Keith G. Dawson,* MD, PhD; John K. McKenzie,t MD; Stuart A. Ross,i MD; Jean-Louis Chiasson,§ MD; ..... Parving HH, Hommel E, Mathiesen E et al: Prevalence of mi- ... Haynes RB, Lacourciere Y, Rabkin SW et al: Report of the Can-.
Report of the Canadian Hypertension Society Consensus Conference: 5. Hypertension and
diabetes Keith G. Dawson,* MD, PhD; John K. McKenzie,t MD; Stuart A. Ross,i MD; Jean-Louis Chiasson,§ MD; Pavel Hamet,§ MD, PhD
Resume: Dans ce dernier article de la serie sur la Conference consensus de la Societe canadienne d'hypertension arterielle, les auteurs examinent de nouvelles informations sur l'hypertension arterielle, la resistance insulinique, l'hyperlipidemie et le traitement antihypertenseur des personnes atteintes de diabete. II est tres important de r6duire la tension arterielle chez des patients souffrant a la fois de diabete et d'hypertension arterielle. De recentes etudes suggerent que les diff6rences apparentes de metabolisme glucosique qui decoulent du traitement antihypertenseur aux thiazidiques et aux B-bloquants peuvent ne pas produire l'incidence accrue d'effets secondaires indesirables chez les personnes atteintes de diabete. ince the last Canadian Consensus Conference on Hypertension and Diabetes, in 1987, new information on hypertension, insulin resistance, hyperlipidemia and antihypertensive therapy in the diabetic patient has become available. It appears that both hypertension and diabetes may be part of a group of risk factors that includes impaired glucose tolerance, noninsulin-dependent diabetes mellitus, obesity, increased serum levels of triglycerides, decreased serum levels of high-density lipoprotein cholesterol and hypertension.' If such risk factors do band together in an individual, it is crucial to avoid choosing therapy for one factor that results in aggravation of another. This is the fifth and last article to report on the 1992 consensus conference of the Canadian Hypertension Society (CHS). In it we review the evidence on the relation between hypertension and diabetes and make recommendations according to that evidence. S
Methods A panel of experts used databank searches to
re-
view the recent evidence on insulin resistance and on the pathophysiologic aspects and treatment of hypertension in patients with diabetes. As well, the experts had recourse to literature reviews and articles. Relevant articles were rated according to the methodologic strengths of the studies reported (see Table 1 of the preceding article, page 816). The recommendations were rated according to the level of evidence (see Table 2 of the preceding article, page 816). During our review it became clear that with regard to the treatment of hypertension in patients with noninsulin-dependent or insulin-dependent diabetes mellitus there were no large trials that had evaluated major end points. It was therefore necessary to identify secondary end points to assess the validity of the therapeutic options. Consequently, our ratings of the strength of the evidence are lower than they might have been had trials of primary end points been carried out. In practical terms this means that indirect conclusions had to be drawn in many instances. For example, there may be no evidence of increased mortality rates when one form of therapy is used, but there is excellent evidence that some recognized adverse consequences occur, such as an increase in the serum level of an undesirable lipid. The inference is that in the future the mortality rate may increase in pa-
tients with diabetes because that type of lipid abnormality is associated with increases in the mortality rate in nondiabetic patients. Recommendations were voted on at the conference, and those reported here achieved a level of support greater than 90%.
Pathogenesis of hypertension in patients with diabetes mellitus Essential hypertension is now known to be associated with insulin resistance even in lean, nondiabetic patients.2'3 It is much more common in the obese, in those with impaired glucose tolerance and in those with
From *University Hospital and the University ofBritish Columbia, Vancouver, BC; tthe Department of Internal Medicine, Health Sciences Centre Hospital, and the University of Manitoba, Winnipeg, Man.; 4:Foothills Provincial General Hospital and the University of Calgary, Calgary, Alta.; and §Centre de Recherche, Hotel-Dieu de Montreal and University of Montreal, Montreal, Que.
Reprint requests to: Dr. Keith G. Dawson, Department of Medicine, University Hospital, Shaughnessy Site, G609-4500 Oak St., Vancouver, BC V6H 3N1 SEPTEMBER 15, 1993
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non-insulin-dependent diabetes.'.'.6 Hyperinsulinemia and reduced glucose disposal have been shown to be directly correlated with elevations in both systolic and diastolic blood pressure. As previously noted,7 features of the hypertensive diabetic patient that differ from those of the nondiabetic hypertensive patient are increased sodium retention and increased pressor responsiveness. Hyperinsulinemia may produce these effects. It is known to increase sodium reabsorption in the renal tubule8 and thus increase sodium retention; in addition, it may increase norepinephrine levels' and thus pressor responsiveness, although such changes are not uniformly seen."' Increased insulin resistance may lead to reduced sodium-potassium adenosine triphosphatase activity in the cell membrane and so to increased levels of sodium and decreased levels of potassium in the cell;" these changes would in turn result in the features already described. Several additional pathophysiologic mechanisms may come into play, since insulin and associated growth factors may lead to vascular endothelial and smooth-muscle growth and thus cause hypertension.'2 Renal mesangial expansion may result in glomerulosclerosis, further contributing to the development of hypertension. In addition, growth factors or hyperglycemia alone may lead to microalbuminuria, which is a harbinger of later overt diabetic nephropathy.`' Once overt proteinuria occurs, hypertension usually develops.'4 Once nephropathy produces renal failure, further aggravation of hypertension ensues. Reports that diabetic nephropathy may be predicted from a family history of essential hypertension'5"' and by an increase in sodium-lithium countertransport in the erythrocytes'7 (also a marker for essential hypertension) are not borne out by other studies.'8-" It is still uncertain whether the type of diabetes insulin-dependent or non-insulin-dependent truly makes a difference in the overall pathogenesis of hypertension. Renal damage seems to be most important in the former but may also occur in the latter.
strong predictor of early death in patients with noninsulin-dependent diabetes mellitus (grade B2 2-4). Recommendation 1: Microalbuminuria should be investigated with the use of a morning urine specimen and a microalbuminuria dipstick. If the dipstick result is positive radioimmunoassay or chemical assay for albumin in a 24-hour urine collection, if available, should be carried out (grade B' "). Recommendation 2: Dipstick screening for microalbuminuria should be annual (grade D). If the results of radioimmunosassay or chemical assay remain positive, closer follow-up is indicated to ensure optimal compliance with antihypertensive therapy (grade B271-3') and therapy for diabetes (grade B 31234).
Assessment of hypertension in patients with diabetes Hypertension increases the rate of death in patients with diabetes 1.8-fold (grade A 3936); in addition, it clearly accelerates all the vascular complications associated with diabetes, including those of the retinal, renal, cardiac and peripheral vascular systems. 7>" The current recommendations of the CHS on the diagnosis of hypertension4' should be followed. The criteria of the Canadian Diabetes Association for the diagnosis of diabetes mellitus42 are also accepted. Previous recommendations on orthostatic hypotension are modified as follows: Recommendation 3: The prevalence of orthostatic hypotension (7 %43) warrants the routine monitoring of standing blood pressure during the assessment and follow-up of patients with evidence of neuropathy.
Ambulatory blood pressure monitoring can be helpful in avoiding white-coat hypertension but is not of proven cost-effectiveness.
Nonpharmacologic therapy
The previous recommendations regarding weight loss, salt restriction and alcohol intake are unchanged.44 * Weight loss in obese patients is beneficial in the treatment of hypertension and diabetes whether or not Recommendations the diabetes is insulin dependent. * Moderate restriction of salt intake (to levels of Assessment of diabetes less than 150 mmol daily) should be considered as an The recommendations made previously' still apply: adjunct to definitive therapy in the hypertensive diabetic * Patients with diabetes should be seen at least patient. More stringent restrictions should be reserved for cases of severe hypertension. twice a year for assessment. * Patients should be counselled about the consump* Special attention should be paid to monitoring of tion alcohol, which increases blood pressure and lowcirculation. arterial the blood pressure and peripheral * Urine albumin levels should be assessed annually. ers blood glucose levels. Since the 1990 report of the CHS consensus confer* Funduscopy should be performed by an ophthalence on nonpharmacologic approaches to hypertension44 mologist at least annually. Microalbuminuria is an excellent predictor of one new recommendation can be made: nephropathy (grade A'3'4) and retinopathy (grade B2') in insulin-dependent diabetes mellitus. It is also a very Recommendation 4: After a patient has consulted with a 822
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physician, regular physical exercise in a carefully controlled manner is likely to ameliorate both hypertension and diabetes (grade B4`).
Initiating therapy A diastolic blood pressure of 100 mm Hg or greater is an indication to start treatment (as it is for nondiabetic patients4).
Recommendation 5: If the diastolic blood pressure is 90 to 99 mm Hg, patients with hypertensive target-organ damage (as indicated by cerebrovascular accident, transient ischemic attack, coronary artery disease, enlargement or failure of the heart, peripheral arterial disease or renal impairment) should receive therapy. Recommendation 6: Patients with a diastolic blood pressure of 90 to 99 mm Hg but no hypertensive or diabetic vascular complications or other cardiovascular risk factors, such as smoking or abnormal serum lipid levels, should be considered on an individual basis in decisions about antihypertensive therapy (grade C4`9). Recommendation 7: For patients with isolated or predominantly systolic hypertension (pulse pressure greater than 80 mm Hg) the recommendations regarding hypertension in the elderly made at the 1992 Canadian consensus conference on hypertension (see page 815 of this issue) should be followed. There is no evidence of significant differences in the treatment requirements of patients with non-insulindependent versus insulin-dependent diabetes in the absence of overt proteinuria. Therefore, the recommendations for these two categories are combined. Qualified recommendations can be made about lower criteria for the initiation of therapy and lower target blood pressure levels in patients with increased microalbuminuria.
Recommendation 8: Diabetic patients with microalbuminuria, overt proteinuria or proliferative retinopathy should be treated for hypertension (grade B27) when the diastolic pressure is greater than 90 mm Hg. The benefits of blood pressure control in retinopathy appear to be limited to patients with insulin-dependent diabetes who are treated for systolic hypertension.40 Recommendation 9: The goal of treatment is a diastolic blood pressure of, at most, 90 mm Hg (grade B50). In patients with microalbuminuria it may be worth attempting to achieve approximately 80 mm Hg (grade D51).
Drug therapy The panel members found sufficient evidence for a number of statements. * The reduction of blood pressure in diabetic patients with microalbuminuria postpones the development of nephropathy (grade B24'29'50,52). * Any antihypertensive treatment with or without diuretics improves twofold the prognosis for renal survival in patients with insulin-dependent diabetes mellitus (grade C53'54). SEPTEMBER 15, 1993
* Therapy with angiotensin-converting enzyme (ACE) inhibitors in normotensive diabetic patients with microalbuminuria has clearly been shown to reduce microalbuminuria in studies of up to 5 years (grade B29 31 55). Those treated showed less progression to overt nephropathy (grade B20'55) in both insulin-dependent and noninsulin-dependent diabetes. The addition of a thiazide diuretic does not adversely affect microalbuminuria (grade B29). * Among calcium entry blockers diltiazem and verapamil appear to reduce albuminuria (grade B 6'87), whereas dihydropyridines are inconsistent in their effects on urine protein (grade B28'3' 570). * There is evidence suggesting that diuretics are less effective in slowing the rate of decline of renal function (grade C6`). * Although death rates may appear higher in diabetic patients treated with diuretics than in those who are treated with other antihypertensive drugs (grade D63M4), more prolonged studies indicate that diuretics may be
beneficial.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 following recommendations apply.
Recommendation 10: ACE inhibitors, calcium entry blockers (grade B68'69) or A-blockers (grade C69-7') should be the first-line antihypertensive agents. Recommendation 11: Thiazides or B-blockers should be second-line antihypertensive agents (grade C69'72-75,8789). Recommendation 12: Centrally acting agents or vasodilators may be used if other agents are contraindicated or if there is difficulty in controlling the hypertension (grade C47'69'75). Recommendation 13: If first-line treatment is ineffective, contraindicated or associated with side effects the following should be tried: (a) change to or add another first-line agent (grade C56'69'76), (b) add a cardioselective B-blocker73'77 to a dihydropyridine calcium entry blocker (grade B77'78) or (c) add a thiazide 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 recommendations apply. Recommendation 14: In patients with nephropathy but normal serum creatinine and potassium levels the treatment recommendations are similar to those for patients without nephropathy (grade B54'80). Recommendation 15: If the serum creatinine level is greater than 200 gmol/L or the serum potassium level greater than 4.6 mmol/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 control blood pressure and volume (grade C47). CAN MED ASSOC J 1993; 149 (6)
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Recommendation 17: In the presence of autonomic neuropathy, A-blockers and centrally acting agents should be used with caution (grade C83 84). Recommendation 18: Beta-blockers should be used with caution in patients with heart failure and peripheral vascular disease (grade C77). Beta-blockers, especially noncardioselective ones, may worsen hyperglycemia and in insulindependent diabetes may prevent recognition of and delay recovery from hypoglycemia (grade B"7785). Recommendation 19: In the presence of impotence centrally acting agents, thiazides and beta blockers should be used with caution (grade C84,8').
propriate level of evidence from large, double-blind studies of major end points. Our concem is that the overwhelming cost of such studies may place them beyond the reach of investigators in the field of diabetes. Nevertheless, one important conclusion is evident. The most important form of therapy in the patient with diabetes and hypertension is one that reduces blood pressure. It is becoming ever more clear that the smaller benefits of specific antihypertensive therapy are of less importance than the major benefit of lowering blood pressure. Indeed, larger studies899 now suggest that the apparent differences in glucose metabolism resulting Research from antihypertensive therapy with thiazides and 13blockers may not produce the increased incidence of diaThe current status of hypertension and diabetes in betes that was seen in the earlier, smaller studies. Also, Canada should be evaluated. An assessment of the the apparent antihypertensive action of agents such as prevalence and incidence, especially in native people, of the ACE inhibitors may not be the most important action hypertension and diabetes is needed to determine re- in selected organs such as the kidney.9' For these reasons gional differences and also any specific differences be- we have developed this set of recommendations to guide tween insulin-dependent and non-insulin-dependent the practitioner today. Knowledge of what will be best diabetes, including the status of their management. tomorrow awaits the completion of the research recomInterventions in the treatment of hypertension and mended. diabetes in patients undergoing renal transplantation should be evaluated (perhaps in collaboration with the References Kidney Foundation of Canada). A knowledge of the evolution of elevated blood pressure in formerly hyperten- 1. Golay A, Chen YDI, Reaven GM: Effect of differences in glucose tolerance on insulin's ability to regulate carbohydrate and free sive patients should provide information on the pathofatty acid metabolism in obese individuals. J Clin Endocrinol genesis of hypertension in patients with diabetes. Metab 1986; 62: 1081-1088 Clinical trials are required to assess the impact of 2. Reaven GM: Role of insulin resistance in human disease. Dicbetes 1988; 37: 1595-1607 drug class on microangiopathy and macroangiopathy as A link reflected in the major end points of morbidity and mor- 3. Modon M, Halkin HL, Almog S et al: Hyperinsulinemia. between hypertension, obesity and glucose intolerance. J Clini 11tality. vest 1985; 75: 809-817 The following areas should be studied intensively: 4. Christlieb AR, Krolewski AS, Warram JH et al: Is insulin the link between hypertension and obesity? Hypertension 1985; 7 (6, pt (a) the relevance of insulinemia for major end points and 2): 11-54-11-57 (b) the determination of genetic markers for individual Manicardi V, Camelleni L, Belloidi G et al: Evidence for an assosusceptibility to the complications of diabetes or hyper- 5. ciation of high blood pressure and hyperinsulinemia in obese tension as well as to the effects of therapy. man. J Cliii Endocrinol Metab 1986; 62: 1302-1304
Discussion The treatment of hypertension in patients with diabetes is a rapidly evolving field. The recent findings in relation to salt-sensitive hypertension, insulin resistance, impaired glucose tolerance and overt diabetes mellitus suggest a common underlying pathophysiologic mechanism amenable to therapy. Such therapy must take into account the effects of the various antihypertensive agents on the endothelium and the glomerulus, on insulin secretion and on glucose and lipid metabolism, even though these effects may have greater significance in animal models or in the individual patient than in large groups of patients. We have tried to review the relevant research and rate the evidence according to objective criteria. In some cases the conclusions are at variance with the data from the research laboratory, but they remain the only conclusions that can guide the clinician if one insists on the ap824
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6. Laakso M, Sarlung H, Mykkanen L: Essential hypertension and insulin resistance in non-insulin-dependent diabetes. Eur J Clin Invest 1989; 19: 518-526 7. Hamet P, Kalant N, Ross SA et al: Recommendations from the Canadian Hypertension Society Consensus Conference on Hypertension 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 glucose infusion on sympathetic nervous system activity in normal man. Diabetes 1981; 30: 219-225 10. Wiedmann P, Beretta-Piccoli C, Trost BN: Pressor factors and responsiveness 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 as cause of increased blood pressure in the elderly; effects on intracellular ion contents. Arch Gerontol Geriatr 1990; 11: 23-32 12. Hadrava V, Kruppa U, Russo RC et al: Vascular smooth muscle cell 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 significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty three year follow-up study. Kidney Int 1992; 41: 836-839 14. Mogensen CE: Prediction of clinical diabetic nephropathy in
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IDDM patients. Alternatives to microalbuminuria? Diabetes 1990; 39: 761-767 15. Seaquist ER, Goetz FC, Rich S et al: Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989; 320: 1161-1165 16. Krolewski AS, Canessa M, Warram JH et al: Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 1988; 318: 140-145 17. Mangili R, Bending JJ, Scott G et al: Increased sodium-lithium countertransport activity in red cells of patients with insulindependent diabetes and nephropathy. Ibid: 146-150 18. Jensen JS, Mathiesen ER, Norgaard K et al: Increased blood pressure and erythrocyte sodium/lithium countertransport activity are not inherited in diabetic nephropathy. Diabetologia 1990; 33: 619-624 19. Norgaard K, Mathiesen ER, Hommel E et al: Lack of familial predisposition 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 countertransport activity in red cells of patients with insulin dependent diabetes and nephropathy and their parents. BMJ 1990; 301: 635-638 21. Parving HH, Hommel E, Mathiesen E et al: Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. BMJ 1988; 296:
156-160 22. Schmitz A, Vaeth M: Microalbuminuria: a major risk factor in non-insulin-dependent diabetes: a 10 year follow-up study of 503 patients. Diabetic Med 1988; 5: 126-134 23. Damsgaard EM, Froland A, Jorgensen OD et al: Eight to nine year mortality in known non-insulin dependent diabetics and controls. Kidney Int 1992; 41: 731-735 24. Mogensen CE, Hansen KW, Osterby R et al: Blood pressure elevation versus abnormal albuminuria in the genesis and prediction
of renal disease in diabetes. Diabetes Care 1992; 15: 1192-1204 25. Bangstad HJ, Try K, Dahl-Jorgensen K et al: New semiquantitative dipstick test for microalbuminuria. Diabetes Care 1991; 14: 1094-1097 26. Nelson RG, Knowler WC, Pettitt DJ et al: Prediction of diabetic nephropathy from untimed urine specimens. Arch Intern Med 1991; 151: 1761-1765 27. Mathiesen ER, Borch-Johnsen K, Jensen DV et al: Improved survival in patients with diabetic nephropathy. Diabetologia 1989; 32: 884-886 28. Jerums G, Allen TJ, Tsalamandris C et al for the Melbourne Diabetic Nephropathy Study Group: Angiotensin converting enzyme inhibition and calcium channel blockade in incipient diabetic nephropathy. Kidney Int 1992; 41: 904-911 29. Mathiesen ER, Hommel E, Giese J et al: Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 1991; 303: 81-87 30. Marre M, Leblanc H, Suarez L et al: Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. BMJ 1987; 294: 1448-1554 31. Mimran A,- Insua A, Ribstein J et al: Comparative effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care 1988; 11: 850-853 32. Bending JJ, Viberti GC, Bilous RW et al for the Kroc Collaborative Study Group: Eight month correction of hyperglycemia in insulin-dependent diabetes mellitus is associated with a significant and sustained reduction of urinary albumin excretion rates in patients with microalbuminuria. Diabetes 1985; 34 (suppl 3): 69-73 33. Feldt-Rasmussen B, Mathiesen ER, Deckert T: Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet 1986; 2: 1300-1306 34. Dahl-Jorgensen K, Hanssen KF, Kierulf P et al: Reduction of urinary albumin excretion after 4 years of continuous subcutaneous infusion in insulin-dependent diabetes mellitus. The Oslo Study. Acta Endocrinol (Copenh) 1988; 117: 19-25 SEPTEMBER 15, 1993
35. Morrish NJ, Stevens LK, Head J et al: A prospective study of mortality among middle-aged diabetic patients (the London cohort of the WHO Multinational Study of Vascular Disease in Diabetics.) II: Associated risk factors. Diabetologia 1990; 33: 542-548 36. Fuller JH, Shipley MI, Rose G et al: Mortality from coronary heart disease and stroke in relation to degree of glycemia; the Whitehall 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 risk and impaired glucose tolerance: the Whitehall Study. Lancet 1980; 1:1373-1376 39. Van Hoeven K, Factor S: A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Cirulation 1990; 82: 848-855 40. Klein R, Klein BEK, Moss SE et al: Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Arch Intern Med 1989; 149: 2427-2432 41. Haynes RB, Lacourciere Y, Rabkin SW et al: Report of the Canadian Hypertension Society Consensus Conference: 2. Diagnosis of 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 and related conditions by the Canadian Diabetes Association. Can MedAssoc J 1982; 126: 473-476 43. Tutsu N, Nunoi K, Yokomizo Y et al: Relationship between glycemic control and orthostatic hypotension in type 2 diabetes mellitus{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 of the Canadian Consensus Conference on Non-pharmacological Approaches 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-insulindependent) diabetes mellitus by diet and physical exercise. Diabetologia 1991; 34: 891-898 46. Working Group on Hypertension in Diabetes: Statement on hypertension in diabetes: final report. Arch Intern Med 1987; 147: 830-842 47. Christlieb AR: Treatment selection considerations for the hypertensive diabetic patient. Arch Intern Med 1990; 150: 1167-1174 48. Fuller JH, Stevens LK: Epidemiology of hypertension in diabetic patients and implications for treatment. Diabetes Care 1991; 14: 8-12 49. Yudkin JS: Factors influencing threshold and choice of treatment for hypertension in NIDDM. Cardiovascular factors. Diabetes Care 1991; 14 (suppl 4): 27-32 50. Mogensen CE, Hansen KW, Pedersen MM et al: Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM. Ibid: 13-26 51. Marr6 M, Chatellier G, Leblanc H et al: Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ 1988; 297: 1086-1091 52. Parving HH, Hommel E: Prognosis in diabetic nephropathy. BMJ 1989; 299: 230-233 53. Parving HH, Hommel E, Smidt UM: Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy. BMJ 1988; 297: 1086-1091 54. Parving HH: Impact of blood pressure and antihypertensive treatment on incipient and overt nephropathy, retinopathy, and endothelial permeability in diabetes mellitus. Diabetes Care 1991; 14: 260-269 55. Ravid M, Savin H, Jutrin I et al: Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118: 577-581 56. Bakris GL, Barnhill BW, Sadler R: Treatment of arterial hypertension in diabetic humans; importance of therapeutic selection. CAN MED ASSOC J 1993; 149 (6)
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