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Anastasios N. Lasaridis, 1 First Department of Internal Medicine, Faculty of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital , Thessaloniki , Greece First Department of Internal Medicine, AHEPA University Hospital , St Kiriakidi 1, 540 06, Thessaloniki , Greece . E-mail: Search for other works by this author on: Panteleimon A. Sarafidis1 First Department of Internal Medicine, Faculty of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital , Thessaloniki , Greece Search for other works by this author on: Received: 09 October 2002 Accepted: 27 February 2003 Published: 01 August 2003
Close Navbar Search Filter Microsite Search Term Search AbstractDiabetic nephropathy is the most serious problem among current issues in nephrology, as 40% of the cases of end-stage renal disease are due to this entity. The close relationship between type 2 diabetes and hypertension makes the problem even more severe. The knowledge of the intrarenal effects of angiotensin II and the greater effect of angiotensin converting enzyme inhibitors (ACEI) on reducing albuminuria suggested in the past a trend toward preferable use of these drugs in diabetic nephropathy. The first relevant clinical trials yielded rather poor conclusions because of lack of blind randomization and short duration. Subsequent double-blind studies with adequate numbers of patients and sufficient duration underlined the importance of blood pressure (BP) control as well as the rather poor response of diabetic nephropathy to any treatment. In most of these studies, the changes in albuminuria or microalbuminuria were a substitute end point for the renal function. Three clinical trials using angiotensin II receptor blockers (ARB), planned specifically to monitor the progression of renal damage, have been recently published. They showed better renal protection by ARB, as compared with placebo or calcium channel blockers (CCB), beyond or independently of the BP reduction. Nevertheless, these recent trials, like the previous ones with similar results, invariably demonstrate slightly better control of BP in the groups of the active drug. Another issue is that the vast majority of the patients need so many nonstudy drugs to keep their pressure under control, that the isolation of advantageous effects of certain drugs seems unrealistic. Diabetes mellitus (DM) is one of the strongest independent risk factors for cardiovascular disease (CVD).1 Over the last decades, a dramatic increase in the incidence of DM has emerged, which affects up to 5% to 6% of the population, particularly in developed societies.2 This increase is the exclusive result of a rise in the incidence of type 2 DM, which is about 15- to 20-fold more frequent than type 1.3 Hypertension is also particularly frequent and shows a strong association with type 2 DM, which starts through the metabolic syndrome.4,5 According to recent views of the so-called physiologic levels of BP in relation to coexisting risk factors for CVD, 70% of type 2 diabetic patients are also hypertensive, and this percentage goes up to 90% if microalbuminuria is present.6,7 In practical terms, this means that the diabetic patient with nephropathy and hypertension presents a unified problem. The first sign of renal involvement in diabetic patients is usually microalbuminuria. Microalbuminuria is defined quantitatively as albumin 30 to 300 mg/24 h urinary excretion; in timed urinary collection as 20 to 200 μg/min; or in spot specimen as 30 to 300 mg albumin/g creatinine.8,9 Every value below the lower limit is taken as indicating normoalbuminuria, whereas every value above the upper limit is taken as macroalbuminuria or simply as albuminuria. Diabetic patients with microalbuminuria are considered as having incipient nephropathy, whereas their progression to macroalbuminuria is considered as a sign of clinical or overt nephropathy.9,10,11 The development of nephropathy is more rapid when micro- or macroalbuminuria is present.9,11,12 Diabetic nephropathy is different between type 1 and type 2 DM in terms of pathology and clinical course. This does not mean, however, that the course is less severe in type 2 DM. Many studies support a similar rate of renal function decline, which can reach a reduction in glomerular filtration rate (GFR) of 7 to 10 mL/min per year.13,14,15,16 Finally, during the past few years, nephrologists have observed that the majority of patients who enter dialysis units are patients with diabetic nephropathy. Extensive statistical series show that their percentage goes up to 40% of the total end-stage renal disease population.17 Thus, interest in finding the most suitable methods to slow down the development of diabetic nephropathy is quite reasonable. Clinical trials using angiotensin converting enzyme inhibitors, calcium channel blockers, β-blockers, and diureticsIn analyzing these studies, we are following a chronological order because we think that this illustrates better the development of methods, inclusion criteria and sample size, and duration of clinical trials so that more and more questions are progressively answered. Many clinical trials concerning the action of drugs (mainly dihydropyridines and ACEI) on the course of diabetic nephropathy were published at the beginning of the 1990s. They were characterized by short duration (usually 6 to 12 months) and small numbers of patients. Sometimes patients with either type 1 or type 2 DM were included in the same study. Changes in albuminuria and renal damage ranged from insignificant to extremely impressive in both drug groups.18 A critical review of these trials reveals that they cannot be considered to make a reliable contribution to understanding the problem. The most well known study, that of the Collaborative Study Group, published in 1993, showed an impressive reduction (43%) in the doubling serum creatinine in the ACEI-treated patients in relation to those on placebo.19 (Table 1). This study was performed in 409 type 1 diabetic patients with nephropathy (albuminuria >500 mg/day) and mild renal insufficiency (serum creatinine ≤2.5 mg/dL). There was a double-blind administration of captopril or placebo in addition to any other regimen for a 3-year period. However, both systolic BP (SBP) and diastolic BP (DBP) were slightly higher in the placebo group during randomization (albeit without statistical significance), a difference that was maintained during the whole follow-up. Baseline albuminuria was also higher in the placebo group than in the captopril group (P < .02). Albuminuria was generally lower in the captopril group during follow-up (P < .001). Table 1 Trials comparing intensive versus regular or active versus placebo blood pressure control: effects on albuminuria and renal function
BP = blood pressure; DBP = diastolic BP; MBP = mean BP; SBP = systolic BP; IND = Renoprotective Effect of the Angiotensin Antagonist Irbesartan in Patients With Nephropathy Due to Type 2 Diabetes; IRMA = Effect of Irbesartan in the Development of Diabetic Nephropathy in Patients With Type 2 Diabetes; NR = not reported; ns = not significant. * DM1/DM2 = diabetes mellitus type 1/or 2; MA = microalbuminuria, subclinical nephropathy; ON = overt nephropathy; † ACEI = angiotensin converting enzyme inhibitors; βB = β-blockers, D = diuretics, CCB = calcium channel blockers, PI = placebo plus nonstudy drugs if needed, ARB = angiotensin receptor blockers (for IRMA the two doses of 300 mg and 150 mg are shown, for IDNT the groups of active drugs are two). ‡ Difference of SBP/DBP mm Hg of the first treatment from the second is shown, (−) = less BP in the first treatment, if one number is shown it represents MBP. § Percent reduction in risk of doubling of serum creatinine. ∥ Absolute decrease in g/day during follow-up. ¶ Percentage of patients progressing to overt nephropathy. # Decrease in glomerular filtration rate mL/min/1.73 m2/month. ** Percentage reduction of proteinuria. †† Median SBP during follow-up. ‡‡ Median MBP during follow-up §§ Percent reduction in risk of approaching the composite end points of the first treatment versus second or third. Renal function deterioration was not an end point in these trials. Table 1 Trials comparing intensive versus regular or active versus placebo blood pressure control: effects on albuminuria and renal function
BP = blood pressure; DBP = diastolic BP; MBP = mean BP; SBP = systolic BP; IND = Renoprotective Effect of the Angiotensin Antagonist Irbesartan in Patients With Nephropathy Due to Type 2 Diabetes; IRMA = Effect of Irbesartan in the Development of Diabetic Nephropathy in Patients With Type 2 Diabetes; NR = not reported; ns = not significant. * DM1/DM2 = diabetes mellitus type 1/or 2; MA = microalbuminuria, subclinical nephropathy; ON = overt nephropathy; † ACEI = angiotensin converting enzyme inhibitors; βB = β-blockers, D = diuretics, CCB = calcium channel blockers, PI = placebo plus nonstudy drugs if needed, ARB = angiotensin receptor blockers (for IRMA the two doses of 300 mg and 150 mg are shown, for IDNT the groups of active drugs are two). ‡ Difference of SBP/DBP mm Hg of the first treatment from the second is shown, (−) = less BP in the first treatment, if one number is shown it represents MBP. § Percent reduction in risk of doubling of serum creatinine. ∥ Absolute decrease in g/day during follow-up. ¶ Percentage of patients progressing to overt nephropathy. # Decrease in glomerular filtration rate mL/min/1.73 m2/month. ** Percentage reduction of proteinuria. †† Median SBP during follow-up. ‡‡ Median MBP during follow-up §§ Percent reduction in risk of approaching the composite end points of the first treatment versus second or third. Renal function deterioration was not an end point in these trials. In the same year, a meta-analysis was published that included 100 studies with 2494 diabetic hypertensive patients. Half of the studies concerned type 1 DM, 32 type 2 DM, and 11 a mixed population. Only 27% of the trials lasted > 6 months and 13% > 1 year. Half of the studies had only one group of patients with active drug treatment, and only 12 had random allocation to the drug groups. The conclusion of this analysis was that ACEI can reduce albuminuria and preserve renal function better than could have been expected due to BP reduction.20 Another meta-analysis, published 2 years later, included 58 studies with 2151 diabetic hypertensive patients. The study population included both type 1 and type 2 diabetic patients. The minimum duration of study, as a criterion for inclusion, was 4 weeks. The mean duration of follow-up was <1 year. The analysis reached the conclusion that ACEI reduce albuminuria and preserve renal function better than other drugs. The antiproteinuric effect of ACEI was independent of BP reduction, and this was not observed in the other drug groups. However, the patient groups presented differences in the initial GFR and albuminuria. In CCB groups, GFR was lower and albuminuria higher than in ACEI groups at baseline.21 In another meta-analysis, only studies that lasted > 6 months were included, of which some were randomized and others not. The researchers finally concluded that the gain in albuminuria and GFR preservation related to BP reduction, and that ACEI (and possibly the nondihydropyridine CCB) confer, a positive effect in addition to reduction of BP.22 The mixed type 1 and type 2 diabetic (DM) population, the very short follow-up, and the lack of blind randomization are the most obvious disavantages of all of these analyses. In 121 hypertensive patients with type 2 DM, clinical or subclinical albuminuria, and GFR 30 to 100 mL/min, Lebovitz et al23 compared the effect of enalapril with control treatment (not including ACEI) for 3 years. The change in albuminuria and rate of decline in GFR in both the clinical nephropathy group and in the study population overall was in favor of the ACEI, but it did not reach statistical significance. Mean BP (MBP) was exactly the same in the two groups with clinical nephropathy during follow-up. In the group of patients with < 300 mg/24 h albuminuria, fewer patients progressed to overt albuminuria (7% v 21%) in the ACEI versus the placebo group, and the rate of GFR decline was 0.20 v −0.33 mL/min/1.73 m2/month, P < .004, respectively (Table 1). The mean BP was 4.9 mm Hg lower in the ACEI group (P < .0001). In another small, double-blind, 3-year follow-up study,24 43 hypertensive patients with type 2 diabetes were randomized to either lisinopril or atenolol, usually combined with a diuretic. Overt albuminuria was 961 mg/24 h and 1578 mg at baseline in the ACEI and β-blocker + diuretic group, respectively. Ambulatory BP was also lower in the ACEI group and had a greater decrease during follow-up. A difference of −4/−1 mm Hg for SBP and DBP was maintained during follow-up in favor of the ACEI group. The reduction of albuminuria was by 48% greater in the ACEI group (−55% and −15% reduction in each group, P < .01), as shown in Table 1. Nevertheless, the sustained change in GFR was pretty much the same in the two groups. One year later, the United Kingdom Prospective Diabetes Study (UKPDS) was published. This study is considered from many different points of view as a landmark in the perception of the hypertensive diabetic patient treatment.25,26,27 It was reported that UKPDS 3325 showed, in 3867 patients with type 2 DM, that strict control of blood glucose significantly improved microangiopathy (retinopathy, nephropathy) but did not affect macroangiopathy (coronary heart disease, brain vascular disease, peripheral vascular disease) in relation to results achieved with conventional treatment. In comparison, UKPDS 3826 showed, in 1148 hypertensive type 2 diabetic patients followed-up for 9 years (about three times the usual duration of other similar studies), that tight control of BP reduced the incidence of acute myocardial infarction by 21% and of stroke by 44% as compared with less tight control. The BP achieved with tight control was 144/82 and with moderate control was 154/87, which means that a systolic/diastolic 10/5 mm Hg difference in BP turned out to be more important than intensive control of the metabolic syndrome. This study, together with the Hypertension Optimal Treatment (HOT) study,28 were the strongest indications for the guidelines of World Health Organization and International Society of Hypertension (WHO–ISH) about the importance of reducing BP to <130/85 mm Hg in diabetic hypertensive patients.29,30 The retardation of microvascular disease in the tight control group was 37%, but this was mainly due to an improvement in retinopathy. The improvement in microalbuminuria and the progression to overt (clinical) nephropathy showed statistically significant differences between patients with tight control of BP and moderate control in year 6 of the study, a difference that disappeared in year 9. There was no difference in serum creatinine concentration or in the proportion of serum creatinine doubling between the two groups. In the third part of the study, UKPDS 39,27 a comparison of the effectiveness of captopril with atenolol as basic therapy took place. Both drugs achieved the same levels of BP with similar percentage of additional, nonstudy drugs, at 27% and 31%, respectively. The progress from subclinical to clinical nephropathy was 5% and 9%, respectively, with no statistically significant difference between them. There was also no difference in plasma creatinine concentration or in the rate of plasma creatinine doubling between the two groups. In a small open study, Steno type 2, published by Gaede et al,31 the results of intensive and regular treatment of hypertension, hyperglycemia, and dyslipidemia were compared in 149 type 2 diabetic patients with microalbuminuria for 4 years. In the end of follow-up, the SBP/DBP was lowered by 7/3 mm Hg in the group with intensive treatment. Development of clinical nephropathy was far less common in this group. We cannot, however, draw conclusions for the advantages of a particular drug treatment, because almost all of the patients received captopril. The Appropriate Blood Pressure Control in Diabetes trial (ABCD) compared enalapril with nisoldipine over a 5-year period in patients with type 2 diabetes, with or without hypertension, and with normo-, micro-, or macroalbuminuria. In addition, the study allocated patients to moderate treatment (DBP goal, 80 to 89 mm Hg) or intensive treatment (DBP goal, <75 mm Hg). In 470 hypertensive type 2 diabetic patients,32 the intensive treatment resulted in 6/8 mm Hg lower SBP/DBP than in the moderate treatment group. Progression of normoalbuminuria to microalbuminuria was 25% v 18% in the intensive and moderate treatment groups, respectively (data not shown). Progression of microalbuminuria to overt albuminuria was 16% v 23%, respectively. Both differences were without statistical significance. Creatinine clearance over the 5-year period was identical in the two groups. The comparison between enalapril and nisoldipine yielded similar numbers of patients progressing from normo- to micro- and macroalbuminuria in the two groups. The mean of the logarithmic transformation of the albumin excretion was lower in the enalapril group up to the 3.5-year point (P < .05). The difference then became insignificant up to the end of the study. The rate of decline in creatinine clearance was identical in the two drug groups. In the Heart Outcomes Prevention Evaluation (HOPE) study, 9247 patients at high risk for CVD, with or without hypertension, were followed-up for 5 years. Of these patients, 3577 had DM, mainly type 2, without clinical nephropathy (MICRO-HOPE study). The patients were randomly allocated into two groups. In the first group, 10 mg ramipril was added, and in the second group, placebo was added to any other prescribed treatment. In patients with DM, SBP decreased by 1.92 mm Hg in the ramipril group, whereas it increased by 0.55 mm Hg in the placebo group. The urinary albumin/creatinine ratio was slightly lower in the ramipril group (P < .02). Progression from subclinical to overt nephropathy was 6% in the ramipril and 7% in the placebo group (P = .07). Overall, the microvascular end points (photocoagulation, hemodialysis, clinical nephropathy) were 16% less in the ramipril group (P < .04). Measurements of renal function were not included in the trial.33 In another study, 44 hypertensive patients with type 2 diabetes and either normo- or microalbuminuria were allocated to cilazapril or amlodipine treatment and followed-up for 3 years.34 A similar decrease in BP was achieved in the two groups, as well as a similar decline in GFR (estimated by 51 Cr-EDTA), which was slightly higher in the microalbuminuric patients. The albumin excretion rate was also equally decreased from the two drugs. The GFR fall was negatively related to the mean BP decrease in total (r = −0.80, P < .0001). In another trial, 52 type 2 diabetic hypertensive patients with overt proteinuria (>2 g/day) and mild renal insufficiency were openly allocated to lisinopril, nondihydropyridine CCB (NDCCB) and atenolol. The mean follow-up was 5.5 years.35 The ACEI and NDCCB decreased proteinuria to a similar degree, whereas atenolol to a significantly smaller degree (P < .01). The rate of GFR decline was also similar in the first two drug groups but in the atenolol one was faster (P < .01). The authors concluded that the slowing of the renal disease progression correlated with the reduction in albuminuria attained by ACEI and NDCCB but not by the β-blocker. Although without statistically significant difference, the atenolol group had a few more African American patients, higher proteinuria, and higher BP at baseline, which remained higher throughout the study. Three double-blind studies tested the action of ACEI versus placebo in patients with DM, normo- or microalbuminuria, and normal BP.36,37,38 Two of these studies concerned type 1 DM and lasted 2 years, and the third concerned type 2 DM and lasted 6 years. Overall, the study investigators found small but significant differences in the level of microalbuminuria or its progression in favor of the active drug. On the other hand, they found BP that was 2 to 7 mm Hg lower in the ACEI groups throughout the follow-up. Recent studies with angiotensin II receptor blockersBefore analyzing the three publications on the use of angiotensin II receptor blockers (ARB) in diabetic nephropathy, we should consider whether ARB act in a way that is different from ACEI from the clinical point of view. These two groups of drugs inhibit the renin-angiotensin system (RAS) at a different point. In the mechanism of action of ACEI bradykinin is very likely to take part, whereas ARB act only via inhibiting the action of angiotensin II. This difference has been shown in experimental studies on renal hemodynamics39 but not in similar studies in humans.40 Apart from that, a large clinical study, the Losartan Heart Failure Survival study (ELITE II) showed similar morbidity and mortality with either losartan or captopril in patients with heart failure over a 2-year follow-up period.41 Smaller but more specific studies showed, in patients with diabetic nephropathy, that the reduction of albuminuria and the retardation of the progress of renal damage were exactly the same in the groups of ACEI and ARB.42,43 In conclusion, so far there are no indications of a difference in action between ACEI and ARB in clinical practice. Three trials studying the effect of ARB on diabetic nephropathy were published at the end of 2001. Two of them used irbesartan: the Effect of Irbesartan in the Development of Diabetic Nephropathy in Patients With Type 2 Diabetes (IRMA) in patients with microalbuminuria,44 and Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients With Nephropathy Due to Type 2 Diabetes (IDNT) in patients with clinical diabetic nephropathy.45 The third trial, Effects of Losartan on Renal and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Nephropathy (RENAAL), used losartan in patients with overt diabetic nephropathy.46 In the IRMA study, 590 diabetic hypertensive patients (BP >130/85 mm Hg) with microalbuminuria were randomly assigned to receive placebo or irbesartan 150 mg or 300 mg daily. The primary end point was the appearance of clinical nephropathy, ie, albuminuria > 200 μg/min and at least a 30% increase from the baseline level. The study lasted for 2 years, and the approach of the three groups to the end point was 14.9%, 9.7%, and 5.2% respectively. The difference was not statistically significant between placebo and irbesartan 150 mg, but it was significant between placebo and irbesartan 300 mg (P < .001). The mean BP throughout the study was 144/83 in placebo group, 143/83 in 150 mg group, and 141/83 in 300 mg irbesartan group, P = .004. It is worth noting that the irbesartan 150 mg and placebo groups with similar BP showed no significant difference in the primary end point percentage. Although the study determined BP >135/85 mm Hg as indicating hypertension, in the placebo group only 56% of the patients received antihypertensive treatment. In the active drug groups, the compliance of patients as determined by the number of tablets taken was 89% in the 300 mg and 81% in the 150 mg group. In the placebo group, the compliance was not reported. Although without statistical significance, GFR presented a decrease in the 300 mg group, which was unchanged until the end of the study. It is also well known that albuminuria declines when GFR decreases.44 In IDNT,45 1715 hypertensive type 2 diabetics were randomly assigned to placebo, 10 mg amlodipine, or 300 mg irbesartan with a BP goal of 135/85 mm Hg. The inclusion criteria required a serum creatinine of 1 to 3 mg/dL and a urinary protein excretion > 900 mg/24 h. The study's end points were doubling of serum creatinine, hemodialysis, or death from any cause. After a mean follow-up of 2.6 years, the composite of end points in the irbesartan group was 20% lower than in the placebo and 23% lower than in amlodipine group, both statistically significant. Proteinuria was decreased by 33% in the irbesartan, 6% in the amlodipine, and 10% in the placebo group. The mean rate of decline of creatinine clearance was −5.5, −6.8, and −6.5 mL/min per 1.73 m2 per year, respectively. The MBP in the placebo group was 3.3 mm Hg higher than in the active drug groups throughout the study (P = .001). The difference in favor of irbesartan in reaching the composite end point remained significant even after statistical adjustment for BP differences. The same holds true for the previous study as well. Regarding the tablets of the nonstudy drugs, all groups received similar numbers. Patients in the placebo group received an average of 3.3 tablets of nonstudy drugs, although they continuously showed worse BP, whereas the active treatment groups received an average of 3.0 nonstudy drugs. As far as the racial assignment is concerned, the placebo and the amlodipine groups had fewer white patients and by 3% and 4%, respectively, more African American patients than the irbesartan group. The authors do not comment on the possibility of this fact to affect the final outcome, taking into account that African American hypertensive patients have a 6-fold higher incidence of end-stage renal insufficiency than corresponding white individuals.47 In the third of these clinical trials,46 50 to 100 mg of losartan was administered daily versus placebo in 1513 patients with type 2 DM and nephropathy for 3.5 years. The patients should have serum creatinine <3 mg/dL and urinary protein should be >0.5 g/24 h. The risk of reaching the primary end points, which were the same with the previous study were 16% lower (P < .02) in the losartan group. The albumin/creatinine ratio decreased by 35% by losartan and remained unchanged in the placebo group (P < .001). The median rate of decline in estimated clearance was 4.4 and 5.2 mL/min/1.73 m2/ per year in the losartan and placebo group, respectively. The SBP was 2 to 4 mm Hg higher in the placebo group throughout the study. The MBP was higher in the placebo group and the difference was significant for the first year (P < .001). The percentages of the addition of non–study drugs in the placebo group versus losartan were only 3% higher for CCB, 3% especially for dihydropyridines, 2.6% for β-blockers, and 0.2% for diuretics. It is important to note at this point that all the secondary end points, which were the fatal or not cardiovascular events, were similar and without any statistically significant difference between the groups in all these three studies. Comments and questionsThe first question that arises is how effective has become the intervention in the progress of diabetic nephropathy with drug treatment. It seems that in the studies enrolling patients with higher levels of proteinuria and consequently overt nephropathy, there is a significant retardation of renal damage. This is more impressive in the case of type 1 diabetic patients with a 43% reduction in the risk of doubling serum creatinine and less impressive in the two recent trials with ARB, where the risk of reaching the composite end points was 20% and 16% lower than in the placebo.19,45,46 This could be attributed to the heterogeneity of type 2 diabetic patients or other methodological problems. This predictive role of the baseline proteinuria for the subsequent benefit of intensified treatment is also supported by Modification of Diet in Renal Disease (MDRD) study.48 In this study only 26 patients with diabetic nephropathy were included among 840 patients with various renal diseases. The intensive treatment goal (MBP <92 mm Hg) versus regular treatment (MBP <107 mm Hg) gave a statistically significant (P < .02) retardation in the rate of GFR decline in the group of the highest proteinuria (> 3 g/day). In these studies all the drug classes were used with preference to ACEI. Based on these results the Working Group Report on Hypertension and Diabetes suggested BP levels <125/75 mm Hg for patients with proteinuria >1 g/day and renal insufficiency regardless of etiology.49 On the other hand, the duration of the trials is an important factor in illuminating the impact of different interventions. Most of the clinical trials in diabetic nephropathy last for about 3 years. The UKPDS and ABCD trials had a mean follow-up of 9 and 5 years, respectively.26,32 These two trials did not find any difference between intensive and regular BP intervention in the progress of albuminuria or GFR decline. In the UKPDS trial the statistically significant difference of albuminuria progress in favor of the intensive treatment group shown in year 6 disappeared in the year 9. In the MICRO-HOPE trial, lasting 4.5 years, the difference in the progress of microalbuminuria was minimal at 1%.33 Both UKPDS and ABCD also compared two different drug regimens, the first ACEI versus β-blockers and the second ACEI versus CCB. Again, no difference was found in the progress of nephropathy or renal function in the two trials. Nevertheless, UKPDS and ABCD had low percentage of patients with overt nephropathy, 2% and 18% respectively. In MICRO-HOPE, there were no patients with overt nephropathy by exclusion criteria. As a result, the probability of having cases with serious renal function deterioration to establish statistically significant differences was small. In normo- or microalbuminuric patients in IRMA, the 300 mg dose of irbesartan produced a slower rate of progression to overt nephropathy within 2 years.44 The shorter duration of IDNT (2.6 years) as compared with that of RENAAL (3.4 years) could be an explanation for the better results (20% and 23% v 16% risk reduction) of the former. This has already been discussed in a recent editorial.50 The sufficient length of time can prove or disprove differences, which are formed in short periods. Another possible explanation for the relatively better results in IDNT than in RENAAL is that according to the inclusion crtiteria the patients had proteinuria >900 mg/day in the first and >500 mg/day in the second, which resulted in higher median proteinuria in the IDNT than in RENAAL. This favorable effect of the higher baseline proteinuria on the renal function outcomes is found in the first important clinical trial on type 1 diabetic patients19 and has been confirmed in others with small number of diabetic patients,48,51 or even in trials with nondiabetic nephropathy.52 Microalbuminuria and especially proteinuria are unequivocally accepted as important predictors of the renal function outcome in diabetic patients.8,9,14,49 Before the recent two trials with ARB, the effect of treatment on proteinuria was considered as an intermediate end point, which presumably would predict the benefit to the renal function. In the vast majority of the studies, drugs interrupting the RAS as compared with placebo or other trial drugs yielded lower amount of proteinuria or lower rate of progress of micro- to macroalbuminuria.19,23,24,31,33,35,45,46 However, there are studies, which did not find any differences between RAS-interrupting drugs and other drug classes.27,32,34 Sometimes the reduction in proteinuria coincides with the preservation of GFR.19,23,34,35,45 In other cases, despite a significantly slower progression of proteinuria under one treatment, the GFR decline does not follow the same scheme.24 In the ABCD trial the amount of proteinuria is statistically higher in the group of CCB as compared with ACEI until the 3.5 year point but the curves of GFR are very similar during follow-up.32 This means that, although it is generally well-known that the lower the degree of proteinuria the better the preservation of renal function, there is no certain proof that after any drug intervention this relationship between proteinuria and renal function remains the same. This also is stated in the Clinical Practice Recommendations of the American Diabetes Association.8 The apparent reason is the strong interference of the certain drug. Nevertheless, there is only one study, as far as we know, which presented a correlation between proteinuria reduction and GFR preservation regardless of BP changes. This is the MDRD study, which included 840 patients with various causes of renal disease but only 26 with DM.48 Strict BP control is considered the most important measure to ameliorate the deleterious consequences of DM on vascular beds. The limits of 130/85 mm Hg, which were suggested mainly by UKPDS 38 and HOT study,26,28 were further lowered to 130/80 mm Hg and 125/75 mm Hg in the presence of proteinuria >1g/day.49 Two recent studies have been the main reason for this: the MDRD,48 as previously mentioned, and the UKPDS 36, a prospective observational study.53 In the latter, in 4801 participants with DM 2, the incidence of clinical complications was significantly associated with SBP, and the lowest risk appeared in those with SBP <120 mm Hg. The problem is that these low limits of “normal” pressure in diabetic patients have so far been unattainable, and no clinical trial has achieved them, as depicted by Mancia and Grassi.54 Even in the latest trials with ARB, the lowest BP, achieved in the third year of the follow-up, were 140/77 mm Hg for the irbesartan group and 141/77 mm Hg for the amlodipine group in IDNT, and were 140/74 mm Hg for the losartan group in RENAAL.45,46 Both trials needed an average of three nonstudy drugs to achieve these levels of BP. The high percentage of additional drugs is stressed in recent reviews, although the leading role of the RAS inhibitors is well accepted.55,56,57 In RENAAL, 78% of the losartan group patients were taking a CCB, which mostly was dihydropyridine.58 In a post hoc analysis of renal function in the Systolic Hypertension in Europe (SystEur) trial, the active treatment, which was dihydropyridine CCB, reduced the risk of overt proteinuria by 71% in 455 diabetics compared with 20% reduction in the nondiabetic patients.59 Small persistent, and sometimes significant, differences exist in BP control in clinical trials on diabetic nephropathy, as illustrated in Table 1. Blood pressure is always slightly lower on the active drug, which is ACEI or ARB versus control (usually β-blockers, diuretics, or other drugs) and versus CCB. In the presence of the growing evidence for the importance of any small variation in the level of BP, these differences cannot be overlooked. All of these trials show better renal protection concerning proteinuria or renal damage progression.19,23,24,26,31,33,44,45,46 Statistical adjustments smooth these BP differences, as stated by the authors. On the other hand, the few clinical trials that yielded similar BP control achieved similar renal protection as well.27,32,34 In IDNT, the comparison between the ARB and amlodipine group under the same BP control gave similar numbers of cardiovascular episodes but a 23% lower risk for renal composite end points in the ARB branch. This difference, however, is probably weakened because of the uneven ethnic allocation of subjects to the study groups.45 It is also worth commenting that the latest two trials using ARB45,46 included only patients with serum creatinine of 1.2 to 3 mg/dL. Patients with more advanced nephropathy, which often, under RAS inhibition, create hyperkalemia and rapid renal deterioration, were excluded.55 These observations do not agree with recent conclusions that ARB are more renoprotective under the same BP reduction and that they are effective in all stages of diabetic renal disease.60 The possibility of a combination treatment of diabetic nephropathy with ACEI and ARB is also discussed. The number of patients included is too small and the follow-up period too short to allow firm conclusions.61 Studies concerning diabetic patients without hypertension and normo- or microalbuminuria using ACEI or ARB versus placebo36,37,38,44 are in line with those concerning overt nephropathy; that is, they demonstrate lower rates of microalbuminuria in the active drug that are always accompanied by significantly lower BP. In a very meticulous recent review,62 the authors summarize that some of the conclusions drawn are a matter of interpretation of the trial results because of the small between drug differences in BP. We believe that drugs blocking the renin-angiotensin system have a theoretical advantage that may be apparent in clinical practice depending on the conditions, ie, the balance between proteinuria and a mild to moderate degree of renal insufficiency. Apart from that, the only available measure to preserve renal function is the aggressive and persistent BP decrease by means of all existing drug classes. It seems that lowering BP is more important than treating hypertension.63 We hope that clinical trials in the future will shed more light in the field. References1., : Evidence-based health policy lessons from the Global Burden of Disease Study . Science 1996 ; 274 : 740 – 743 . 2., , , , , , : Diabetes trends in the US: 1990–1998 . 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What medication is used for hypertension and diabetic nephropathy?Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (AIIR) have both been shown to have a protective effect on the progression of diabetic nephropathy and have thus become the first choice for treatment of hypertension and/or renal involvement in patients with diabetes.
What is the first line medication for hypertension in diabetes?In diabetic hypertensives, angiotensin converting enzyme inhibitors (ACEIs) are the first line in management of hypertension, and can be replaced by angiotensin II receptor blockers (ARBs) if patients are intolerant of them.
Which hypertensive drug is the first choice for diabetic and renal failure?Renin–angiotensin aldosterone inhibitors are considered the mainstay treatment for hypertension in diabetic patients, especially in the presence of albuminuria. Whether strict blood pressure reduction entails a favorable renal outcome also in non-albuminuric patients is at present unclear.
What is the best first line treatment for hypertension?There are three main classes of medication that are usually in the first line of treatment for hypertension: 1. Calcium Channel Blockers (CCB) 2. Angiotensin Converting Enzyme inhibitors (ACE inhibitors or ACE-I) and Angiotensin Receptor Blockers (ARBs) 3. Diuretics.
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What is the first line treatment of choice for hypertensive patient with diabetic nephropathy?
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