The Use Of Antihypertensive Agents In Dm Subjects With Established Diabetic Nephropathy

The impact of angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), calcium channel blockers (CCB) and conventional antihypertensive agents on renal function has been evaluated in both normotensive and hypertensive DM2 subjects with persistent proteinuria and variable degrees of renal impairment. In hypertensive DM2 subjects with persistent proteinuria studied for periods of greater than 6 months, ACEI [1321], ARB [4, 6] and certain CCB [19, 21-23] reduced albuminuria. In general, the earlier reports showed that ACEI were very effective in reducing blood pressure and urinary albumin excretion [13-15, 17-21]. The decrease in blood pressure and albuminuria was usually associated with a slowing of the progression of renal failure. Parving's group has reported a disparity in effects on albuminuria and renal function [15]. Whereas lisinopril was more effective than atenolol in reducing albuminuria, both agents were similar in efficacy in terms of rate of decline in GFR. A number of studies have confirmed that ACE

inhibitors are superior to other antihypertensive agents including dihydropyridine CCB [16-19] as well as the vasodilator, hydralazine [20], in reducing albuminuria in hypertensive DM2 subjects with macroproteinuria. Veelken et al have described the use of ACEI in an unselected group of patients [24].

In their group of 2504 DM2 patients, 328 had nephropathy, as defined as a serum creatinine concentration >1.3 mg/dl. The addition of 2.5 mg of cilazapril to their usual treatment resulted in improved blood pressure control, improved renal function and a reduction in urinary albumin excretion (UAE) as assessed at one year. That study showed that even in an unselected group of patients one is able to achieve results similar to those obtained in the randomized controlled studies.

The past two years have seen the publication of the results of major studies using ARB (See Tables 1 and 2).

In the RENAAL study [4] 1513 patients with DM2 and nephropathy (albuminuria in the range of macroalbuminuria) were randomized to receive losartan (n=751) or placebo (n=762) in addition to their usual antihypertensive therapy (excluding ACEI or ARB). Over 90% of patients in both groups were receiving antihypertensive therapy and a high percentage had additional co-morbid conditions.

These patients were followed for a mean period of 3.4 years. Blood pressure was significantly reduced to a similar degree in both groups, the only difference between the two groups being at one year. Treatment with losartan led to an average reduction of 35% in UAE, whereas in the placebo group there was no change. Analysis of the primary composite outcome (doubling of serum creatinine concentration, end-stage renal failure or death), according to an intention to treat analysis showed a 16% reduction in the patients receiving losartan. Analyzing for the individual end-points, losartan treatment was associated with a 25% reduction in doubling of serum creatinine and a 28% reduction in end-stage renal failure, whereas the risk for death was similar in both groups.

An additional finding was a 32% decrease in the risk for first hospitalization for heart failure in the losartan group.

Table 1. The effect of antihypertensive agents in albuminuria, renal function and blood pressure in hypertensive DM2 subjects with established nephropathy

Agent

Duration

n

AER(%)*

RF

BP

Reference

Lisinopril (L)

5 years

18

i-)

i

i

Bakris et al [13]

Atenolol V

16

-

i i

i

or Diltiazem

16

i-)

i

i

Verapamil

>4 years

18

i-)

i

i

Bakris et al [22]

Atenolol

16

i-)

ii

i

Lisinopril

12 months

16

i (-8

i

i

Nielsen et al [15]

Atenolol i

Atenolol

Enalapril Nifedipine

5 years i i

Ramipril Nitrendipine

2 years

26 25

Fogari et al [19]

Enalapril Nifendipine

12 months

18 12

Ferder et al [18]

Captopril Hydralazine

18 months

24 18

Captopril Hydralazine

Lisinopril

18 months

10

i (-4}

-

i

Slataper et al [21]

Diltiazem

10

i (-9

-

i

Frus & Atenolol

10

i

i

i

V

12 months

14

-

i

Bakris et al [14]

Trandolapril

12

i-8

-

i

(T)

11

-

i

T + V

Losartan

3.4 years

751

i (-8

i

i

Brenner et al [4]

Placebo

762

-

i

i

Irbesartan

2.6 years

579

i (-3

i

i

Lewis et al. [6]

Amlodipine

567

i (-6)

i

i

Placebo

569

i(-P

i

i

Abbreviations: AER, Albumin excretion rate. RF, renal function. BP, Blood pressure.

V, Verapamil, Frus, Frusemide. * In some of these studies proteinuria rather than AER was measured.

Abbreviations: AER, Albumin excretion rate. RF, renal function. BP, Blood pressure.

V, Verapamil, Frus, Frusemide. * In some of these studies proteinuria rather than AER was measured.

Table 2. Comparison of the results in the RENAAL and IDNT studies

Composite

Losartan

Irbesartan

Irbesartan

Amlodipine

and individual

vs

vs

vs

vs

end-points

placebo*

placebo#

amlodipine#

placebo#

RR (%)

RR (%)

RR (%)

RR (%)

DsCr, ESRD

16

20

23

-4

or death

p=0.024

p=0.024

p=0.006

NS

DsCr

25

33

37

-6

p=0.006

p=0.003

p=0.001

NS

ESRD

28

23

23

0

p=0.002

NS (p=0.074)

NS (p=0.074)

NS

Death

NS

NS

NS

NS

ESRD or

20

N/A

N/A

N/A

death

p=0.01

Abbreviations: RR = risk reduction, DsCr= doubling of serum creatinine. ESRD = end-stage renal disease. NS = not significant. N/A = not analyzed. * RENAAL [4] # IDNT [6]

Abbreviations: RR = risk reduction, DsCr= doubling of serum creatinine. ESRD = end-stage renal disease. NS = not significant. N/A = not analyzed. * RENAAL [4] # IDNT [6]

Lewis et al reported the results of a similar study (IDNT) comparing treatment with either irbesartan, amlodipine or placebo [6]. In that study 1715 hypertensive patients with DM2 and proteinuria in excess of 900 mg/day were randomized to receive irbesartan (n=579), amlodipine (n=567) or placebo (n=569) in addition to their usual antihypertensive therapy (excluding ACEI, ARB or CCB). Similar to the RENAAL study, these patients had a high percentage of comorbid conditions. The participants were followed for a mean period of 2.6 years. The mean blood pressure decreased significantly in all three groups, the mean arterial pressure being slightly, but significantly higher in the placebo group than in the two treatment groups. Treatment with irbesartan led to an average reduction of 33% in proteinuria, whereas there was a small decrease in the amlodipine and placebo groups. Analysis of the primary composite outcome (doubling of serum creatinine concentration, endstage renal failure or death), according to an intention to treat analysis, showed a 20% reduction in this endpoint in the patients receiving irbesartan as compared to placebo and a 23% reduction as compared to amlodipine. Analysis of the individual end-points showed a 33% reduction in risk for doubling of serum creatinine as compared to placebo and 37% as compared to amlodipine and a 23% reduction in risk for end-stage renal failure in the irbesartan group as compared to both the placebo and amlodipine groups. However, the risk of death was similar in all the three groups. These two studies in DM2 patients with overt nephropathy have demonstrated that treatment with ARB in addition to other antihypertensive agents significantly reduces blood pressure and proteinuria. Moreover both studies showed that ARB treatment has a beneficial effect on progression of diabetic renal disease as measured by a doubling of serum creatinine and the percentage of patients reaching end-stage renal failure. This beneficial effect seemed to be partly independent of blood pressure reduction. Moreover, in the IDNT study the reduction in blood pressure in those patients receiving amlodipine was similar to that of patients receiving irbesartan, yet there was no improvement in proteinuria or progression of renal disease in the CCB treated cohort. The results of the RENAAL study have been used to estimate the possible savings of treating suitable patients in the European Union with losartan [25]. The authors came to the conclusion that this treatment could potentially lead to a decrease in 44100 patients with end-stage renal failure and a saving of Euro2.6 billion over 3.5 years.

There have been significant differences in the effect on albuminuria obtained with various CCB, which has been attributed by Bakris and others to the particular class of CCB [21, 26, 27]. Bakris [27] initially demonstrated in hypertensive, nephrotic NIDDM subjects that diltiazem, a benzothiazepine CCB, had a comparable affect to lisinopril in decreasing albuminuria. This author has also reported an anti-proteinuric effect with the CCB, verapamil [23]. In contrast, nifedipine, a dihydropyridine CCB, given for 6 weeks to 14 hypertensive NIDDM patients with baseline renal impairment, led to an increase in albuminuria and deterioration in renal function, despite equivalent blood pressure reduction to diltiazem [28]. Other groups have also reported this lack of efficacy, particularly on proteinuria, of the dihydropyridine class of CCB [17, 18]. In a study in African American NIDDM subjects with hypertension and macroproteinuria, isradipine was associated with an increase in proteinuria whereas captopril reduced proteinuria [29]. Finally the study by Lewis et al showed that the addition of amlodipine to other antihypertensive agents did not reduce proteinuria and had no additional effect on renal function decline or kidney survival [6].

Bakris et al have reported the findings of 2 studies in hypertensive NIDDM subjects with overt proteinuria followed for at least 4 years [13, 22]. In both studies, the beta blocker atenolol was associated with a more rapid decline in GFR and less efficacy in terms of reduction in albuminuria than the non-dihydropyridine CCBs, verapamil and diltiazem [13, 22] or the ACEI, lisinopril [22].

The role of alpha blockers in macroproteinuric DM2 patients has not been as well documented. Nevertheless, Rachmani et al reported in a cross-over study which included predominantly macroproteinuric but also microalbuminuric

NIDDM subjects, that the alpha blocker doxazosin tended to reduce albuminuria, although possibly to a lesser extent than the ACEI, cilazapril [30].

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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