Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy
Open accessAbstract
BACKGROUND: Diabetic 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. METHODS: A 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. RESULTS: A 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). CONCLUSIONS: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
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- Premisecitation§ DISCUSSION · p. 7
In related studies in patients with type 1 and type 2 diabetes, the benefits of captopril or irbesartan were not tested in the presence of concurrent calcium-channel-antagonist therapy.
“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.”
Quote in the paperSubstantial claim1 of 3 sources checked - Findingown data§ A BSTRACT · p. 1
The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).
“The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).”
Quote in the paperNot a substantial claim - Findingown data§ Primary Outcomes · p. 3
Losartan reduced the risk of end-stage renal disease by 28 percent (P=0.002).
“Losartan also reduced the risk of end-stage renal disease by 28 percent (P=0.002)”
Quote in the paperSubstantial claim - Findingown data§ Primary Outcomes · p. 3
In the per-protocol analysis, among 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).
“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).”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION · p. 7
There was a significant difference in favor of losartan with regard to the rate of a first hospitalization for heart failure, a component of the secondary composite end point.
“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.”
Quote in the paperSubstantial claim
- Findingown data§ Primary Outcomes · p. 3
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).
“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)”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 7
In this population, losartan plus conventional antihypertensive therapy demonstrated excellent tolerability similar to placebo plus conventional antihypertensive therapy, as evidenced by similar numbers of patients in the two groups discontinuing study treatment because of adverse events.
“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.”
Quote in the paperNot a substantial claim - Findingown data§ Primary Outcomes · p. 3
Treatment with losartan resulted in a 16 percent reduction in the risk of the primary composite end point (P=0.02).
“Treatment with losartan resulted in a 16 percent reduction in the risk of the primary composite end point (P= 0.02)”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION · p. 7
Simultaneous therapy with calcium-channel antagonists did not detract from the beneficial effects of losartan.
“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”
Quote in the paperNot a substantial claim - Findingown data§ Secondary Outcomes · p. 4
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).
“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).”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION · p. 7
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.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Primary Outcomes · p. 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).
“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)”
Quote in the paperSubstantial claim - Findingown data§ Primary Outcomes · p. 3
The decrease in risk of the primary composite end point remained essentially unchanged (15 percent) after adjustment for blood pressure (P=0.03).
“The decrease in risk remained essentially unchanged (15 percent) after adjustment for blood pressure (P=0.03).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 7
The addition of losartan to a conventional antihypertensive treatment regimen did not increase the incidence of adverse events.
“The addition of losartan to a conventional antihypertensive treatment regimen did not increase the incidence of adverse events.”
Quote in the paperNot a substantial claim - Findingown data§ Blood Pressure · p. 3
The trough blood pressure declined progressively during the course of the study.
“The trough blood pressure declined progressively during the course of the study.”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION · p. 4
The risk of the primary composite end point (doubling of serum creatinine concentration, end-stage renal disease, or death from any cause) was reduced by 16 percent with losartan.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Primary Outcomes · p. 3
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).
“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)”
Quote in the paperSubstantial claim - Findingown data§ Secondary Outcomes · p. 4
There was no significant difference between the losartan group and the placebo group in the composite end point of morbidity and mortality from cardiovascular causes.
“There was no significant difference between the losartan group and the placebo group in the composite end point of morbidity and mortality from cardiovascular causes.”
- Also stated in: § A BSTRACT · p. 1 · plain
“The composite of morbidity and mortality from cardiovascular causes was similar in the two groups”
Quote in the paperNot a substantial claim - Also stated in: § A BSTRACT · p. 1 · plain
- Findingown data§ DISCUSSION · p. 4
The risk of a doubling of the serum creatinine concentration was reduced by 25 percent with losartan.
“The risk of a doubling of the serum creatinine concentration was also reduced by 25 percent with losartan.”
Quote in the paperSubstantial claim - Findingown data§ Secondary Outcomes · p. 4
Losartan reduced the rate of decline in renal function, assessed by the reciprocal of the serum creatinine concentration, by 18 percent compared with placebo (median slope, ¡0.056 dl per milligram per year in the losartan group vs. ¡0.069 dl per milligram per year in the placebo group; P=0.01).
“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).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS · p. 2
Adverse clinical events resulted in discontinuation in 17.2 percent of patients in the losartan group, as compared with 21.7 percent of those in the placebo group.
“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.”
Quote in the paperNot a substantial claim - Findingown data§ Secondary Outcomes · p. 4
Losartan was associated with a 15.2 percent reduction in the estimated decline in glomerular filtration rate compared with placebo (median rate of decline, 4.4 ml per minute per 1.73 m2 per year in the losartan group vs. 5.2 ml per minute per 1.73 m2 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 m 2 of body-surface area per year in the losartan group, as compared with 5.2 ml per minute per 1.73 m 2 per year in the placebo group; P= 0.01). 12,13”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12] Levey AS, 1999, Ann Intern Med source
- cites [13] Levey AS, 2000, J Am Soc Nephrol
- Findingown data§ DISCUSSION · p. 4
The risk of end-stage renal disease was reduced by 28 percent with losartan during an average follow-up of 3.4 years.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Primary Outcomes · p. 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).
“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).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 6
The risk of the combined end point of doubling of serum creatinine concentration and end-stage renal disease was reduced by 21 percent with losartan (95 percent CI 5 to 34; P=0.01).
“Doubling of serum creatinine concentration and end-stage | 226 (30.1) | 11.0 | 263 (34.5) | 13.2 | 0.01 | 21 (5 to 34)”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 6
Death from any cause did not differ significantly between the losartan and placebo groups (risk reduction ¡2 percent; 95 percent CI ¡27 to 19; P=0.88).
“Death | 158 (21.0) | 6.8 | 155 (20.3) | 6.6 | 0.88 | ¡2 (¡27 to 19)”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION · p. 6
The risk of end-stage renal disease or death was reduced by 20 percent with losartan (95 percent CI 5 to 32; P=0.01).
“End-stage renal disease or death | 255 (34.0) | 11.7 | 300 (39.4) | 14.1 | 0.01 | 20 (5 to 32)”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 6
The average follow-up was longer in the losartan group than in the placebo group.
“the longer average follow-up in the losartan group than in the placebo group”
Quote in the paperNot a substantial claim - Study design and conductown data§ RESULTS · p. 2
The baseline characteristics were similar in the two groups.
“The base-line characteristics were similar in the two groups (Table 1).”
Quote in the paperSubstantial claim - Study design and conductown data§ Study Design · p. 2
The results reported represent a mean follow-up time of 3.4 years (range, 2.3 to 4.6).
“Therefore, the results reported here represent a mean follow-up time of 3.4 years (range, 2.3 to 4.6).”
Quote in the paperNot a substantial claim - Study design and conductown data§ DISCUSSION · p. 5
Statistical analysis that corrected for the small differences in trough blood pressure confirmed that the renal protection conferred by losartan exceeded that attributable to any small differences in blood pressure.
“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.”
Quote in the paperSubstantial claim - Interpretationcitation§ DISCUSSION · p. 7
The augmentation of angiotensin II production by calcium-channel antagonists may be counteracted by concomitant angiotensin-II-receptor blockade.
“a response that may be counteracted by concomitant angiotensin-II-receptor blockade.”
Quote in the paperNot a substantial claim - Premisecitation§ DISCUSSION · p. 7
The evaluation of a subgroup of the HOPE population with renal insufficiency did not show a significant effect on hospitalization 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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Mann JFE, 2001, Ann Intern Med source
- Interpretationown data§ DISCUSSION · p. 4
Extrapolating from the observed data, the reduction in end-stage renal disease risk with losartan corresponds to an average delay of two years in the need for dialysis or transplantation.
“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.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ DISCUSSION · p. 7
The similarity of incidence in the composite secondary cardiovascular end point may have resulted in part from the relatively small sample and the strict enrollment criteria that excluded patients at high risk for cardiovascular events including heart failure.
“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.”
Quote in the paperSubstantial claim - Interpretationcitation§ Secondary Outcomes · p. 4
The reductions in the rate of decline in renal function observed with losartan are far smaller than those reported for captopril as compared with placebo in patients with type 1 diabetes nearly a decade earlier.
“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. 1”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] source
- Interpretationown data§ DISCUSSION · p. 4
The difference between the slopes of the reciprocals of serum creatinine values and the lower level of proteinuria provide further evidence of global renal protection 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.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION · p. 7
Angiotensin II blockade in patients with renal disease decreases the risk of overt heart failure resulting in hospitalization.
“Our findings suggest that angiotensin II blockade in patients with renal disease decreases the risk of overt heart failure resulting in hospitalization.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION · p. 4
The primary benefit of losartan appeared to be its effect on the renal components of the primary composite end point.
“The primary benefit appeared to be the effect on the renal components of this composite end point.”
Quote in the paperSubstantial claim - Interpretationcitation§ DISCUSSION · p. 7
The finding of a reduced rate of first hospitalization for heart failure in patients without clinical heart failure at baseline accords well with findings from the Studies of Left Ventricular Dysfunction Prevention study.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] source
- Premisecitation§ DISCUSSION · p. 7
The Studies of Left Ventricular Dysfunction Prevention study did not include patients with impaired renal function.
“That study, however, did not include patients with impaired renal function.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] source
- Interpretationown data§ DISCUSSION · p. 4
Losartan, along with conventional antihypertensive treatment as needed, confers strong renal protection in patients with type 2 diabetes and nephropathy.
“Our study establishes that losartan, along with conventional antihypertensive treatment as needed, confers strong renal protection in patients with type 2 diabetes and nephropathy.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION · p. 7
Calcium-channel antagonists have been shown to augment the production of angiotensin II.
“Furthermore, calcium-channel antagonists have been shown to augment the production of angiotensin II, 30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Bauer JH, Reams GP. Antihypertensive drugs. In: Brenner BM, ed. The kidney. 6th ed. Philadelphia: W.B. Saunders, 2000:2253-97.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data§ A BSTRACT · p. 1
The benefit of losartan exceeded that attributable to changes in blood pressure.
“The benefit exceeded that attributable to changes in blood pressure.”
Quote in the paperSubstantial claim - Interpretationown data§ A BSTRACT · p. 1
Losartan was generally well tolerated.
“it was generally well tolerated”
Quote in the paperNot a substantial claim - Interpretationown data§ A BSTRACT · p. 1
Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy.
“Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy”
Quote in the paperSubstantial claim - Study design and conductown data§ DISCUSSION · p. 6
When patients with preexisting heart failure were excluded from the analysis of first hospitalization for heart failure, there remained a significant difference in the rate of first hospitalization for heart failure between the two treatment groups.
“When these patients were excluded from the analysis of this component, there remained a significant difference in the rate of first hospitalization for heart failure between the two treatment groups.”
Quote in the paperNot a substantial claim - Study design and conductown data§ DISCUSSION · p. 6
There were 88 patients (44 in each group) who had preexisting heart failure at the time of randomization.
“There were 88 patients (44 in each group) who had preexisting heart failure at the time of randomization.”
Quote in the paperNot a substantial claim - Interpretationown data§ DISCUSSION · p. 8
In summary, losartan led to significant improvement in renal outcomes beyond that attributable to blood-pressure control in patients with type 2 diabetes and nephropathy.
“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.”
Quote in the paperSubstantial claim
- May combine two claims. 14
- Classified as probably not a substantial claim. 16
- The quote only partly states this claim. 1
May combine two claims.
Findingown data§ Secondary Outcomes · p. 4There 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).
“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).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingnone given§ DISCUSSION · p. 4There was a small, time-averaged difference in trough blood pressure between the losartan group and the placebo group.
“There was a small, time-averaged difference in the trough blood pressure between the losartan group”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Primary Outcomes · p. 3Approximately 20 percent of the patients died, but there was no significant difference in mortality between the two groups (P=0.88).
“Approximately 20 percent of the patients died, but there was no significant difference in mortality between the two groups (P=0.88).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Secondary Outcomes · p. 4In patients with type 2 diabetes and nephropathy, losartan led to an average reduction in proteinuria (urinary albumin-to-creatinine ratio) of 35 percent, whereas the placebo group's urinary albumin-to-creatinine ratio tended to increase (P<0.001 for the overall treatment effect).
“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) (Fig. 3).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Blood Pressure · p. 3At the end of the study, mean arterial pressure was 95.9 mm Hg in the losartan group and 96.8 mm Hg in the placebo group (P=0.59), and pulse pressure was 66.7 mm Hg and 67.4 mm Hg, respectively (P=0.77).
“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]”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Blood Pressure · p. 3At two years, mean arterial pressure was 99.1 mm Hg in the losartan group and 99.7 mm Hg in the placebo group (P=0.38), and pulse pressure was 66.2 mm Hg and 67.1 mm Hg, respectively (P=0.37).
“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]”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Blood Pressure · p. 3At one year, mean arterial pressure averaged 100.9 mm Hg in the losartan group and 103.1 mm Hg in the placebo group (P<0.001), and pulse pressure averaged 67.8 mm Hg and 69.8 mm Hg, respectively (P=0.05).
“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]”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Secondary Outcomes · p. 4There were no significant differences in the rates of most cardiovascular end points; the exception was first hospitalization with heart failure (89 patients in the losartan group [11.9 percent] vs 127 in the placebo group [16.7 percent]), for which the risk was reduced by 32 percent (P=0.005).
“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)”
- Also stated in: § A BSTRACT · p. 1 · plain
“although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005)”
Quote in the paperNot a substantial claim- Also stated in: § A BSTRACT · p. 1 · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Blood Pressure · p. 3At baseline, 93.5 percent of patients were receiving antihypertensive therapy (92.3 percent in the losartan group and 94.6 percent in the placebo group).
“At 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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ DISCUSSION · p. 7The benefits of losartan were observed among patients many of whom were already receiving other therapies, such as aspirin, beta-blockers, and lipid-lowering agents, as part of sound medical practice.
“The benefits of losartan were observed among our patients, many of whom were already receiving other therapies, such as aspirin, beta-blockers, and lipidlowering agents, as part of sound medical practice.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ RESULTS · p. 2Increased serum concentrations of creatinine or potassium led to discontinuation of the study medication in 1.5 percent and 1.1 percent, respectively, of patients in the losartan group, as compared with 1.2 percent and 0.5 percent of patients 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.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown data§ Statistical Analysis · p. 2Analyses of the primary and secondary end points were performed according to the intention-to-treat principle, including data from all randomized patients except three lost to follow-up.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone given§ Study Design · p. 1An 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.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ RESULTS · p. 2More patients discontinued the study treatment in the placebo group (53.5 percent) than in the losartan group (46.5 percent).
“More patients discontinued the study treatment in the placebo group (53.5 percent) than in the losartan group (46.5 percent).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown data§ Study Design · p. 1The 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 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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoning§ Statistical Analysis · p. 2Because one interim analysis used a stopping boundary based on an alpha spending function of the O'Brien-Fleming type, a critical P value of 0.048 was required for the primary hypothesis.
“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.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data§ Statistical Analysis · p. 2A per-protocol analysis excluded patients who violated the inclusion and exclusion criteria and censored patients' data 14 days after permanent discontinuation of the study medication.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given§ Study Design · p. 1The study protocol was approved by the institutional review board of each center, and all patients gave written informed consent.
“The study protocol was approved by the institutional review board of each center, and all patients gave written informed consent.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data§ Study Design · p. 1The study was discontinued early by a unanimous vote of the steering committee, whose members were unaware of the treatment assignments.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown data§ DISCUSSION · p. 5The possibility cannot be excluded that the small time-averaged difference in trough blood pressure had a beneficial effect on the renal outcomes.
“We cannot exclude the possibility that this small difference had a beneficial effect on the renal outcomes.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ DISCUSSION · p. 7The Heart Outcomes Prevention Evaluation (HOPE) Study and its diabetes substudy MICRO-HOPE showed benefits of angiotensin-I-converting enzyme inhibition in terms of signs and symptoms of heart failure but failed to show significant differences in hospitalizations for heart failure.
“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.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ DISCUSSION · p. 5Previous studies involving angiotensin-I-converting enzyme inhibitors demonstrated beneficial effects on proteinuria but did not demonstrate the superiority of renin-angiotensin system blockade in slowing progression to end-stage renal disease over nonblockade forms of therapy.
“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”
Quote in the paperSubstantial claim0 of 7 sources checkedProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Interpretationreasoning§ DISCUSSION · p. 7In the absence of a direct comparison between angiotensin-I-converting enzyme inhibitors and angiotensin II antagonists, any extrapolation from results obtained with different classes of drugs is speculative at best.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ RESULTS · p. 3The status of all patients except three in the losartan group who could not be contacted was determined with respect to dialysis, transplantation, and death.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ DISCUSSION · p. 6Subsequent hospitalizations for heart failure were not assessed.
“Subsequent hospitalizations for heart failure were not assessed.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ DISCUSSION · p. 6The Cox model accounts for baseline proteinuria (a stratification factor) and geographic region, as prespecified in the data analysis plan.
“In addition, the Cox model accounts for the base-line level of proteinuria (which was a stratification factor) and the geographic region, as prespecified in the data analysis plan.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone given§ DISCUSSION · p. 6The Cox regression model accounts for time at risk.
“The difference results in part from the fact that the Cox regression model accounts for the time at risk - i.e., the longer average follow-up in the losartan group than in the placebo group.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Diabetic nephropathy is the leading cause of end-stage renal disease.
“Diabetic nephropathy is the leading cause of end-stage renal disease.”
The paper relies on this without support.
Type 2 diabetes is the most common form of diabetes.
“type 2, the most common form of diabetes”
The paper relies on this without support.
Similar data on interruption of the renin-angiotensin system are not available for patients with type 2 diabetes.
“similar data are not available for patients with type 2, the most common form of diabetes”
The paper relies on this without support.
Postponing end-stage renal disease in patients with type 2 diabetes remains an elusive goal.
“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”
The paper relies on this without support.
Type 2 diabetes is the leading cause of chronic renal failure in many countries.
“type 2 diabetes, the leading cause of chronic renal failure in many countries”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the IDNT trial, treatment with irbesartan compared with placebo resulted in a 33% decrease in the risk of doubling of serum creatinine concentration.
“In the IDNT trial, treatment with irbesartan compared with placebo resulted in a 33% decrease in the risk of doubling of serum creatinine concentration and was associated with a nonsigni fi cant reduction in the incidence of kidney failure, which was independent of blood pressure.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [13]
The Primary Outcomes section (p. 3) reports a 25% lower risk of doubled serum creatinine with losartan versus placebo, not a 33% reduction with irbesartan. The paper lists a separate irbesartan study in its References (p. 9), but does not report the claimed IDNT result. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAmong people with type 1 or 2 diabetes with established CKD (eGFR <60 mL/min/1.73m2 and UACR >=300 mg/g creatinine), ACE inhibitor or ARB therapy reduces the risk of progression to ESKD.
“Antihypertensive therapy reduces the risk of albuminuria (67)(68)(69)(70), and among people with type 1 or 2 diabetes with established CKD (eGFR <60 mL/min/1.73m 2 and UACR $300 mg/g creatinine), ACE inhibitor or ARB therapy reduces the risk of progression to ESKD (71)(72)(73)(74)(75)(76)(77)(78)(79)(80).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [71]
The Discussion (p. 4) reports that adding the ARB losartan reduced end-stage renal disease risk by 28% in patients with type 2 diabetes and nephropathy. The Patients section (p. 2) says type 1 diabetes was excluded; the trial did not test an ACE inhibitor and defined eligibility using albuminuria or protein excretion and serum creatinine, not the stated eGFR cutoff. Thus this paper supports the type 2 ARB portion, not the full population and treatment claim. (LLM, conf=0.91)
Experimental — accuracy not yet measuredTreatment with ACE inhibitors or ARBs prevents major adverse kidney outcomes in people with diabetes and is recommended by clinical practice guidelines for people with type 2 diabetes who have or are at high risk of kidney disease.
“Treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been shown to prevent major adverse kidney outcomes in people with diabetes, and these drugs are recommended by clinical practice guidelines for the treatment of people with type 2 diabetes who have, or are at high risk of, kidney disease.[4][5][6][7][8]”
From SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis (2019) · cites this paper as [6]
The Discussion (p. 4) reports that losartan, an ARB, reduced end-stage renal disease and doubling of serum creatinine in patients with type 2 diabetes and established nephropathy. The paper does not establish the same major kidney-outcome benefit for ACE inhibitors in this population, address people merely at high risk of kidney disease, or report the claimed clinical-practice guideline recommendation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe only currently approved treatment for renoprotection in patients with type 2 diabetes is renin-angiotensin system blockade.
“The only currently approved treatment for renoprotection in patients with type 2 diabetes is reninangiotensin system blockade, which was first shown to be effective 18 years ago.3,4”
From Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (2019) · cites this paper as [3]
The Discussion (p. 4) reports that losartan, a renin–angiotensin system blocker, provides renal protection in patients with type 2 diabetes and nephropathy. The paper does not establish that renin–angiotensin system blockade is the only approved renoprotective treatment, or extend its finding to all patients with type 2 diabetes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe eGFR ≥57% decrease outcome was selected because it is a classic outcome in diabetic nephropathy studies and is a more robust kidney failure surrogate outcome than a ≥40% decrease in eGFR, particularly when initial changes in eGFR occur.
“However, a sustained ≥57% decrease in eGFR (equivalent to doubling of serum creatinine) was selected in FIDELITY because it is a classic outcome in diabetic nephropathy studies2 , 12–14 and is a more robust kidney failure surrogate outcome than a ≥40% decrease in eGFR, particularly when initial changes in eGFR occur.14 , 15”
From Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis (2022) · cites this paper as [13]
The Outcome Measures section (p. 2) confirms that this diabetic-nephropathy trial used a sustained doubling of serum creatinine as part of its primary outcome, supporting its use as an established trial outcome. The paper does not compare that outcome with a ≥40% eGFR decrease or say it is a more robust kidney-failure surrogate when initial eGFR changes occur. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Among people with type 1 or type 2 diabetes with established CKD (eGFR <60 mL/min/1.73m2 and UACR ≥300 mg/g creatinine), ACE inhibitor or ARB therapy reduces the risk of progression to kidney failure.
“Antihypertensive therapy reduces the risk of albuminuria (68-71), and among people with type 1 or 2 diabetes with established CKD (eGFR <60 mL/min/1.73m 2 and UACR ≥300 mg/g creatinine), ACE inhibitor or ARB therapy reduces the risk of progression to kidney failure (72)(73)(74)(75)(76)(77)(78)(79)(80)(81).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [72]
The Results (p. 1) report that losartan, an ARB, reduced end-stage renal disease in patients with type 2 diabetes and nephropathy. The Patients section (p. 2) specifies an albumin-to-creatinine ratio of at least 300 or substantial protein excretion, but defines renal impairment using serum creatinine rather than eGFR <60. The paper mentions ACE-inhibitor benefits in type 1 diabetes as background; its trial excluded people with type 1 diabetes and did not test an ACE inhibitor. (LLM, conf=0.87)
Experimental — accuracy not yet measuredACE inhibitors or ARBs are the preferred first-line agents for blood pressure treatment among people with diabetes, hypertension, eGFR <60 mL/min/1.73m2, and UACR ≥300 mg/g creatinine because of their proven benefits for prevention of CKD progression.
“ACE inhibitors or ARBs are the preferred first-line agents for blood pressure treatment among people with diabetes, hypertension, eGFR <60 mL/min/1.73m 2 , and UACR ≥300 mg/g creatinine because of their proven benefits for prevention of CKD progression (72,73,75).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [72]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredRCTs demonstrated decreased risk of CKD progression with a maximally dosed RAS inhibitor compared with placebo or an active antihypertensive drug comparator in patients with albuminuria.
“This recommendation is based on RCTs where findings demonstrated decreased risk of CKD progression, for which patients with albuminuria are at elevated risk, with a maximally dosed RAS inhibitor compared with placebo or an active antihypertensive drug comparator (42–44).”
From Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022) · cites this paper as [42]
The Patients section (p. 2) describes participants with type 2 diabetes and nephropathy who met a urinary albumin or protein threshold, and the Discussion (p. 4) reports reduced renal progression with losartan versus placebo. But the Results (p. 2) say doses ranged from 50 to 100 mg and only 71% received 100 mg, so this trial does not establish that all patients received a maximally dosed RAS inhibitor. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn patients with diabetic kidney disease and increased albuminuria, large placebo-controlled trials have shown that RAS inhibitors, SGLT2 inhibitors, and finerenone each reduced the risk of progression to kidney failure.
“In patients with diabetic kidney disease with increased levels of albuminuria, large placebo-controlled trials have shown that renin-angiotensin system (RAS) inhibitors,3–5 sodium-glucose cotransporter 2 (SGLT2) inhibitors,6,7 and the non-steroidal mineralocorticoid receptor antagonist finerenone8,9 all reduced the risk of progression to kidney failure.”
From Empagliflozin in Patients with Chronic Kidney Disease (2023) · cites this paper as [3]
In the IDNT trial, irbesartan was associated with a nonsignificant reduction in the incidence of kidney failure, independent of blood pressure.
“In the IDNT trial, treatment with irbesartan compared with placebo resulted in a 33% decrease in the risk of doubling of serum creatinine concentration and was associated with a nonsigni fi cant reduction in the incidence of kidney failure, which was independent of blood pressure.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [13]
The Primary Outcomes (p. 3) report a significant reduction in end-stage renal disease with losartan, not a nonsignificant reduction with irbesartan in IDNT. The Discussion (p. 7) and References (p. 9) mention irbesartan studies, but our copy does not report the claimed IDNT kidney-failure result or its independence from blood pressure. (LLM, conf=0.78)
Experimental — accuracy not yet measuredACE inhibitors or ARBs have demonstrated benefit in slowing kidney disease progression.
“For many years, the only agents that had demonstrated benefit in slowing kidney disease progression were the renin angiotensin aldosterone system blockers of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) [11], [12], [13].”
From Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: a review of their kidney and heart protection (2023) · cites this paper as [11]
ARBs (irbesartan/telmisartan) slowed progression from microalbuminuria (albuminuria stage A2) to overt nephropathy.
“ARBs (irbesartan/telmisartan) also slowed progression from microalbuminuria (albuminuria stage A2) to overt nephropathy.708,709”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [708]
Antagonism of the RAAS with ACE inhibitors or angiotensin II receptor blockers attenuates, but may not completely halt, the progression of kidney injury in patients with obesity, hypertension, and type 2 diabetes mellitus.
“Antagonism of the RAAS with ACE inhibitors or AngII receptor blockers also attenuates, but may not completely halt, the progression of kidney injury in patients with obesity, hypertension and T2DM67,68.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [67]
ACE inhibitors and ARBs improve endothelium-dependent vasodilation.
“Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)s improve endothelium-dependent vasodilation and reduce morbidity and mortality in heart failure and nephropathy, including diabetic nephropathy.218-221”
From The Vasculature in Prediabetes (2018) · cites this paper as [219]
ACE inhibitors and ARBs reduce morbidity and mortality in heart failure and nephropathy, including diabetic nephropathy.
“Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)s improve endothelium-dependent vasodilation and reduce morbidity and mortality in heart failure and nephropathy, including diabetic nephropathy.218-221”
From The Vasculature in Prediabetes (2018) · cites this paper as [219]
ARBs reduce the rate of progression from micro- to macroalbuminuria as well as ESRD in patients with type 2 diabetes.
“ARBs have also been shown to reduce the rate of progression from micro- to macroalbuminuria as well as ESRD in patients with type 2 diabetes (234–236).”
From Standards of Medical Care in Diabetes—2009 (2009) · cites this paper as [235]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Mean follow-up of 3.4 years is not 42 months
MinorAt 12 months per year, 3.4 years is 40.8 months, not 42 months. Forty-two months is 3.5 years.
Reported 42 · recomputed 40.8
“The mean follow-up time was 3.4 years (42 months).”
Patients with prior heart failure were both excluded and included
MinorThe eligibility criteria excluded anyone with a history of heart failure before enrollment, but the paper later says 88 patients had preexisting heart failure at randomization. This affects the description of the population used for the heart-failure analysis.
“who had any history of heart failure before enrollment.”
“There were 88 patients (44 in each group) who had preexisting heart failure at the time of randomization.”
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- Authors
- Brenner, B. M., Cooper, M. E., de Zeeuw, D., Keane, W. F., Mitch, W. E., Parving, H.-H., Remuzzi, G., Snapinn, S. M., Zhang, Z., & Shahinfar, S.
- Affiliations
- Brigham and Women's Hospital (US)
- The University of Melbourne (AU)
- Hennepin County Medical Center (US)
- Emory University (US)
- Mario Negri Institute for Pharmacological Research (IT)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2001-09-20
- Volume
- 345
- Issue
- 12
- Pages
- 861-869
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2056976690
- Semantic Scholar
- 842bf4da2a50ee13464536c9dfa502f4eb80c5f1
- Cited by
- 7,493
- References
- 37
- Citations by year
- 2026: 180 · 2025: 233 · 2024: 211 · 2023: 248 · 2022: 235 · 2021: 240 · 2020: 263 · 2019: 204 · 2018: 212 · 2017: 233 · 2016: 243 · 2015: 249 · 2014: 289 · 2013: 288 · 2012: 341
- FWCI
- 280.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, public-domain)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- losartan, type 2 diabetes, diabetic nephropathy, angiotensin receptor blockers, renin-angiotensin system blockade, end-stage renal disease, kidney disease progression, proteinuria, cardiovascular morbidity and mortality, heart failure hospitalization, serum creatinine doubling, antihypertensive therapy
- MeSH terms
- Adult, Aged, Antihypertensive Agents, Cardiovascular Diseases, Creatine, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Humans, Hypertension, Kidney Failure, Chronic, Male, Middle Aged, Proteinuria, Disease Progression, Losartan, Angiotensin Receptor Antagonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-16.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-16.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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