Renoprotective role of ACE inhibitors in diabetic

Transcription

1 S 38 Medial Department M, ndorinology and Diabetes, Aarhus Kommunehospital, University Hospital of Aarhus, Aarhus, Denmark C Mogensen Correspondene to: Dr C Mogensen, Medial Department M, ndorinology and Diabetes, Aarhus Kommunehospital, University Hospital of Aarhus, DK-8 Aarhus C, Denmark. Table 1,ug/mm Renoprotetive role of AC inhibitors in diabeti nephropathy Carl rik Mogensen lassifiation, by about 4 mm Hg per year.6 In this paper I will review data on intervention with AC inhibitors throughout the ourse of diabetes. ditorials in three major develop miroalbuminuria. This is journals reently disussed this important issue.8' Table 1 shows an outline of the stages of diabeti renal involvement and disease in patients with insulin dependent diabetes from the time of diagnosis of albumin exretion membrane during stress) above but quite thikness variable damage not loated exretion > 2 redution inrease by severe mesangial 5% volume inhibition) Patients with diabetes mellitus and overt proteinuria have a poor prognosis.' Reent studies show that appreiable proteinuria is assoiated with a muh more rapid progression of disease than is moderate albuminuria.2 Progression is also losely assoiated with raised blood pressure, but appreiable albuminuria in itself seems to be an important prognosti indiator. Before linial proteinuria ours (maroalbuminuri patients always go through a stage of miroalbuminuria, often lasting 1 years. Diabeti renal disease develops in stages, espeially in patients with insulin dependent diabetes.3-5 Classifiation aording to the degree of albuminuria is important beause patients with perfetly normal albumin exretion rates usually have a good long term prognosis, although some (about 4% per year) of them will progress from normoalbuminuria to miroalbuminuria.6 On the other hand, patients with persistent miroalbuminuria have (without intervention) a muh poorer prognosis, with a muh higher risk of progression to overt renal disease over the following deade.3 Aording to new morphometri studies, this is not surprising beause miroalbuminuria indiates that patients are in a more advaned stage of glomerular disease.7 Stages of renal disease* in patients with insulin dependent diabetes Br Heart (Supplement) 1994; 72: diabetes. Poor glyaemi ontrol is an important fator determining transition to miroalbuminuria and probably progression of the miroalbuminuri state,6 1" 2 but metaboli ontrol is diffiult in these patients. Ourrene of raised blood pressure in renal diabeti disease INSULIN DPNDNT DIABTS MLLITUS The prevalene of hypertension in patients with insulin dependent diabetes defined aording to the World Health Organisation's and inluding patients reeiving treatment, is similar in patients with normoalbuminuria and the general population.'3 The prevalene of hypertension inreases sharply in patients with miroalbuminuria, and most patients with overt proteinuria have lassi hypertension. Soon after the ourrene of miroalbuminuria, blood pressure may inrease Therefore the main group of patients with insulin dependent diabetes that are given antihypertensive treatment are those with miroalbuminuria or overt renal disease. On the other hand, some patients with insulin dependent diabetes may have raised blood pressure before miroalbuminuria-that is, oinidental essential hypertension. Also, it is important to note that some patients with normoalbuminuria will part of the natural ourse of the disease beause during the first few years of diabetes most patients after metaboli stabilisation will have normoalbuminuria. Renal damage learly inreases the longer the duration of diabetes. Stage Designation Main harateristis Main strutural Glomerular Urinary albumin Blood pressure Comments hanges filtration rate exretion (mllmin) I (at diag- Hyperfuntion/ Glomerular Glomerular 15 May be inreased Normal Glomerular nosis) hypertrophyt hyperfiltration hypertrophy volume/pressure inrease (reversible) II Normoalbuminuria Normal urinary Inreasing basal Hyperfiltrationt Normal (high Normal Changes as indiated Transition Transition phase High normal urinary Not known Hyperfiltration Inreasing Inreasing Somewhat poor from albumin exretion metaboli ontrol II - III III Inipient diabeti Raised urinary Urinary albumin Still high 2-2,g/min Raised ompared Advaning glomerular nephropathy, albumin exretion exretion orrelated with stage II lesions; miroalbuminuria to strutural permeability defet IV Overt diabeti Clinial proteinuria Advaned strutural "Normal" to > 2 ( 1 Often frank High rate of nephropathy or urinary albumin damage advaned,ug/min) hypertension glomerular losure; yearly expansion V nd stage renal disease Uraemia General glomerular losure Very low Dereasing albuminuria Often high, related to Death/uraemia (postponed by AC expansion *Applied when blood pressure remains untreated. Reduing blood pressure often redues albuminuria (proteinuria miroalbuminuria normoalbuminuri. tchanges present probably in all states when ontrol imperfet. tmarker of future nephropathy. Br Heart J: first published as /hrt.72.3_Suppl.S38 on 1 September Downloaded from on 15 November 218 by guest. Proteted by opyright.

2 Renoprotetive role of AC inhibitors in diabeti nephropathy S 39.3 fa.25.2 NON-INSULIN DPNDNT DIABTS MLLITUS The situation in patients with typial noninsulin dependent (type 2) diabetes is somewhat different.'4 Many of these patients have hypertension when diabetes is diagnosed, and they may have renal ompliations when they are first seen. Aording to a reent survey in general pratie in Denmark, more than 3% of patients with newly diagnosed diabetes had miroalbuminuria and about 6% linial proteinuria, with a male preponderane.'4 There is a weak orrelation between the degree of albuminuria and blood pressure. Also, many patients are already reeiving antihypertensive treatment. Albuminuria also orrelated with degree of glyaemia and with triglyeride onentrations. With more advaned renal disease blood pressure tended to inrease further, and an even larger proportion of patients require antihypertensive treatment when overt renal disease is present." Transition from normoalbuminuria to miroalbuminuria INSULIN DPNDNT DIABTS MLLITUS New studies measuring ambulatory blood pressure have learly indiated that transition from normoalbuminuria to miroalbuminuria is assoiated with a onomitant inrease in ambulatory blood pressure over 24 hours. The onset of miroalbuminuria is always assoiated with a rise in blood pressure, but the onverse is not neessarily true.6 In patients developing miroalbuminuria the inrease in blood pressure was fourfold ompared with that in those patients who did not do as well as healthy ontrols. Therefore, early in the ourse of renal ompliations, raised blood pressure is important, although it is diffiult to outline learly the prime abnormality as patients developing miroalbuminuria already have albumin exretion rates in the upper part of the normal range, around 1,ug/min. These observations suggest a radial new preventive approah. Maybe patients with normoalbuminuria at risk of renal progression should in the future be treated with antihypertensive agents even if they do not have high blood pressure. An important reent prospetive study also shows that transition from normo- I x C _253 xq C o I 4 Plaebo nalapril U- Figure 1 Filtration fration and frational albumin lears plaebo or enalapril 3 mg per day in nine patients with ii normoalbuminuria. 8 albuminuria (defined as < 3 Vig/min: a rather high value) to miroalbuminuria (. 3 p.g/min) is assoiated with higher initial albumin exretion as well as some hypertension.'2 In patients with miroalbuminuria even slight inrease in blood pressure promotes progression.3 NON-INSULIN DPNDNT DIABTS MLLITUS Usually there is a gradual inrease in albuminuria with time in patients with noninsulin dependent diabetes. In the normoalbuminuri stage, however, many patients remain stable despite a long duration of diabetes.'6 Albuminuria inreases by about 2% per year, and this is related to the attained blood pressure (A Shmitz, personal ommuniation). This again suggests the deleterious effet of even a slight inrease in blood pressure in type 2 diabetes. Glyaemi ontrol is also likely to be affeted, but so far there are no published long term studies on optimised diabetes ontrol in patients with type 2 diabetes, although important work is in progress."' Many patients with type 2 diabetes are elderly and have onfounding risk fators, so it is hazardous to extrapolate the enouraging data on glyaemi ontrol in patients with type 1 diabetes to this population. l Clinial trials in patients with normoalbuminuria INSULIN DPNDNT DIABTS MLLITUS AC inhibition in patients with albuminuria is assoiated with a signifiant redution in filtration fration and frational albumin learane (fig 1).18 Importantly, in this study there was no signifiant hange in lini based blood pressure, although ambulatory blood pressure over 24 hours was not measured. The redution in filtration fration ould, in theory, be assoiated with a derease in hydrauli glomerular pressure, whih in turn ould explain the redution in albuminuria. Although it is too early to reommend antihypertensive treatment in suh patients, this study underlines interest in linial trials in this area. Patients at risk of developing miroalbuminuria-namely, patients with poor metaboli ontrol (glyated haemoglobin (HbA,) > 9-1%), some persistent borderline inrease in albumin exretion already (> 1-12,ug/min), and possibly severe hyperfiltration (glomerular filtration rate > 15 ml/ min)-should be enrolled in linial trials to see whether the development of miroalbuminuria an be prevented. 22- = NON-INSULIN DPNDNT DIABTS MLLITUS -o 92 Reent studies show that AC inhibitors redue blood pressure effetively in patients with non-insulin dependent diabetes, but to redue albuminuria within normal exretion seems to be diffiult. No adverse effet on Plaebo nalapril onentrations of gluose, lipids, or uri aid was seen.'9 2 Interestingly, low dose diureti asulin dependent diabetes and treatment is also effetive, whih may be beause these patients usually retain sodium Br Heart J: first published as /hrt.72.3_Suppl.S38 on 1 September Downloaded from on 15 November 218 by guest. Proteted by opyright.

3 S 4 Mogensen Table 2 Trials resulting in slightly redued blood pressure in young non-hypertensive patients with insulin dependent diabetes and miroalbuminuria or early nephropathy Referene (year) Nature of trial Intervention No of patients; Miroalbuininuria Conunents duration of treatmtient Christensen and Self ontrolled, open, bloker + diuretis 6; 5 years Redued Gradual reversal of albuminuria by Mogensen2' (1985) antihypertensive treatment Marre et al22 (1988) Double blind, randomised AC inhibition 2; 1 year Redued by AC inhibition Untreated patients showed rapid with parallel ontrols inrease in urinary albumin exretion (also see figure 2) Brihard et al23 (1989) Open AC inhibition 7; 1 year Redued by AC inhibition Rudberg et al24 (199) Open AC inhibition 12; 6 months Redued by AC inhibition Young patients Cook et a?2' (199) Cross over, double blind AC inhibition 12; 3 months Redued by AC inhibition Children Melbourne Diabeti Open, randomised with AC inhibition v 43; 1 year Redued by AC inhibition ffet mostly seen with raised Nephropathy Study parallel ontrols alium bloker and by alium bloker blood pressure Group26 (1991) Mathiesen et al27 (1991) Open, randomised with AC inhibition 44; 4 years Redued by AC inhibition First study to indiate preservation parallel ontrols of glomerular filtration rate; proteinuria prevented Marre et al28 (1991) Double blind, randomised AC inhibition 16; 6 weeks Redued ffet surprisingly not dose with parallel ontrols dependent Mau Pedersen et al 29 Open, ross over 13, Bloker + thiazide + 8; 3 months Albuminuria redued Triple treatment may be useful (1991) AC inhibition (early nephropathy) Mau Pedersen et al3 Cross over, double blind,b, Bloker + thiazide + 1; 4 months Albuminuria redued Triple treatment may be useful (1992) AC inhibition (early nephropathy) Hallab et al3' (1993) Randomised with parallel AC inhibition 21; 1 year Redued by AC inhibition AC inhibition more effiient than ontrols thiazide Viberti et al32 (1994) Multientre, double blind, AC inhibition 92; 2 years Redued by AC inhibition First large sale double blind m~ 3_ s Loa, 1_ x C 3 -. Time effet: P =.1 Linearity: NS randomised with parallel ontrols I-t - 3, 3 1 x CD. 3. O Time effet: P <.5 Linearity: P =.1 study; inrease in albuminuria and proteinuria signifiantly prevented (S Nielsen, personal ommuniation) ). It is not transition of miroalbuminuria to maroredution albuminuria there is always a fall in glomerular yet known whether blood pressure in these patients will result in li:ng term filtration rate.33 On the other hand, patients preservation of renal funtion. who remain miroalbuminuri usually have well preserved renal funtion. These observations suggest that antihypertensive Clinial trials in patients with intervention, partiularly AC inhibition, miroalbuminuria should be started early in the phase of miro- INSULIN DPNDNT DIABTS MLLI[TUS albuminuria. Blood pressure was not raised Over the past deade many linial t:rials have aording to the WHO riteria, rather it was been onduted in patients with ir iiroalbu- lose to normal mean values. This suggests minuria, espeially patients with insul Lin depen- that intervention should be started irrespetive dent diabetes.2"-32 Firstly, a P1 blo( ker plus of blood pressure. However, patients with a diuretis were tested, but latterrly AC moderate inrease in blood pressure usually inhibitors have been studied in partiular show a more rapid progression in albuminuria (table 2). Clearly, a redution in or staibilisation and a greater risk of progression to overt renal of miroalbuminuria is onsistently observed, disease.3 Therefore some inrease in blood and progression to overt proteiinuria is pressure strengthens the indiation for anti- some hypertensive treatment. In linis patients prevented by AC inhibition iin studies This observation is iimportant should be frequently monitored for miro- in the albuminuria, and in the ase of inrease over beause in the natural ourse of diabetes several months or even a year antihypertensive treatment should be started. At the same time Plaebo nalapril metaboli ontrol and general diabetes are should be optimised. One long term study learly suggests that a drop in glomerular Figure 2 Median logarithm of albumin exretion in 1 patients with insulin dependent diabetes treated with plaebo and 1 treated with enalapril. Shading shows raznge of values. Blood pressure dereased signifiantly with enalapril and inreased wit filtration rate is prevented by AC inhibition ombined with diuretis.27 This study has now reahed eight years with onsistent results ( R Mathiesen, personal ommuniation). Only a few side effets were observed in all the trials in table 2. The risk of suh intervention is limited and the potential benefit enormous. Reent studies learly show that from a ostbenefit point of view early antihypertensive treatment in the miroalbuminuri state is advisable.34 It is not yet known if early antihypertensive treatment will ameliorate the ourse of the other ompliations seen at a muh higher prevalene in patients with miroalbuminuria, espeially heart disease (left ventriular hypertrophy) and advaned diabeti *h plaebo.22 retinopathy. New studies suggest, however, Br Heart J: first published as /hrt.72.3_Suppl.S38 on 1 September Downloaded from on 15 November 218 by guest. Proteted by opyright.

4 Renoprotetive role of AC inhibitors in diabeti nephropathy S 41 Table 3 Observations from linial trials of AC inhibition in patients with insulin dependent diabetes Observation No trials in patients with newly diagnosed disease Normoalbuminuria redued, blood pressure not signifiantly hanged, filtration fration redued Blood pressure redued (diastoli and systoli), miroalbuminuria redued, fall in glomerular filtration rate prevented (8 year follow up) Blood pressure redued (diastoli and systoli), proteinuria redued, rate of fall in glomerular filtration rate redued nd stage renal disease and death postponed 34 " 3 26 ' X 14 o -o - L- ' o.._ r 15 1 [- 95K Time (years) Time (years) Figure 3 Albuminuria and reiproal serum reatinine onentrations during five years offollow up of patients with non-insulin dependent diabetes treated with enalapril or plaebo. Less proteinuria ourred in the enalapril group ompared with plaebo group after the seond year, and the mean rate of deline in reiproal reatinine onentration differed between the two groups.36 that antihypertensive treatment redues left ventriular hypertrophy.35 NON-INSULIN DPNDNT DIABTS MLLITUS Aumulating evidene suggests that AC inhibition might be indiated in young patients with type 2 diabetes. Chan et al showed that AC inhibitors effetively redued miroalbuminuria, an effet whih was superior to that of the alium bloker nifedipine, but this was a fairly short study.2 The most impressive study was onduted by Ravid et al, omparing enalapril with onventional antihypertensive treatment, to ontrol for hanges in blood pressure (fig 3).36 The group given AC inhibitors showed an initial redution in albuminuria followed by stabilisation for five years.36 A steady inrease was observed in the ontrol group. More importantly, an index of glomerular filtration rate-namely, reiproal serum reatinine onentration-was stabilised by enalapril, whereas in the ontrol group the reiproal steadily delined. (ight year follow up provides similar results (M Ravid, personal ommuniation).) The reent study by Laouriere et al, shows that miroalbuminuria an be redued by an AC inhibitor in ontrast to onventional treatment,19 but they did not find an effet on glomerular filtration rate in the three years of the study. Also, the development of maroalbuminuria was prevented in the patients with onsistent miroalbuminuria. These three studies point to the importane of early intervention in patients with diabetes and slight albuminuria. Inrease in blood pressure further strengthens this indiation, as reently shown by Lebovitz et al, who found that a fall in glomerular filtration rate was redued in miroalbuminuri patients by AC inhibitors.37 Overt diabeti renal disease INSULIN DPNDNT DIABTS MLLITUS Antihypertensive treatment not only redues albuminuria in patients with overt renal disease but also learly redues the rate of deline in glomerular filtration rate.8 The initial studies used a ombination of P blokers and diuretis. Reent studies suggest that AC inhibitors may have a more pronouned antiproteinuri effet. The most extended study on this subjet, by Bjork et al, finds that in advaned diabeti nephropathy AC inhibitors are more effiient, not only in their antiproteinuri effet but also in reduing the rate of deline in glomerular filtration rate (fig 4).38 Clearly, muh of the effet of antihypertensive agents on the rate of deline in glomerular filtration rate in diabeti patients with nephropathy is related to the effet on blood pressure.3 The study by Bjork et al suggests that an additional effet is obtained using AC inhibitors, at least when ombined with diuretis.38 The superiority of AC inhibitors was, however, not observed in all studies.39 NON-INSULIN DPNDNT DIABTS MLLITUS Bakris et al studied patients with type 2 diabetes and linial proteinuria.4 Lisinopril and ertain alium blokers not only redued proteinuria but also redued the rate of fall in glomerular filtration rate.4 4' These studies were, however, fairly short term, with a maximal follow up of 1-5 years.4' Further studies are needed. Patients with advaned renal disease INSULIN DPNDNT DIABTS MLLITUS An interesting end point is the effet on the rate of deline in glomerular filtration rate. In one study aptopril delayed the time to doubling of the serum reatinine onentration in patients with overt renal disease and insulin dependent diabetes (fig 5),42 reduing mortality and the need for dialysis or renal transplantation. AC inhibitors were highly effetive in reduing the blood pressure in these patients, and this may have aounted for muh of the benefit. This is the first ontrolled study to doument a signifiant effet on ritial end points. Table 3 shows that AC inhibition seems to be effetive throughout the ourse of renal disease in Br Heart J: first published as /hrt.72.3_Suppl.S38 on 1 September Downloaded from on 15 November 218 by guest. Proteted by opyright.

5 S 42 Mogensen U- C C a. -C Cq x B. Co Co C a n C) CL,. ~ _ 1 H 8 6 I- 4K 2 5 ACr m 45.) 4 o -, 35 L- CD 3 Plaebo P B D 25 2 P 17 'm " 1 ~ ~ a t p i Years of follow up Plaebo Captopril C 4 C - 4 OC 3 io t5 * &- ~ X 3 Plaebo s6 os 2 2 5~~~~~~~~~~~~~~~r~?o P = -6 i o,e 3: 2 1 CO CD115, ~.1 MJ C- LoJ - l- Captopril [U/?> Years of follow up Plaebo Captopril Figure 5 Cumulative inidene of events in patients with diabeti nephropathy given aptopril or plaebo. Top: Cumulative perentage of patients with the primary end point: a doubling of the baseline serum reatinine onentration to at least 2- mg per 1 ml. Bottom: Cumulative perentage of patients who died or required dialysis or renal transplantation. The numbers refer to the numbers of patients in eah group at risk for the event at baseline and after eah six month period.42 Reprinted by permission of the "New ngland Jtournal of Mediine" (1993;329: ). sreening patients with type 2 diabetes for miroalbuminuria so that treatment is started early. O 6I Possible mehanisms of the antiproteinuri effet of AC inhibitors Time (months) The benefits of AC inhibition are lear in Figure 4 Deline in glomerularfiltration rate (GFR), animal studies, reduing proteinuria and urmina y albumin exretion, and blood pressure before and strutural glomerular damage in the rat model during treatment with enalapril () or metoprolol () in of diabetes." The antiproteinuri and renal 4 pat~ients with insulin dependent diabetes and diabeti nephroopathy.38 protetive effet of AC inhibitors probably operate through several mehanisms. A redution in systemi blood pressure is insuliin dependent diabetes mellitus. The important, reduing the transmission of the effet is likely to be a lass effet, rather than abnormal systemi pressure to the glomerular assoiated with a partiular AC inhibitor. vessels. This may be espeially important in diabeti patients, who may have disturbed NON-] INSULIN DPNDNT DIABTS MLLITUS autoregulation at the afferent arteriole.45 A bernefiial effet is also seen in some patients Interestingly, filtration fration is redued by with type 2 diabetes, but the most onvining AC inhibition,'8 whih probably reflets resultts are obtained in those with efferent arteriolar dilatation assoiated with a mir)albuminuria. With more advaned derease in hydrauli glomerular pressure. disease strutural vasular damage is probably Some studies suggest that there may be a more advaned,43 and the effiay of diret effet on the permeability of the antihypertensive treatment may not be so glomerulus,46 but this may also be explained ouned. This emphasises the need for by dereased pressure indued streth of the pronm Br Heart J: first published as /hrt.72.3_Suppl.S38 on 1 September Downloaded from on 15 November 218 by guest. Proteted by opyright.

6 Renoprotetive role of AC inhibitors in diabeti nephropathy S 43 glomerular vessels. If the hypothesis is orret that proteinuria in itself provokes renal damage by inreased mesangial and interstitial flux of protein, a redution in proteinuria would learly be benefiial.47 Inhibition of growth fators may also be operating. There are many other reports on the effets of AC inhibitors on renal funtion and proteinuria, most of whih, but not all, have shown benefit and broadly support one or more of the above hypotheses.48-9 When to start antihypertensive treatment in insulin dependent diabetes The most reent studies suggest that antihypertensive treatment should be started in the miroalbuminuri phase. This treatment should probably be introdued irrespetive of blood pressure, but of ourse with low blood pressure a more onservative attitude should apply. Blood pressure usually inreases without treatment during follow up. Some evidene suggests that glomerular filtration rate will remain well preserved if patients remain miroalbuminuri or show redution to normoalbuminuria. AC inhibitors, often ombined with small doses of diuretis, are then partiularly useful with limited or no effet on gluose and lipid homoeostasis. Triple treatment with diuretis, AC inhibitors, and 3, blokers also seems to be effetive.29 3 Obviously, areful monitoring for hanges in serum potassium onentration as well as glomerular filtration rate (serum reatinine onentration) is warranted, as well as areful ontrol of blood pressure and monitoring of other side effets, espeially in more advaned renal disease. Pregnany or the desire for pregnany is a lear ontraindiation for treatment. The disease proess is to some extent similar in the miroalbuminuri and maroalbuminuri stages. Sine preserving glomerular filtration rate is learly benefiial in overt renal disease, similar benefits may be assumed among patients with miroalbuminuria. This onept is supported by several studies. Importantly, the role of optimising diabetes ontrol has reently been emphasised. "l A low protein diet may also result in a benefiial effet on renal funtion.9' Brief suggestions for young and middle aged patients with type 2 diabetes From a theoretial point of view the same guidelines an be used in patients with noninsulin dependent diabetes as for those with insulin dependent diabetes. Of ourse, higher blood pressures should be aepted to allow for the age dependent rise in pressure. Patients under 6 years old may be treated similarly to patients with insulin dependent diabetes after the effet of age on blood pressure has been taken into onsideration. So far there are no long term linial trials in older patients. xperiene indiates that AC inhibition and onventional antihypertensive treatment redue blood pressure effetively in older patients with insulin dependent diabetes. Miroalbuminuria may also be redued, but there are no long term data that glomerular filtration rate is preserved. Generally, the guidelines for younger patients may be aeptable, but a higher blood pressure should be tolerated. If antihypertensive treatment redues blood pressure and albuminuria with stable glomerular filtration rate, this is probably benefiial. Patients should be arefully monitored for hypotensive and other side effets, whih are likely to be more prevalent in older people. 1 Mogensen C, ed. Definition of diabeti renal disease in insulin-dependent diabetes mellitus based on renal funtion tests. In: The kidney and hypertension in diabetes mellitus. 2nd ed. Dordreht: Kluwer Aademi Publishers, 1994: Rossing P, Hommel, Smidt UM, Parving H-H. Impat of arterial blood pressure and albuminuria on the progression of diabeti nephropathy in IDDM patients. Diabetes 1993;42: Mogensen C, Damsgaard M, Froland A, et al Redued glomerular filtration rate and ardiovasular damage in diabetes: a key role for abnormal albuminuria. Ata Diabetologia 1992;29: Mogensen C. Management of renal disease and hypertension in insulin-dependent diabetes, with an emphasis on early nephropathy. Current Opinion in Nephrology and Hypertension 1992; 1: Mogensen C. Miroalbuminuria, early blood pressure elevation, and diabeti renal disease. Current Opinion in ndorinology and Diabetes 1994;1: Poulsen PL, Hansen KW, Mogensen C. Ambulatory blood pressure in the transition from normo- to miroalbuminuria: a longitudinal study in IDDM. Diabetes (in press). 7 Bangstad H-J, sterby R, Dahl-Jorgensen K, Berg KJ, Hartmann A, Hanssen KF. Improvement of blood gluose ontrol retards the progression of morphologial hanges in early diabeti nephropathy. Diabetologia 1994;37: Mogensen C. Angiotensin onverting enzyme inhibitors and diabeti nephropathy: their effets on proteinuria may be independent of their effets on blood pressure. BMJ 1992;34: Bakris GL. Angiotensin-onverting enzyme inhibitors and progression of diabeti nephropathy. Ann Intern Med 1993;118: Remuzzi G, Ruggenenti P. Slowing the progression of diabeti nephropathy. N ngl J' Med 1993;329: Diabetes Control and Compliations Trial Researh Group. The effet of intensive treatment of diabetes on the development and progression of long-term ompliations in insulin-dependent diabetes mellitus. N nglj Med 1993;329: Miroalbuminuria Collaborative Study Group, United Kingdom. Risk fators for development of miroalbuminuria in insulin dependent diabeti patients: a ohort study. BMJ 1993;36: Norgaard K, Feldt-Rasmussen B, Borh-Johnsen K, Saelan H, Dekert T. Prevalene of hypertension in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 199;33: de F Olivarius N, Andreasen AH, Keiding N, Mogensen C. pidemiology of renal involvement in newlydiagnosed middle-aged and elderly diabeti patients. Cross setional data from the population-based study "Diabetes Care in General Pratie," Denmark. Diabetologia 1993;36: Gall M-A, Rossing P, Sktt P, et al. Prevalene of miro- and maroalbuminuria, arterial hypertension, retinopathy and large vessel disease in uropean type 2 (non-insulin-dependent) diabeti patients. Diabetologia 1991;34: Mogensen C, Shmitz A. Systoli blood pressure relates to the rate of progression of albuminuria in non-insulindependent diabetis [abstrat]. Diabetologia (in press). 17 UK Prospetive Diabetes Study Group (UKPDS). VIII. Study design, progress and performane. Diabetologia 1991 ;34: Mau Pedersen M, Shmitz A, Pedersen B, Danielsen H, Christiansen JS. Aute and long-term renal effets of angiotensin onverting enzyme inhibition in normotensive, normoalbuminuri insulin-dependent diabeti patients. Diabeti Med 1988;5: Laouriere Y, Nadeau A, Poirier L, Tanrede G. Captopril or onventional therapy in hypertensive type-ii diabetis: 3-year analysis. Hypertension 1993;21: Chan JCN, Cokram CS, Niholls MG, Cheung CK, Swaminathan R. Comparison of enalapril and nifedipine in treating non-insulin dependent diabetes assoiated with hypertension: one year analysis. BMJ 1992; 35: Br Heart J: first published as /hrt.72.3_Suppl.S38 on 1 September Downloaded from on 15 November 218 by guest. Proteted by opyright.

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