NEFROLOGIA. Vol. XIV. Núm. 3. 1994 Blood presure management in diabetic patients of the Division of Endocrinology Escola Paulista de Medicina, Sao Paulo, Brazil. *** Associated Professor of the Departament of Internal Medicine Faculdade de Medicina de Jundiai, Sao Paulo, Brazil. * * * * Assistant Professor of the Minas Gerais, Brazil. ***** Fellow of the Dision of Nephrology Escola Paulista de Medicina, Sao Paulo, Brazil. * * * * * * Profesor of Medicine, Hypertension and Diabetes Section Escola Paulista de Medicina, Sao Paulo, Brazil. S. R. G. Ferreira, MD, PhD *; M. T. Zanella, MD, PhD **; M. B. Freire, MD, PhD ***; R. Milagres, MD ****; D F. L. Plavinik, MD *****, and A. B. Ribeiro ******. * Associated Professor of the Department of Preventive Medicine Escola Paulista de Medicina, Sao Paulo, Brazil. ** Associated Professor p r e s s u r e (BP) in diabetes-asociated hypertension. S e v e r a l metabolic and hormonal abnormalities are Diabetes is a major risk factor for cardiovascular involved in renal sodium retention, such as hyperglymorbidity and mortality. It has long been known the cemia, hyperinsulinemia and altered secretion or acincreased prevalence of hypertension in diabetic pation of atrial natriuretic peptide. High body sodium tients, that is approximately 2 times greater than in may potentiate the pressor role of angiotensin II 9 1,2. The coexistence matched non-diabetic population Therefore, sodium excretion promoting drugs could of hypertension in the diabetic subject act as an adbe desirable when treating hypertension at least in a ditive risk factor for vascular complications. While subset of diabetic subjects. h y p e r t e n s i o n in insulin-dependent diabetes mellitus Besides common pressor mechanisms, IDDM and (IDDM) is almost exclusivesly attributed to the diabe- N I D D M have some particularities concerning their physiopathogenesis. In IDDM, BP elevation parallels tic renal disease, in non-insulin-dependent diabetes the development of nephropathy and most studies (NIDDM) is frequently related to insulin resistance. have suggested that hypertension is a consequence D i f f e r e n t physiopathogenic factors may determine of diabetic renal disease 10 Renal hemodynamic disd i f f e r e n t antihypertensive approaches in diabetes. turbances, such as intraglomerular hypertension and T h e r e is an apparent consensus that hypertension hyperfiltration, are implicated in the genesis of nephshould be aggressively treated in diabetic patients. r o p a t h y in IDDM. Slightly abnormal loss of albumin I n 1987, the Working Group on Hypertension in in urine (microalbuminuria) could unmask the renal Diabetes published the "final report" proposing a Iist injury, that is commonly associated with increased of drugs as first-line therapy for hypertensive diabetic blood pressure levels. Early intervention on this stage patients 3 . Further reports showed that the final chapof incipient diabetic nephropathy, where aggressive ter on this issue is still to be written 4 , 5 . We review a n t i h y p e r t e n s i v e treatment is included, has shown part of the therapy currently recommended for hypert h e best results in postponing its progression 11. tensive subjects with diabetes. Particular adverse efWhereas patients with IDDM usually remain normofects on carbohydrate and lipid metabolism are focutensive before the development of proteinuria, a gresed, as well as on the chronic angio and neuropathic a t proportion of NIDDM are already hypertensive complications of diabetes. when the disease is diagnosed 1 2 , although the high prevalence of hypertension in this population also increases markedly as proteinuria develops13. Thus, in Physiopathogenic considerations NIDDM hypertension seems to be related not only to the presence of diabetic nephropathy but mainly to Increased exchangeable sodium pool is observed other factors. such as insulin resistance and hyperinin patients with IDDM 6 - 8 and the excess body sodium s u l i n e m i a . In fact, it has been described a multifaceaccompained by fluid retention may play an imported syndrome responsibls for both, NIDDM and hytant role in elevation and maintenance of high blood p e r t e n s i o n , besides obesity, dyslipidemia and atherosclerotic cardiovascular disease14. C o n s i d e r i n g the pathogenic aspects of hypertenCorrespondencia: Dra. Sandra R. C. Ferreira. sion in diabetes, it is reasonable to suppose that ideal Departamento de Medicina Preventiva. a n t i h y p e r t e n s i v e therapy in IDDM should also coEscola Paulista de Medicina. rrect early renal hemodynamic disturbances, attempRua Botucatu, 740 CEP 04023.062. ting to preserve renal function. On the other hand, Sao Paulo, SP (Brazil). 267 Introduction S. R. G. FERREIRA et al h y p e r t e n s i o n in NIDDM may be seen as part of the large spectrum of insulin resistance syndrome, where the pharmacological reduction of BP is only a part of its treatment. Antihypertensive treatment in diabetes Although long-term trials demonstrated effectiveness of antihypertensive treatment in reducing death due to stroke and heart failure in nondiabetics, the decrease in coronary artery disease mortality was not shown yet 1 5 . In diabetic patients, a particular group at high risk for death from coronary artery disease, randomised studies concernins the benefits of antihypertensive therapy on its prevention, have not been cond u c t e d yet. On the other hand, convincent data focusing the microangiopathy in IDDM, have emphasized the importance of adequate BP control for the decline in the rate of deterioration in renal function 16. Some investigators have even proposed certain levels of mean BP for maintaining or decreasing microalbuminuria and glomerular filtration rate in diabetic patients at risk for clinical nephropathy17. Once the diagnose of hypertension is established in the diabetic patient, initial non-pharmacological a p p r o a c h (weight loss, sodium restriction, lifestyle modifications, physical exercise) is recommended. Some of the pharmacological options in treating these patients will be focused herein. Recent studies have suggested a preferential use of angiotensin-convert i n g enzyme (ACE) inhibitors and also c a l c i u m channel blockers (CCB) when treating hypertension in diabetic patients. However, diuretics and betablockers are the only classes of drugs shown thus far t o reduce morbidity and mortality in a significant number of nondiabetic hypertensive subjects in longterm clinical trials. However, the adverse effects on carbohydrate and lipid metabolism have motivated some controversy in using in diabetic subjects. Indeed, increased mortality associated with diuretic therapy in a selected group of diabetic patients was recently reported 22. Besides, speculation persists concerning the idea that diuretic-treated hypertensive diabetics could become harder to achieve euglycemic control. It is well established that potassium plays a central role in normal regulation of insulin secretion and that its repletion c a n correct such insulin secretion inhibition23. Decreased insulin secretion and enhanced insulin res i s t a n c e have been considered mechanisms underlying the diuretic associated disturbances on glucose metabolism24, although conflicting results were obtained concerning the latter mechanism 25,26. A study c o n d u c t e d in our clinic27 confirmed previous ones 2 8 showing deterioration in glucose homeostasis during chlorthalidone therapy and suggested that potassium depletion may to be involved in the increase in insulin resistance. Thus, in a subset of diabetic patients, diuretic therapy appears be related to changes in glycemic control. However, Moser and Ross experiences suggested that the long-term use of this medication will occasionally make control more difficult5. They also considered of debatable clinical significanc e the elevation in serum cholesterol that occurs early in thiazide therapy 29, in spite of blunting, to some extent, the beneficial effects of a low-fat diet. Until this moment, available data do not support the warning to exclude diuretics in the treatment of hypertensive diabetic patients. b) A complex mechanism, involving cardiovascular and renal effects, mediates the BP reduction follow i n g the use of beta-adrenergic blocking agents. They may be contraindicated in a subset of diabetic patients that are particularly at risk for cardiovascular c o m p l i c a t i o n s , such as congestive heart failure and peripheral arterial disease. On the other hand, a protective effect on the reoccurence of ischemic heart attack has been shown. Their potential adverse effects on glucose and lipid metabolism may also limit the use in diabetics. It is well documented the beta-adrenergic effects on insulin secretion and hepatic glucose output30. Blockade of beta receptors decreases insulin secretion and can potentially deteriorate glucose homeostasis in NIDDM 31, but the use of cardioselective blockers seems to minimize these effects 32. Episodes of hypoglycemia can be more difficult to be recovered in beta-blockers treated diabetic patients. Hepatic mechanisms responsible for glucose release a ) Diuretics Although diuretic therapy has been associated with t h e occurrence of glucose intolerance in several clinical trials for hypertension18, these drugs are still considered a first-line therapy for hypertensive subjects with diabetes19. Their use is mainly based on the sodium excretion promoting effects, since diabetics have frequently an i n c r e a s e d p o o l o f s o d i u m . T h i a z i d e s have been shown effective in treating hypertension in this population and, in microalbuminuric IDDM, the BP lowering effect is accompanied by decreased urinary albumin excretion and renal functional deterioration'". In our series, the changes in alb u m i n u r i a were correlated to BP reductions21. 268 BLOOD PRESSURE MANAGEMENT IN DIABETIC PATIENTS in response to hypoglycemia are inhibited by these drugs. In addition, in IDDM beta-blockers compromise the counteregulation process following hypoglycemia33, besides blunting the usual hypoglycemic symptoms. Unfavorable effects of beta-blocker therapy have been described, including increase in serum triglyceride and VLDL-cholesterol and decrease in HDL-cholesterol levels 3 4 . This aspect gains importance if the patient has dyslipidemia besides NIDDM, as features of the insulin resistance syndrome. Considering the effectiveness of these antihypertensive drugs, beta-blockers have still being indicated for the treatment of diabetic patients, keeping in mind the possibility of such adverse effects. Cardioselective agents should be preferred. c) Angiotensin-converting enzyme inhibitors This class of antihypertensive drugs has been the most studied in recent years. The main mechanism involved on the vasodepressor action of ACE inhibitors is related to the decrease in the pressor substance, angiotensin ll, and also to the increase in bradikinin production, resulting in diminished peripheral vascular resistance. Several experimental and human studies have suggested the ACE inhibition as the first-line therapy for hypertensive patients with diabetes 35-39. This indication is based not only on their effectiveness in reducing BP without deterioration of glucose and lipid metabolism, but mainly on their «renal protective» properties. A recent study verified a better preservation of renal function with the ACE inhibitor enalapril than with beta-blocker metoprolol 39. Actually, the beneficial effects of ACE inhibition in diabetic nephropathy are observed independently of changes in BP and appear to depend on its intrarenal effects. Glomerular capillary hypertension and increased glomerular basement membrane permeability occur during the development of renal disease. ACE inhibitors were able to ameliorate glomerular hypertension in experimental models and to reduce proteinuria35. This is achieved by decreasing efferent arteriolar resistance to a greater extent than afferent resistance, determining lower perfusion pressure and single nephron glomerular filtration rate. Studies in humans confirmed the uselfulness of these agents in slowing the progression of nephropathy37-39 and proposed an action on intrinsic membrane properties of the glomerular barrier, enhancing the size selectivity to macromolecules38. Our experience with different antihyp e r t e n s i v e agents showed that captopril in hypertensive IDDM patients reduced mean BP and albuminuria without significant changes in renal hemodynamic parameters21. Nor there was correlation between the changes in BP and those in albumin excretion. This lack of correlation contrasted with the correlations observed for hydrochorthiazide and nitrendipine. In accordance to others 4 0 . Our data suggested that captopril lowers albumin excretion by mechanism that are not as closely related to BP reduction. Therefore, particularly in microalbuminuric IDDM patients, in whom the nephropathy is the main cause of increased morbidity and mortality, ACE inhibitors have been recommended in order to prevent progression of such complication, even in absence of hypertension41. The favorable metabolic profile of ACE inhibitors, associated with preliminary observations of the reversal of left ventricular hypertrophy 42 and also improvement of insulin resistance 25, make these drugs also attractive for NIDDM hypertensive patients. Unfortunately, the high cost of this therapy may limit compliance in a number of patients. Orthostatic hypotension secondary to diabetic autonomic neuropathy may be aggravated with ACE inhibition. The presente of renal failure represents another limitant factor due to its potassium retaining effect. Long-term prospective studies comparing the impact of ACE inhibitors with other antihypertensive drugs are needed to confirm advantages of the former in the treatment of hypertensive patients with diabetes. Neverthless they seem very promissing drugs for diabetic patients. d) Calcium channel blockers As well as the others, CC8 are suitable for initial therapy in diabetic hypertensive patients. The blockade of calcium influx to cells induces systemic and renal vasodilation. Besides lowering BP this class of drugs has been used for patients with ischaemic heart disease even with renal impairment. In contrast to other vasodilators, they cause natriuresis and diuresis. There are controversies concerning the effects of the CCB on the renal hemodynamics. Particularly in diabetes, studies showed variable effects on renal plasma flow, glomerular filtration rate and albumin excretion that may be related to the time in the disease process 11,43-45. In our experience, in IDDM patients nitrendipine reduced BP and urinary protein excretion whose percentage falls were correlated 21. Renal plasma flow increased and glomerular filtration rate decreased and both filtration fraction and renal vascular resistance were reduced. Our data are in accordance to previous suggestion that these drugs dilate afferent arteriole without change efferent arteriollar resistance 46. Other studies similar to ours have also observed a antiproteinuric effect, indicating that the 269 S. R. G. FERREIRA et al. systemic BP fall is the main determinant of the decrea s e in urinary protein excretion induced by the CCB 11, 44. However, some reports have indicated that CCB may not aher urinary albumin excretion and m a y even increase it 43,45. Longer studies with a greater number of patients are necessary to clarify these aspects. Because of the effectiveness, of this class of antihypertensive drugs and lack of deleterious effect on glucose and Iipoprotein metabolism, they have been considered a first-line therapy for hypertension i n NIDDM or IDDM. They became a very interesting option in the diabetic patient with coronary artery disease associated with left ventricular hypertrophy. 14 De Fronzo RA, Ferranini E: Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 14:173-194, 1991. 15 C o l l i n s A, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KH et al: Blood pressure, stroke, and heart coronary disease. Part 2. Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiologic context. Lancet 335:827-838, 1990. 16 Parving HH, Smidt JM, Andersen AR, Svendsen PA: Early agg r e s s i v e antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1 :1175-1178, 1983. 17 ressure threshold and choice d o f treatment for hypertension in IDDM. Diabetes Care 14 (suppl 4):13-26, 1991. 18. Lithell HOL: Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care 14:203-209, 1991. 19. Moser M, Ross H: The treatment of hypertension in diabetic patients. Diabetes Care 16:542-547, 1993. 20. Parving H, Andersen A, Smidt U, Christiansen JS, Oxenhoff B, Svendsen PA: Diabetic nephropathy and arterial hypertension: t h e effect of antihypertensive treatment. Diabetes 32 (suppl 2):83-87, 1983. 21. Zanella MT, Freire MBS, Milagres R, Ferreira S, Bonomo PP, K o h l m a n n Jr 0, Ribeiro AB: Blood pressure disturbance in diabetes mellitus. J Hypertens 10 (suppl 7): S59-70, 1992 2 2 . W a r r a m JH, Laffel LM, Valsania P, Christlieb AR, Krolewski AS: Excess mortality associated with diuretic therapy in diabetes mellitus. Arch Intern Med 151 :1350- 1356, 1991. 2 3 . H e l d e r m a n J, Elahi 0, A n d e r s e n 0, Raizes G, Tobin J, S c h o c k e n D, Andres R: Prevention of glucose intolerance of thiazide diuretics by maintenance of boby potassium. Diabetes 32 106-11, 1983. 24. Stein P, Black H: Drug treatment of hypertension in patients with diabetes mellitus. Diabetes Care 14:425-429, 1991. 25. Pollare T, Lithell H, Berne C: A comparison of the effects of h y d r o c h l o r o t h i a z i d e and captopril on glucose and lipid metabolism in patients with hypertension. N Eng l J Med 321 :868873, 1989. 2 6 . Prince M, Stuart C, Padia M, Bandi Z, Holland 0: Metabolic e f f e c t s of hydrochlorothiazide and enalapril during treatment o f hypertensive diabetic patient. Arch Intern Med 1 4 8 : 2 3 6 3 2 3 6 8 , 1988. 27. P l a v i n i k F L , R o d r i g u e s C I S , Z a n e l l a M T , R i b e i r o A B : Hypokalemia, glucose intolerance, and hyperinsulinemia during diuretic therapy. Hypertension 19 (suppl ll):ll-26-ll- 29, 1992. 28. G o r d e n P: Glucose intolerance with hypokalemia. D i a b e t e s 2:544-551, 1973. 29. G r i m m Jr RH, Leon A, Hunninghake D, Hannon P, Blackburn H : Increased lipids and Iipoproteins in diuretic-treated mild hypertensives. Am J CardioI 43:419, 1979. 30. Day J: The metabolic consequences of adrenergic blockade: a r c v i e w . Metabolism 24:987-996, 1975. 31. Holm G, Johansson S, Veden A, Wilhelmsson C, Smith U: The effect of B blockade on glucose tolerance and insulin release in adult diabetics. Acta Med Scand 208:187-191, 1980. 32. Micossi P, Pollavini G, Raggi U, Librenti M, Garimberti B, Beggi P: Effects of metoprolol and propranolol on glucose tol e r a n c e and insulin secretion in diabetes mellitus. H o r m Metab Res 16:59-63, 1984. 33. Bolli G, DeFeo P, Comapagnucci P, Cartechini M, Angeletti G, Santeusiano F, Brunetti P: Important role of adrenergic mec h a n i s m s in acute glucos counterregulation following insulini n d u c e d hypoglycemia in type 1 diabetes: Evidence for an effect m e d i a t e d b y b e t a - a d r e n e r g i c r e c e p t o r s . D i a b e t e s 31:641-647, 1982. References 1. Turner R, Mann J, Oakes S, Nugent Z, Moore J, Peto R et al: U n i t e d Kingdom prospective diabetss study: III. Prevalence of hypertension and hypotensive therapy in patients with newly diagnosed diabetes. Hypertension 7 (suppl II):II8-II13, 1985. 2. Krolewski AS, Warran JH, Cupples A, Gorman CK, Szabo A, C h r i s t l i e b AR: Hypertension, orthostatic hypotension and mic r o v a s c u l a r complications of diabetss. J Chronic-Dis 38:319326, 1985. 3. W o r k i n g Group on Hypertension in Diabetes: Statement on h y p e r t e n s i o n in diabetes mellitus: final report. Arch Int Med 147:830-842,1987. 4. C a r o JF: Diabetes and hypertension: not the final chapter. Diabetes Care 16:540-541, 1993. 5. Moser M, Ross H: The treatment of hypertension in diabetic patients. Diabetss Care 16:542-547, 1993. 6. De Chatel R, Weidmann P, Flammer J, Ziegler WH, BerettaPiccoli C, Vetter W, Reubi FC: Sodium, renin, aldosterone, catecholamines and blood pressure in diabetes mellitus. Kidney Int 12:412-421, 1977. 7. O'Hare JP, Anderson JV, Millar ND, Bloom SR, Corrall RJM: T h e relationship of the renin-angiotensin-aldosterone system to atrial natriuretic peptids and natriuresis of volme expansion in diabetics with or without proteinuria. Postgrad Med J 64:35-38, 1988. 8. Trevisan R, Fioretto P, Semplicini A, Opocher G, Mantero F, Rocco S et al: Role of insulin and atrial natriuretic peptide in s o d i u m retention in insulin-treated IDDM patients during isotonic volume expansion. Diabetes 39:289-298, 1990. 9 Pusterla C, Beretta-Piccoli C, Stadler P, Weidmann P, Shaw S: Sodium and responss to infused noradrenaline and angiotensin II in s u b j e c t s p r e d i s p o s e d t o h y p e r t e n s i o n . J Hum Hypertension 1: 267-276, 1988. 10 M a t h i e s e n E R , Ronn B, Jensen T, Storm B, Deckert T: Relationship between blood pressure and urinary albumin exc r e t i o n in d e v e l o p m e n t o f m i c r o a l b u m i n u r i a . D i a b e t e s 39:245-249, 1990 1 1 M e l b o u r n e Diabetic Nephropathy Study Group: Comparison b e t w e e n perindopril and nifedipine in hypertensive and norm o t e n s i v e diabetic patients with microalbuminuria. B M J 302:21O-21 6, 1991 . 1 2 C h r i s t l i e b AR: Diabetes and hypertensive vascular disease: mechanisms and treatment. Am J CardioI 32:592-602, 1973. 1 3 . Baba T, Marabyashi S, Aoyagi K, Sasaki X, lamura K, Kudo M et al: Prevalence of hypertension in diabetss mellitus: its relation to diabetic nephropathy. Toboku J Exp Med 145:167-173, 1985. 270 BLOOD PRESSURE MANAGEMENT IN DIABETIC PATIENTS 34. Weidmann P, Ferrier C, Saxenhofer H, Uehlinger D, Trost B: S e r u m proteins during treatment with antihypertensive drugs. Drugs 35: (suppl 6):118- 134, 1988. 3 5 . Zatz R, Dunn BA, Meyer TW, Anderson A, Rennke HG, B r e n n e r BM: Prevention of diabetic glomerulopathy by pharm a c o l o g i c a l amelioration of glomerular capillary hypertension.J Clin Invest 77:1925-1930, 1986. 36. Cooper ME, Allen TJ, Macmillan PA, Clarke BE, Jerums, Doyle AE: Enalapril retards glomerular basement membrane thickning and albuminuria in diabetic rat. Diabetologia 32:326-328, 1989. 37. Parving HH, Hommel E, Nielsen MD, Giese J: Effect of captopril on blood pressure and kidney function in normotensive insulin-dependent diabetes. BMJ 299:533-536, 1989. 38. Morelli E, Loon N, Meyer T, Peters W, Myers BD: Effects of c o n v e r t i n g - e n z y m e inhibition on barrier function in diabetic glomerulopathy. Diabetes 39:76-82, 1990. 39. Bjorck S, Mulec H, Johnsen SA, Norden G, Aurell M: Renal p r o t e c t i v e effect of enalapril in diabetic nephropathy. B M J 304:339-343, 1992. 40. Rudberg G, Aperia A, Freyschuss U, Persson B: Enalapril reduc e s microalbuminuria in young normotensive type I (insulindependent) diabetic patients irrespective of its hypotensive effect. Diabetologia 33:470-476, 1990. 4 1 . Mathiesen ER, Hommel E, Giese J, Parving HH: Efficacy of c a p t o p r i l in postponing nephropathy in normotensive insulin d e p e n d e n t diabetic patients with microalbuminuria. B M J 303:81-87,199l. 42. Dahlof B, Pennert K, Hansson L: Regression of left vent r i c u l a r h y p e r t r o p h y in hypertensive patients. A metaan a l y s i s of 109 treatment studies. Am J Hypertens 5:95110,1992. 4 3 . M i m r a n A , I n s ú a A , R i b s t e i n J, B r i n g e r J, Monnier L: C o m p a r a t i v e effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care l11:850-853, 1988. 4 4 . Baba T, Murabayashi S, Takebe K: Comparison of renal effects of angiotensin convertrng enzyme innibitor and c a l c i u m a n t a g o n i s t in hypertensive type 2 (non-insulindependent) d i a b e t i c p a t i e n t s w i t h m i c r o a l b u m i n u r i a : a randomized controlled trial. D i a b e t o l o g i a 3 2 : 4 0 - 4 4 , 1989. 45. Demarie BK, Bakris GL: Effects of different calcium antagon i s t s on proteinuria associated with diabetes mellitus. Am Intern Med 1113:987-988, 1990. 46. Loutzenhiser R, Epstein M: Renal microvascular actions of cal. cium antagonists. J Am Soc Nephrol. 1:S3-S11 2, 1990 271