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arznei-telegramm 2001; 32: 97-8

 


A NEW LEGEND: AT-II ANTAGONISTS RENOPROTECTIVE IN TYPE 2 DIABETES?

Effective control of blood pressure is the most important therapeutic measure in order to stop the progression of diabetic nephropathy. Until today, there has been no sufficient proof of a specificic, i.e. blood pressure independent renoprotective effect of angiotensin-converting-enzyme (ACE) inhibitors in diabetes, as has been stated time and time again (see a-t 2000; 31:2). Now, this "renoprotective" effect is supposed to be "proven" even with the use of angiotensin-II-receptor antagonists (AT-II antagonists), according to statements made by Sanofi-Synthelabo for its product irbesartan (APROVEL). (1) The company refers to two of three relevant studies which have recently been published simultaneously. (2-4) However, neither of the three studies conducted with active participation of the pharmaceutical industry, allows for such a conclusion.

In spite of opposing announcements in the headlines, not merely patients with diabetic nephropathy were enrolled, but rather a mixed population of patients with type 2 diabetes mellitus, hypertension and a variety of syndromes causing increased urinary protein excretion. However, according to the internationally accepted definition of diabetic nephropathy, this diagnosis requires the presence of diabetic retinopathy in addition to increased urinary protein excretion. (5,6) An increase in albuminuria in type 2 diabetes is more likely a sign of atherosclerosis, heart failure, urinary tract infections, poorly controlled hypertension, nephrosclerosis or other renal diseases than of diabetic glomerulopathy. (7,8)

Since all three studies preclude the use of ACE inhibitors, specific diagnostic efforts should have assured that no patients with heart failure would participate. This was not the case. In one study patients were merely asked about known heart failure (3), the second study only excluded patients with severe heart failure. The latter as well as the third study lacked information as to what diagnostic measures were taken to assure exclusion. (2,4) Thus effective treatment was withheld from at least some study participants. Heart failure is the most frequent cause of death in type 2 diabetic patients.

The first study (2) included 590 patients with diabetes mellitus and microalbuminuria. The study ran for two years. In addition to other antihypertensive drugs, participants received a daily dosage of 150 mg or 300 mg of irbesartan (APROVEL, KARVEA) or placebo, respectively. Especially during the first 12 months, the blood pressure was higher in the placebo group than in the AT-II-antagonist group. Albuminuria decreased more significantly with 300 mg irbesartan than with 150 mg, and remained unchanged in the placebo group. However, according to the glomerular filtration rate (GFR), renal function worsened under the higher dose of irbesartan. There was no difference between the lower dose and the placebo group. Nonfatal cardiovascular events were seen almost twice as often in the placebo group (8.7%) than in the high dose irbesartan group (4.5%). The reduction of albuminuria was most likely caused by a decrease in blood pressure and a modified charge of the glomerular basement membrane under the AT-II antagonist. (9) It appears that AT-II-antagonists lower albuminuria in type 2 diabetic patients similarly to ACE inhibitors. (10) Ramipril (e.g. DELIX) is reported to cause a reduction of the GFR in patients with type 2 diabetes and nephropathy as compared to conventional antihypertensive drugs. (11)

The second study (3) included 1,513 patients with type 2 diabetes and macroalbuminuria who received, in addition to conventional antihypertensive treatment, a daily dose of 50 mg to 100 mg losartan (LORZAAR) or placebo, respectively. After a mean of 3.4 years, the study had to be stopped early due to ethical concerns. Blood pressure remained poorly controlled with placebo with values that averaged 150/80 mmHg after the first year, 144/77 mmHg after two years and 142/74 mmHg at the end of the study. The pressure remained 1 to 4 mmHg lower with losartan as compared to the placebo group. The risk of end-stage renal disease decreased substantially and statistically significant from 25.5% in the placebo group to 19.6% under losartan (NNT/year = 58 [NNT=Number Needed to Treat]). Hospitalizations due to heart failure also decreased from 16.7% to 11.9% (NNT/year = 71). However, paradoxically, the overall mortality rate under losartan was 21.0% as compared to 20.3% in the placebo group. The published data do not clarify what caused the higher mortality rate in spite of the positive effects of a controlled blood pressure on renal and cardiac function.

The third study (4) included 1,715 patients with type 2 diabetes and proteinuria (more than 900 mg per 24 hours average) who either took a daily dose of 300 mg irbesartan or 10 mg amlodipine (NORVASC) or a placebo over a mean period of 2.6 years in addition to other antihypertensive drugs. The average blood pressure over the time of the study was 140/77 mmHg in the irbesartan group, 141/77 mmHg in the amlodipine group and 144/80 mmHg in the placebo group. The mean arterial pressure in the two verum groups was significantly lower (-3,3 mmHg) than in the placebo group. The risk of a doubling of the serum creatinine level, of end-stage renal disease or death decreased from 39% under placebo to 32.6% under irbesartan (NNT/year = 41), but remained unchanged under amlodipine with 41.1% in spite of its blood pressure lowering effect. The risk of congestive heart failure in the amlodipine group was significantly higher than in the placebo or irbesartan group (see a-t 2000; 31:40). Although irbesartan had a positive effect on heart failure as compared to placebo, there was no difference in the rate of hospitalizations due to heart failure or cardiac death, myocardial infarctions, cerebrovascular events with permanent neurologic deficits or amputations under irbesartan (23.8%) as compared to amlodipine (22,6%). The published data do not clarify which negative effects of the AT-II antagonist contributed to these results. There was no significant difference in the overall mortality rate between irbesartan with 15% as compared to 14.6% in the amlodipine and 16.3% in the placebo group.

The three studies with AT-II antagonists in patients with type 2 diabetes, hypertension and albuminuria are marketing studies of the pharmaceutical industry.
In all three studies, patients who would urgently have required treatment for hypertension, were assigned to placebo groups and thus were deprived of necessary blood pressure control. In spite of the participation of patients with heart failure, use of ACE inhibitors was prohibited. This exclusion from effective treatment is reflected in a higher risk of end-stage renal disease as well as in more frequent cardiovascular complications and a higher risk of heart failure in the control groups. While one study was stopped early due to ethical concerns, according to the Helsinki Declaration, none of the three studies should have been started at all.
A specific renoprotective effect of irbesartan (APROVEL) or losartan (LORZAAR) has not been proven, since a comparison with standard antihypertensive drugs such as diuretics, beta-blocker or ACE inhibitors is missing.
Surprisingly, the control of blood pressure by AT-II antagonists has no effect on the overall mortality rate. Possible negative effects are obscured by the way data are presented. Thus, the value of AT-II antagonists for antihypertensive treatment in patients with type 2 diabetes is still unclear. We advise against the routine usage of these drugs.
The most important findings from these data are: the calcium antagonist amlodipine (NORVASC) does not prevent the progression of nephropathy in patients with type 2 diabetes any better than placebo. In spite of an effective reduction in blood pressure, amlodipine increases the risk of heart failure.

 

(R = randomised study)

 

1

Sanofi-Synthelabo: APROVEL-Werbung; Ärzte Zeitung vom 25. Sept. 2001

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2

PARVING, H.H. et al.: N. Engl. J. Med. 2001; 345: 870-8

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3

BRENNER, B.M. et al.: N. Engl. J. Med. 2001; 345: 861-9

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4

LEWIS, E.J. et al.: N. Engl. J. Med. 2001; 345: 851-60

 

5

HASSLACHER, C. et al.: Dt. Ärztebl. 1999; 95: A-51-3

 

6

CHRISTENSEN, P.K. et al.: Diabet. Med. 1999; 16: 388-94

 

7

Scottish Intercollegiate Guidelines Network: Management of Diabetic Renal Disease 1997

 

8

MOGENSEN, C.E.: Diabetologia 1999; 42: 263-85

 

9

ANDERSEN, S. et al.: Abstract 13th, EDNSG Meeting, Lund 2000

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10

MOGENSEN, C.E.: BMJ 2000; 321: 1440-4

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11

RUGGENENTI, P. et al.: Am. J. Kidney Dis. 2000; 35: 1155-65



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