Prevention and slowing down the progression of the diabetic nephropathy through antihypertensive therapy

ELSEVIER

Prevention and Slowing Down the Progression of the Dialkic Nephropathy Through Antihypertensive Therapy Reinhard G. Bretzel

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ABSTRACT Diabetic nephmpathy is the major cause of illness and premature death in people with diabetes, largely through accompanying cardiovascular disease and end-stage renal failure. Diabetic patients are several times as prone to kidney disease as nondiabetic people and the accumulative risk of diabetic nephropathy in in.sulin+lependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) is about 30%-50% after 25 years of disease. Diabetic nephmpathy is a pmgressive disease that takes several years to develop, ending in chronic renal insufficiency. Proteinuria heralds the onset of diabetic nephropathy, and the worsening of proteinmia parallels the pmgression of renal disease. The main risk factors for the frequency, severity, and progression of diabetic nephropathy are the degree of hyperglycemia and associated metabolic disturbances, hypertension, protein overload, cigarette smoking, as well as the duration of diabetes. Interventional strategies for primary, secondary, and tertiary prevention of diabetic

nephropathy therefore include meticulous glycemic control, appropriate treatment of associated lipid abnormalities, rigorous control of the blood pressure, reduction in dietary protein intake, in particular animal protein, and of fat intake, and stopping cigarette smoking. Randomized clinical trials indicate that antihypertensive therapy is beneficial in preventing and slowing down the pmgression of diabetic nephropathy. There is now increasing evidence that angiotensin-converting enzyme inhibitors and certain calcium antagonists produce a more beneficial effect on diabetic nephropathy in terms of reducing pmteinuria and slowing the progression to diabetic renal failure. These drugs are attributed nephmprotective capacity beyond their blood pressure lowering capacity and initial clinical trials with combinations have revealed even additive protective effects on end organs. (Journal of Diabetes and Its Complications 11;2:1l2-122, 1997.) 0 Elsevier Science Inc., 1997 -

INTRODUCTION

D

iabetic nephropathy, characterized by resistent proteinuria, hypertension and progressive loss of renal function, can develop with either insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Recent data from a German clinical study -

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Third Medical bpartment, University of Giessen, Giessen, Germany Reprint requests to be sent to: Dr. Reinhard G. Bretzel, Professor of Medicine, Third Medical Department, University of Giessen, Rodthohl 6, D-35385 Giessen, Germany. louma of Diabetes and Its Complications 1 I:1 12-122 C Elsevier Science Inc., 1997 655 Avenue of the Americas, New York, NY 10010

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based on more than 700 diabetic patients showed a 48% and 57% cumulative risk of overt nephropathy (proteinuria) after 25 years of diabetes in IDDM and NIDDM patients, respectively. Once initiated, the course of diabetic nephropathy is one of progressive and relentless declining renal function, ending in chronic renal failure. The incidence of diabetes mellitus is itself increasing in Europe, both for IDDM and NIDDM.23 The prevalence of IDDM patients younger than 40 years and NIDDM patients in Germany is currently calculated to 0.22% and 4.82%, respectively.“,j It therefore comes as no surprise to any diabetologist and nephrologist to be told that diabetic nephropathy 10%8727/97/$17.00 PI1 SlO56-8727(96)00105-S

] Diab Camp 1997; 11:212-222

is now the commonest single cause of endstage renal disease. The most recent EDTA-Registry data for Europe available show that now the number of diabetic patients alive on renal replacement therapy is likely to be approached in 100,000.6 The overall rate of new patients accepted for renal replacement therapy was recorded as 17% for diabetics in 1992.6 The most recent report of the United States Renal Data System (USRDS) shows that, in 1992,33.8% of all new patients accepted for renal replacement therapy were either IDDM or NIDDM patients.7 A recent survey of 28 hemodialysis units all over Germany reported that 24.2% (16.6%41.6%) of individuals on dialysis were diabetic patients, of whom 34% had IDDM and 66% NIDDM6 and the estimated annual incidence of terminal renal failure with diabetes in a period from January 1993 to June 1994 was recently described as 52 per million per year in the lower Neckar region (Heidelberg, Germany)? The natural course and stages of diabetic nephropathy (glomerulopathy) have been well described for patients with IDDM and NIDDM.‘O,” Microalbuminuria (urinary albumin excretion rate of 30-300 mg/24 h) is an established marker of early renal damage (incipient nephropathy) and a reliable predictor of proteinuria (overt nephropathy) in patients with IDDM and NIDDM.12,13 A substantial number of patients with diabetic nephropathy die before reaching endstage renal failure, since diabetic nephropathy confers an increased risk of macrovascular disease.14 A stratified random sample of almost 5000 diabetic patients aged 35-55 years participating in the World Health Organization (WHO) Multinational Study of Vascular Disease in Diabetes has been followed up from 1975 to 1987. The recent report of the study clearly indicated that patients with both hypertension and proteinuria experienced a strikingly high mortality risk: 11-fold for men with IDDM, 18-fold for women with IDDM, fivefold for men with NIDDM, and eightfold for women with NIDDM.15 A recent cohort study on the predictive effect of slightly elevated urinary albumin excretion in development of atherosclerotic vascular disease clearly demonstrated that patients with microalbuminuria had 2.5 times higher risk of atherosclerotic vascular disease than those with lower excretion rates.16 They also found that a 5 mg increase in 24 h urinary albumin excretion increased the risk of atherosclerotic vascular disease by 6%. The predictive effect of albuminuria was independent of conventional atherogenic risk factors and of development of diabetic nephropathy, and duration and control of diabetes. The pathogenesis of diabetic nephropathy is multifactorial, and hypertension is one of the most relevant factors involved in the progression of diabetic nephropathy and in the development of endstage renal disease in both IDDM and NIDDM.‘7-20 Because the kidney of the diabetic patient is more susceptible to

PREVENTION

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any threshold, and because these individuals carry an increased risk of atherosclerosis and cardiovascular disease, it has been proposed that blood pressure control should commence as early as possible and, at the latest, when microalbuminuria becomes apparent.21 Prevention of diabetic nephropathy can be considered at the primary, secondary, and tertiary level. This paper does not deal with primary prevention, i.e., prevention of the development of incipient nephropathy (microalbuminuria), as there is no reliable marker available to identify subjects at risk of developing microalbuminuria. From the several measures to prevent and slow down the progression of diabetic nephropathy, only antihypertensive therapy will be considered on both the secondary level, i.e., the halt of the progression of incipient nephropathy to overt nephropathy, and on the tertiary level, i.e., the attempt to arrest the development of endstage renal failure in patients with established diabetic nephropathy (macroalbuminuria). PATHOGENESIS DIABETIC

AND RISK FACTORS NEPHROPATHY

OF

The classical histopathological features of diabetic nephropathy are thickening of the glomerular and tubular basement membranes, mesangial expansion, and nodular (Kimmelstiel-Wilson) and diffuse glomerulosclerosis due to progressive accumulation of extracellular matrix components, tubular interstitial fibrosis, and hypertrophy of both glomerular and tubular elements. These features are identical in IDDM and NIDDM.” The pathogenesis of diabetic nephropathy is still not fully understood but is likely to be multifactorial. Intrarenal hemodynamic alterations, accumulation of sorbitol, and glycosylation of glomerular proteins are all thought to be involved in the pathogenesis of diabetic nephropathy. 2s26 In insulin-dependent diabetic patients with poor glucose control, which may initially increase albumin excretion rate, an early rise of arterial pressure and smoking were implicated in the development of persistent microalbuminuria.27 There is evidence that genetic predisposition plays a major role in the development of diabetic nephropathy, clustering within families, both in IDDM and NIDDM.2S,29 The responsible gene is not known, but the genes of the renin-angiotensin systems have been considered candidate genes. Recent data, however, indicated that, in patients with IDDM, the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene is related to the presence of nephropathy,30 but this was not confirmed in another study.31 Furthermore, it has been suggested that the risk of developing clinical nephropathy in IDDM patients is associated with a genetically determined predisposition to essential hypertension mediated by an altered Na/Li-countertransport activity assessed in red blood

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1997; 71:112-12’

Normoglycemia (by Islet-TX) (3)

t t

Protein r?fMriction (4) Antihypertensives (5)

TGF-P mRNA TGF-0 Serumconc.

TGF-/3 Antibody (6) Protein restriction (7)

FIGURE 1 Simplified schematic drawing of the pathophysiology 44; (5) 45; (6) 40,46; and (7) 47,48.

of diabetic nephropathy.

ce11s,32,33 whereas in two other studies these data could not be confirmed.34,35 Hyperglycemia and hypertension play a crucial part in the development and progression of diabetic nephropathy (see Figure 1). Growth factors, and among them transforming growth factor-B (TGF-B) as a key factor, may act as mediators between hyperglycemia/ hypertension and the stimulation of mesangial cells toward overproduction of extracellular matrix (collagen type Iv, type V) (see Figure 1). It has been clearly demonstrated in animal experiments that glomerular expression of the key mediator TGF-B is stimulated by hyperglycemia and/or hypoinsulinemia, hemodynamic factors, the renin-angiotensin system (angiotensin II), insulinlike growth factor (IgF-I) and by activation of protein kinase C.36 The pathogenetic factors involved in the development and progression of diabetic nephropathy and interventions on different levels have been investigated in extended animal experiments.3742 Interventions, such as establishing normoglycemia by islet transplantation, dietary protein restriction, antihypertensive treatment, and application of TGF-B antibodies, proved as efficient in prevention of the development and progression of diabetic glomerulosclerosis.m8 From clinical work, it is accepted that poor glycemic control is an important risk factor for the development of diabetic nephropathy.49 It is therefore reasonable to propose that meticulous glycemic control is important in prevention and delaying the progression of diabetic nephropathy. This has been best demonstrated by two prospective studies in IDDM.50,51 The benefits of strict glycemic control should apply in NIDDM as well. In-

deed, a recent prospective study of NIDDM patients clearly demonstrated the beneficial effects of strict glycemic control on the progression of nephropathy in NIDDM,52 although these Japanese patients were quite different from NIDDM patients in Western countries, as they were lean, normotensive, and normolipemic. Hyperlipoproteinemia (hypercholesterimia) was implicated as a possible risk factor for diabetic nephropathy in IDDM and NIDDM, and patients with diabetic nephropathy and low serum cholesterol tend to show a slower decline in renal function than those with a high serum cholesterol. 5354It is therefore reasonable that, in patients with nephropathy and nephrotic syndrome, treatment with lipid-lowering substances was accompanied by a delay of the progression of nephropathy, at least two studies.55,56 Renal function and structure are significantly influenced by dietary protein load. Therefore, dietary protein restriction has been shown to delay the progression of renal failure in patients with IDDM and NIDDM patients may also benefit from it.57-M) Earlier findings that cigarette smoking may contribute to the development and progression of diabetic renal disease have been recently confirmed in two larger studies.61,62 Besides these multiple factors mentioned, hypertension plays a crucial part in the development and progression of nephropathy, both in IDDM and ‘NIDDM. Several recent studies have reconfirmed earlier findings that high blood pressure is associated with microalbuminuria or a decline in glomerular filtration rate, or both.63”5 In subjects with IDDM, elevated blood pressure may accompany rather than precede an in-

References: (1) 37-40; (2) 41,42; (3) 43; (4)

] Diab Comp 1997; 11:112-122

PREVENTION

crease in microalbuminuria, whereas, in NIDDM patients, elevated blood pressure may be detected prior to elevated albumin excretion rates. These findings suggest that high blood pressure may be a consequence, as well as a cause of diabetic nephropathy, even in its earliest stages. According to the latest guidelines regarding blood pressure control by the National High Blood Pressure Education Program Working Group on Hypertension in Diabetes, intervention (change in life-style and, if required, pharmacologic therapy) has been recommended for blood pressure of 140/90 mm Hg or greater, with target blood pressure of 130/85 mm Hg or less.‘j6 In an earlier study, the risk for progression of diabetic nephropathy was unlikely if a target mean arterial blood pressure of 100 mm Hg or less was met.67 ANTIHYPERTENSIVE AND DIABETIC

TREATMENT NEPHROPATHY

As early as 1907, Geheimrat van Noorden had described elevated blood pressure in diabetes associated with albuminuria, nephritis and renal atrophy.@ The syndrome of diabetes, hypertension, and albuminuria first appeared as the title of a paper in 1939.‘j9 Initial intervention studies with antihypertensive treatment were published in the early 198O~.~O,~lBoth studies clearly demonstrated that antihypertensive treatment could ameliorate the decline in glomerular filtration rate in patients with IDDM. Microalbuminuria and Glomerular Filtration Rate. Microalbuminuria, defined as urinary albumin excretion rate of 30-300 mg/24 h, is a strong indicator of incipient nephropathy and a strong predictor of overt nephropathy both in IDDM and NIDDM. As such, it serves two important roles in the design of secondary and tertiary prevention strategies. First, it can be used to identify subjects at higher risk for progression to overt nephropathy (urinary albumin excretion > 300 mg/24 h) and second, it can serve as an outcome in itself in trials aimed at preventing the progression of albuminuria into or through the microalbuminuric range. Twenty-four hour, overnight, timed, and spot urine collections have been used to estimate the albumin excretion rate, and reliable and predictive bedside screening tests are already available to analyze the urine for albumin.72 Microalbuminuria may develop very early in the course of diabetes as demonstrated in the cross-sectional EURODIAB IDDM Complications Study.” The prevalence of microalbuminuria among subjects who had had diabetes for less than 5 years was found to be 19%. In subjects with newly diagnosed NIDDM, urinary albumin concentration was found to be twice as high as in age-matched nondiabetic controls.74 In a recent overview on 14 studies in a wide NIDDM

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population, a cumulative prevalence rate of 24% was describedY5 According to data from several studies, an annual progression rate of 20%-35% for the microalbuminuria is to be expected.76 Albuminuria was ascribed a surrogate end point for the cause of diabetic nephropathy. There is now a bulk of evidence, however, that urinary albumin excretion rate will also predict long-term renal function, and may not simply represent a marker of renal disease. It may even pathogenetically contribute to its evolution: reduction in albuminuria predicted diminished progression in diabetic nephropathy;77 short-term antiproteinuria response to antihypertensive treatment predicted long-term glomerular filtration rate (GFR) decline in patients with nondiabetic renal disease;78 proteinuria may be a direct cause of renal morbidity and in particular glycated albumin affects mesangial cells and may play an important role in the pathogenesis of diabetic nephropathy.79,80 Trials in IDDM and NIDDM Patients with Incipient Nephropathy (Microalbuminuria). The presence of microalbuminuria indicates the need to search for cardiovascular risk factors, treatment, where appropriate, for titer glycemic control, for modest restriction of protein intake, and cessation of smoking. It further needs the treatment of even modest elevations of blood pressure by inventing nonpharmacological measures as reduction of salt intake and life-style changes. The choice of antihypertensive drug therapy represents special problems in the diabetic patient. Most recently, it has become clear that essential hypertension widespread in diabetic patients is an insulin resistant state.81,82Moreover, it has been shown that treatment with diuretics and B blockers aggravates insulin resistant and leads to a worsening of glucose tolerance, despite an increase in circulating plasma insulin levels.83,84Unfortunately, hyperinsulinemia has been implicated in the development of hypertension, dislipidemia, and atherosclerotic cardiovascular disease.76 Furthermore, both diuretics and B blockers promote a more atherogenic plasma lipid profile.85 These observations have led to a re-evaluation of the treatment of hypertension in both IDDM and NIDDM patients with emphasis on the use of angiotensin-converting enzyme inhibitors and calcium antagonists, drugs that either enhance insulin sensitivity or are metabolically neutral with regard to both glucose and lipid metabolism.86 Therefore, the following considerations of antihypertensive treatment on the primary, secondary, and tertiary prevention level are strictly devoted to observational studies using either ACE inhibitors or calcium antagonists. After the first intervention study in microalbuminuric patients several other studies have confirmed the

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TABLEl. PROSPECTIVE WITH MICROALBUMINURIA Substance

LONG-TERM STUDIES TREATED WITH

Patient Type

Duration

20* (I/II)

1

Perindopril

(31 YEAR) IN HYPERTENSIVE ANGIOTENSIN-CONVERTING Change in Albuminuria

(year)

Perindopril

49-35 (68-16 (51-19 (-

3 CA 10 (1)

Enalapril

1

mg/24 29%) mg/24 77%) mg/24 63%)

cornp

DIABETIC PATIENTS ENZYME INHIBITORS

Change in Kidney Function h

1997: 11:172-I.??

References

138-123 mL/min ( -11%) 94-96 mL/min ( + 2%) 103-87 mL/min (- 16%)

h h

(90) (91)

(92)

Enalapril

(93) tip, 6

Enalapril

1 1.25

(EL, 5844 ma/24 (-2&!&)

(11) Total/Mean *About

-~ 70%

...--. of the patients

60 with

.-. nomal

--.. blood

l-3

pressure

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- 53% ..-.

( -‘;‘R,, 59-79 mL/min ( + 34%)

h

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z 0%

_

(94) .~_

__

at start.

beneficial effect of antihypertensive treatment on the progression of diabetic nephropathy.s749 Based on these more or less short-term studies in hypertensive IDDM and NIDDM patients with microalbuminuria, prospective long-term studies with a follow-up of at least 1 year performed with either ACE inhibitors or calcium antagonists have been meanwhile reported (Tables 1 and 2). These long-term studies clearly show that strict blood pressure control in this early stage of diabetic nephropathy significantly reduces albuminuria, thus preventing progression to macroalbuminuria (overt nephropathy). As far as the effect on kidney function is concerned, the outcome was lessclear. Using ACE inhibitors, glomerular filtration rates either were maintained or slightly reduced, whereas, using the calcium antagonist nitrendipine (dihydropyridine type calcium antagonist), a 20%40% increase of glomerular filtration rate was observed along with significant reduction of albuminuria. It is still unclear whether the short-term diminution in glomerular filtration rate under the treatment with ACE inhibitors indicates a potentially adverse effect or simply the correction of hyperfiltration.These observational studies support the hypothesis that angiotensin-converting enzyme inhibitors and certain calcium antagonists have a unique ability, independent of their antihypertensive effect, to slow the progression of diabetic nephropathy. This hypothesis is further supported by the interesting findings that treatment with ACE inhibitors or calcium antagonists prevented progression to macroalbuminuria even in normotensive IDDM and NIDDM patients with microalbuminuria (see Table 3).97-‘“z Trials in IDDM and NIDDM Patients with Overt Nephropathy (Macroalbuminuria). Ten years ago, a beneficial effect of captopril on heavy proteinuria in

diabetic patients was first described.‘” Later on, additional studies have documented the beneficial effect of ACE inhibitors on macroalbuminuria and renal function in patients with IDDM and NIDDM.‘&‘Oh However, most of these studies have been relatively small, open-label, and of short duration and have not addressed critical end points such as mortality or progression to endstage renal disease. In this respect, the paper published by Lewis et al. in 1993 was regarded as a landmark study. In7In this study, the effects of captopril in IDDM patients with macroalbuminuria and serum creatinine levels of 2.5 mg/dL or greater, but normotensive (otherwise treated but not ACE inhibitors or calcium antagonists) were randomized to receive either captopril25 mg three times daily or placebo. The primary end point of the study was the rate of doubling of serum creatine, secondary end points included death or the need for dialysis or transplantation. The medium length of follow-up was 3 years and ACE treatment resulted in a 50% risk reduction for primary and secondary end points. As opposed to ACE inhibitors, the role of calcium antagonists in overt diabetic nephropathy is unclear because of the lack of large-scale trials. Diltiazem, verapamil, and nicardipine appeared to be of equal efficacy to ACE inhibitors, whereas isradipine was found to be less effective.‘@-“* Studies with the dihydropyridine type calcium antagonist of the first generation, nifedipine, are contradictory. In most of the short-term studies on overt albuminuria a worsening was observed.“) At least three meta-analyses of the effect of different antihypertensive drugs on diabetic nephropathy were published. “c116The recent extended meta-analysis of Weidmann’s group revealed the ACE inhibitors tend to preserve GFX in such patients better than conventional antihypertensive drugs or nifedipine117(see also Table 4). Considering the changes of mean blood pressure,

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TABLE

PREVENTION

2997; 11:212-122

2. PROSPECTIVE LONG-TERM WITH MICROALBUMINURIA Patient Type

Change in Albuminuria

1

59-48 mg/24 (-20%)

Nitrendipine

1 1

Nitrendipine

1

Nitrendipine

1.25

( -E& 114-58 mg/24 (-49%) 42-24 mg/24 (-54%) 47-29 mg/24 (-40%)

Total/Mean

1

Nifedipine

SLOWING

STUDIES (21 YEAR) IN HYPERTENSIVE DIABETIC TREATED WITH CALCIUM ANTAGONISTS

Duration (year)

Substance

AND

PATIENTS

Change in Kidney Function h

References

150-136 mL/min (-9%)

(90)

Nifedipine

*About

(93)

70% of the patients

with normal

blood pressure

Combination

Therapy.

This question is of clinical relevance because many diabetic patients with hypertension and renal disease

TABLE 3. STUDIES WITH ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITOR OR CALCIUM ANTAGONIST THERAPY IN NORMOTENSIVE INSULIN-DEPENDENT DIABETES MELLITUS (IDDM) OR NON-INSULINDEPENDENT DIABETES MELLITUS (NIDDM) PATIENTS WITH MICROALBUMINURIA (PREVENTION OF PROGRESSION TO MACROALBUMINURIA IN EACH STUDY) Type of Treatment ACE-inhibitors Type I diabetes

Type II diabetes Calcium-antagonists Type II diabetes

Substance Captopril Captopril Captopril Enalapril Nifedipine

h h h

(95) (92) (94)

-+15%

at start.

and GFR under treatment with different antihypertensives in diabetic subjects with micro- or macroalbuminuria, and adding data from three different studies with nitrendipine,9294,96 the following results emerged: Changes in GFR per year averaged -8% in patients on placebo; -9% in patients on diuretics and/ or l3blockers; -1% in patients on ACE inhibitors; +2% in patients on calcium antagonists other than nifedipine/nitrendipine; -48% in patients on nifedipine; and +30% in patients on nitrendipine. The differences observed within the group of calcium antagonists may be partially explained by different hemodynamic effects or by proposed different patterns of calcium channels and receptors on different target organs. for Antihypertensive

(Z%) 108-133 mL/min (+21%) 107-148 mL/min (+38%) 70-97 mL/min (+39%)

-36%

proteinuria,

Request

117

DOWN

References 97 (99,91soO) 101 102

require the combination of various antihypertensive drugs to effectively control their hypertension. The concept of combination therapy is attractive also from a pathophysiological aspect, as it is likely that, in arresting progression of renal failure, the salutary effects of ACE inhibitors and calcium antagonists are complementary and probably synergistic.“8-‘20 Two initial reports of such long-term combination therapy in IDDM or NIDDM with nephropathy are very promising.‘21,‘22 However, whether combination therapy will offer any

TABLE 4. CHANGES (%/YEAR) OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE (GFR) UNDER TREATMENT WITH DIFFERENT ANTIHYPERTENSIVES IN INSULINDEPENDENT DIABETES MELLITUS (IDDM) AND NON-INSULIN-DEPENDENT DIABETES MELLITUS (NIDDM) SUBJECTS WITH MICROOR MACROALBUMINURIA Type of Treatment Placebo Conventional* ACE inhibitors Calcium antagonists l all except Nif/Nit l Nifedipine l Nitrendipine * Diuretics

and/or

n

AMBP (%)

AUProt (%)

AGFR (%)

244 213 489

-2 -10 -16

+39 -20 -52

-1

63 63 39

-16 -12 -17

-42 +2 -48

i-2 -48 +30

-8 -9

p blockers.

n, number of patients included; MBP, urinary protein; ACE, angiotensin-converting nitrendipine.

mean blood pressure; UProt, enzyme; Nif, n$dipine; Nit,

Data adaptedfiom the meta-analysis of Weidman et al. 1995 (reference 117) and of three different studies using nitrendipine (references 92, 94, and 96).

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KRETZEL

benefits in prolonging yet known.

overall

or renal survival

is not

CONCLUSION People with diabetes are prone to many other complications, both acute and late. The complications of diabetes result in increased hospitalizations, disability, and death. In the United States where the prevalence of diabetes is approximately 7% in adults, between 1987 and 1992, the total (direct and indirect) costs of diabetes more than quadrupled, from U.S. $20.4 billion to U.S. $91.8 billion, and the direct medical costs (U.S. $45.2 billion) alone represent 5.8% of the total personal health-care expenditures in the United States.m The estimated prevalence of IDDM and NIDDM worldwide was reported for 1994 as 11.5 million people and 98.9 million, respectively. lz4 The authors expect more than a doubling of these prevalence rates by the year 2010 with 23.7 million people having IDDM and 215.6 million people having NIDDM worldwide. Due to the increasing numbers of diabetic patients, the excessive morbidity and mortality particularly of those with nephropathy, and the high costs associated with dialysis and renal transplantation, the present huge socioeconomic burden of diabetes may even exponentially increase. Therefore, prevention would be beneficial in economic terms quite apart from the benefits to the health of individuals and society. Recently published data provide a basis for preventive strategies both on the secondary and tertiary level. In particular, aggressive blood pressure control, especially monotherapy or combined therapy with ACE inhibitors and the calcium antagonists of the verapamil, dilthiazem, or nitrendipine classes, promises to reduce the risk of diabetic endstage renal disease by 50% or more. It is thus of particular interest that a recent computer-simulated cost-benefit study on the impact of screening and intervention for microalbuminuria, the indicator and predictor of renal and cardiovascular lesions in IDDM, described that, assuming treatment effects of 33% and 67%, respectively, the medium life expectancy increased by 4-14 years, respectively, and the need for dialysis or transplantation decreased by 21% and 63%.12” Costs and savings would balance if the annual rate of increase of albuminuria was decreased from 20 to 18% a year. Moreover, data based on the Lewis et al. triallo suggested that if all diabetic patients (both IDDM and NIDDM) with nephropathy were started on ACE inhibitor, captopril, in 1994, it would prolong life and save the health-care system over U.S. $2 billion by the year 2004. ‘26 Another cost-benefit analysis on the economic savings with ACE-inhibitor therapy (captopril) was recently published.127 To conclude, screening programs or detection of the earliest stage of diabetic nephropathy (microalbuminu-

ria) should be performed on a regular basis, and intervention programs, including strict blood pressure control, should commence as early as possible or at the latest, when microalbuminuria becomes apparent. This screening and intervention strategy is likely to improve quality of life, have life-saving effects, and lead to considerable economic savings. REFERENCES 1.

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