Do angiotensin converting enzyme inhibitors represent a progress in hypertension care in diabetes mellitus?

Diabetologia, Aug 1991

K. Rett, P. T. Sawicki

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Do angiotensin converting enzyme inhibitors represent a progress in hypertension care in diabetes mellitus?

Diabetologia 0 Yours sincerely, K. Rett , M. Wicklmayr, G. Dietze and H. Mehnert 1 Yours sincerely, E T. Sawicki , I. Mtihlhauser and M. Berger D o a n g i o t e n s i n c o n v e r t i n g e n z y m e inhibitors represent a progress in h y p e r t e n s i o n care in diabetes mellitus? Dr. K. Rett Diabetes Research Unit and Third Medical Department Schwabing Hospital K61ner Platz 1 W-8000Mtinchen 40 FRG - "Bona meliora tuluntnr" Dear Sir, In the article by Sawicki et al. [ 1 ],the authors make an attempt to challenge the present view that angiotensin converting enzyme (ACE) inhibitors offer a series of advantages in the treatment of hypertensive diabetic patients. We feel, however, that the authors ask the wrong question and give a number of wrong answers. First of all, Type i (insulin-dependent)and Type 2 (non-insulindependent) diabetes should be kept apart as strictly as possible when talking about hypertension, since both metabolic disturbance and pathogenesis of hypertension differ largely between both types of diabetes. Approximately 40% of Type I diabetic patients are known to develop secondary hypertension as a consequence of nephropathy [ 2 ] after years of being diabetic. The basis of the metabolic disturbance is insulin deficiency. In striking contrast, more than 50% of Type 2 diabetic patients already have essential hypertension and more than 30% suffer from coronary artery disease at the onset of their diabetes [ 3, 4 ]. They have been insulinresistant and hyperinsulinaemic before. The therapeutic aim of antihypertensive treatment is long-term prevention of renal failure in Type 1 diabetes and reduction of the dramatically elevated cardiovascular risk in Type 2 diabetes. Two parameters which are currently regarded as being of central importance in nephropathy and the syndrome of metabolic cardiovascular risk factors [ 5 ] have been shown to be positively influenced by angiotensin converting enzyme inhibitors, namely glomerular hypertension [ 6 ] and insulinresistance [ 7, 8 ]. Insulin resistance not only occurs in manifest Type 2 diabetes, but also in impaired glucose tolerance, obesity, essential hypertension and even in 25% of subjects with normal glucose tolerance [ 9 ], i.e. in a variety of "pre-diabetic states". The question therefore, is not how to reduce blood pressure, but how to slow down renal function loss in Type 1 and to reduce coronary risk in Type 2 diabetes and all other insulinresistant states. Thus, angiotensin converting enzyme inhibitors offer the progress of an intervention that may correct an underlying defect (i. e. glomerular hypertension and insulin resistance, respectively) instead of treating one symptom (hypertension) at the cost of aggravating the apparently causal disturbance (hyperinsulinaemia).This applies not only for hypertension care in diabetes, but in general. Finally, we would like to adress a number of wrong statements given by the authors: (1)There is no doubt, that beta-blocking agents are effective drugs in the secondary prevention of coronary heart disease. However, due to serious methodological shortcomings of the studies quoting it, this is still fiction rather than fact in primary prevention [ 10 ]. (2) The argument, that Type 2 diabetic patients are in "geriatric age range" and have already developed atherosclerotic disease is not an argument against, but rather for early interventionwith ACE inhibitors, since the underlyinginsulin resistance as well as structural changes of the arterial wall are obviouslybeing positivelyinfluenced [ 8,11 ]. (3) We do not understand, why special caution should be warranted concerningACE inhibitor 9 Springer-Verlag 1991 treatment in severe chronic heart failure, since its beneficial effect is well established already in moderate and even milder forms of heart failure [ 12 ]. (4) It may be true, that Type 2 diabetic patients frequently show renal arterial stenoses on autopsy [ 1 ]. However, the haemodynamic and thus the clinical relevance of such post mortem data remain obscure. Response from the Authors Dear Sir, We feel that Rett et al. are asking the right question: " . . . Not how to reduce blood pressure, but how to slow down renal function l o s s . . , and reduce coronary r i s k . . . ? " , or more precisely: How to prolong life in hypertensive Type i (insulin-dependent)and Type 2 (non-insulin-dependent)diabetic patients? In our article, we intended to provide answers exactly to these questions based on controlled studies rather than on pathophysiological speculation. Beta-blocking agents have been shown to reduce mortality in Type i [ 1, 2 ] and Type 2 [ 3 ] diabetes and in patients with essential hypertension [ 4 ].We agree with Rett et al. that some methodological aspects of these prospective controlled long-termtrials may be questionable. However, such trials still represent the best and only available rationale for any therapeutic interventionsince mortality rather than risk factors/indicators have been defined as end-pointsof these studies. No such trials have ever been performed for angiotensin convertingenzyme (ACE) inhibitors. Rett et al. propose a specific advantage of ACE inhibitors over conventionaltreatment regarding diabetic nephropathy and insulin resistance. Such a hypothetical advantage can only be documented by studies comparing ACE inhibitors with other antihypertensive treatments. There is only one prospective study comparing ACE inhibitors with beta-blockers in overt diabetic nephropathy [ 5 ]. This short-term study showed a significantrise in serum creatinine and a drop in proteinuria only in the enalapril group while no change occurred in the metoprolol group. These results could actuallybe interpreted as a specific adverse effect of ACE inhibitors in diabetic nephropathy [ 6 ]. A meta-analysis of different antihypertensive treatments in diabetic nephropathy demonstrated a significantly lower decrease in blood pressure and proteinuria with ACE inhibitors while no differences in the decrease of glomerular filtration rate were noticed when compared to conventional antihypertensive treatment [ 7 ]. Preliminary results of antihypertensive treatment in incipient diabetic nephropathy showed no difference in reduction of albuminuriabetween perindopril and nifedipine [ 8 ].Hence, specific nephroprotection by ACE inhibitors still remains wishful thinking than proven fact. Improvement of insulin sensitivityhas been suggested not only for ACE inhibitors but also for prazosin [ 9 ], metoprolol [ 10 ] and atenolol [ 10 ]. However, these were placebo controlled trials and a non-specific effect of blood pressure reduction independent of the antihypertensive drug used has not been excluded. In studies comparing several antihypertensive drugs the adverse potentially confounding side-effects of potassium loss and weight gain on glucose sensitivity need be taken into account. Studies not including such data [ 11 ] or demonstrating a significant drop in serum potassium after thiazide administration [ 12 ] or weight gain after beta-blockade [13] must be interpreted with caution: Under such circumstances any specific effect of a drug is impossible to demonstrate. In any case, the clinical relevance of such experimental investigations remains uncertain. Recent preliminary results of a double-blind, placebo controlled, prospective study in Type 2 diabetes showed no change in HbAI~ and other parameters of insulin sensitivity and metabolic control after ACE inhibitors vs beta-blocker treatment [141. We still do not accept that the evidence as available in present literature provides any justification for replacing an antihypertensive therapy (i. e. conventional antihypertensive treatment with diuretics, cardioselective beta-blockers and vasodilators) which has been proven to reduce morbidity and mortality in hypertensive diabetic patients by a newer, as yet incompletelyevaluated therapeutic principle (i. e. ACE inhibitors). This cautious attitude based upon considerations of efficacy,safety and cost-effectiveness has most recently been confirmed by an official statement issued jointlyby the German Hypertension League and the German Diabetes Association [151. 1. Sawicki PT , Mt~hlhauser I, Baba T , Berger M ( 1990 ) Do angiotensin converting enzyme inhibitors represent a progress in hypertensioncare in diabetes mellitus ? Diabetologia33: 121 - 124 2. Borch-Johnsen K ( 1988 ) Incidenceof nephropathy in insulin-dependent diabetes as related to mortality . In: Mogensen CE (ed) The kindney and hypertension in diabetes mellitus . Martinus Nijhoff , Boston, pp 33 - 40 3. Standl E , Stiegler H , Roth R , Schulz K , Lehmacher W ( 1989 ) On the impact of hypertension on the prognosis of NIDDM. Results of the Schwabing GP-program . Diab Metabo115 : 352 - 358 4. Panzram G ( 1987 ) Mortality and survival in Type 2 (non-insulindependent) diabetes mellitus . Diabetologia 30 : 123 - 131 5. Reaven GM ( 1988 ) Role of insulinresistance in human disease . Diabetes 37 : 1595 - 1607 6. Parving H-H , Hommel E , Smidt UM ( 1988 ) Protection of kidney function and decrease in albuminuriaby captopril in insulin dependent diabetics with nephropathy . Br Med J 297 : 1086 - 1091 7. Rett K , Lotz N , Wicklmayr M , Fink E , Jauch KW , Giinter B , Dietze G ( 1988 ) Verbesserte Insulinwirkungdurch ACE-Hemmung beim Typ 2-Diabetiker . Dtsch Med Wochenschr 113 : 243 - 249 8. Pollare T , Lithell H , Berne C ( 1989 ) A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension . N Engl J Med 321 : 868 - 873 9. Hollenbeck C , Reaven GM ( 1987 ) Variations in insulin-stimulated glucose uptake in healthy individualswith normal glucose tolerance . J Ctin Endocrin Metab 64 : 1169 - 1173 10. Kaplan NA ( 1988 ) Critical comments on recent literature: Scraaphy about Maphy from Happhy . Am J Hypertension 1 : 428M30 11. Asmar RG , Pannier B , Santoni JR Laurent S , London GM , Levy BI , Safar ME ( 1988 ) Reversion of cardiac hypertrophy and reduced arterial compliance after converting enzyme inhibitionin essential hypertension . Circulation78 : 941 - 950 12. Kleber FX , Niem611erL, Kronski D , H6tte C , Osterkorn K , DOring W ( 1990 ) Prognostic implicationsof ACE-inhibitionin mild heart failure . Circulation 82 : 674 1. Parving HH , Hommel E ( 1989 ) Prognosis in diabetic nephropathy . Br Med J 299 : 230 - 233 2. Mathiesen ER , Borch-Johnsen K , Jensen DV , Deckert T ( 1989 ) Improved survival in patients with diabetic nephropathy . Diabetologia 32 : 884 - 886 3. Kjekshus J , Gilpin E , Cali G , Blackey AR , Henning H , Ross J ( 1990 ) Diabetic patients and beta-blockers after acute myocardial infarction . Eur Heart J 11 : 43 - 50 4. Wilkstrand J , Warnold I , Olsson G , Tuomilehto J , Elmfeldt D , Berglund G ( 1988 ) Primary prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY Study . JAMA 259 : 1976 - 1982 5. Bj6rck S , Mulec H , Johnsen SA , Nyberg G , Aurell M ( 1990 ) Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy . Br Med J 300 : 904 - 907 6. Baba T , Kodama T , Takabe K ( 1990 ) Enalaprii and metoprotot in diabetic nephropathy . Br Med J 300:1399 7. Sawicki PT , Heinemann L , Miihlhauser I ( 1990 ) Enalapril and metoprolol in diabetic nephropathy . Br Med J 300:1446 8. Cooper ME , Doyle AE , Allen TJ , Jerums G , Alford F , Mashford ML , Hammond J , de Luise M ( 1990 ) Angiotensfu converting enzyme inhibition postpones the development of diabetic nephropathy . Diabetologia 33 [Suppl]: A75 9. Pollare T , Lithell H , SelinusI, Berne C ( 1988 ) Applicationof prazosin is associated with an increase of insulinsensitivityin obese patients with hypertension . Diabetologia 31 : 415 - 420 10. Fagerberg B , Berglund A , Holme E , Wilhelmsen L , Elmfeldt D ( 1990 ) Metabolic effects of controlled-release metoprolol in hypertensive men with impaired or diabetic glucose tolerance: a comparison with atenolol . J Int Med 227 : 37 - 43 11. Rett K , Lotz N , Wicktmayr M , Fink E , Jauch KW , Giinther B , Dietze G ( 1988 ) Verbesserte Insulinwirkungdurch ACE-Hemmung beim Typ2 Diabetiker . Dtsch Med Wochenschr 113 : 243 - 249 12. Pollare T , Lithell H , Berne C ( 1989 ) A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension . N Engl J Med 321 : 868 - 873 13. Pollare T , Lithell H , Selinus I , Berne C ( 1989 ) Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients . Br Med J 298 : 1152 - 1157 14. Gall MA , Rossing R Hommel E , Mathiesen ER , Skott E Gerdes U , Beck-Nielsen H , ParvingHH ( 1990 ) Comparison of captopril, metoprolol and hydrochlorothiazide in hypertensive Type 2 (non-insulin-dependent) diabetic patients . Diabetologia 33 [Suppl]: A75 15. German Hypertension League ( 1989 ) Statment on Hypertension in Diabetes , Heidelberg


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K. Rett, P. T. Sawicki. Do angiotensin converting enzyme inhibitors represent a progress in hypertension care in diabetes mellitus?, Diabetologia, 1991, 137-138, DOI: 10.1007/BF00500388