末期腎病變或死亡的複合終點
次要終點
包括心血管疾病相關發生率和死亡率、
蛋白尿以及腎臟疾病進展速度的複合終點。
結果：
Losartan組共有327例患者達到主要終點，而安慰劑組為359例（風險降低16%；P=0.02）。
Losartan 降低了血清肌酸酐濃度倍增（風險降低25%；P=0.006）和末期腎病變（風險降低28%；P=0.002）的發生率，但對死亡率無影響。
其獲益超過了血壓變化帶來的益處。
兩組患者的心血管疾病發生率和死亡率複合指標相似，但Losartan組首次因心臟衰竭住院的發生率顯著降低（風險降低32%；P=0.005）。
Losartan使蛋白尿濃度下降了35%（與安慰劑組相比，P<0.001）。
結論：
Losartan 可顯著改善第2型糖尿病合併腎臟病患者的腎臟功能，且整體耐受性良好。
使用ARB 阻斷腎素-血管緊張素系統，可以延緩第1型糖尿病患者和非糖尿病腎病變患者的腎臟疾病進展。
然而，對於第2型糖尿病患者而言，延緩末期腎病的發生仍然是一個難以實現的目標，而末期腎病是許多國家慢性腎衰竭的主要原因。
我們進行了一項針對第2型糖尿病合併腎病變患者的研究，旨在確定血管緊張素II受體拮抗劑Losartan 單藥或合併常規降血壓治療是否能夠延長血清肌酸酐濃度倍增時間、延緩終末期腎病的發生或延緩死亡。
此外，我們也評估了Losartan和安慰劑對以下次要終點的影響：心血管疾病相關發生率和死亡率的複合指標、蛋白尿以及腎臟疾病進展速度。
Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy NEJM September 20, 2001
AbstractBackgroundDiabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin–angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II–receptor antagonist losartan in patients with type 2 diabetes and nephropathy.
MethodsA total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
ResultsA total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).
ConclusionsLosartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
Interruption of the
renin–angiotensin system with
angiotensin-I–converting enzyme inhibitors slows the progression of renal disease both in patients with type 1 diabetes and in nondiabetic patients who have overt nephropathy.
1–3 However, postponing end-stage renal disease in patients with type 2 diabetes, the leading cause of chronic renal failure in many countries, remains an elusive goal. We undertook a study in patients with type 2 diabetes and nephropathy in order to determine whether the
angiotensin-II–receptor antagonist losartan, alone or in combination with conventional antihypertensive therapy, would increase the time to a
doubling of the serum creatinine concentration, the onset of end-stage renal disease, or death. In addition, we assessed the effects of losartan and placebo on the following
secondary end points: a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
Methods
Study Design
這篇是跨國研究是大型跨國雙盲隨機對照實驗. 共28個國家.分布於亞洲.歐洲.中美.南美.北美 250個醫學中心參與. 共收納 1513 個患者.
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study was an investigator-initiated, multinational, double-blind, randomized, placebo-controlled study designed to evaluate the renoprotective effects of losartan in 1513 patients with type 2 diabetes and nephropathy. The study design has been described previously.
4 In brief, 250 centers in 28 countries in Asia, Europe, Central America, South America, and North America participated.
The study protocol was approved by the institutional review board of each center, and all patients gave written informed consent. The study was overseen by steering and safety committees, each of which contained one nonvoting member who was an employee of the sponsoring pharmaceutical company. The steering committee oversaw the study design, the conduct of the trial, and the management and analysis of the data. A writing subcommittee of the steering committee prepared this report. An independent end-points committee whose members were unaware of the patients' treatment assignments reviewed the data to determine which patients had reached the end points.
We planned to complete the study 3.5 years after the last patient underwent randomization, which would have resulted in a mean follow-up time of 4.5 years. However, the study was discontinued early (February 10, 2001) by a unanimous vote of the steering committee, whose members were unaware of the treatment assignments. Their decision was based on new evidence suggesting that
angiotensin-I–converting enzyme inhibitors, which were excluded by design from the study, may be effective in reducing the incidence of cardiovascular events in patients with renal impairment, including those with diabetes.
5 Therefore, the results reported here represent a mean follow-up time of 3.4 years (range, 2.3 to 4.6).
Patients
收案條件. T2DM且有DKD. 年齡分布 31-70歲.
Nephropathy 腎病變定義. UACR > 300. Cr 1.3~3.0 (體重60公斤以上的男性須 Cr >1.5 才收案)
The study involved male and female patients, ranging in age from 31 to 70 years, who had received diagnoses of type 2 diabetes and nephropathy. Nephropathy was defined by the presence on two occasions of a ratio of urinary albumin (measured in milligrams per liter) to urinary creatinine (measured in grams per liter) from a first morning specimen of at least 300 (or a rate of urinary protein excretion of at least 0.5 g per day) and serum creatinine values between 1.3 and 3.0 mg per deciliter (115 and 265 μmol per liter), with a lower limit of 1.5 mg per deciliter (133 μmol per liter) for male patients weighing more than 60 kg.
排除條件
T1DM
非糖尿病引起的腎病變(含腎動脈夾窄)
近期幾個月曾發生AMI或做過CABG
過去六個月內曾中風或做過 PTCA
過去一年曾發生TIA
已經有心臟衰竭病史
Patients were excluded if they had received a diagnosis of type 1 diabetes or
nondiabetic renal disease, including
renal-artery stenosis. We also excluded patients who had had a
myocardial infarction or had undergone
coronary-artery bypass grafting within the previous month, who had had a cerebrovascular accident or had undergone percutaneous transluminal coronary angioplasty within the previous six months, who had had a transient ischemic attack within the previous year, or who had any history of heart failure before enrollment.
4
開始的六周, 高血壓患者繼續使用原先的降血壓藥物. 但如果患者已經服用 ACEI 或 ARB 則會停用. 改使用其他降血壓藥物(藥物種類名稱不需隱藏)
Treatment
During the six-week screening phase, patients with hypertension continued to receive their standard antihypertensive therapy. If they had been taking angiotensin-I–converting enzyme inhibitors or angiotensin-II–receptor antagonists, however, these medications were discontinued and replaced by alternative open-label medications (diuretics, calcium-channel antagonists, alpha- or beta-blockers, centrally acting agents, or some combination of these types of medication).
依照尿蛋白程度將個案分類. UACR ≥ 2000. 及 UACR < 2000
之後在隨機分配到實驗組(使用 losartan 50mg QD) ,或對照組(使用安慰劑)
Patients were stratified according to their base-line level of proteinuria (a urinary albumin-to-creatinine ratio <2000 or ≥2000) and randomly assigned to receive either losartan (50 mg) or placebo once daily, along with conventional antihypertensive therapy.
血壓控制目標是 < 140/90 mmHg
治療四周後. 若血壓 > 140/90 mmHg(任一項超過都算), 實驗組的藥物劑量改為 losartan 100mg qd
之後再治療八周. 若血壓仍超過140/90 , 則增加其他類型的降血壓藥物(ACEI和ARB除外)
After four weeks, the dose of losartan or placebo was increased to 100 mg or the placebo equivalent once daily if the trough blood pressure with the patient sitting was above the target level of a systolic blood pressure of less than 140 mm Hg and a diastolic blood pressure of less than 90 mm Hg. After an additional eight weeks, antihypertensive agents of the types described above (but not angiotensin-I–converting enzyme inhibitors or angiotensin-II–receptor antagonists) were added or their doses increased to achieve the target blood pressure.
個案每三個月回診(或更短時間) . 接受DM常規治療與檢驗追蹤. 評估是否已經到達主要終點
Throughout the study, patients received the standard of care for the treatment of diabetes, including measurements of glycosylated hemoglobin and fasting serum glucose concentrations. Visits were scheduled every three months, or more often if necessary, to monitor the blood pressure and laboratory measurements and to assess whether adverse events had occurred or end points had been reached.
早期就停用研究藥物的患者仍繼續三個月回診一次. 直到研究結束
未按時回診的個案. 以電話追蹤是否到達實驗終點: 洗腎. 腎移植, 死亡
Patients who discontinued the study drugs early had follow-up visits every three months until the end of the study; at these visits, the primary and secondary end points reached were recorded, the blood pressure was measured, and laboratory measurements were performed. Those who could not return for clinic visits or a family member was contacted by telephone to determine whether they had reached the end points of the initiation of dialysis, renal transplantation, or death.
Outcome Measures
主要終點有三個. 血清Cr超過初始值兩倍. 發生 ESRD. 死亡
三個任一項發生. 即達到主要終點
計算血清 Cr 是否倍增. 初始治療超過四周才可抽血驗 Cr
The primary efficacy measure was the time to the first event of the composite end point of a doubling of the serum creatinine concentration, end-stage renal disease, or death. The doubling of the serum creatinine concentration was defined as the first serum creatinine value that was twice the base-line value, as confirmed by a second serum creatinine value obtained at least four weeks after the initial doubling.
ESRD定義: 需長期洗腎. 或已經接受腎臟移植手術.
End-stage renal disease was defined by the need for long-term dialysis or renal transplantation.
次要終點: 發生心血管疾病, 死於心血管疾病
心血管疾病包括: 心肌梗塞. 中風. 第一次因心衰竭住院. 不穩定心絞痛, 冠狀動脈或周邊動脈重建(包括傳統手術. 微創手術. PCI冠狀動脈介入性治療等等)
其他次要終點: 腎病惡化. 尿蛋白變化
The prespecified secondary end point, morbidity and mortality from cardiovascular causes, was a composite of myocardial infarction, stroke, first hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, or death from cardiovascular causes.
Analyses of the components of both the primary and secondary composite end points were also prespecified. Other secondary end points included the progression of renal disease
6 and changes in the level of proteinuria.
Statistical Analysis
Analyses of the primary and secondary end points were performed according to the intention-to-treat principle; we included data from all randomized patients (with the exception of three patients who were lost to follow-up), from the time of randomization through the date of study termination. In a second, per-protocol analysis, we excluded patients who violated the criteria for inclusion and exclusion and censored patients' data 14 days after they permanently discontinued the study medication.
A Cox regression model
7 that included the base-line level of proteinuria as a stratification factor and the geographic region as a covariate was used to determine the hazard ratio for the primary end point and its 95 percent confidence interval.
The risk reduction was calculated as 100 percent × (1 – hazard ratio). In analyses of
nonfatal end points, data for the patients who had died were considered to have been censored. Event curves are based on Kaplan–Meier analysis.
8 We examined the effect of differences between the groups in the control of blood pressure by adding the
mean arterial pressure during treatment as a time-dependent covariate in the Cox model and comparing the effect of losartan estimated by this model with that estimated by the primary analysis.
The analyses of the progression of renal disease and changes in the level of proteinuria were based on an on-treatment approach. For the analysis of the progression of renal disease, we compared the slopes of the reciprocal of the serum creatinine concentration
6 of the two treatment groups using a linear random-effects model. Changes in the level of proteinuria in the two groups were compared by means of a mixed-effects model
9 whose terms included the
treatment at each point and the base-line level of proteinuria.
Because one interim analysis used a stopping boundary that was based on an alpha spending function of the O'Brien–Fleming type,
10 a critical P value of 0.048 was required for the primary hypothesis. For other outcomes, a P value of less than 0.05 was considered to indicate statistical significance. All statistical tests were two-sided.
Results
總共1513名患者, 分成實驗組和對照組. 實驗組服用 losartan 50mg qd~100mg qd. 其中 71% 使用 100mg qd 劑量
A total of 1513 patients were randomly assigned to receive losartan or placebo once daily, along with conventional antihypertensive therapy as needed but excluding angiotensin-I–converting enzyme inhibitors and angiotensin-II–receptor antagonists. The daily dose of losartan ranged from 50 to 100 mg, with 71 percent of the patients receiving 100 mg.
研究過程. 對照組有 53.5% 病患退出研究. 實驗組有 46.5% 病患退出研究
分析這些患者退出研究的原因, 包括不良臨床事件 adverse clinical events. 血清肌酸酐上升. 血鉀上升. 整理於下表 (我自己整理的)
The base-line characteristics were similar in the two groups (
Table 1). More patients discontinued the study treatment in the placebo group (53.5 percent) than in the losartan group (46.5 percent).
Adverse clinical events resulted in discontinuation in 17.2 percent of the patients in the losartan group, as compared with 21.7 percent of those in the placebo group.
Increased serum concentrations of creatinine or potassium led to the discontinuation of the study medication in 1.5 percent and 1.1 percent, respectively, of the patients in the losartan group, as compared with 1.2 percent and 0.5 percent of the patients in the placebo group. A total of 7.5 percent of the patients in the losartan group and 7.8 percent of those in the placebo group withdrew their consent. We were able to determine the status of all patients (except for three patients in the losartan group who could not be contacted) with respect to dialysis, transplantation, and death.
Table 1
Base-Line Characteristics of the Patients.Blood PressureAt base line, 93.5 percent of the patients (92.3 percent in the losartan group and 94.6 percent in the placebo group) were receiving antihypertensive therapy. An additional 3 percent of the patients had hypertension but were not receiving antihypertensive therapy. The trough blood pressure declined progressively during the course of the study. The trough blood pressure at base line averaged 152/82 mm Hg in the losartan group and 153/82 mm Hg in the placebo group; the mean arterial pressure was 105.5 mm Hg in the losartan group and 106.0 mm Hg in the placebo group (P=0.38); and the pulse pressure was 69.4 mm Hg in the losartan group and 70.8 mm Hg in the placebo group (P=0.13). At one year, the values averaged 146/78 mm Hg in the losartan group and 150/80 mm Hg in the placebo group (mean arterial pressure, 100.9 mm Hg and 103.1 mm Hg, respectively [P<0.001]; pulse pressure, 67.8 mm Hg and 69.8 mm Hg, respectively [P=0.05]); at two years, the values were 143/77 mm Hg and 144/77 mm Hg, respectively (mean arterial pressure, 99.1 mm Hg and 99.7 mm Hg, respectively [P=0.38]; pulse pressure, 66.2 mm Hg and 67.1 mm Hg, respectively [P=0.37]); and at the end of the study they were 140/74 mm Hg and 142/74 mm Hg, respectively (mean arterial pressure, 95.9 mm Hg and 96.8 mm Hg, respectively [P=0.59]; pulse pressure, 66.7 mm Hg and 67.4 mm Hg, respectively [P=0.77]). The various classes of conventional antihypertensive drugs that were used before and during the study are listed in
Table 2.
Table 2
Use of Conventional Antihypertensive Medications at Base Line and during Study Treatment.
Primary Outcomes
主要研究終點包括 1. 血清肌酸酐加倍 2.進展成 ESRD 3.死亡
將這三項一起計算. 任一個發生即達到主要研究終點. 所以將這個稱為複合主要研究終點.
計算風險降低時. 需考量兩組各自追蹤時間不同. 對照組發病事件較多. 比較快到達主要終點. 實驗組追蹤時間長. 時間越長. 到達主要終點的比例會上升. 因此這篇研究計算 risk reduction 是採 the number of event per 100 patient-yr of follow-up. (統計學我不擅長. 直接相信研究者提供的數據就好)
到達複合主要研究終點, 實驗組風險降低16%
According to the intention-to-treat analysis, the primary composite end point of a doubling of the serum creatinine concentration, end-stage renal disease, or death was reached in 327 patients in the losartan group (43.5 percent), as compared with 359 in the placebo group (47.1 percent) (
Figure 1A). Treatment with losartan resulted in a 16 percent reduction in the risk of the primary composite end point (P=0.02) (
Table 3).
依照血壓重新校正風險降低的比例. 結果仍相同. 風險降低 15%
The decrease in risk remained essentially unchanged (15 percent) after adjustment for blood pressure (P=0.03). Furthermore, according to the per-protocol analysis, among the patients who continued to receive their assigned study treatment, losartan conferred a 22 percent reduction in the risk of the primary composite end point (P=0.008).
Figure 1
Kaplan–Meier Curves of the Percentage of Patients with the Primary Composite End Point (Panel A) and Its Individual Components, a Doubling of the Serum Creatinine Concentration (Panel B), End-Stage Renal Disease (Panel C), and the Combined End Point of End-Stage Renal Disease or Death (Panel D).
Table 3
實驗組, 血清肌酸酐上升(加倍)的風險可降低 25%, 進展至 ESRD 風險降低 28%. 有20% 個案死亡, 但兩組死亡率差異並無統計學上的意義.
The intention-to-treat analyses of the individual components of the primary composite end point are also shown in
Table 3. The risk of a doubling of the serum creatinine concentration was
25 percent lower in the losartan group than in the placebo group (P=0.006) (
Figure 1B). Losartan also reduced the risk of end-stage renal disease by 28 percent (P=0.002) (
Figure 1C). Approximately
20 percent of the patients died, but there was no significant difference in mortality between the two groups (P=0.88).
進展為 ESRD或死亡, 這兩項結合一起比較. 實驗組可降低 20% 風險
使用血壓再次校正之後, 風險降低的數值稍微變動
進展為ESRD 風險降低 26%
進展為ESRD or 死亡, 風險降低 19%
The risk of
the combined end point of end-stage renal disease or death was 20 percent lower in the losartan group than in the placebo group (P=0.01) (
Figure 1D and
Table 3). The reductions in
the risk of end-stage renal disease and
of end-stage renal disease or death changed little after correction for blood pressure (26 percent, P=0.007, and 19 percent, P=0.02, respectively).
Secondary OutcomesThere was no significant difference between the losartan group and the placebo group in the composite end point of morbidity and mortality from cardiovascular causes. Approximately one third of the patients had a fatal or nonfatal cardiovascular event (247 in the losartan group [32.9 percent] and 268 in the placebo group [35.2 percent]; risk reduction, 10 percent; P=0.26). There were no significant differences in the rates of most of the cardiovascular end points; the exception was the first hospitalization with heart failure (89 patients in the losartan group [11.9 percent], as compared with 127 in the placebo group [16.7 percent]), for which the risk was reduced by 32 percent (P=0.005) (
Figure 2). There was a difference between the number of myocardial infarctions in the losartan group (50 patients [6.7 percent]) and the number in the placebo group (68 patients [8.9 percent]; risk reduction, 28 percent), but this difference was not statistically significant (P=0.08).
Figure 2
Kaplan–Meier Curves of the Percentage of Patients with a First Hospitalization for Heart Failure in the Losartan and Placebo Groups.
Losartan also led to an average reduction in the level of proteinuria (the urinary albumin-to-creatinine ratio) of 35 percent, whereas in the patients in the placebo group, the urinary albumin-to-creatinine ratio tended to increase (P<0.001 for the overall treatment effect) (
Figure 3). Losartan reduced the rate of decline in renal function, as assessed by the reciprocal of the serum creatinine concentration, by 18 percent (median slope, –0.056 dl per milligram per year in the losartan group, as compared with –0.069 dl per milligram per year in the placebo group; P=0.01). Likewise, losartan was associated with a 15.2 percent reduction in the estimated decline in the glomerular filtration rate (median rate of decline, 4.4 ml per minute per 1.73 m2 of body-surface area per year in the losartan group, as compared with 5.2 ml per minute per 1.73 m2 per year in the placebo group; P=0.01).
12,13 These reductions in the rate of decline are far smaller than those reported for captopril as compared with placebo in patients with type 1 diabetes nearly a decade ago.
1Figure 3
Median Changes from Base Line in the Level of Proteinuria.
DiscussionOur study establishes that losartan, along with conventional antihypertensive treatment as needed, confers strong renal protection in patients with type 2 diabetes and nephropathy. The risk of the primary end point, a composite of a doubling of the serum creatinine concentration, end-stage renal disease, or death from any cause, was reduced by 16 percent with losartan. The primary benefit appeared to be the effect on the renal components of this composite end point. In particular, the risk of end-stage renal disease was reduced by 28 percent with losartan during an average follow-up of 3.4 years. Extrapolating from the observed data, we estimate that this reduction corresponds to an average delay of two years in the need for dialysis or transplantation. The risk of a doubling of the serum creatinine concentration was also reduced by 25 percent with losartan. The difference between the slopes of the reciprocals of the serum creatinine values and the lower level of proteinuria provide further evidence of global renal protection with losartan.
There was a small, time-averaged difference in the trough blood pressure between the losartan group and the placebo group. We cannot exclude the possibility that this small difference had a beneficial effect on the renal outcomes. However, statistical analysis that corrected for these small differences confirmed that the renal protection conferred by losartan exceeded that attributable to any small differences in blood pressure. This study extends our knowledge of the efficacy of antihypertensive therapy in patients with type 2 diabetes and nephropathy. Previous studies involving angiotensin-I–converting enzyme inhibitors have demonstrated beneficial effects on proteinuria but have not demonstrated the superiority of blockade of the renin–angiotensin system in slowing the progression to end-stage renal disease over nonblockade forms of therapy.
14–20 Indeed, studies of the effects of angiotensin-I–converting enzyme inhibitors on the progression of renal disease and end-stage renal failure have yielded conflicting results.
14,15,20–24 Therefore, in the absence of a direct comparison between angiotensin-I–converting enzyme inhibitors and angiotensin II antagonists, any extrapolation from the results obtained with different classes of drugs is speculative at best.
The benefits of losartan were observed among our patients, many of whom were already receiving other therapies, such as aspirin, beta-blockers, and lipid-lowering agents, as part of sound medical practice. Similarly, simultaneous therapy with calcium-channel antagonists did not detract from the beneficial effects of losartan, despite the recent controversy regarding the role of calcium-channel antagonists in the protection of the kidneys and the heart.
25–27 In this regard, it should be noted that in related studies in patients with type 1 and type 2 diabetes,
1,28,29 the benefits of captopril or irbesartan were not tested in the presence of concurrent calcium-channel–antagonist therapy. Furthermore, calcium-channel antagonists have been shown to augment the production of angiotensin II,
30 a response that may be counteracted by concomitant angiotensin-II–receptor blockade.
There was no significant difference between the losartan group and the placebo group in the composite secondary end point of morbidity and mortality from cardiovascular causes. This similarity of incidence may have resulted in part from the relatively small sample and the strict criteria for enrollment that excluded patients at high risk for cardiovascular events including heart failure. We did find a significant difference in favor of losartan with regard to the rate of a first hospitalization for heart failure, a component of this secondary composite end point. This finding in patients without clinical heart failure at base line accords well with findings from the Studies of Left Ventricular Dysfunction Prevention study.
31 That study, however, did not include patients with impaired renal function. The Heart Outcomes Prevention Evaluation (HOPE) Study
32 and its substudy of patients with diabetes, MICRO-HOPE,
20 showed benefits of angiotensin-I–converting enzyme inhibition in terms of the signs and symptoms of heart failure but failed to show significant differences in hospitalizations for heart failure. Furthermore, the evaluation of a subgroup of the HOPE population with renal insufficiency
5 did not show a significant effect on this outcome. Our findings suggest that angiotensin II blockade in patients with renal disease decreases the risk of overt heart failure resulting in hospitalization.
In this population, losartan (plus conventional antihypertensive therapy) demonstrated excellent tolerability, similar to that of placebo (plus conventional antihypertensive therapy), as evidenced by the similar numbers of patients in the two groups in whom the study treatment was discontinued because of adverse events. The addition of losartan to a conventional antihypertensive treatment regimen did not increase the incidence of adverse events.
End-stage renal disease continues to be a worldwide public health concern. Recent estimates by the National Institutes of Health indicate that diabetes represents the single largest cause of end-stage renal disease, accounting for approximately 40 percent of all cases in the United States between 1994 and 1998.
33 Furthermore, the incidence of end-stage renal disease in patients with type 2 diabetes is rising sharply in many regions of the world and is expected to double by 2010. The annual costs associated with end-stage renal disease in the United States reached $12 billion in 1998 and are expected to surpass $28 billion by 2010.
34 Preventing or delaying the progression of diabetic nephropathy is therefore an essential management goal. We believe our findings go a long way toward achieving this goal and may also have an important economic effect.
In summary, losartan led to significant improvement in renal outcomes that was beyond that attributable to blood-pressure control in patients with type 2 diabetes and nephropathy.
