Report of the Canadian Hypertension SocietyConsensus Conference: 5. Hypertension anddiabetes

Keith G. Dawson,* MD, PhD; John K. McKenzie,t MD; Stuart A. Ross,i MD; Jean-Louis Chiasson,§ MD;Pavel Hamet,§ MD, PhD

S ince the last Canadian Consensus Conference on

Hypertension and Diabetes, in 1987, new informa-tion on hypertension, insulin resistance, hyperlipi-

demia and antihypertensive therapy in the diabeticpatient has become available. It appears that both hyper-tension and diabetes may be part of a group of riskfactors that includes impaired glucose tolerance, non-insulin-dependent diabetes mellitus, obesity, increasedserum levels of triglycerides, decreased serum levels ofhigh-density lipoprotein cholesterol and hypertension.' Ifsuch risk factors do band together in an individual, it iscrucial to avoid choosing therapy for one factor that re-sults in aggravation of another.

This is the fifth and last article to report on the 1992consensus conference of the Canadian Hypertension So-ciety (CHS). In it we review the evidence on the relationbetween hypertension and diabetes and make recom-

mendations according to that evidence.

Methods

A panel of experts used databank searches to re-

view the recent evidence on insulin resistance and on thepathophysiologic aspects and treatment of hypertensionin patients with diabetes. As well, the experts had re-course to literature reviews and articles. Relevant arti-cles were rated according to the methodologic strengthsof the studies reported (see Table 1 of the preceding ar-ticle, page 816). The recommendations were rated ac-cording to the level of evidence (see Table 2 of thepreceding article, page 816).

During our review it became clear that with regardto the treatment of hypertension in patients with non-insulin-dependent or insulin-dependent diabetes mellitusthere were no large trials that had evaluated major endpoints. It was therefore necessary to identify secondaryend points to assess the validity of the therapeutic op-tions. Consequently, our ratings of the strength of the ev-idence are lower than they might have been had trials ofprimary end points been carried out. In practical termsthis means that indirect conclusions had to be drawn inmany instances. For example, there may be no evidenceof increased mortality rates when one form of therapy isused, but there is excellent evidence that some recog-nized adverse consequences occur, such as an increase inthe serum level of an undesirable lipid. The inference isthat in the future the mortality rate may increase in pa-tients with diabetes because that type of lipid abnormal-ity is associated with increases in the mortality rate innondiabetic patients.

Recommendations were voted on at the conference,and those reported here achieved a level of supportgreater than 90%.

Pathogenesis of hypertension in patientswith diabetes mellitus

Essential hypertension is now known to be associ-ated with insulin resistance even in lean, nondiabeticpatients.2'3 It is much more common in the obese, inthose with impaired glucose tolerance and in those with

From *University Hospital and the University ofBritish Columbia, Vancouver, BC; tthe Department ofInternal Medicine, Health SciencesCentre Hospital, and the University ofManitoba, Winnipeg, Man.; 4:Foothills Provincial General Hospital and the University of Calgary,Calgary, Alta.; and §Centre de Recherche, Hotel-Dieu de Montreal and University ofMontreal, Montreal, Que.

Reprint requests to: Dr. Keith G. Dawson, Department ofMedicine, University Hospital, Shaughnessy Site, G609-4500 Oak St., Vancouver, BCV6H 3N1

CAN MED ASSOC J 1993; 149 (6) 821

Resume: Dans ce dernier article de la serie sur laConference consensus de la Societe canadienne d'hy-pertension arterielle, les auteurs examinent de nou-velles informations sur l'hypertension arterielle, laresistance insulinique, l'hyperlipidemie et le traite-ment antihypertenseur des personnes atteintes de dia-bete. II est tres important de r6duire la tensionarterielle chez des patients souffrant a la fois de dia-bete et d'hypertension arterielle. De recentes etudessuggerent que les diff6rences apparentes de metabo-lisme glucosique qui decoulent du traitement anti-hypertenseur aux thiazidiques et aux B-bloquantspeuvent ne pas produire l'incidence accrue d'effetssecondaires indesirables chez les personnes atteintesde diabete.

SEPTEMBER 15, 1993

non-insulin-dependent diabetes.'.'.6 Hyperinsulinemiaand reduced glucose disposal have been shown to be di-rectly correlated with elevations in both systolic and di-astolic blood pressure. As previously noted,7 features ofthe hypertensive diabetic patient that differ from those ofthe nondiabetic hypertensive patient are increasedsodium retention and increased pressor responsiveness.Hyperinsulinemia may produce these effects. It is knownto increase sodium reabsorption in the renal tubule8 andthus increase sodium retention; in addition, it may in-crease norepinephrine levels' and thus pressor respon-siveness, although such changes are not uniformlyseen."' Increased insulin resistance may lead to reducedsodium-potassium adenosine triphosphatase activity inthe cell membrane and so to increased levels of sodiumand decreased levels of potassium in the cell;" thesechanges would in turn result in the features already des-cribed.

Several additional pathophysiologic mechanismsmay come into play, since insulin and associatedgrowth factors may lead to vascular endothelial andsmooth-muscle growth and thus cause hypertension.'2Renal mesangial expansion may result in glomeru-losclerosis, further contributing to the development ofhypertension.

In addition, growth factors or hyperglycemia alonemay lead to microalbuminuria, which is a harbinger oflater overt diabetic nephropathy.`' Once overt proteinuriaoccurs, hypertension usually develops.'4 Once nephropa-thy produces renal failure, further aggravation of hyper-tension ensues.

Reports that diabetic nephropathy may be predictedfrom a family history of essential hypertension'5"' and byan increase in sodium-lithium countertransport in theerythrocytes'7 (also a marker for essential hypertension)are not borne out by other studies.'8-"

It is still uncertain whether the type of diabetesinsulin-dependent or non-insulin-dependent trulymakes a difference in the overall pathogenesis of hyper-tension. Renal damage seems to be most important in theformer but may also occur in the latter.

Recommendations

Assessment of diabetes

The recommendations made previously' still apply:* Patients with diabetes should be seen at least

twice a year for assessment.* Special attention should be paid to monitoring

blood pressure and the peripheral arterial circulation.* Urine albumin levels should be assessed annually.* Funduscopy should be performed by an ophthal-

mologist at least annually.Microalbuminuria is an excellent predictor of

nephropathy (grade A'3'4) and retinopathy (grade B2') ininsulin-dependent diabetes mellitus. It is also a very

strong predictor of early death in patients with non-insulin-dependent diabetes mellitus (grade B2 2-4).

Recommendation 1: Microalbuminuria should be investigatedwith the use of a morning urine specimen and a microalbumin-uria dipstick. If the dipstick result is positive radioimmunoassayor chemical assay for albumin in a 24-hour urine collection, ifavailable, should be carried out (grade B' ").Recommendation 2: Dipstick screening for microalbumin-uria should be annual (grade D). If the results of radioim-munosassay or chemical assay remain positive, closerfollow-up is indicated to ensure optimal compliance with anti-hypertensive therapy (grade B271-3') and therapy for diabetes(grade B 31234).

Assessment of hypertension in patientswith diabetes

Hypertension increases the rate of death in patientswith diabetes 1.8-fold (grade A 3936); in addition, it clearlyaccelerates all the vascular complications associatedwith diabetes, including those of the retinal, renal, car-diac and peripheral vascular systems. 7>"

The current recommendations of the CHS on the di-agnosis of hypertension4' should be followed. The cri-teria of the Canadian Diabetes Association for thediagnosis of diabetes mellitus42 are also accepted.

Previous recommendations on orthostatic hypoten-sion are modified as follows:

Recommendation 3: The prevalence of orthostatic hypoten-sion (7%43) warrants the routine monitoring of standing bloodpressure during the assessment and follow-up of patients withevidence of neuropathy.

Ambulatory blood pressure monitoring can be help-ful in avoiding white-coat hypertension but is not ofproven cost-effectiveness.

Nonpharmacologic therapy

The previous recommendations regarding weightloss, salt restriction and alcohol intake are unchanged.44

* Weight loss in obese patients is beneficial in thetreatment of hypertension and diabetes whether or notthe diabetes is insulin dependent.

* Moderate restriction of salt intake (to levels ofless than 150 mmol daily) should be considered as anadjunct to definitive therapy in the hypertensive diabeticpatient. More stringent restrictions should be reservedfor cases of severe hypertension.

* Patients should be counselled about the consump-tion of alcohol, which increases blood pressure and low-ers blood glucose levels.

Since the 1990 report of the CHS consensus confer-ence on nonpharmacologic approaches to hypertension44one new recommendation can be made:

Recommendation 4: After a patient has consulted with a

822 CAN MED ASSOC J 1993; 149 (6) LE 15 SEPTEMBRE '993

physician, regular physical exercise in a carefully controlledmanner is likely to ameliorate both hypertension and diabetes(grade B4`).

Initiating therapy

A diastolic blood pressure of 100 mm Hg or greateris an indication to start treatment (as it is for nondiabeticpatients4).

Recommendation 5: If the diastolic blood pressure is 90 to99 mm Hg, patients with hypertensive target-organ damage(as indicated by cerebrovascular accident, transient ischemicattack, coronary artery disease, enlargement or failure of theheart, peripheral arterial disease or renal impairment) shouldreceive therapy.Recommendation 6: Patients with a diastolic blood pressureof 90 to 99 mm Hg but no hypertensive or diabetic vascularcomplications or other cardiovascular risk factors, such assmoking or abnormal serum lipid levels, should be consideredon an individual basis in decisions about antihypertensivetherapy (grade C4`9).Recommendation 7: For patients with isolated or predomi-nantly systolic hypertension (pulse pressure greater than 80mm Hg) the recommendations regarding hypertension in theelderly made at the 1992 Canadian consensus conference onhypertension (see page 815 of this issue) should be followed.

There is no evidence of significant differences inthe treatment requirements of patients with non-insulin-dependent versus insulin-dependent diabetes in theabsence of overt proteinuria. Therefore, the recommen-dations for these two categories are combined.

Qualified recommendations can be made aboutlower criteria for the initiation of therapy and lower tar-get blood pressure levels in patients with increased mi-croalbuminuria.

Recommendation 8: Diabetic patients with microalbumin-uria, overt proteinuria or proliferative retinopathy should betreated for hypertension (grade B27) when the diastolic pres-sure is greater than 90 mm Hg. The benefits of blood pressurecontrol in retinopathy appear to be limited to patients with in-sulin-dependent diabetes who are treated for systolic hyper-tension.40Recommendation 9: The goal of treatment is a diastolicblood pressure of, at most, 90 mm Hg (grade B50). In patientswith microalbuminuria it may be worth attempting to achieveapproximately 80 mm Hg (grade D51).

Drug therapy

The panel members found sufficient evidence for anumber of statements.

* The reduction of blood pressure in diabetic pa-tients with microalbuminuria postpones the developmentof nephropathy (grade B24'29'50,52).

* Any antihypertensive treatment with or withoutdiuretics improves twofold the prognosis for renal sur-vival in patients with insulin-dependent diabetes mellitus(grade C53'54).

* Therapy with angiotensin-converting enzyme(ACE) inhibitors in normotensive diabetic patients withmicroalbuminuria has clearly been shown to reduce mi-croalbuminuria in studies of up to 5 years (grade B2931 55).Those treated showed less progression to overt neph-ropathy (grade B20'55) in both insulin-dependent and non-insulin-dependent diabetes. The addition of a thiazidediuretic does not adversely affect microalbuminuria(grade B29).

* Among calcium entry blockers diltiazem and ver-apamil appear to reduce albuminuria (grade B 6'87),whereas dihydropyridines are inconsistent in their ef-fects on urine protein (grade B28'3' 570).

* There is evidence suggesting that diuretics areless effective in slowing the rate of decline of renal func-tion (grade C6`).

* Although death rates may appear higher in dia-betic patients treated with diuretics than in those who aretreated with other antihypertensive drugs (grade D63M4),more prolonged studies indicate that diuretics may bebeneficial.88

* Beta-blockers as well as thiazides markedly re-duce insulin sensitivity (grade C65).

* Indapamide may decrease microalbuminuria(grade C66'67).

For patients without overt nephropathy the follow-ing recommendations apply.

Recommendation 10: ACE inhibitors, calcium entry block-ers (grade B68'69) or A-blockers (grade C69-7') should be thefirst-line antihypertensive agents.Recommendation 11: Thiazides or B-blockers should be sec-ond-line antihypertensive agents (grade C69'72-75,8789).Recommendation 12: Centrally acting agents or vasodilatorsmay be used if other agents are contraindicated or if there isdifficulty in controlling the hypertension (grade C47'69'75).Recommendation 13: If first-line treatment is ineffective,contraindicated or associated with side effects the followingshould be tried: (a) change to or add another first-line agent(grade C56'69'76), (b) add a cardioselective B-blocker73'77 to a di-hydropyridine calcium entry blocker (grade B77'78) or (c) add athiazide to an ACE inhibitor (grade B53'68'79).

For patients with hypertension and nephropathy(urine protein excretion greater than 300 mg in 24 hours,as determined by routine dipstick test) the following rec-ommendations apply.

Recommendation 14: In patients with nephropathy but nor-mal serum creatinine and potassium levels the treatment rec-ommendations are similar to those for patients withoutnephropathy (grade B54'80).Recommendation 15: If the serum creatinine level is greaterthan 200 gmol/L or the serum potassium level greater than 4.6mmol/L additional caution is required in using ACE inhibitors(grade C69'8'82) and potassium-sparing diuretics.Recommendation 16: Diuretics, especially Ioop diuretics,may be required in cases of reduced renal function to controlblood pressure and volume (grade C47).

CAN MED ASSOC J 1993; 149 (6) 823SEPTEMBER 15, 1993

Recommendation 17: In the presence of autonomic neuropa-thy, A-blockers and centrally acting agents should be usedwith caution (grade C83 84).Recommendation 18: Beta-blockers should be used withcaution in patients with heart failure and peripheral vascu-lar disease (grade C77). Beta-blockers, especially noncardio-selective ones, may worsen hyperglycemia and in insulin-dependent diabetes may prevent recognition of and delayrecovery from hypoglycemia (grade B"7785).Recommendation 19: In the presence of impotence centrallyacting agents, thiazides and beta blockers should be used withcaution (grade C84,8').

Research

The current status of hypertension and diabetes inCanada should be evaluated. An assessment of theprevalence and incidence, especially in native people, ofhypertension and diabetes is needed to determine re-gional differences and also any specific differences be-tween insulin-dependent and non-insulin-dependentdiabetes, including the status of their management.

Interventions in the treatment of hypertension anddiabetes in patients undergoing renal transplantationshould be evaluated (perhaps in collaboration with theKidney Foundation of Canada). A knowledge of the evo-lution of elevated blood pressure in formerly hyperten-sive patients should provide information on the patho-genesis of hypertension in patients with diabetes.

Clinical trials are required to assess the impact ofdrug class on microangiopathy and macroangiopathy asreflected in the major end points of morbidity and mor-tality.

The following areas should be studied intensively:(a) the relevance of insulinemia for major end points and(b) the determination of genetic markers for individualsusceptibility to the complications of diabetes or hyper-tension as well as to the effects of therapy.

Discussion

The treatment of hypertension in patients with dia-betes is a rapidly evolving field. The recent findings inrelation to salt-sensitive hypertension, insulin resistance,impaired glucose tolerance and overt diabetes mellitussuggest a common underlying pathophysiologic mecha-nism amenable to therapy. Such therapy must take intoaccount the effects of the various antihypertensiveagents on the endothelium and the glomerulus, on in-sulin secretion and on glucose and lipid metabolism,even though these effects may have greater significancein animal models or in the individual patient than inlarge groups of patients.

We have tried to review the relevant research andrate the evidence according to objective criteria. In somecases the conclusions are at variance with the data fromthe research laboratory, but they remain the only conclu-sions that can guide the clinician if one insists on the ap-

propriate level of evidence from large, double-blindstudies of major end points. Our concem is that the over-whelming cost of such studies may place them beyondthe reach of investigators in the field of diabetes.

Nevertheless, one important conclusion is evident.The most important form of therapy in the patient withdiabetes and hypertension is one that reduces blood pres-sure. It is becoming ever more clear that the smaller ben-efits of specific antihypertensive therapy are of lessimportance than the major benefit of lowering bloodpressure. Indeed, larger studies899 now suggest that theapparent differences in glucose metabolism resultingfrom antihypertensive therapy with thiazides and 13-blockers may not produce the increased incidence of dia-betes that was seen in the earlier, smaller studies. Also,the apparent antihypertensive action of agents such asthe ACE inhibitors may not be the most important actionin selected organs such as the kidney.9' For these reasonswe have developed this set of recommendations to guidethe practitioner today. Knowledge of what will be besttomorrow awaits the completion of the research recom-mended.

References

1. Golay A, Chen YDI, Reaven GM: Effect of differences in glucosetolerance on insulin's ability to regulate carbohydrate and freefatty acid metabolism in obese individuals. J Clin EndocrinolMetab 1986; 62: 1081-1088

2. Reaven GM: Role of insulin resistance in human disease. Dic-betes 1988; 37: 1595-1607

3. Modon M, Halkin HL, Almog S et al: Hyperinsulinemia. A linkbetween hypertension, obesity and glucose intolerance. J Clini 11-vest 1985; 75: 809-817

4. Christlieb AR, Krolewski AS, Warram JH et al: Is insulin the linkbetween hypertension and obesity? Hypertension 1985; 7 (6, pt2): 11-54-11-57

5. Manicardi V, Camelleni L, Belloidi G et al: Evidence for an asso-ciation of high blood pressure and hyperinsulinemia in obeseman. J Cliii Endocrinol Metab 1986; 62: 1302-1304

6. Laakso M, Sarlung H, Mykkanen L: Essential hypertension andinsulin resistance in non-insulin-dependent diabetes. Eur J ClinInvest 1989; 19: 518-526

7. Hamet P, Kalant N, Ross SA et al: Recommendations from theCanadian Hypertension Society Consensus Conference on Hyper-tension and Diabetes. Can Med Assoc J 1988; 139: 1059-1062

8. DeFronzo RA: The effect of insulin on renal sodium metabolism.A review with clinical implications. Diabetologia 1981; 21:165-171

9. Rowe JW, Young JB, Minaker KL et al: Effect of insulin and glu-cose infusion on sympathetic nervous system activity in normalman. Diabetes 1981; 30: 219-225

10. Wiedmann P, Beretta-Piccoli C, Trost BN: Pressor factors and re-sponsiveness in hypertension accompanying diabetes mellitus.Hvpertension 1985; 7 (6, pt 2): 11-33-11-42

11. Paolisso G, Marrazzo G, De Riu S et al: Insulin resistance ascause of increased blood pressure in the elderly; effects on intra-cellular ion contents. Arch Gerontol Geriatr 1990; 11: 23-32

12. Hadrava V, Kruppa U, Russo RC et al: Vascular smooth musclecell proliferation and its theraputic modulation in hypertension.Am Heart J 1991; 122 (4, pt 2): 1198-1203

13. Messent JWC, Elliott TG, Hill RD et al: Prognostic significanceof microalbuminuria in insulin-dependent diabetes mellitus: atwenty three year follow-up study. Kidney Int 1992; 41: 836-839

14. Mogensen CE: Prediction of clinical diabetic nephropathy in

824 CAN MED ASSOC J 1993: 149 (6) LE 15 SEPTEMBRE 1993

IDDM patients. Alternatives to microalbuminuria? Diabetes1990; 39: 761-767

15. Seaquist ER, Goetz FC, Rich S et al: Familial clustering of dia-betic kidney disease. Evidence for genetic susceptibility to dia-betic nephropathy. N Engl J Med 1989; 320: 1161-1165

16. Krolewski AS, Canessa M, Warram JH et al: Predisposition to hy-pertension and susceptibility to renal disease in insulin-dependentdiabetes mellitus. N Engl J Med 1988; 318: 140-145

17. Mangili R, Bending JJ, Scott G et al: Increased sodium-lithiumcountertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. Ibid: 146-150

18. Jensen JS, Mathiesen ER, Norgaard K et al: Increased blood pres-sure and erythrocyte sodium/lithium countertransport activity arenot inherited in diabetic nephropathy. Diabetologia 1990; 33:619-624

19. Norgaard K, Mathiesen ER, Hommel E et al: Lack of familial pre-disposition to cardiovascular disease in type I (insulin-dependent)diabetic patients with nephropathy. Diabetologia 1991; 34:370-372

20. Walker JD, Tariq T, Viberti et al: Sodium-lithium countertrans-port activity in red cells of patients with insulin dependent dia-betes and nephropathy and their parents. BMJ 1990; 301:635-638

21. Parving HH, Hommel E, Mathiesen E et al: Prevalence of mi-croalbuminuria, arterial hypertension, retinopathy and neuropathyin patients with insulin dependent diabetes. BMJ 1988; 296:156-160

22. Schmitz A, Vaeth M: Microalbuminuria: a major risk factor innon-insulin-dependent diabetes: a 10 year follow-up study of 503patients. Diabetic Med 1988; 5: 126-134

23. Damsgaard EM, Froland A, Jorgensen OD et al: Eight to nineyear mortality in known non-insulin dependent diabetics and con-trols. Kidney Int 1992; 41: 731-735

24. Mogensen CE, Hansen KW, Osterby R et al: Blood pressure ele-vation versus abnormal albuminuria in the genesis and predictionof renal disease in diabetes. Diabetes Care 1992; 15: 1192-1204

25. Bangstad HJ, Try K, Dahl-Jorgensen K et al: New semiquantita-tive dipstick test for microalbuminuria. Diabetes Care 1991; 14:1094-1097

26. Nelson RG, Knowler WC, Pettitt DJ et al: Prediction of diabeticnephropathy from untimed urine specimens. Arch Intern Med1991; 151: 1761-1765

27. Mathiesen ER, Borch-Johnsen K, Jensen DV et al: Improved sur-vival in patients with diabetic nephropathy. Diabetologia 1989;32: 884-886

28. Jerums G, Allen TJ, Tsalamandris C et al for the Melbourne Dia-betic Nephropathy Study Group: Angiotensin converting enzymeinhibition and calcium channel blockade in incipient diabeticnephropathy. Kidney Int 1992; 41: 904-911

29. Mathiesen ER, Hommel E, Giese J et al: Efficacy of captopril inpostponing nephropathy in normotensive insulin dependent dia-betic patients with microalbuminuria. BMJ 1991; 303: 81-87

30. Marre M, Leblanc H, Suarez L et al: Converting enzyme inhibi-tion and kidney function in normotensive diabetic patients withpersistent microalbuminuria. BMJ 1987; 294: 1448-1554

31. Mimran A,- Insua A, Ribstein J et al: Comparative effects of cap-topril and nifedipine in normotensive patients with incipient dia-betic nephropathy. Diabetes Care 1988; 11: 850-853

32. Bending JJ, Viberti GC, Bilous RW et al for the Kroc Collabora-tive Study Group: Eight month correction of hyperglycemia in in-sulin-dependent diabetes mellitus is associated with a significantand sustained reduction of urinary albumin excretion rates in pa-tients with microalbuminuria. Diabetes 1985; 34 (suppl 3): 69-73

33. Feldt-Rasmussen B, Mathiesen ER, Deckert T: Effect of twoyears of strict metabolic control on progression of incipientnephropathy in insulin-dependent diabetes. Lancet 1986; 2:1300-1306

34. Dahl-Jorgensen K, Hanssen KF, Kierulf P et al: Reduction of uri-nary albumin excretion after 4 years of continuous subcutaneousinfusion in insulin-dependent diabetes mellitus. The Oslo Study.Acta Endocrinol (Copenh) 1988; 117: 19-25

35. Morrish NJ, Stevens LK, Head J et al: A prospective study ofmortality among middle-aged diabetic patients (the London co-hort of the WHO Multinational Study of Vascular Disease in Dia-betics.) II: Associated risk factors. Diabetologia 1990; 33:542-548

36. Fuller JH, Shipley MI, Rose G et al: Mortality from coronaryheart disease and stroke in relation to degree of glycemia; theWhitehall study. BMJ 1983; 287: 867-870

37. Kannel WB, McGee DL: Diabetes and cardiovascular risk factors:the Framingham Study. Circulation 1979; 59: 8-13

38. Fuller JH, Shipley MJ, Rose G et al: Coronary-heart-disease riskand impaired glucose tolerance: the Whitehall Study. Lancet1980; 1:1373-1376

39. Van Hoeven K, Factor S: A comparison of the pathological spec-trum of hypertensive, diabetic, and hypertensive-diabetic heartdisease. Cirulation 1990; 82: 848-855

40. Klein R, Klein BEK, Moss SE et al: Is blood pressure a predictorof the incidence or progression of diabetic retinopathy? Arch In-tern Med 1989; 149: 2427-2432

41. Haynes RB, Lacourciere Y, Rabkin SW et al: Report of the Can-adian Hypertension Society Consensus Conference: 2. Diagnosisof hypertension in adults. Can Med Assoc J 1993; 149: 409-418

42. Ad Hoc Committee on Diagnostic Criteria for Diabetes Mellitus,Clinical and Scientific Section, Canadian Diabetes Association:Acceptance of new criteria for diagnosis of diabetes mellitus andrelated conditions by the Canadian Diabetes Association. CanMedAssoc J 1982; 126: 473-476

43. Tutsu N, Nunoi K, Yokomizo Y et al: Relationship betweenglycemic control and orthostatic hypotension in type 2 diabetesmellitus{M}a survey by the Fukuoka Diabetes Clinical Group.Diabetes Res Clin Pract 1990; 8: 115-123

44. Chockalingam A, Abbott D, Bass M et al: Recommendations ofthe Canadian Consensus Conference on Non-pharmacologicalApproaches to the Management of High Blood Pressure, Mar.21-23, 1989, Halifax, Nova Scotia. Can Med Assoc J 1990; 142:1397-1409

45. Eriksson KF, Lindgarde F: Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. Dia-betologia 1991; 34: 891-898

46. Working Group on Hypertension in Diabetes: Statement on hy-pertension in diabetes: final report. Arch Intern Med 1987; 147:830-842

47. Christlieb AR: Treatment selection considerations for the hyper-tensive diabetic patient. Arch Intern Med 1990; 150: 1167-1174

48. Fuller JH, Stevens LK: Epidemiology of hypertension in diabeticpatients and implications for treatment. Diabetes Care 1991; 14:8-12

49. Yudkin JS: Factors influencing threshold and choice of treatmentfor hypertension in NIDDM. Cardiovascular factors. DiabetesCare 1991; 14 (suppl 4): 27-32

50. Mogensen CE, Hansen KW, Pedersen MM et al: Renal factors in-fluencing blood pressure threshold and choice of treatment for hy-pertension in IDDM. Ibid: 13-26

51. Marr6 M, Chatellier G, Leblanc H et al: Prevention of diabeticnephropathy with enalapril in normotensive diabetics with mi-croalbuminuria. BMJ 1988; 297: 1086-1091

52. Parving HH, Hommel E: Prognosis in diabetic nephropathy. BMJ1989; 299: 230-233

53. Parving HH, Hommel E, Smidt UM: Protection of kidney func-tion and decrease in albuminuria by captopril in insulin dependentdiabetics with nephropathy. BMJ 1988; 297: 1086-1091

54. Parving HH: Impact of blood pressure and antihypertensive treat-ment on incipient and overt nephropathy, retinopathy, and en-dothelial permeability in diabetes mellitus. Diabetes Care 1991;14: 260-269

55. Ravid M, Savin H, Jutrin I et al: Long-term stabilizing effect ofangiotensin-converting enzyme inhibition on plasma creatinineand on proteinuria in normotensive type II diabetic patients. AnnIntern Med 1993; 118: 577-581

56. Bakris GL, Barnhill BW, Sadler R: Treatment of arterial hyper-tension in diabetic humans; importance of therapeutic selection.

SEPTEMBER 15, 1993 CAN MED ASSOC J 1993; 149 (6) 825

Kidney Int 1992; 41: 912-91957. Baba T, Murabayashi S, Takebe K: Comparison of the renal ef-

fects of angiotensin converting enzyme inhibitor and calcium an-tagonist in hypertensive type 2 (non-insulin-dependent) diabeticpatients with microalbuminuria: a randomised controlled trial.Diabetologia 1989; 32: 40-44

58. Bakris GL: Effects of diltiazem or lisinopril on massive protein-uria associated with diabetes mellitus. Ann Initern Med 1990; 112:707-708

59. Melbourne Diabetic Nephropathy Study Group: Comparison be-tween perindopril and nifedipine in hypertensive and normoten-sive diabetic patients with microalbuminuria. BMJ 1991; 302:210-216

60. DeMarle BK, Bakris GL: Effects of different calcium antagonistson proteinuria associated with diabetes mellitus. Ann Intern Med1990; 113: 987-988

61. Walker WG, Hermann J, Yin D et al: Diuretics accelerate diabeticnephropathy in hypertensive insulin-dependent and non-insulin-dependent subjects. Tran.s Assoc Am Physicians 1987; 100:C305-C315

62. Pollare T, Lithell H, Berne C: A comparison of the effects of hy-drochlorothiazide and captopril on glucose and lipid metabolismin patients with hypertension. N Engl J Med 1989; 321: 868-873

63. Warram JH, Laffel WJH, Valsania P et al: Excess mortality asso-ciated with diuretic therapy in diabetes mellitus. Arch Intern Med1991; 151: 1350-1356

64. Klein R, Moss SE, Klein BEK et al: Relation of ocular and sys-temic factors to survival in diabetes. Arch Intern Med 1989; 149:266-272

65. Berne C, Pollare T, Lithell H: Effects of antihypertensive treat-ment on insulin sensitivity with special reference to ACE in-hibitors. Diabetes Care 1991: 14 (suppl 4): 39-47

66. Gambardella S, Frontoni S, Felici MG et al: Efficacy of inda-pamide in type II diabetic patients with persistent microalbumin-uria. Am J Cardiol 1990; 65: 46H-50H

67. Gambardella S, Frontoni S, Lala A et al: Regression of microal-buminuria in type II diabetic, hypertensive patients after long-term indapamide treatment. Am Heart J 1991; 122: 1232-1238

68. Lacourciere Y, Nadeau A, Poirier L et al: Comparative effects ofconverting enzyme inhibition and conventional therapy in hyper-tensive non-insulin dependent diabetics with normal renal func-tion. Clin Invest Med 1991; 14: 652-660

69. Stein PP, Black HR: Drug treatment of hypertension in patientswith diabetes mellitus. Diabetes Care 1991; 14: 425-448

70. Leren P, Foss PO, Helgeland A et al: Effect of propranolol andprazosin on blood lipids. The Oslo Study. Lancet 1980; 2: 4-6

71. Swislocki A, Hoffman B, Sheu WH et al: Effect of prazosin treat-ment on carbohydrate and lipoprotein metabolism in patients withhypertension. Am J Med 1989; 86: 14-18

72. Wright A, Barber S, Kendall M et al: Beta-adrenoceptor-blockingdrugs and blood sugar control in diabetes mellitus. BMJ 1979; 1:159-161

73. Holm G, Johansson S, Vedin A et al: The effect of beta-blockadeon glucose tolerance and insulin release in adult diabetics. ActaMed Scanid 1980; 208: 187-191

74. Dornhorst A, Powell S, Pensky J: Aggravation by propranolol ofhyperglycemic effect of hydrochlorothiazide in type II diabeticswithout alteration in insulin secretion. Lancet 1985; 1: 123-126

75. Johnston CI, Cooper ME, Nicholls GM: Meeting report of the In-ternational Society of Hypertension Conference on Hypertensionand Diabetes. J Hvpertens 1992; 10: 393-397

76. Ferrier C, Ferrari P, Weidmann P et al: Antihypertensive therapywith Ca2+ antagonist verapamil and/or ACE inhibitor enalapril inNIDDM patients. Diabetes Care 1991; 14: 911-914

77. Bolli P, Fernandez PG, Buhler FR: Beta blockers in the treatmentof hypertension. In Laragh JH, Brenner BM (eds): Hypertensioni:Pathophvsiology. Diagnosis, and Maniagemnenit, Raven. NewYork, 1990: 2181-2205

78. Frishman WH: B-adrenergic receptor blockers. Adverse effects anddrug interactions. Hypertension 1988; 11 (suppl II): 11-21-11-29

79. Townsend RR, Holland OB: Combination of converting enzymeinhibitor with diuretic for the treatment of hypertension. Arc/h In-tern Med 1990; 150: 1175-1183

80. Parving HH, Hommel E, Nielsen MD et al: Effect of captopril onblood pressure and kidney function in normotensive insulin-dependent diabetics with nephropathy. BMJ 1989; 299: 533-536

81. Zanella M, Santiago R, De Sa J et al: Hypertension and diabetes:clinical problems. Drugs 1988; 35 (suppl 6): 135-141

82. Rimmer J, Horn J, Gennari JF: Hyperkalemia as a complication ofdrug therapy. Arch Intern Med 1987; 147: 867-869

83. Levy P: Effects of prazosin on blood pressure and diabetic controlin patients with type II diabetes mellitus and mild essential hyper-tension. Am J Med 1989; 86 (suppl 1 B): 59-62

84. Lipson LG: Treatment of hypertension in diabetic men: problemswith sexual dysfunction. Am J Cardiol 1984; 53: 46A-SOA

85. Corrall RJ, Frier BM, Davidson NM et al: Hormonal and sub-strate responses during recovery from hypoglycaemia in man dur-ing beta,-selective and non-selective beta-adrenergic blockade.Eur J Clin Invest 1981; 11: 279-283

86. Lipson LG: Special problems in treatment of hypertension in thepatient with diabetes mellitus. Arch Intern Med 1984: 144:1829-1831

87. Slataper R, Vicknair N, Sadler R et al: Comparative effects of dif-ferent antihypertensive treatments on progression of diabetic renaldisease. Arch Intern Med 1993; 153: 973-980

88. Walker WG, Hermann JA, Anderson JE: Randomized doublyblinded comparison of ACE inhibitor and hydrochlorothiazide asantihypertensive therapy for preservation of renal function in dia-betic nephropathy: early vs. late results [abstr 810]. Presented atthe European Society of Hypertension 6th European Meeting onHypertension, Milan, June 4-7, 1993

89. Gurwitz JH, Bohn RL, Glynn RJ et al: Antihypertensive therapyand the initiation of treatment for diabetes mellitus. Ann Intern1Med 1993; 118: 273-278

90. Morales PA, Mitchell BD, Valdez RA et al: Incidence of NIDDMand impaired glucose tolerance in hypertensive subjects. The SanAntonio Heart Study. Diabetes 1993; 42: 154-161

91. Kasiske BL, Kalil RSN, Ma JZ et al: Effect of antihypertensivetherapy on the kidney in patients with diabetes: a meta-regressionanalysis. Ann Initerni Med 1993; 118: 129-138

826 CAN MED ASSOC J 1993; 149 (6) LE 15 SEPTEMBRE 1993