The Use Of Antihypertensive Agents In Hypertensive Dm Patients With Normoalbuminuria And Microalbuminuria

Comparison of the use of ACEI versus placebo in DM2 subjects with hypertension and normoalbuminuria or microalbuminuria has not been well studied A double blind study compared captopril with conventional therapy (metoprolol and hydrochlorothiazide) in normoalbuminuric and microalbuminuric hypertensive DM2 subjects over a 3 year period [31]. Both regimens reduced blood pressure without altering UAE in the normoalbuminuric DM2 subjects. However, their findings in hypertensive DM2 patients with microalbuminuria indicated that despite a comparable reduction in blood pressure, only the ACEI induced a persistent decline in albuminuria during the 36 months of therapy. Sano et al found in a small number of normotensive and well controlled hypertensive patients with microalbuminuria, treated with enalapril for a period of four years, that there was a 47% decrease in albuminuria, whereas in the placebo group there was no change [32]. Trevisan et al reported similar findings when comparing ramipril to placebo over a period of 6 months [33]. Veelken et al treated a large unselected group of hypertensive, diabetic patients (2176 patients) with normal renal function, with cilazapril for 52 weeks [24]. Treatment resulted in a significant decrease in blood pressure in 75% of patients, with 56.4% of them achieving the target value of less than or equal to 140/90 mmHg. Renal function and urine protein excretion remained stable during the treatment period.

The emphasis in the more recent studies has been to analyze the effects of treatment with ARB. Lacourciere et al compared the effects of enalapril to losartan in 103 hypertensive patients. Both these medications, given alone or in combination with other antihypertensive agents (the study medications and CCB were excluded) resulted in a significant but similar decrease in albuminuria and a similar decrease in renal function, which had stabilized by 52 weeks [34]. In a similar study, Muirhead et al, compared the effects of valsartan (dosages of 80 mg and 160 mg daily) to captopril and placebo over a period of 12 months [35].

Table 3. The effect of antihypertensive agents on albuminuria, renal function and blood pressure in DM2 with normo- and microalbuminuria

Patients Agent

Duration of study

A in AER

Reference

Normo HT Micro HT

Enalapril (E) Nifedipine (N) Enalapril Nifedipine

5 yrs

18 25 21 13

Normo HT Micro HT

Captopril M or HCTZ Captopril M or HCTZ

36 mths

25 28 9 12

Micro NT

Nifedipine Perindopril

12 mths

13 11

MDNSG [43]

Micro HT

Micro NT

E + N Nifedipine Enalapril Untreated

48 mths

Micro NT

Micro

Enalapril

12 mths

8

¿(-9

T

¿

Ruggenenti et al [39]

HT

Nitrendipine

8

¿(-17)

T

¿

Micro

Cilazipril

3 years

9

¿(-27)

¿

¿

Velussi et al [40]

HT

Amlodipine

9

¿(-3D

¿

¿

Micro

Lisinopril

12 mths

156

¿(-37)

¿

Agardh et al [41]

HT

Nifedipine

158

¿

Micro

R ± Felodipine

12 mths

46

¿

Schnack et al [38]

HT

At ± HCTZ

45

T

¿

¿

Micro NT

Enalapril Placebo

5 years

49 45

Micro NT

Enalapril Placebo

5 years

52 51

Normo NT

Enalapril Placebo

6 years

97 97

Normo, micro,

Nifedipine Enalapril

2 years

228 208

Valsartan Amlodipine

24 weeks

169 163

Viberti et al [48]

HT, micro

Losartan Enalapril

52 weeks

52 51

Lacourciere et al. [34]

Table 3. (cont.)

HT, Amlodipine 4 years

103

-

¿

Fogari et al. [44]

micro Fosinopril (F)

102

¿(-541

-

¿

Amlodipine + F

104

-

U

HT, Irbesartan 150 2 years

195

¿(-3)

¿

¿

Parving et al. [37]

micro Irbesartan 300

194

¿(-38)

¿

¿

Placebo

201

¿(-3)

¿

¿

HT, NT, Valsartan 80 52 weeks micro Valsartan 160 Captopril Placebo

Abbreviations: Normo, Normoalbuminuria. Micro, Microalbuminuria. HT, Hypertensive. NT, Normotensive. N/D, not done. AER, Albumin excretion rate. GFR, glomerular filtration rate. BP, Blood pressure. HCTZ, hydrochlorothiazide. M, metoprolol. At, atenolol.

HT, NT, Valsartan 80 52 weeks micro Valsartan 160 Captopril Placebo

Abbreviations: Normo, Normoalbuminuria. Micro, Microalbuminuria. HT, Hypertensive. NT, Normotensive. N/D, not done. AER, Albumin excretion rate. GFR, glomerular filtration rate. BP, Blood pressure. HCTZ, hydrochlorothiazide. M, metoprolol. At, atenolol.

The patients were normotensive or receiving treatment for hypertension. All three-treatment groups showed a significant decrease in albuminuria, when compared to the placebo group. There was no difference in the anti-albuminuric effect between the ACEI and ARB treated groups. However, treatment with captopril was associated with the most side effects. In a small crossover study involving 64 hypertensive patients, receiving irbesartan (150 mg/day) or placebo for 60 days, treatment was associated with a significant decrease both in UAE and blood pressure as compared to placebo [36].

These studies of the efficacy of ARB have been complemented by a large randomized study (IRMA-2), in which Parving et al compared the effects of irbesartan, 150 mg and 300 mg to placebo, given over a period of two years to 590 hypertensive patients with type 2 diabetes and microalbuminuria [37]. Significantly fewer patients receiving 300 mg irbesartan per day reached the primary end-point (overt nephropathy, defined as macroalbuminuria), than in the placebo group (See fig 1). However, in the patients receiving 150 mg daily, the difference between the placebo and irbesartan treated groups, did not reach statistical significance, but was intermediate between the two other groups. The decrease in systolic blood pressure was also significantly greater in the patients receiving 300 mg irbesartan daily than in the placebo group. These studies have shown that both ACEI and ARB have significant beneficial effects in hypertensive type 2 diabetic patients with normo- or microalbuminuria. However, only the study of Parving et al had the power to demonstrate that the optimal dose of a therapeutic agent, an ARB in this case, could delay progression to overt nephropathy [37].

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