Renin Angiotensin Aldosterone System Blockade and Renal Disease in Patients With Type 2 Diabetes: An Asian perspective from the RENAAL study

The RENAAL study was a double-blind, randomized, placebo-controlled study that compared the renal protective effects of the angiotensin II (AII) antagonist losartan plus conventional antihypertensive therapy with placebo plus conventional antihypertensive therapy in 1,513 patients with type 2 diabetes and nephropathy. In this multiethnic study, 252 patients were of Asian ethnicity; most of these patients resided in Asia (n = 220). Of these 220 patients, 96 were from Japan and the remainder were predominantly Chinese from Hong Kong (n = 92), Malaysia (n = 21), and Singapore (n = 11). The remaining 32 Asian patients were geographically located worldwide. The study rationale, design, and results have been described previously (8). Briefly, type 2 diabetic patients aged 31–70 years with nephropathy (presence, on two occasions, of urinary albumin-to-creatinine ratio from first morning specimen ≥300 mg/g or rate of urinary protein excretion of ≥0.5 g/day) and serum creatinine level of 115–265 μmol/l (133–265 μmol/l for men weighing >60 kg) were studied. Exclusion criteria have been described previously (7). The study was approved by all local research ethics committees, and all patients gave written informed consent before entry into the study.

Analysis of the primary and secondary end points was performed by the intention-to-treat method, and all of the data from the randomized Asian patients were included in the analysis. A Cox regression model (9) that included baseline proteinuria as a stratification factor and the geographical region as a covariate was used to determine the hazard ratio for the primary composite end point. The risk reduction was calculated as percent × (1 –hazard ratio). Event curves are based on Kaplan-Meier analysis (10).

The analyses of the progression of renal disease and changes in proteinuria were performed using an on-treatment approach. For the analysis of the progression of renal disease, we compared the slopes of the treatment groups using a linear random-effects model (11). Changes in the level of proteinuria in the two groups were compared by means of a mixed-effects model, the terms of which included the treatment at each point and the baseline level of proteinuria (12).

The calculated glomerular filtration rate was estimated using the formula based on the Modification of Diet in Renal Disease Study using body weight and serum creatinine (13). All data are expressed as mean ± SD or median (range). A Cox proportional model was performed to estimate the hazard ratio (95% CI) followed by a multivariate model to determine the baseline risk predictors for the renal end points using prespecified baseline covariates. A P value of <0.01 was required for the variable to remain in the model. The prespecified baseline covariates were age, sex, BMI, history of smoking, insulin use, systolic blood pressure, diastolic blood pressure, serum creatinine, estimated glomerular filtration rate, proteinuria, serum albumin, total cholesterol, lipoprotein(a), serum triglycerides, serum calcium, Hb, serum uric acid, GHb, white blood cell count, and dihydropyridine calcium channel blocker use. A P value <0.05 (two-tailed) was considered significant.

In the Asian subpopulation, the mean follow-up time for the RENAAL study was 3.2 years. The baseline characteristics of the two treatment groups were similar (Table 1). Dihydropyridine calcium channel blockers were used in >70% of patients at baseline; diuretics were the second most common antihypertensive medication used (34.5%).

At baseline, 92% of the Asian patients were receiving one or more antihypertensive medications (91% in the losartan group and 94% in the placebo group). The trough blood pressure declined in both treatment groups over the course of the RENAAL study from 152/82 to 140/73 mmHg in the losartan group and from 152/83 to 144/74 mmHg in the placebo group (P = NS). During the study, 27% of the Asian patients were receiving losartan 50 mg once daily and 71% received losartan 100 mg once daily. The use of various classes of conventional antihypertensive medications changed between baseline and during the study with increased use of β-blockers (baseline 15.5 vs. 30.5% during the study), diuretics (baseline 35 vs. 67% during the study), and α-blocker (baseline 19.5 vs. 34.5% during the study). Dihydropyridine calcium channel blockers continued to be used in ∼77% of the Asian patients. In accordance with the protocol, use of ACE inhibitors and other AII antagonists was discontinued at baseline.

Losartan was associated with a 35% risk reduction (P = 0.02) for the primary composite outcome in the RENAAL Asian population (Fig. 1A). In addition, losartan reduced the risk of the renal outcomes of ESRD or DsCr (36%, P = 0.034) (Fig. 1B). There was a difference in the incidence of ESRD and the composite of ESRD or death, but the risk reduction was not statistically significant (Fig. 1C and D). Death in Asian patients was lower in the losartan group; however, this was not statistically significant (Table 2).

Of Asian patients, ∼30% (n = 78) had a cardiovascular event; hospitalization for heart failure was most common (∼13%, 33 patients). In addition, <8% (n = 19) of the Asian patients died of cardiovascular causes. There was no significant difference in the treatment effect of losartan on the composite end point of cardiovascular morbidity and mortality (Table 2).

Losartan reduced the level of proteinuria (determined from the albumin:creatinine concentration in a morning spot specimen) by 47% (P < 0.001) (Fig. 2). In addition, the rate of decrease in renal function was reduced by 30.7% (P = 0.0074; median slope −0.0521 mg/dl per year in the losartan group, as compared with −0.0752 mg/dl per year in the placebo group).

In the Asian cohort, overall discontinuations throughout the study were lower in the losartan group than the placebo group (losartan 28% versus placebo 43%). Before the primary composite event, fewer patients treated with losartan discontinued treatment (losartan 10.3% versus placebo 17.8%, P = 0.089). Treatment compliance, defined as taking 80% or more of the test drugs determined by tablet counting, was 87.3% in the Asian population, and the mean length of time on the drug was 2.9 years. The most common adverse events experienced by the Asian subpopulation that led to discontinuation of the study drug (losartan and placebo combined) were ESRD (n = 9), renal insufficiency (n = 8), congestive heart failure (n = 4), myocardial infarction (n = 3), and cerebral infarction (n = 2). Losartan was not associated with increased incidence of cough when compared with placebo (losartan 22.2% versus placebo 20.0%, P = NS).

By univariate analysis, the strongest baseline predictors of renal risk were proteinuria, serum albumin, serum calcium, Hb, lipoprotein(a), serum creatinine, and estimated glomerular filtration rate.

From this, we constructed a multivariate Cox proportional hazards model, which showed that baseline proteinuria and Hb were strong predictors of risk for both the primary composite end point (DsCr, ESRD, or death) and the renal composite end point (DsCr or ESRD) and ESRD alone (Table 3). Three additional baseline variables were significantly associated with the risk of ESRD: serum calcium, younger age (per 10 years), and serum creatinine (Table 3).

There is now consensus on the importance of optimal control of blood pressure to preserve renal function in high-risk patients such as those with diabetes and/or hypertension (14). Given the deleterious effects of AII on hemodynamics and cellular growth, inhibition of the renin angiotensin aldosterone system has been shown to have organ-protective effects beyond blood pressure reduction (5). Both the RENAAL study (7) and the Irbesartan Diabetic Nephropathy Trial (15) have now confirmed the renal protective effects of AII receptor antagonists in type 2 diabetic patients with established nephropathy. As a result of its multinational, multiethnic patient recruitment strategy, the RENAAL study database represents a unique resource for understanding the disease progression and treatment responses in different ethnic groups.

Losartan was effective in reducing the risk of developing the primary composite end point of DsCr, ESRD, and all-cause mortality in the Asian subpopulation of the RENAAL study. Although there was no interaction between race and treatment effect of losartan in the RENAAL study (8), the robust treatment effect of losartan in this Asian subpopulation was consistent with the results of the main study. This would support the importance of specific blockade of AII in addition to blood pressure reduction to reduce the continued decrease of kidney function in Asian patients with type 2 diabetes. No difference between losartan and placebo was observed for the secondary cardiovascular morbidity and mortality end point. This is most likely associated with the low number of cardiovascular events in the Asian population in general.

There are also reports suggesting that Asian patients with diabetes are at increased risk for renal complications (16–18). In addition, recent data from the Irbesartan Diabetic Nephropathy Trial suggest that calcium channel blockers, particularly dihydropyridine calcium channel blockers, are not the optimal antihypertensive agent for treating type 2 diabetic nephropathy (15). Despite the high use of dihydropyridine calcium channel blockers and their popularity in Asians (19), patients treated with losartan strongly benefited despite any potentially deleterious effects of dihydropyridine calcium channel blockers. Therefore, the demonstrated importance of adequate AII blockade must now, in addition to adequate control of blood pressure, become a major point of emphasis in this population.

The Asian patients had the lowest discontinuation rates of any subgroup in the RENAAL study. This is due, in part, to the tolerability of losartan in this patient population, which is supported by the similar incidence of cough in the losartan and placebo groups. The high adherence rate of Asian patients to losartan therapy has potential socioeconomic implications given the predicted increase in the incidence of type 2 diabetes in Asia over the next two decades. The increasing cost of ESRD to the healthcare sector in Asia is expected to be profound and is likely to overburden an already heavily taxed system. Economic evaluation of the overall RENAAL study shows that losartan therapy would result in a net savings of $3,522 per patient over 3.5 years (20). This may potentially bring some needed relief to the increasing cost of type 2 diabetic nephropathy in this region. In areas where access to renal replacement therapy is suboptimal, the delay in developing ESRD by losartan may also become very important to patient survival (21).

In a recent post hoc analysis of RENAAL data, the following risk factors for renal end points (DsCr or ESRD) were identified: proteinuria, serum creatinine, low serum albumin, and low Hb (8). In this respect, proteinuria and Hb were also identified as significant risk predictors for the same renal end points in Asian patients. The association between low Hb and renal end points requires further elucidation. Whereas low Hb might be a more sensitive marker for renal dysfunction, it is plausible that the relatively high prevalence of α- and β-thalassemia traits (reported to be 6–8% in Asians) (22) might have adverse effects on tissue function(s) through increased oxidative stress and iron overload. In this context, patients with thalassemia major, especially if hypertransfused, are known to have increased risk of insulin resistance (23) and diabetic nephropathy (24). More recently, thalassemia minor has been found to be a risk factor for gestational diabetes (25), which was associated with excess maternal iron in Chinese women (26).

In conclusion, despite potential limitations due to its post hoc nature, our analysis shows that treatment with losartan significantly reduces the risk of developing the primary composite end point of DsCr, ESRD, and all-cause mortality in Asian patients with type 2 diabetes and nephropathy. In addition, losartan reduced proteinuria and the progression of renal disease and was well tolerated in these patients with a similar incidence of cough observed. In the Asian population of the RENAAL study, baseline proteinuria and Hb were significant predictors of risk for the renal end points of doubling of the serum creatinine concentration and ESRD. In light of the increasing epidemic of diabetes in Asia, our current results furnish important health care implications for Asian patients.

The following investigators have participated in the RENAAL study in Asia. Japan: R. Abe, Y. Ando, T. Fujita, T. Hanafusa, M. Haneda, T. Haneda, Y. Hashimoto, T. Ida, Y. Iino, S. Ishibashi, S. Ito, S. Kadoto, H. Kakuta, M. Kanazawa, T. Kanda, M. Kasuga, M. Kato, Y. Kida, T. Koike, H. Kurahachi, H. Kuzuya, F. Marumo, K. Matoba, K. Murakami, D. Nagasaku, K. Ohshiro, S. Oikawa, K. Okada, S. Owada, T. Saito, H. Sakai, T. Sawada, J. Seino, C. Shigemasa, K. Shikata, T. Shoji, M. Sone, C. Takahashi, T. Tamai, Y. Tsubakihara, N. Ujihara, N. Ura, T. Watanabe, N. Yamada, I. Yamaji, Y. Yamasaki, M. Yoshinari, N. Yoshioka; Hong Kong: J.C.N. Chan, W.Y. So, J.A.J.H. Critchley, M.K.W. Lo, K.F. Lee, G.T.C. Ko, W.B. Chan, K.S.L. Lam, N.M.S. Wat; Malaysia: C.T. Chua, Z. Morad; Singapore: K.S. Wong.

This study was supported by Merck (West Point, PA).