, elevated plasma in­sulin levels leading to sodium retention, renal ab­normalities, etc. Thus, 'the hypertensive' and 'thediabetic' patient are merely abstract ciphers of muchmore complex realities, and exact numerical WHOdefinitions of both entities - although useful fordiscussion and rough comparisons - are in factarbitrary and empirical. Optimal treatment of dis­orders like hypertension accompanying diabetesmellitus is based on knowledge of the underlyingindividual pathophysiology and the possibility ofreversal of pathological into physiological condi­tions. It is therefore evident that today's therapycan only rarely be optimal in a strict sense (e.g. inphaeochrornocytorna, Conn's syndrome, Cushing'sdisease, acromegaly, etc.) due to lack of fulfilmentof these prerequisites.

The 2 entities - hypertension and diabetes ­however, are each associated with a substantiallyincreased cardiovascular morbidity and mortality,which is additive when they occur together (Kan­nel 1986). Thus, it is commonly agreed that some­thing needs to be done, not just to combat hyper­tension or diabetes mellitus alone, but against thecombined risk factors. The overall situation of thepatient must also be considered, including his orher life expectancy, and social and familial back­ground, before undertaking any potentially harm­ful or fruitless therapeutic steps.

1. Prevention and Non-PharmacologicalTreatment1.1 Prevention

The prevention of disease should be the firstaim . Genetic counselling is a rather theoretical pos­sibility, and genetic intervention even more so. Afuture option against diabetes mellitus type I (inwhich hypertension is usually associated withnephropathy), could be vaccination against virusescausing insulitis. The incidence of hypertension and

Drugs 38 (4) /989

type II diabetes mellitus would also be lower ifmembers of families prone to these conditionscould keep their bodyweights close to normal val­ues.

1.2 Non-Pharmacological Measures

Non-pharmacological measures should alwaysbe considered, and discussed with the patient be­fore any drugs are prescribed. Statistically, the singlemost important treatment for more than 50% ofhypertensive diabetics (type II) is to lose weight,which leads to improvement in both conditions andalso in the hyperlipidaemia frequently associatedwith them. The value of a diversified, weight-re­ducing diabetes diet with frequent small meals, lowin salt and rich in vegetables, with their high fibreand potassium content, cannot be overemphasised(Dodson et al. 1984). Smoking and high alcoholintake should be stopped, and all medications whichelevate blood pressure or glycaemia or interfere ne­gatively with sequelae of hypertension and/or dia­betes mellitus are to be avoided. Physical exercise,reduction of stress (or education aimed at betterstress management), relaxation training, as well asalleviation of emotional burdens through a goodtherapeutic relationship between patient and doc­tor, may be of some help. Treatment with anti­hypertensive drugs is indicated only if these meas­ures fail or are not acceptable to the individualpatient.

2. Antihypertensive Drug Treatment inDiabetic Patients2.1 General Considerations

The time-honoured therapeutic principle pri­mum nil nocere (first of all, do no harm) cannotalways be followed easily in a patient who presentswith several pathogenic conditions and their vari­ous sequelae, as is often the case in hypertensivediabetics. Nevertheless, a better overview may bemaintained with the help of a few guidelines.

2.1.1 Aims a/TherapyThe aim(s) of antihypertensive (long term)

therapy should be clear. Lowering high blood pres­sure in an elderly type II diabetic patient with signs

Antihypertensive Drugs in Diabetic Patients

and symptoms of arteriosclerosis is a different taskfrom normalising elevated blood pressure in ayoung individual with diabetes mellitus type I andearly nephropathy; whereas the former may farebetter with a slow adjustment of blood pressure in

the area of borderline hypertension (141/91 to 159/94mm Hg), the latter should be treated more ag­gressively to delay the decline in renal function(Parving et al. 1987) and other complications.

Can other problems be solved at the same timeby using a particular antihypertensive drug? Forexample, by treating hypertension and coronaryheart disease with a calcium antagonist alone,hypertension and mild congestive heart failure withan angiotensin converting enzyme (ACE) inhibitor,or hypertension and diabetic complications liketachycardia and frequent loose stools with vera­pamil? In orthostatic hypotension, normalisationof supine hypertension does not have first priority;this is given to optimal quality of life, which usu­ally means elevation of blood pressure during theday.

2.1.2 Drug EffectsThe effect of the antihypertensive drug(s) must

be anticipated and controlled, preferably togetherwith the control of glucose homeostasis, body­weight and other risk factors. First doses should besmall and administered under supervision if pos­sible. The latter also becomes necessary if lack ofcompliance is suspected later on.

2.1.3 Monitoring Adverse EffectsAdverse effects, expected and unexpected, are to

be discussed and asked about (e.g. impotence) con­tinuously. If they are not tolerable, even after re­ducing the dose, an alternative medication must bechosen . The same applies to the physician's find­ings: should the ant ihypertensive regimen ad­versely affect glucose homeostasis, diabetic com­plications or associated cardiovascular risk factorssuch as blood lipids, potassium etc. or induce newones, e.g. bradycardia, a change is advisable.

623

2.1.4 Overall RegimenSimplicity of the overall drug regimen is of the

utmost importance because many patients withhypertension and diabetes may need several othermedications (Rendell et al. 1983); moreover, theymay use antihypertensive drugs for decades. A reg­imen of I tablet every morning should be at­tempted. If a given preparation at an appropriatedosage does not reach the goal and compliance isassured , a second or a third drug should not beadded ; rather, first try all other possible mono­therapies. If, however, a single drug regimen is in­sufficient or causes unacceptable side effects and 2drugs are found optimal over a period of time, aswitch to a tablet which combines the 2 drugs wouldbe indicated.

2.1.5 Cost of TreatmentCosts should also be taken into account. Actual

drug costs, however, are only I factor, and the fre­quency of monitoring procedures, the need to treatside effects with other medications, quality of lifeetc. are all important, as are personal and com­munity resources. More controversial are cost­benefit analyses, since the effects of a precociousstroke or myocardial infarction are hardly meas­urable in terms of cost.

2.2 Specific Drug Groups

The advantages and disadvantages of each ofthe main groups of drugs used in the treatmentofhypertension in diabetic patients are outlined inthe following sections. Table I summarises the ad­vantages, problems and recommendations for eachdrug group.

2.2.1 DiureticsEfficacy, simplicity and low cost are all factors

which favour therapy with a low dose of a thiazidediuretic [e.g. 12.5 to 25mg of hydrochlorothiazideor chlorthalidone (Vardan et al. 1987) every morn­ing] as long as kidney function is normal ; if plasmacreatinine levels rise above 150 to 200~moI/L, loopdiuretics such as frusemide (furosemide) or me­tolazone are used. Furthermore, diuretics amelio-

624 Drugs 38 (4) /989

Table I. The advantages anddrawbacks of various groups of antihypertens ive drugs in the treatment of hypertension with diabetesmellitus

Advantages

DiureticsMonotherapy lowers high blood

pressure effectivelyOnce daily regimenInexpensivePathophysiologically sound (lower

elevated exchangeable sodium andreduce exaggerated noradrenalinereactivity)

tl-BlockersMonotherapy lowers high blood

pressure effectivelyOnce daily regimenCardioprotectionAntianginal/antiarrythmogenic properties

Calcium antagonistsMonotherapy lowers high blood

pressure effectivelyOnce daily regimen possibleAntianginal effectsAntiarrhythmic properties (verapamil,

diltiazem)Metabol ic 'neutrality' (glucose, lipids,

potass ium)Cardioprotection (?)Antiarteriosclerotic (?)Preserve physical exercise performanceRelative rarity of orthostatic and

impotence problems (?)

ACE inhibitorsMonotherapy lowers high blood

pressure effectivelyOnce daily regimen possibleEffective in heart failureMetabolic 'neutrality' [glucose , lipids (?),

no hypokalaemiajRelative rarity of orthostatic and

impotence problems (?)

Problems

Impair glucose homeostasis potassiumdepletion , insulin receptors (?)

Serum lipid alterationsIncrease plasma uric acidHyperosmolar comaErectile impotenceOrthostatic hypotension

tl2-Blockade impairs insulin outputHypoglycaemia: prolonged by tl2-blockers ;

altered perception of the symptoms;hypertensive crisis (tl2-blockers)

Serum lipid alterationsDecrease physical exercise performance

Impair insulin secretion in vitro; in highdoses in vivo (?)

Headache (often transient)Flushing, ankle oedema, paradoxical angina

(dihydropyridines)Constipat ion (verapamil)

Proteinur ia (rare)Dose adjustment with declining renal

functionRenal failure (reversible) in renal artery

stenosesEnhancement of hyperkalaemia in

hyporeninaemic hypoaldosteronism (rare)False positive test for acetone

Recommendations

Low doseControl : potassium; glucose; lipidsPotassium substitution if needed (diet,

KCI, combination with potassium­sparing diuretic)

Cardioselective (tldblocker (i.e. atenolol ,metoprolol , acebutolol)

Low (-moderate) doseInstruction : hypoglycaemia problemsControl : cardiac performance; AV

conduction ; serum lipoproteins

Low to moderate doseControl: AV conduction (verapamil,

diltiazem); glucose (at higher dosages)

Low to moderate doseControl : renal function; proteinuria ;

plasma potassium

rate both of the pathophysiological features thoughtto be most relevant in hypertension accompaniedby diabetes mellitus , namely abnormal sodium re­tention and exaggerated cardiovascular pressorreactivity (De Chatel et al. 1977; Weidmann ct al.1979).

However , these agents, at least at higher dos­ages, may impa ir glucose homeostasis both inpatients with type II diabetes mellitus and in non­diabetic and glucose-intolerant individuals (Ameryet al. 1978; Goldner et al. 1960; Murphy et al. 1982;Shapiro et al. 1961 ; Vardan et al. 1987; Wilson et

al. 1986). They may thus hamper the beneficial ef­fect of improved hypertension on coronary heartdisease and other vascular complications (Ames1983). This effect usually accompanies potassiumdepletion (Grunfield & Chappell 1983; Heldermanet al. 1983) but may also depend on a failure ofpatients with diabetes mellitus to increase thenumber of their insulin receptors , as occurs withnon-diabetic patients during thiazide treatment(Gill et al. 1984). Administering potassium-sparingdiuretics or supplemental potassium may be onlya partial solution , which is not without danger if

Antihypertensive Drugs in Diabetic Patients

declining renal function or hyporeninaemic hy­poaldosteronism should complicate the situation.The cardiovascular benefits of normalised bloodpressure are probably also lessened by anothermetabolic drawback: diuretics can cause additionalelevation of the potentially atherogenic very lowdensity and low density serum lipoprotein-chol­esterol fractions , without changing the potentiallyanti-atherogenic high density lipoprotein-choles-.terol concentrations; however, this effect may beattenuated after several months (Ames 1983;Weidmann et al. 1985). The role of the diuretic­induced rise in serum uric acid in the context ofcardiovascular risk factors is much less clear; inrare cases it may lead to gout. Three further po­tential drawbacks are likely to be at least as rele­vant clinically. Diuretics may provoke , usually inelderly diabetic patients with impaired thirst sen­sation, a hyperosmolar non-ketotic syndrome withcoma and death (Fonseca & Phear 1982; Rowe &Mather 1985). In addition, 2 complications of dia­betes mellitus may be aggravated, as with someother antihypertensive regimens, namely erectileimpotence (Lipson 1984; Stevenson & Umstead1984) and orthostatic hypotension.

If diuretics are to remain among the first choicemonotherapies in hypertensive patients with dia­betes mellitus , which is controversial at present,low doses should be prescribed (for example, notmore than 25 rug/day of chlorthalidone or hydro­chlorothiazide). Bearing in mind financial consid­erations, we need to remember that continuousmonitoring and control not only of glucose homeo­stasis, but also of potassium and lipids as well askidney function , are mandatory. Where a diet richin potassium would be unrealistic or insufficient,potassium chloride or a combined diuretic with apotassium-sparing component will usually help, butwill also add to the costs and complicate the reg­imen. Thus, diuretics should be started as the in­itial drugs only under special circumstances, for ex­ample if oedema is a problem or if heart failure ispresent and ACE inhibitors contraindicated.Nevertheless , low-dose diuretics are often a rea­sonable complement in cases where the therapeutic

625

aim is not reached by monotherapy with anotherdrug.

2.2.2 ;3-BlockersCardioprotection and antianginal effects, the

main advantages of {3-blockers, are welcome in hy­pertensive diabetic patients because most of themortality associated with these conditions is as­sociated with cardiovascular complications. Many{3-blockers normalise blood pressure when admin­istered on a once daily schedule, and all reducetachycardia, often the first sign of autonomic neu­ropathy . Further advantages , in relation to diuret­ics, are somewhat less orthostasis and perhaps alsoless erectile dysfunction; however, this may be trueonly in relation to the high-dose diuretic regimensthat were formerly in use, but should not now beused in diabetic patients.

There are also several drawbacks to {3-blockers.Since insulin secretion is stimulated through {32­receptors, non-selective blockade of both {3\- and{32-receptors could theoretically lead to impairedglucose homeostasis by a decreased insulin outputin patients with type II diabetes (Christlieb & Maki1980). This has only partially been substantiated,however, in practical clinical trials in non-insulin­dependent diabetic patients taking propranolol, al­beit at a low dosage of 80mg twice daily (Groop &Totterrnan 1982; Groop et al. 1982; Micossi et al.1984; Wright et al. 1979). The same is true for low­dose timolol (Gundersen & Kjekshus 1983) or al­prenolol (Holm et al. 1980) therapy. On the otherhand, with a daily dose of propranolol 240mg, ahyperosmolar non-ketotic diabetic coma could beprecipitated (Podolsky & Pattavina 1973).

Apart from this, several other problems may oc­cur during hypoglycaemia which involve type IIdiabetics on oral hypoglycaemic agents or insulin,and all type I patients, in particular the labile onesand those on an intensified regimen, for examplewith an insulin pump. First, {32-blockade can pro­long hypoglycaemic episodes by blocking glyco­genolysis in muscles and lipolysis in adipose tissue,thereby reducing the substrates for both gluconeo­genesis and ketogenesis (Christlieb & Maki 1980;Deacon et al. 1977; Lager et al. 1979); at twice the

626

dosages used by Lager et al. (1979), Popp et al.(1984) found no differences between the ,6,-ant­agonist metoprolol and the nonselective ,6-blockerpropranolol in this respect. Since glucagon secre­tion is also stimulated through /h receptors, its re­lease, badly needed in such a situation, can behampered; in patients with neuropathy this alreadyoccurs, without therapeutic ,6-blockade. Both com­plications can mostly be prevented by using acardioselective ,6[-blocker, for example atenolol,metoprolol or acebutolol, at a low dosage.

The second problem is that the perception ofsymptoms of hypoglycaemia may become im­paired or altered by nonselective ,a-blockade, whileonly tachycardia and palpitations are dampened ifa cardioselective type is used. In prospective shortterm (Ryan et al. 1985) and long term (Barnett etal. 1980; Kelendorf et al. 1982) trials of both in­sulin-treated type II and type I diabetic patients,however, problems of this kind were exceptionaland sweating was even more pronounced.

Thirdly , ,62-blockade can pro voke hypertensi vecrises during hypoglycaemia, as overstimulated (X ­

receptor-dominated arteriolar constriction is nolonger counterbalanced by ,a2-mediated dilation(Christlieb & Mak i 1980; Ryan et al. 1985). Peri­pheral microvascular disease may be aggravated bythe same mechanism and develop into gangrene .Again, this can probably be avoided by choosing,aI-selective blockers.

Although little is known about the clinical sig­nificance of serum lipid alterations induced by along term ,a-blocking regimen , even for non-dia­betic and particularly for diabetic patients , it isnecessary to bear in mind the possib ility of aggra­vating the already disadvantageous situation byraising serum triglyceride levels furth er and alsoreducing the potentially antiatherogenic high den­sity lipop rotein cholesterol fraction. This tend encyis again less pronounced with cardioselectiveblockers and may be almost absent when an agentwith considerable intrinsic sympathomimetic ac­tivity (ISA) is used.

Finall y, there is the well-known problem ofphysical exercise - a major point in diab etes edu­cation - under ,a-blockade. Younger pati ents in

Drugs 38 (4) 1989

particular will often not ice a decline in their per­formance and consequently not compl y with sucha regimen.

Thus, as for diuretics, the prescription of ,6­blockers as a first-line monotherapy in diabeticpatients is controversial. Only card ioselective typesof ,a-blockers should be used and only at low tomoderate dosages (e.g. not more than 50 mg/dayof atenolol, 150 rug/da y of metoprolol, or 600 mg/day of acebutolol), because the higher the dose, themore cardioselectivity is lost. For each patient it isnecessary to establish before treatment with ,6­blockers that there is an adequate cardiac reserve,no heart failure, no heart block, no angiopathic skinproblem or impending gangrene , and no obstruc­tive pulmonary disease.

Neither the pleasure of physical exercise nor ag­gravat ion of an unfavourable lipid profile in a givendiabetic patient should be jeopardised by ,6-block­ing therap y; it should also not be used in first-linetreatment together with very tight diabetes control.Ifadvising such treatment, pati ents , as well as theirfamilies , need to be instructed about possible al­terations during hypoglycaemia, and serum lipidlevels should be regularly mon itored.

2.2.3 Calcium AntagonistsIn patients with diabetes mellitus, calcium ant­

agonists have several advantages. Once daily form­ulations exist, and as monotherapy they lower bloodpressure efficientl y (by vasodilation, but withoutsalt retention), particularly in the large group ofelderly type II diabetics. In these patients , the anti­anginal, antiarrhythmic and/or cardioprotectiveproperties of these agents are often desired, in ad­dition to their peripheral vasodilating properti es.In contrast to diuretics, calcium antagonists usu­ally preserve cerebral and renal blood flow. Phys­ical exercise performance is not impaired (Kinder­mann et al. 1986a). Whether they act against orprevent art eriosclerosi s, as suggested by some ani­mal experiments, has not yet been determined innon-diabetic or diabetic patients. The sam e appliesto the platelet aggregation inh ibit ion shown in vi­tro.

Apart from the well-kno wn ad verse effects that

Antihypertensive Drugs in Diabetic Patients

may occur, depending on the subgroup used (head­ache, flushing, palpitations, ankle oedema not re­lated to heart failure, constipation, atrial conduc­tion disturbances etc.), the main objections toprescribing calcium antagonists have been basedon the knowledge that calcium is needed for in­sulin secretion. In early experiments with thesedrugs, albeit in isolated pancreas and pancreatic {3­cell preparations obtained from animals, a dose­related decrease in insulin output after glucosestimulation was observed. Although this problemdoes not concern type I diabetics, it could be cru­cial for the much larger group of type II patientsand individuals with borderline glucose intoler­ance. However, in a recent extensive review of thissubject in non-diabetic and diabetic individuals(Trost & Weidmann 1987), it was concluded thatcalcium antagonists do not alter glucose homeo­stasis to a clinically relevant degree over a periodof weeks or months in non-diabetic and non­insulin-dependent diabetic subjects , although athigher dosages minor acute and transient changes,especially after glucose challenges, cannot be ex­cluded . This was corroborated by a continuing longterm stud y in elderly type II diabetics on anti­hypertensive monotherapy with nitrendipine inthat , antidiabetic regimen and bodyweight re­maining constant, no change in carbohydratehomeostasis was found for up to 5 years (Trost &Weidmann 1988a). Furthermore, in the reviewmentioned above , which included 30 long termlipid trials , it was also concluded that calcium ant­agoni sts give no indication of an adverse effect onthe serum lipid pattern in non-diabetic or non-in­sulin-dependent diabetic patients. The same holdstrue for plasma potassium and uric acid levels(Trost & Weidmann 1988b).

Therefore, although the long term outcome oftype II diabetics treated with calcium antagonistsremains to be investigated further and there is asyet almost no substantial literature concerning thetherapy in patients with type I disease , it would bepreferred to start antihypertensive treatment indiabetics with a low to moderate dose ofa calciumantagonist (e.g. 10 to 20mg nitrendipine, 120 to240mg slow release verapamil, 90 to 180mg slow

627

release diltiazem) rather than a diuretic or a {3­

blocker. Atrio ventricular conduction should bewatched under verapamil and also diltiazem, andcarbohydrate and lipid homeostasis should bemonitored with all high-dose calcium antagonists.

2.2.4 ACE InhibitorsACE inhibitors are less well investigated than

calcium antagonists with reference to diabeticpatients. However, as monotherapy they lowerblood pressure effectively in both types of diabeticsand can be given once a day. Moreover, their pro­file makes them most appropriate in patients withhypertension with limited cardiac reserve or openheart failure , not uncommon in diabetic patients.Most important, in hypertensive diabetics ACE in­hibitors seem to be as metabolically neutral as cal­cium antagonists (D'Angelo et al. 1988; Domin­guez et al. 1986; Escobar-Jiminez et al. 1988; Lanzaet al. 1985, 1987; Matthews et al. 1986; Passa etal. 1987; Shionoiri et al. 1987; Sullivan et al. 1985;Winocour et al. 1986a), and this has also been foundwhen they are adm inistered in combination withconstant dosages of other antihypertensive drugs(Eto et al. 1988; Riobo et al. 1988). Results of 2acute studies with captopril and the glucose clamptechnique (Ferriere et al. 1985; Rett et al. 1988a)suggest that glucose disposal rate, i.e. total bodyglucose uptake , was even enhanced by ACE inhi­bition, and in 15 hypertensive patients with dia­betes type II, captopril therapy for I week reducedboth blood pressure and postprandial blood glu­cose concentrations (Rett et al. 1988b). In diabeticnephropathy, captopril seemed to exhibit benefic­ial effects on blood pressure as well as on renalfunction , both alone (Hommel et al. 1986) and incombination with other antihypertensive drugs(Bjorck et al. 1986; Taguma et al. 1985), whereasin hypertensive diabetics without establishednephropathy, this may not be the case (Winocouret al. 1986b). Conversely, 2 recent papers on hy­pertensive patients with nephropathy report no sig­nificant change in renal function, proteinuria andglycosylated haemoglobin on captopril monother­apy (Valvo et al. 1988) or an increase in both serumcreatinine and proteinuria, but a fall in glycosy-

628

lated haemoglobin on captopril combined withother antihypertensive drugs (Hay et al. 1988).

There are also some potential disadvantages toACE inhibitors. Very rarely, proteinuria may be in­duced (Vidt et al. 1982)and falsely suggest diabeticnephropathy. The individual dosage needs to beadjusted to renal function, and since most type Idiabetics become hypertensive with the onset ofnephropathy, this means continuous control ofrenal parameters. This includes potassium, not onlybecause of the problem of hyperkalaemia in de­clining renal function aggravated by the drug, butalso in the (rather rare) presence of hyporeni­naemic hypoaldosteronism in advanced diabetes.In renal artery stenosis, reversible kidney damagemay occur (Hricik et al. 1983). Finally, captoprilcan give a false positive test for urinary acetone(Warren 1980).

Thus, although much long term clinical researchin hypertensive diabetic patients remains to bedone, it would be preferred to try an ACE inhibitorat low to moderate dosage (e.g. enalapril 2.5 to 10rug/day or, less simply, captopril 6.25 to 25mg twicedaily) as first-line monotherapy rather than a di­uretic or ,,-blocker, especially with declining card­iac performance. Renal artery stenosis should beruled out beforehand and renal function and po­tassium monitored closely.

2.2.5 Drugs Affecting the Adrenergic System(Other than fJ-Blockers)Sympatholytic agents (e.g. reserpine, guaneth­

idine or debrisoquine), as well as central az-agon­ists (e.g. clonidine, guanfacine, guanabenz, and alsoa-methyldopa), do not usually alter glucosehomeostasis or serum lipoproteins in non-diabet­ics, but there is little substantial information aboutthis point in patients with diabetes mellitus (Ben­field & Hunter 1982; Coves et al. 1987; Dvorak etal. 1987; Ferlito et al. 1985; Fetkovska et al. 1987;Guthrie et al. 1983; Gutin & Tuck 1988; Hauger­Klevene & Scornavacchi 1985; Mpoy et al. 1988;Nilsson-Ehle et al. 1988; Passa et al. 1982; Stor­nello et al. 1982; Wallin et al. 1985; Weber et al.1984). As combination therapy with diuretics isusually needed to counteract sodium retention, the

Drugs 38 (4) /989

regimen is not simple . Adverse effects are usuallymore noticeable than with calcium antagonists orACE inhibitors, and orthostatic hypotension andsexual dysfunction in particular may aggravate al­ready existing problems in diabet ics with even mi­nor neuropathy. On the whole, these agents can nolonger be considered as first-line medication in hy­pertensive diabetics.

A notable exception, however, may be at­adrenoceptor inhibitors like prazosin , indoraminor doxazosin, the latter on a once daily schedule.Information about such treatment in diabetics isscarce (Barbieri et al. 1980; Ferlito et al. 1983;Konigstein 1978; Kwan et al. 1988; Leichter &Baumgardner 1981; Shionoiri et al. 1986; Sood etal. 1986), but glucose homeostasis seems not to bedisturbed, modification of the lipid profile is po­tentiall y beneficial (Trost et al. 1987; Weidmannet al. 1985), and impotence rare (Lipson 1984).Nevertheless, adverse effects such as orthostatichypotension and drowsiness seem to occur fre­quently.

2.2.6 Direct Arteriolar Vasodilation andCombination TherapyIn the main the hydralazine group and minox­

idil must be given in combination with other anti­hypertensive drugs and therefore are not first-linemedications in diabetics, although they seem notto affect serum glucose and lipoprotein homeosta­sis. Information about antihypertensive combina­tion therapy in diabetics is very limited; whereasdiuretics with cardioselective ,,-blockers seem toact favourably (Corcoran et al. 1987; Garrett et al.1980; Gentile & Coltorti 1984), findings with a di­uretic-non-cardioselective ,,-blockade combinationare more controversial (Chazan et al. 1981; Dorn­horst et al. 1985; Janka et al. 1980).

3. Control of Therapy, and Outlook

As for all chronic diseases, sympathetic attend­ance should be combined with attentive control. Ifpossible, the patient or a family member should beactively involved in monitoring treatment. Controlof both blood sugar or urine sugar and blood pres-

Antihypertensive Drugs in Diabetic Patients

01tler pre-existing diseases?

No .. .. Yes

Calcium antagonist or ACE Inhibitor at Choose an antihypertensive drug,

low, or If necessary moderate, dosage considering its beneficial and adverse

~effects in relation to pre-existingdiseases, type and sequelae of diabetesand/or hypertension

BP remains elevated or adverse effectsunacceptable

Continue drug ~Try ACE inhibitor if calcium antagonist

~.... No Yes .. unsuccessful, and vice versa, at low, or

monotherapy .. If necessary moderate, dosage

IBP remains elevated or adverse effects ....unacceptable I"""

~Continue drug _No • Yes Switch to a-adrenoceptor inhibitor,

monotherapy .... cardioselecdve ~blocker or diuretic, atlow, or If necessary moderate, dosage

BP remains elevated or adverse effects ..... Iunacceptable -

Try low-dose combination of 2 of lheabove agents, preferably dihydropyrld-

~Continue drug .... No .IF Yes ... ine-type calcium antagonist + cardiose-

m0n0ltlerapy .... .. lective B-blocker, or ACE inhibitor +diuretic: increase 1, or if necessaryboth, to moderate dosage

BP remains elevated or adverse effects Iunacceptable ....

Continue Re-evaluation of ltIe overall situation bycombined ,.. a specialist (get more Information, e.g.

14- regimen, If sue- .... No Yes ~ 24-hour-profile of BP; rule out secon-cessful, In fixed dary forms of hypertension and/orform diabetes; ascertain compliance wiltl

non-pharmacological measures etc.)

Simplify regimen. If BP excellent,decrease dosage or switch back fromcombined therapy to monolherapy. ~..lifelong control and adjustment aremandatory

Fig. 1. Algorithm for antihypertensive drug treatment of hypertensive diabetic patients .

629

630

sure by the patient, routinely and at the same time,should be encouraged. The best therapy is alwaysfound in cooperation with the individual patient,never against the patient, if adverse effects causetrouble. In terms of prognosis, extrapolation fromnon-diabetic hypertensive patients would suggestthat antihypertensive therapy should diminishstrokes and heart failure, whereas a beneficial in­fluence on coronary heart disease and myocardialinfarction remains unclear, at least for the conven­tional diuretic and {1-blocker regimens. Final1y,since pathophysiological understanding of hyper­tension and diabetes mel1itusand their association,and consequently of their rational treatment, is in­complete at best, it is advisable to remain open­minded (but not uncritical) about new progress inthis field.

For the time being, selection of an optimal anti­hypertensive drug regimen for a given diabeticpatient can be summarised as follows (see fig. I).Because of their metabolic neutrality, low-dosetherapy with either a calcium antagonist or an ACEinhibitor should be tried first, taking into accountthe individual disposition and the anticipatedbeneficial and adverse effects. If the type of drugchosen is not successful, even at a moderate dosageand with compliance assured, the other type maybe prescribed. Should this not work, an a-blocker,a cardioselective {1-blocker or a diuretic, always asmonotherapy and at a low to moderate dosage,should be tried next. Low-dose combinations, pref­erably a dihydropyridine-type calcium antagonistwith a cardioselective {1-blocker, or an ACE inhib­itor with a diuretic, should be tried if monotherapyfails. For the sake of simplicity (to be attemptedunder all circumstances) combinations ofthe agentsmentioned above may be administered in a once­daily fixed form later in the course of therapy, iffound to be acceptable and successful. Lifelongmonitoring and adjustment are mandatory.

References

Amery A, Berthaux P, Bulpitt C, Deruyttere M, De SchaepdryverA, et al. Glucose intolerance during diuretic therapy . LancetI: 681-683, 1978

Ames RP. Metabolic disturbances increasing the risk of coronary

Drugs 38 (4) 1989

heart disease during diuretic-based antihypertensive therap y:lipid alterations and glucose intolerance . American Heart Jour­nal 106: 1207-1215, 1983

Barbieri C, Ferrari C, Borzio M, Piepoli V, Caldara R. Metaboliceffects of chronic prazosin treatment. Hormone and MetabolicResearch 12: 331-334, 1980

Barnett AH, Leslie D, Watkins PJ. Can insulin-treated diabeticsbe given beta-adrenergic blocking drugs? British Medical Jour­nal 280: 976-978, 1980

Benfield GFA, Hunter KR. Oxprenolol, methyldopa and lipidsin diabetes mellitus , British Journal of Clinical Pharmacology13: 219-222, 1982

Bjorck S, Nyberg G, Mulec H, Granerus G, Herlitz H, et al. Bene­ficial effects of angiotensin converting enzyme inhibition onrenal function in patients with diabetic nephropathy. BritishMedical Journal 293: 471-474, 1986

Chazan BI, Old JM, Venkataraman G, Snape J, Cameron EGM.A beta blocker-thiazide combination in the treatment of hyper­tension in diabetics . British Journal of Clinical Practice 35:393-398, 1981

Christlieb AR, Maki Pc. The effect of beta-blocker therapy onglucose and lipid metabolism. Primary Cardiology (Suppl.): 47­54, 1980

Corcoran JS, Perkins JE, Hoflbrand BI, Yudkin JS. Treatinghypertension in non-insulin-dependent diabetes: a comparisonof atenolol, nifedipine , and captopril combined with bendro­tluazide. Diabetic Medicine 4: 164-168, 1987

Coves MJ, Gomis R, Goday A, Casarnitjana R, Rivera F, et al.Tratamiento hipotensor con guanfacina en pacientes afectos dediabetes mellitus tipo II. Medicina Clinica (Barcelona) 88: 315­317,1987

D'Angelo A, Giannini S, Benetollo P, Castrignano R, Lodetti MG,et al. Efficacy of captopril in hypertensive diabeti c patients.American Journal of Medicine 84 (Suppl. 3A): 155-158, 1988

Deacon SP, Karunanayake A, Barnett D. Acebutolol, atenolol ,and propranolol and metabolic responses to acute hypogly­caemia in diabetics. British Medical Journal 2: 1255-1257, 1977

De Chatel R, Weidmann P, Flammer J, Ziegler WH, Beretta­Piccoli C, et al. Sodium , renin , aldosterone, catecholamines,and blood pressure in diabetes mellitus. Kidney International12: 412-421, 1977

Dodson PM, Pacy PJ, Bal P, Kubicki AJ, Fletcher RF, et al. Acontrolled trial of a high fibre, low fat and low sodium dietfor mild hypertension in type 2 (non-insulin-dependent) dia­betic patients: Diabetologia 27: 522-526, 1984

Dominguez JR, De La Calle H, Hurtado A, Robles RG, Sancho­Rof J. Effect of converting enzyme inhib itors in hyperten sivepatients with non-in suiin-dependent diabetes mellitus. Post­graduate Medical Journal 62 (Suppl. I): 66-68, 1986

Dornhorst A, Powell SH, Pensky J. Aggravation by propranololof hyperglycaemic effect of hydrochlorothiazide in type II dia­betics without alteration of insulin secretion . Lancet I: 123­126, 1985

Dvorak I, Podrouzkova B, Kocourkova J, Kubesova H, Spac J,et al. Guanfacine in the treatment of hypertensives with a pro­nounced response to exercise and diabetes mellitus. Cor et Vasa29: S30-S36, 1987

Escobar-Jiminez F, Soto MLF, Lobon JA, Aguilar M, Campos­Pastor MM, et al. Effect of captopril at 2 different dosage reg­imens in hypertensive non-insulin dependent patients, Post­graduate Medical Journal 64 (Suppl. 3): 65-68, 1988

Eto M, Watanabe K, Otake Y, Morikawa A, Takebe T, et al.Effectsof captopril on blood pressure, metabolic control, plasma

Antihypertensive Drugs in Diabetic Patients

lipids. and pro teinuria in elderly hypertensive diabetics. Cur­rent Therapeutic Research 43: 427-434 . 1988

Ferlito S. Indelicato G. Di Vincenzo S. Del Ca mpo F, La VigneraA. et al. Effect of clonidine on glucose. insulin and glucagonresponses to a protein meal in type 2 diabetics. Jou rnal of En­docrinological Investigation 8: 185-187, 1985

Ferl ito S. Puleo F. Carra G. Dam ante G. Di Vincenzo S. et al.Effect of alpha-I-blockade by prazosin on blood sugar. insulinand glucagon levels in normals and non -insu lin depende nt dia ­betics . Journal of Endocrinological Investigation 6: 199-202.1983

Ferriere M. Lachkar H, Richard J L. Bringer J . Orsetti A. et al.Captopri l and insul in sensi tivity. Anna ls of Internal Medici ne102: 134- 135, 1985

Fetkovska N, Brim ichova G. Sebekova K. Dzurik R. Long-termclinica l experience with guanfacine. Cor et Vasa 29: S23-S29.1987

Fonseca V, Phear DN. Hyperosmolar non-k etot ic dia betic syn­drom e precipitated by treatm ent with diu ret ics. British Medi ­cal Jo urna l 284: 36-37, 1982

Garrett BN, Raskin P, Kaplan NM. Metop rolol in diabetes mel­litus: effect on glucose homeostasis. Clinical Science 59: 469S­472S, 1980

Ge ntile S. Co ltorti M. Hypotensive effect of the associa tion at ­enolol -chlorthalido ne in hypertensive diabetics. Journal ofIntern ation al Medical Research 12: 281-285 , 1984

Gill JS. AI-Hussary N, Atki ns T W. Taylor KG, Beevers DG. Pos­sible role for insulin receptors in the mechanism of th iazideinduced glucose tolerance. Jou rnal of Hypertension 2: S573­S576, 1984

Goldner MG, Zarowitz H, Akgun S. Hyperglycemia and glyco­suria due to thiazide derivat ives administered in diabetesmell itus . New England Jo urnal of Med icine 262: 403-405,1960

Groop L. To tterrnan n KJ. Propranolol does not inhibit sul­phonylurea-stimu lated insulin secret ion in patien ts with non­insulin depe ndent diabetes mellitus. Acta Endocri nologica 100:4 10-4 15, 1982

Groop L, Totterrnann KJ, Harno K, Go rdi n A. Influence of beta ­blocki ng drugs on glucose metabolism in pat ien ts with non­insulin depend ent diabetes mellitus. Acta Medica Scandi nav ­ica 2 11: 7- 12, 1982

Grunfield C, Chappell DA. Hypokalem ia and diabetes mellitu s.Amer ican Jo urna l of Medicine 75: 553-554, 1983

G underse n T, Kjekshu s J. Timolol treatm ent after myocard ialinfarc tion in diabet ic patients. Diabetes Care 6: 285-290, 1983

G uthrie GP , Miller RE, Kotchen TA, Koenig SH. Clonidi ne inpatien ts with dia betes and mild hypert ension. Clin icalPharm acology and Therapeutics 34: 713-717, 1983

Gu tin M, Tuc k ML. Metabolic control during guanabenz anti­hypertensi ve therapy in diabet ic patients with hypertension.Current T herapeutic Research 43: 775-785, 1988

Hauger-Klevene JH, Scornavacchi Je. Improvem ent of glucosetolerance in hypertensive diabetic patients treated with guan­facine for one year. European Journal of Clinical Pharmacol­ogy 29: 39 1-393, 1985

Hay U, Ludv ik B, Gisi nger C, Schernthaner G. Fehlender Effektde r ACE-In hibition auf die Makroproteinurie bei diabetischerNep hropathie: eine Langzeitstudie uber 6 Mo nate . Schwe iz­erische Mediz inische Wochensc hrift 118: 165-169, 1988

Helderman JH , Elahi D, Andersen DK, Raizes GS, Tob in JD, et

631

al. Prevention of the glucose into lerance of thiazide diu reticsby maintenan ce of body potassium. Diabetes 32: 106-111,1983

Hol m G, Johansson S, Vedin A, Wilhelmsson C. Smith U. Theeffect of beta-blockade on glucose to lerance and insu lin releasein adult diabete s. Acta Medica Scandinavica 208: 187-191,1980

Hommel E, Parvi ng HH , Mathiesen E, Edsberg B, Nielse n MD,et al. Effect of capto pril on kidney funct ion in insulin-de­pend ent diabet ic patients with nephro pathy. British MedicalJou rnal 293: 467-470, 1986

Hricik DE, Browning PJ, Kopelman R, Goo rno WE, Madias NE,et al. Capto pril-induced functional renal insufficiency in patientswith bilatera l renal-artery stenoses or renal-art ery stenosis ina solitary kidney. New England Journ al of Med icine 308: 373­376, 1983

Janka HU, StandI R, Vollm ar J, Bauer G, Mehn ert H. Der Ein­fluss einer ant ihypertensiven Kombinati onstherapie auf denStoffwechsel von Diabet ikern . Th erap ie der Gegenwar t 119:74-89, 1980

Kannel WB. Hypertension: relat ion ship with other risk factors .Drugs 31 (Suppl. I): I- II , 1986

Kindermann W, Lehrmann S, Schmi tt W. Korperl iche Leistungs­fahigkeit und Metabo lismus. Einfluss einer Kombination vo nNifedipin und Mefrusid. Munc hener Medizinische Wochen ­schrift 128: 53-56, 1986a

Kinde rman n W, Schmitt W, Wolfing A, Korperliche Leistungs­fahigkeit , Metabolismus und hormonelles Verhalten unter Dil­tiazem . Zeitsc hrift fur Kardio logie 75: 99-106, 1986b

Kele ndorf K, Bonnevie-Nielsen V, Broch-Mel ler B. A trial of me­toprolol in hypertensive insulin-depe nde nt diabet ic patients.Acta Med ica Scandinav ica 211: 175-178; 1982

Konigste in RP. Die Behandlun g der Hypertonie mit Prazosi n bei'Altersdiabetikern', Wiener Medizinische Wochensc hrift (Suppl,I): 27-30, 1978

Kwan CM, Shep herd AMM , Johnson J, Taylor WF. Forearm andfinger hemodynamics, blood pressure contro l, and lipid changesin patients with diabetic hypertension treated with atenolol andprazosin. Clinica l Pharmacology and Therape utics 44: 202-210,1988

Lager I, Blohrn e G, Smith U. Effect of cardiose lective and non­selective J3-blockade on the hypoglycaem ic response in insulin­de pende nt diabetics. Lancet I: 458-462, 1979

Lanza G, Barbera R, Fon tana S. Trat tam ent o dell' ipertensionenel diabetico con Captopril. Minerva Medica 76: 183-184,1985

Lanza G, Barbera R, Travaglino F, Font ana S. Tratta mento pro­lungato dell'ipertensione nel diabetico con Ena lapril. MinervaMed ica 78: 1601-1606, 1987

Leichter SB, Baumgardner B. Effects of chronic prazosi n therapyon intermed iary metabolism in diabet ic patient s. Journal ofCardiovasc ular Medicine (Suppl.): 38-42, 1981

Lipson LG. Treatm en t of hypertension in diabetic men: problem swith sexual dysfunc tio n. American Journal of Cardiology 53:46A-50A, 1984

Matthews DM , Collier DA, Clarke BF, Wathen CH, Bell D, etal. T he role of captopril in the treatment of hypertension innon-insuli n depe ndent diabetes; Postgrad uate Medical Jou rna l62 (Suppl. I): 73-75, 1986

Micossi P, Pollavini G, Raggi U, Librenti MC, Garimberti B, etal. Effects of meto prolo l and prop ran olol on glucose toleran ce

632

and insulin secretion in diabetes mellitus. Horm one and Meta­bolic Research 16: 59-63. 1984

Mpoy M. Vandeleene B. Ketelslegers JM. Lambert AE. Treat­ment of systemic hypertension in insulin-treated diabetes mel­litus with rilmetidine. American Journ al of Cardiology 61(Suppl. D): 91O-94D. 1988

Murphy MB. Lewis PJ. Kohner E. Schum er B. Dollery CT. Glu­cose intolerance in hypertensive patient s treated with diuretics;a fourt een-year follow-up. Lancet 2: 1293-1295. 1982

Nilsson-Ehle P. Ekberg M. Fridstrom P. Ursing D. Lins LE. Lipo­proteins and metabolic control in hyperten sive type II diabet­ics treated with c1on idine. Acta Medica Scandinavica 224: 131­134. 1988

Parving HH. Andersen AR. Smidt UM. Homm el E. MathiesenER. et al. Effect of antih ypertensi ve treatment on kidney func­tion in diabetic nephropathy. British Medical Journal 294: 1443­1447. 1987

Passa P. LeBlanc H. Gauville C. Tabuteau F. Canivet J. Effetsde la clonidine adrninistree au long cours sur la secretiond'h ormone de croissance chez Ie diabetique hypertendu. Dia­bete et Metaboli srne 8: 295-298. 1982

Passa P. LeBlanc H. Marre M. Effects of enalapril in insulin­dependent diabetic subjects with mild to moderate uncompl i­cated hypertension. Diabetes Care 10: 200-204, ' 1987

Podolsky S. Patt avina CG. Hyperosmolar nonketotic diabeti ccom a: a complication of propranolol therap y. Metabolism 22:685-693, 1973

Popp DA. Tse TF, Shah SD, Clutter WE. Cryer PE. Oral pro­pranolol and rnetoprolol both impair glucose recovery frominsulin-induced hypoglycemia in insulin-dependent diabetesmellitu s. Diabetes Care 7: 243-247, 1984

Rendell M. Lassek WD. Ross DA, Smith C. Kernek S. et al. Apharmaceutical profile of diabet ic pat ients. Journal of ChronicDiseases 36: 193-202. 1983

Rett K, Lotz N. Wicklmayr M, Fink E. Jauch KW. et al. Ver­besserte Insulinwirkung durch ACE-Hemmung beim Typ 11­Diabetiker. Deut sche Medizinische Wochenschrift 113: 243­249. 1988a

Rell K. Wicklmayr M. Tschollar W; Dietze G. Mehnert H. Roleof angiotensin-converting enzyme inhibit ors in early anti­hypertensive treatment in non-insulin dependent diabetesmellitus. Postgradu ate Medical Journal 64 (Suppl. 3): 69-73,1988b

Ricci PD, Fazzi K, Ricci F. II captopril nel controllo dell'ip erten­sione arteriosa essenz iale dell soggetto diabetico. Clinica Ter­apeutica 113: 33-38. 1985

Riobo P. Garcia-Robles R. Estopinan V, Hurt ado A, Sancho-RofJ. Effect of long-term inhibition of convert ing enzyme on car­bohydrate metabolism in non-insulin dependent diabeti cpatient s with essential hypertension. Abstract. PostgraduateMedical Journ al 64 (Suppl, 3): 63-64. 1988

Rowe PA, Mather HG. Hyperosmolar non-ketotic d iabetes mel­litus associated with metolazone. British Medical Journ al 291:25-26. 1985

Ryan JR , LaCorte W. Jain A, McMahon FG. Hypertension inhypoglycemic diabetics treated with Il-adrenergic anta gonists.Hypertension 7: 443-446. 1985

Shap iro AP, Benedek TG , Small JL. Effect of thiazides on car­bohydrate metabolism in patients with hypertension. NewEngland Journ al of Medicine 265: 1028-1033, 1961

Shionoiri H, lino S. Inoue S. Glucose metabolism durin g cap-

Drugs 38 (4) / 989

topril mono- and combination therapy in diabetic hypcrten­sive patient s: a multicl inic tria l. Clinical and ExperimentalHypertension - Theory and Practice 9 (2-3): 67 1-674. 1987

Shionoiri H. Noda K. Miyamoto K. Hiroto S. Umemura S. et al.Glucose tolerance dur ing chronic prazosin therapy in patientswith essential hypertension. Current Therapeutic Research 40:171-180,1 986

Sood VP. Stannard M, Beastall G, Weir RJ. Indoramin in thehypertensi ve diabet ic patien t. Journ al of Cardiovas cularPharm acology 8: S80-S83, 1986

Stevenson JG, Umstead GS. Sexual dysfunction due to anti­hypertensive agents. Drug Intelligence and Clinical Pharmacy18: I13-121, 1984

Stornello M. Di Rao G, lachello M, Bosco V, Pantan o S, et al.Valutazione c1inica del trattarn ento anti ipertensivo con alfa­metildopa di pazienti affetti da ipertensione arteriosa e diabetemellito. Clinica Terapeutica 101: 257-265, 1982

Sullivan PA, Kelleher M, Twomey M, Dineen M. Effects of con­vert ing enzyme inhibition on blood pressure. plasma renin ac­tivity (PRA) and plasma aldosterone in hypertensive diabeticscompared to patients with essential hypertension. Journ al ofHypertension 3: 359-363, 1985

Taguma Y, Kitamoto Y, Futaki G, Ueda H, Monma H, et al.Effect of captopril on heavy prote inur ia in azotemic diabetics.New England Journ al of Medicine 313: 1617-1620, 1985

Trost BN, Weidmann P. Effects of calcium anta gonists on glucosehomeostasis and serum lipids in non-d iabetic and diabetic sub­jects: a review. Journ al of Hypertension 5: S81-S104, 1987

Trost BN, Weidmann P. Five years of ant ihypertensive mono­therapy with nitrend ipine do not alter carbohydrate homeo­stasis in diabetic pat ients. Abstract. Journal of CardiovascularPharmacology 12 (Suppl. 6): SI 84, 1988a

Trost BN, Weidm ann P. Metabol ic effects of calcium antagonistsin man, with emphasis on carbohydrate, lipid, potassium anduric acid homeostases. Journal of Cardiovasc ular Pharmacol­ogy 12 (Suppl. 6): S86-S92, 1988b

Trost BN, Weidmann P, Riesen W, Claessen J, Streulens Y, etal. Comparative effects of doxazosin and hydrochloroth iazideon serum lipids and blood pressure in essential hypertension.American Journ al of Cardiology 59: 99G-104G, 1987

Valvo E, Bedogna V, Casagrande P, Antiga L, Zamboni M, et al.Captopril in patients with type II diabetes and renal insuffi­ciency: systemic and renal hemodynamic alterati ons. Ameri­can Journal of Medicine 85: 344-348, 1988

Vardan S, Mehrotra KG, Mookherjee S, Willsey GA, Gens JD ,et al. Efficacy and reduced metabolic side effects of a l5mgchlorthalidone formulation in the treatment of mild hyperten­sion. Journal of the American Medical Association 258: 484­488, 1987

Vidt DG, Bravo EL, Fouad FM. Captopril. New England Journalof Medicine 306: 214-219, 1982

Wallin JD , Krane NK, Bergman S, Morgan M. The use of trans­cutaneous clonidine hydrochloride in the patient with diabetesmellitus and.mild hypertens ion. Journal of Clinical Hyperten­sion 4: 315-321, 1985

Warren SE. False-positive urine ketone test with captopril. NewEngland Journa l of Medicine 303: 1003-1004, 1980

Weber MA, Drayer JIM, Deitch MW. Hypertension in patientswith diabetes mellitu s; treatm ent with a centrally acting agent.Journal of Cardiovascular Pharmacology 6: S823-S829,1984

Antihypertensive Drugs in Diabetic Patients

Weidmann P, Beretta-Piccoli C, Keusch G, Gliick Z, Mujagic M,et al. Sodium-volume factor, cardiovascular reactivity andhypotensive mechanism of diuret ic therapy in mild hyperten­sion associated with diabetes mellitus. American Journal ofMedicine 67: 779-784, 1979

Weidmann P, Uehlinger DE, Gerber A. Antihypertensive treat­ment and serum lipoproteins . Journal of Hypertension 3: 297­306, 1985

Wilson PWF, Anderson KM, Kannel WB. Epidemiology of dia­betes mellitus in the elderly: the Framingham study. AmericanJournal of Medicine 80 (Suppl, SA): 3-9, 1986

Winocour P, Waldek S, Anderson DC. Captopril and blood glu-cose. Lancet 2: 461, 1986a .

633

Winocour P, Waldek S, Johns CW, Dhar H, Anderson DC. Cap­topril may adversely affect renal function in hypertensive dia­betics without established nephropathy . Journal of Endocrin­ology 108 (Suppl.): 216, 1986b

Wright AD, Barber SG, Kendall MJ, Poole PH. Beta-adrenocep­tor-blocking drugs and blood sugar control in diabetes melli­tus. British Medical Journal I: 159-161, 1979

Author's address: Dr Bernhard N. Trost, Medizinische Univer­sitatspoliklinik , Inselspital, CH-30 10 Bern, Switzerland.

22nd Annual Symposium

Societe de Toxicologie du Canada

Date: 28-29 November 1989Venue: Le Grand Hotel, Montreal, Quebec, Canada

For further information, please contact:Dr Gordon Krip

Executive DirectorSociete de Toxicologie du Canada

CP/PO Box 517 BeaconsfieldQuebec H9W 5V1

CANADA