Introduction

Several studies have demonstrated that increased urinary albumin excretion (UAE) predicts clinical proteinuria and increased mortality in maturity onset diabetes(1). Moreover, increased UAE also predicts increased morbidity, especially hypertension and cardio-vascular disease in type 2 diabetes mellitus or non-insulin dependent diabetes mellitus (NIDDM)(2).

Several clinical studies have shown that treatment with angiotensin converting enzyme inhibitors (ACE-I) lowers the blood pressure (BP) and also reduces both albuminuria and glomerular filteration rate (GFR) in hypertensive patients with type 2 diabetes mellitus which results in slowing the deterioration of renal functions(3).

Angiotensin II type 1 (AT₁) receptor antagonists are new generation medications that interrupt the renin-angiotensin-aldosterone system (RAAS) by blocking the AT_l receptors. Although they were developed to treat hypertension, these agents are currently used to treat heart failure (HF) as well. They also have much lower incidence of causing cough than ACE-Is, and were found to reduce proteinuria and maintain GFR in patients with renal disease as effective as ACE-Is(4).

Recent reports from clinical trials show the beneficial effect of the use of AT₁ antagonists on the progression of nephropathy in hypertensive and type 2 diabetic patients(5).

The incidence of end stage renal disease in patients with type 2 diabetes is sharply rising in many regions in the world and is expected to be doubled by 2010. The annual costs associated with end-stage renal disease in the United States reached 12 billion dollars in 1998 and are expected to increase to 28 billion dollars by 2010. Preventing or delaying the progression of diabetic nephropathy is an essential goal to reduce the economic burden of this complication(6).

Patients

The study population was selected from patients attending the Cardiology and Nephrology outpatient clinics in multiple medical centers in Saudi Arabia and Egypt.

Table 1: Baseline demographics of the studied groups

Table 2: Baseline and follow-up systolic and diastolic BP in both groups

Table 3: Changes in ABP (Mean Values) in both groups

By the end of one year, the number of patients was still the same, 24 patients in the enalapril arm and 23 patients in the losartan arm. The base line data of both groups was comparable regarding the gender, age, race, and body weight.

In the losartan group, 11 patients were receiving 100 mg losartan alone (48%), 10 patients were receiving 100 mg losartan plus 25mg HCTZ (43%), while 9% (2 patients) required triple therapy by adding b-blockers to one patient (Tenormin 50 mg daily) while the other patient was already receiving carvedilol 25 mg twice daily when presented to the clinic.

In the enalapril group, 12 patients were receiving enalapril 10 mg twice daily (50%), 11 patients required adding 25 mg of HCTZ (45%) and the remaining patient (5%) required the addition of a b-blocker (Tenormin 100mg daily) to control the blood pressure.

There were no significant differences in the use of combination therapy (P = 0.423) or in the use of other antihypertensive agents (P= 0.10) for the two groups of patients. There was no significant change in the body weight as well as in dietary protein intake during the trial. There were no statistical differences in regards to the fasting lipid profile at base line including total cholesterol, triglycerides, low-density lipoproteins and high-density lipoproteins (Table 1).  There was no statistically significant difference in UAE and GFR at base line between both groups as well.

Regarding the effect on blood pressure, both medications administered alone or in combination resulted in significant decrease (P< 0.005) in sitting systolic BP (SISBP). The decrease in SIDBP was also statistically significant for both groups (P< 0.005). However, there was no statistical difference between the two groups themselves.

Losartan was found to decrease the blood pressure from 165.5 ±14.2 / 98.9 ± 4.3 mmHg to 138.3 ± 11.1 / 83.8 ± 3.6 mmHg. On the other hand, Enalapril decreased the sitting BP from 167 ± 15 / 97.2 ± 3.8 mmHg to 135.5 ± 18.2 / 84.4 ± 2.4 (Table 2).

Both medications demonstrated effective reduction in blood pressure during 24 hours as well as during daytime and nighttime recordings with (P< 0.001) for both groups but with no statistical difference between the two groups (Table 3).

Most patients managed to achieve their diastolic BP target of <85 mmHg, the percentage was 96% for the losartan group and 97% for the enalapril group.  Again, there was no statistical difference in ABP measurements between the two groups.

Assessment of UAE (microalbuminuria) showed that the mean decrease in UAE was most significant by the 6^th month (P< 0.027) in both groups and remained significantly lower (P<0.001) than baseline values throughout the study period. Microalbuminuria decreased in the losartan group from 65.28 µg/min at base line to 56.2 µg/min at 3 months and then 42.4 µg/min at 6 months and finally 37.5 µg/min at 12 months. As for enalapril, UAE decreased from 75.34 µg/min to 51.7 µg/min at 3 months, then 40.2 µg/min at 6 months and finally 34.2 µg/min at one year. There was no significant difference between the two groups with respect to the change from baseline (figure 1).

Figure 1: Changes in UAE in both groups.

Changes in UAE significantly correlated with changes in 24 hours systolic and diastolic ABP (P< 0.05) at the end of the study. There was a progressive decline in UAE associated with the BP becoming more controlled in both groups, although no statistical significance between both groups was found. The correlation was best with 24 hours diastolic BP with the correlation being r = 0.34, P = 0.40 for losartan and r= 0.41, P < 0.05 for the enalapril group. A weaker coloration (P = 0.65) was found between changes in the clinic blood pressure and UAE (figure 2).

Figure 2: Relation between mean diastolic ABP and Changes in UAE.

Figure 3: Changes in GFR in the two groups losartan, enalapril.

Diabetes mellitus was well controlled throughout the study when HbA₁C values were compared in both groups from baseline to one year. As for the lipid profile, there were statistically significant changes (P<0.05) at the end of the study in total cholesterol, 3% and 7% decrease in the losartan and enalapril groups respectively, triglycerides (11.25% decrease in enalapril group and 10.7% decease in losartan group) and LDL cholesterol 16.5% decrease in losartan group and 4.9% decrease in Enalapril group).

Treatment related cough was more frequently observed in the enalapril group, with the p = 0.006 making this trend of a high statistical significance. Most importantly is the fact that there were no reports of cardiovascular events or any other complications or deaths during the course of the study.

DISCUSSION

The aim of the present study was to compare the long-term effects of AT₁ blockers and ACE-Is on systemic hypertension and renal functions in hypertensive patients with type II diabetes and early nephropathy.

The results clearly indicate that both drugs were very effective at controlling both systolic and diastolic BP in more than half of the patients alone or in combination with HCTZ and/or another medication in minority of patients. This was previously documented by Tikkanen and colleagues(7) who compared the effect of losartan and enalapril in patients with hypertension. They concluded that both drugs were effective in lowering blood pressure with no statistical significance between the two medications(7).

Other studies also demonstrated the beneficial effects of ACE-Is in delaying renal damage in hypertensive diabetic patients. Investigators studied the renal protective effects of enalapril in hypertensive type 2 diabetic patients and reported encouraging results(8,9).

Moreover, the results also revealed significant decrease in UAE with the use of both losartan and enalapril. Our findings come in agreement with the results of Gansevoort and coworkers(10) as they observed the anti-albuminuric effect of losartan in hypertensive patients with renal disease. The results of the present study are also consistent with results recently reported by Lacourciere and colleagues(11) who found that the use of losartan resulted in significant decrease in UAE in hypertensive patients with type 2 diabetes mellitus and early nephropathy. The same results were reported by Brenner et al.,(12) from the RENAAL study where losartan was found to offer renal protection in patients with type II diabetes and nephropathy along with the other antihypertensive medications.

This anti-proteinuric effect of both AT_l antagonists and ACE-Is involves several mechanisms including renal microcirculation changes and tissue remodeling rather than only BP lowering (l3). The concept that the renal effects of AT₁ antagonists and ACE-Is are mediated by interference on the RAAS rather than the kinin-kallikrin system is supported by the results of other studies showing similar systemic and hemodynamic effects of these agents(14).

Ambulatory BP monitoring is a well established method that allows a non invasive determination of the circadian variation of BP during antihypertensive treatment(15). Moreover, ABP monitoring has been found to be more closely related to target organ damage(16) and to cardiovascular mortality and morbidity than clinic BP(17). Furthermore, clinic BP has been found to be less closely related to microalbuminuria than ABP in patients with essential hypertension alone(18) or in hypertensive patients with type 2 diabetes mellitus.

The results of the present study revealed a significant correlation between ABP and UAE. The results comes in agreement with previous reports (11, 20) which observed improvement in UAE in correlation with ABP in hypertensive patients with type 2 diabetes and early nephropathy when using both ACE inhibitors or AT₁ antagonists.

Another important finding in this study is the favourable effect of AT₁ antagonists on GFR as compared for ACE-Is. AT₁ antagonist were found to have beneficial results on reducing GFR to the same extent as ACE-Is did. Similar effects were reported by lewis and co-workers using the AT₁ blocker, irbesartan(21), by Tatti et al.(22) using Fosinopril and was recently reported in the HOPE study(23).

A probable mechanism for such effect is believed to be secondary to abrupt lowering of systemic blood pressure, which results in hemodynamic redistribution of the kidney blood flow. 

Many investigators also found that this beneficial effect of AT₁ antagonist goes beyond diabetic patient to benefit also non-diabetics with renal disease. They reported a composite 16% reduction in doubling of serum creatinine, end-stage renal disease or death from any cause with the use of losartan compared to the control group. Risk of end stage renal disease was reduced by 28% alone by losartan during an average follow up of 3.4 years estimating an average delay of 2years in the need for dialysis or transplantation(10)

Both medications were properly tolerated by the treated groups. However, 13% of the enalapril group reported suffering bouts of cough while the prevalence in the losartan treated patients was 0%. This is a well-known complication with the use of ACE-Is. These findings were also noticed by Lacourciene et al.(24) who reported that cough does not occur with losartan while its prevalence with ACE-Is was 14%.

CONCLUSION

This study concludes that treatment with losartan or enalapril in hypertensive patients with type 2 diabetes and early nephropathy reduces UAE significantly with no statistical difference between the two groups. A b correlation was also found between the decline in ABP and UAE adding to the beneficial effects of both medications.

REFERENCES