Hans-henrik Parving - Academia.edu (original) (raw)

Papers by Hans-henrik Parving

Research paper thumbnail of Years of Life Gained by Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria - 21 Years Follow-Up on the Steno-2 Study

Endocrine Abstracts, 2016

Aims/hypothesis The aim of this work was to study the potential long-term impact of a 7.8 years i... more Aims/hypothesis The aim of this work was to study the potential long-term impact of a 7.8 years intensified, multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria in terms of gained years of life and years free from incident cardiovascular disease. Methods The original intervention (mean treatment duration 7.8 years) involved 160 patients with type 2 diabetes and microalbuminuria who were randomly assigned (using sealed envelopes) to receive either conventional therapy or intensified, multifactorial treatment including both behavioural and pharmacological approaches. After 7.8 years the study continued as an observational follow-up with all patients receiving treatment as for the original intensive-therapy group. The primary endpoint of this follow-up 21.2 years after intervention start was difference in median survival time between the original treatment groups with and without incident cardiovascular disease. Non-fatal endpoints and causes of death were adjudicated by an external endpoint committee blinded for treatment allocation. Results Thirty-eight intensive-therapy patients vs 55 conventional-therapy patients died during follow-up (HR 0.55 [95% CI 0.36, 0.83], p = 0.005). The patients in the intensivetherapy group survived for a median of 7.9 years longer than the conventional-therapy group patients. Median time before first cardiovascular event after randomisation was 8.1 years longer in the intensive-therapy group (p = 0.001). The hazard for all microvascular complications was decreased in the intensivetherapy group in the range 0.52 to 0.67, except for peripheral neuropathy (HR 1.12). Conclusions/interpretation At 21.2 years of follow-up of 7.8 years of intensified, multifactorial, target-driven treatment of type 2 diabetes with microalbuminuria, we demonstrate a median of 7.9 years of gain of life. The increase in lifespan is matched by time free from incident cardiovascular disease. Trial registration: ClinicalTrials.gov registration no. NCT00320008. Funding: The study was funded by an unrestricted grant from Novo Nordisk A/S.

Research paper thumbnail of Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial

Diabetologia, 2008

Aims/hypothesis The purpose of this study was to evaluate the optimal renoprotective effect of ul... more Aims/hypothesis The purpose of this study was to evaluate the optimal renoprotective effect of ultrahigh doses of lisinopril, as reflected by short-term changes in urinary albumin excretion rate (UAER), in type 1 diabetic patients with diabetic nephropathy. Methods At the Steno Diabetes Center, 49 type 1 diabetic patients with diabetic nephropathy completed this doublemasked randomised crossover trial consisting of an initial washout period followed by three treatment periods each lasting 2 months, where all patients received lisinopril 20, 40 and 60 mg once daily in randomised order in addition to slow-release furosemide. Allocation was concealed by sequentially numbered opaque sealed envelopes. UAER, 24 h ambulatory blood pressure (ABP) and estimated GFR were determined at baseline and after each treatment period. Results All 49 patients completed all three treatment periods. Baseline values were: UAER (geometric mean [95% CI]) 362 (240-545) mg/24 h, 24 h ABP (mean [SD]) 142 (14)/74 (8) mmHg and estimated GFR 75 (29) ml min −1 1.73 m −2. Reductions in UAER from baseline were 63%, 71% and 70%, respectively, with the increasing doses of lisinopril (p<0.001). Compared with lisinopril 20 mg there was a further reduction in UAER of 23% with lisinopril 40 mg and 19% with 60 mg, p<0.05. ABP was reduced from baseline by 10/5, 13/7 and 12/7 mmHg (p<0.001 vs baseline, p<0.05 for diastolic ABP 20 vs 40 mg, otherwise NS between doses). The difference in UAER between 20 and 40 mg lisinopril was significant after adjustment for changes in ABP (p<0.01). Two patients were excluded from the study because of an increase in plasma creatinine and one because of high BP; otherwise the study medication was well tolerated with few, mild, dose-independent adverse effects. Conclusions/interpretation Lisinopril 40 mg once daily is generally safe and offers additional reductions in BP and UAER in comparison with the currently recommended dose of 20 mg. Lisinopril 60 mg offers no further beneficial effect. Trial registration: ClinicalTrials.gov NCT00118976 Funding: This study was financed out of local funds and was not supported by the medical industry.

Research paper thumbnail of Decreasing Incidence of Severe Diabetic Microangiopathy in Type 1 Diabetes

Diabetes Care, 2003

OBJECTIVE—Conflicting evidence of a decline in incidence of microvascular complications in type 1... more OBJECTIVE—Conflicting evidence of a decline in incidence of microvascular complications in type 1 diabetes during the last decades has been reported. To assess recent trends in the cumulative incidence of diabetic microangiopathy in type 1 diabetes, we analyzed data from long-term prospective observational studies lasting ≥20 years. RESEARCH DESIGN AND METHODS—A total of 600 Caucasian patients with onset of type 1 diabetes between 1965 and 1984 were followed until death or until the year 2000. Patients were divided into four groups based on the year of diabetes onset: group A, 1965–1969 (n = 113); group B, 1970–1974 (n = 130); group C, 1975–1979 (n = 113); and group D, 1979–1984 (n = 244). Group A, B, and C are prevalence cohorts identified in 1984; group D is an inception cohort. RESULTS—In patients followed for ≥20 years, the cumulative incidence (95% CI) of diabetic nephropathy after 20 years of diabetes (urinary albumin excretion >300 mg/24 h) was reduced in patients with mor...

Research paper thumbnail of Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease

Journal of the Renin-Angiotensin-Aldosterone System, 2012

Renin-angiotensin-aldosterone system (RAAS) blockade may reduce levels of biomarkers of chronic l... more Renin-angiotensin-aldosterone system (RAAS) blockade may reduce levels of biomarkers of chronic low-grade inflammation and endothelial dysfunction. We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies. Materials and methods: The studies were double-blind, randomised, placebo-controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro-or macroalbuminuria treated with angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin receptor blocker (ARB), and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days.

Research paper thumbnail of Toe-brachial index as a predictor of cardiovascular disease and all-cause mortality in people with type 2 diabetes and microalbuminuria

Diabetologia, Jan 5, 2017

The study aimed to evaluate toe-brachial index (TBI) and ankle-brachial index (ABI) as determinan... more The study aimed to evaluate toe-brachial index (TBI) and ankle-brachial index (ABI) as determinants of incident cardiovascular disease (CVD) and all-cause mortality in people with type 2 diabetes and microalbuminuria. This was a prospective study including 200 participants. Unadjusted and adjusted (traditional risk factors and additional inclusion of N-terminal pro-brain natriuretic peptide [NT-proBNP] and coronary artery calcification) Cox regression models were performed. C statistics and relative integrated discrimination improvement (rIDI) evaluated risk prediction improvement. Median follow-up was 6.1 years; 40 CVD events and 26 deaths were recorded. Lower TBI was associated with increased risk of CVD (HR per 1 SD decrease: 1.55 [95% CI 1.38, 1.68]) and all-cause mortality (1.41 [1.22, 1.60]) unadjusted and after adjustment for traditional risk factors (CVD 1.50 [1.27, 1.65] and all-cause mortality 1.37 [1.01, 1.60]). Lower ABI was a determinant of CVD (1.49 [1.32, 1.61]) and a...

Research paper thumbnail of Symmetric and asymmetric dimethylarginine as risk markers of cardiovascular disease, all-cause mortality and deterioration in kidney function in persons with type 2 diabetes and microalbuminuria

Cardiovascular diabetology, Jan 11, 2017

To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk mark... more To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model's improved ability to discriminate events from n...

Research paper thumbnail of Intensified multifactorial intervention in type 2 diabetics with microalbuminuria leads to long-term renal benefits

Kidney International, 2017

In the present post hoc analyses we studied the impact of intensified, multifactorial treatment o... more In the present post hoc analyses we studied the impact of intensified, multifactorial treatment on renal outcomes in patients with type 2 diabetes and microalbuminuria enrolled in the Steno-2 Study. Outcome measures were progression to macroalbuminuria, decline in the glomerular filtration rate (GFR), and development of end stage renal disease (ESRD). In total, 160 patients with type 2 diabetes and microalbuminuria were recruited and assigned to conventional or intensified therapy targeting multiple risk factors. The mean duration of the intervention was 7.8 years after which all patients were offered intensified therapy over a total follow-up up to 21 years on albuminuria, GFR, ESRD and mortality. Progression to macroalbuminuria was significantly reduced in the intensive-therapy group with hazard ratio of 0.48 [95% confidence interval 0.31, 0.84]. The decline in GFR was significantly different with 3.1 ml/min/year in the intensivetherapy group compared to 4.0 in the conventionaltherapy group. Progression to ESRD trended towards a decreased hazard with an adjusted ratio in the intensive group of 0.36 [0.12, 1.05]. ESRD combined with death had a significantly reduced hazard ratio of 0.53 [0.35, 0.8]. Thus, intensified, multifactorial treatment slowed progression in nephropathy and renal function loss reducing the risk of ESRD.

Research paper thumbnail of Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study

Scandinavian Journal of Clinical and Laboratory Investigation, 2008

To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy... more To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides). IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n = 269, 68 %). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-beta) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information. In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28 % increase ( = 1 SD) in Z-score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75 % increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p = 0.038). Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915.

Research paper thumbnail of Aliskiren Combined with Losartan in Diabetes and Nephropathy

New England Journal of Medicine, 2008

To the Editor: In the report on the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID... more To the Editor: In the report on the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study by Parving et al. (June 5 issue),1 there is convincing evidence that aliskiren, in addition to losartan, has a significant antiproteinuric effect, which supports the potential therapeutic role of a renin inhibitor in diabetic nephropathy. However, the authors do not indicate specifically the type of calcium-channel blocker the patients were concomitantly taking. Non-dihydropyridine calcium-channel blockers, such as diltiazem, have been shown to have antiproteinuric and renoprotective properties.2 Since more than 50% of the patients were taking a calcium-channel blocker, this may have partially contributed to the observed decrease in proteinuria. Furthermore, the superiority of telmisartan over losartan in reducing proteinuria in patients with diabetes was recently reported.3 We question whether aliskiren would have resulted in the same magnitude of reduction in proteinuria had telmisartan been used instead of losartan. Mandip Panesar, M.D. Amar Damodar, M.D.

Research paper thumbnail of Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria

Diabetes Care, 2009

OBJECTIVE We investigated whether the antiproteinuric effect of the direct renin inhibitor aliski... more OBJECTIVE We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS Placebo geometric mean albuminuria was 258 mg/day (range 84–2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m2. Aliskiren treatment reduced albuminuria by 48% (95% CI 27...

Research paper thumbnail of Aliskiren in Combination with Losartan Reduces Albuminuria Independent of Baseline Blood Pressure in Patients with Type 2 Diabetes and Nephropathy

Clinical Journal of the American Society of Nephrology, 2011

Background and objectives Elevated BP contributes to development and progression of proteinuria a... more Background and objectives Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study. Design, setting, participants, & measurements In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), Ͻ130/80 mmHg (n ϭ 159); Group B, Ͻ140/90 mmHg but Ն130/80 mmHg (n ϭ 189); and Group C (insufficient BP control), Ն140/90 mmHg (n ϭ 251). Results Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P ϭ 0.013). Conclusions Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control.

Research paper thumbnail of Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

New England Journal of Medicine, 2012

Background This study was undertaken to determine whether use of the direct renin inhibitor alisk... more Background This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. Methods In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. Results The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = 0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). Conclusions The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful.

Research paper thumbnail of Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

New England Journal of Medicine, 2008

Background Diabetic nephropathy is the leading cause of end-stage renal disease in developed coun... more Background Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin−angiotensin−aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. Methods We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an earlymorning urine sample, at 6 months. Results The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-tocreatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P = 0.07] and diastolic, 1 mm Hg lower [P = 0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. Conclusions Aliskiren may have renoprotective effects that are independent of its bloodpressure−lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955.

Research paper thumbnail of Baseline characteristics in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)

Journal of the Renin-Angiotensin-Aldosterone System, 2012

Introduction: Patients with type 2 diabetes are at enhanced risk for macro- and microvascular com... more Introduction: Patients with type 2 diabetes are at enhanced risk for macro- and microvascular complications. Albuminuria and/or reduced kidney function further enhances the vascular risk. We initiated the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Aliskiren, a novel direct renin inhibitor, which lowers plasma renin activity, may thereby provide greater cardio-renal protection compared with angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) alone. Materials and methods: ALTITUDE is a randomized, double-blind, placebo-controlled study in high risk type 2 diabetic patients receiving aliskiren 300 mg once daily or placebo added to recommended cardio-renal protective treatment including ACEi or ARB, but not both. The number of patients randomized was 8606. Results: Baseline characteristics (median, IQR) are: age 65 (58, 72) years, male 68%, BMI 29.1 (25.7, 32.2) kg/m2, cardiovascular disease 47.9%, blood pressure 134.7 (1...

Research paper thumbnail of Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes

Kidney International, 2008

Background. Blockade of the renin-angiotensin system is the primary target in the treatment of di... more Background. Blockade of the renin-angiotensin system is the primary target in the treatment of diabetic kidney disease. Angiotensin II subtype 1 (AT1) receptor antagonists reduce albuminuria and lower blood pressure, but the initial time course of these effects after initiation of treatment is unknown. We evaluated the time course of the antihypertensive and antialbuminuric effect after initiation of AT1 receptor blockade by losartan in diabetic nephropathy. Methods. Ten hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, patients received losartan 100 mg once daily for 28 days. Every morning, one urine sample was collected for daily determination of albuminucreatinine ratio. Twentyfour hour blood pressure (Takeda TM2420), plasma renin and plasma creatinine were measured at baseline and days 7, 14 and 28. Results. Baseline levels of urinary albuminucreatinine ratio and 24 h mean arterial blood pressure were 676 (402-1136) mgug (geometric mean and 95% CI, respectively) and 100"3 mmHg (mean"SEM). Albuminucreatinine ratio was significantly reduced after 7 days of treatment by 29% (15-41) (95% CI) without significant further reductions during the 28 day study period (P-0.01 vs baseline). Mean arterial blood pressure was significantly lowered by 7 mmHg after 7 days of treatment and remained unchanged throughout the study (P-0.01 vs baseline). Plasma renin was significantly increased from baseline after initiation of losartan treatment and stabilized after 7 days (P-0.01). We found no changes in plasma creatinine during the study. Conclusions. The initial time course of the reduction in arterial blood pressure and albuminuria are concordant, which suggests that systemic and renal haemodynamic mechanisms are of primary importance in the reduction of albuminuria.

Research paper thumbnail of The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy

Journal of the American Society of Nephrology, 2014

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with typ... more Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m 2 in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria$30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Research paper thumbnail of Urinary proteomics predict onset of microalbuminuria in a cohort of normoalbuminuric type 1 diabetic patients in the DIRECT 1 study

Early prevention of diabetic nephropathy is not successful as early interventions have shown conf... more Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria. We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics. Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273-classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4-4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75-0.84; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043). In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273-classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy.

Research paper thumbnail of Number and Frequency of Albuminuria Measurements in Clinical Trials in Diabetic Nephropathy

Background and objectives Albuminuria change is often used to assess drug efficacy in interventio... more Background and objectives Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-today variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits. Design, setting, participants, & measurements This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements. Results Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4-to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone. Conclusions Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Research paper thumbnail of Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

New England Journal of Medicine, 2008

A nefropatia diabética é a principal causa de doença renal terminal no mundo desenvolvido. O fato... more A nefropatia diabética é a principal causa de doença renal terminal no mundo desenvolvido. O fator marcante dessa condição é a proteinúria persistente, situação associada a aumento dos níveis pressóricos, diminuição da taxa de filtração glomerular e elevado risco de desenvolvimento de eventos cardiovasculares. O grau de proteinúria está diretamente associado às taxas de eventos cardiovasculares e renais. A redução do grau de proteinúria tem sido usada, com freqüência, como desfecho substituto para proteção renal.

Research paper thumbnail of Years of Life Gained by Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria - 21 Years Follow-Up on the Steno-2 Study

Endocrine Abstracts, 2016

Aims/hypothesis The aim of this work was to study the potential long-term impact of a 7.8 years i... more Aims/hypothesis The aim of this work was to study the potential long-term impact of a 7.8 years intensified, multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria in terms of gained years of life and years free from incident cardiovascular disease. Methods The original intervention (mean treatment duration 7.8 years) involved 160 patients with type 2 diabetes and microalbuminuria who were randomly assigned (using sealed envelopes) to receive either conventional therapy or intensified, multifactorial treatment including both behavioural and pharmacological approaches. After 7.8 years the study continued as an observational follow-up with all patients receiving treatment as for the original intensive-therapy group. The primary endpoint of this follow-up 21.2 years after intervention start was difference in median survival time between the original treatment groups with and without incident cardiovascular disease. Non-fatal endpoints and causes of death were adjudicated by an external endpoint committee blinded for treatment allocation. Results Thirty-eight intensive-therapy patients vs 55 conventional-therapy patients died during follow-up (HR 0.55 [95% CI 0.36, 0.83], p = 0.005). The patients in the intensivetherapy group survived for a median of 7.9 years longer than the conventional-therapy group patients. Median time before first cardiovascular event after randomisation was 8.1 years longer in the intensive-therapy group (p = 0.001). The hazard for all microvascular complications was decreased in the intensivetherapy group in the range 0.52 to 0.67, except for peripheral neuropathy (HR 1.12). Conclusions/interpretation At 21.2 years of follow-up of 7.8 years of intensified, multifactorial, target-driven treatment of type 2 diabetes with microalbuminuria, we demonstrate a median of 7.9 years of gain of life. The increase in lifespan is matched by time free from incident cardiovascular disease. Trial registration: ClinicalTrials.gov registration no. NCT00320008. Funding: The study was funded by an unrestricted grant from Novo Nordisk A/S.

Research paper thumbnail of Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial

Diabetologia, 2008

Aims/hypothesis The purpose of this study was to evaluate the optimal renoprotective effect of ul... more Aims/hypothesis The purpose of this study was to evaluate the optimal renoprotective effect of ultrahigh doses of lisinopril, as reflected by short-term changes in urinary albumin excretion rate (UAER), in type 1 diabetic patients with diabetic nephropathy. Methods At the Steno Diabetes Center, 49 type 1 diabetic patients with diabetic nephropathy completed this doublemasked randomised crossover trial consisting of an initial washout period followed by three treatment periods each lasting 2 months, where all patients received lisinopril 20, 40 and 60 mg once daily in randomised order in addition to slow-release furosemide. Allocation was concealed by sequentially numbered opaque sealed envelopes. UAER, 24 h ambulatory blood pressure (ABP) and estimated GFR were determined at baseline and after each treatment period. Results All 49 patients completed all three treatment periods. Baseline values were: UAER (geometric mean [95% CI]) 362 (240-545) mg/24 h, 24 h ABP (mean [SD]) 142 (14)/74 (8) mmHg and estimated GFR 75 (29) ml min −1 1.73 m −2. Reductions in UAER from baseline were 63%, 71% and 70%, respectively, with the increasing doses of lisinopril (p<0.001). Compared with lisinopril 20 mg there was a further reduction in UAER of 23% with lisinopril 40 mg and 19% with 60 mg, p<0.05. ABP was reduced from baseline by 10/5, 13/7 and 12/7 mmHg (p<0.001 vs baseline, p<0.05 for diastolic ABP 20 vs 40 mg, otherwise NS between doses). The difference in UAER between 20 and 40 mg lisinopril was significant after adjustment for changes in ABP (p<0.01). Two patients were excluded from the study because of an increase in plasma creatinine and one because of high BP; otherwise the study medication was well tolerated with few, mild, dose-independent adverse effects. Conclusions/interpretation Lisinopril 40 mg once daily is generally safe and offers additional reductions in BP and UAER in comparison with the currently recommended dose of 20 mg. Lisinopril 60 mg offers no further beneficial effect. Trial registration: ClinicalTrials.gov NCT00118976 Funding: This study was financed out of local funds and was not supported by the medical industry.

Research paper thumbnail of Decreasing Incidence of Severe Diabetic Microangiopathy in Type 1 Diabetes

Diabetes Care, 2003

OBJECTIVE—Conflicting evidence of a decline in incidence of microvascular complications in type 1... more OBJECTIVE—Conflicting evidence of a decline in incidence of microvascular complications in type 1 diabetes during the last decades has been reported. To assess recent trends in the cumulative incidence of diabetic microangiopathy in type 1 diabetes, we analyzed data from long-term prospective observational studies lasting ≥20 years. RESEARCH DESIGN AND METHODS—A total of 600 Caucasian patients with onset of type 1 diabetes between 1965 and 1984 were followed until death or until the year 2000. Patients were divided into four groups based on the year of diabetes onset: group A, 1965–1969 (n = 113); group B, 1970–1974 (n = 130); group C, 1975–1979 (n = 113); and group D, 1979–1984 (n = 244). Group A, B, and C are prevalence cohorts identified in 1984; group D is an inception cohort. RESULTS—In patients followed for ≥20 years, the cumulative incidence (95% CI) of diabetic nephropathy after 20 years of diabetes (urinary albumin excretion >300 mg/24 h) was reduced in patients with mor...

Research paper thumbnail of Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease

Journal of the Renin-Angiotensin-Aldosterone System, 2012

Renin-angiotensin-aldosterone system (RAAS) blockade may reduce levels of biomarkers of chronic l... more Renin-angiotensin-aldosterone system (RAAS) blockade may reduce levels of biomarkers of chronic low-grade inflammation and endothelial dysfunction. We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies. Materials and methods: The studies were double-blind, randomised, placebo-controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro-or macroalbuminuria treated with angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin receptor blocker (ARB), and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days.

Research paper thumbnail of Toe-brachial index as a predictor of cardiovascular disease and all-cause mortality in people with type 2 diabetes and microalbuminuria

Diabetologia, Jan 5, 2017

The study aimed to evaluate toe-brachial index (TBI) and ankle-brachial index (ABI) as determinan... more The study aimed to evaluate toe-brachial index (TBI) and ankle-brachial index (ABI) as determinants of incident cardiovascular disease (CVD) and all-cause mortality in people with type 2 diabetes and microalbuminuria. This was a prospective study including 200 participants. Unadjusted and adjusted (traditional risk factors and additional inclusion of N-terminal pro-brain natriuretic peptide [NT-proBNP] and coronary artery calcification) Cox regression models were performed. C statistics and relative integrated discrimination improvement (rIDI) evaluated risk prediction improvement. Median follow-up was 6.1 years; 40 CVD events and 26 deaths were recorded. Lower TBI was associated with increased risk of CVD (HR per 1 SD decrease: 1.55 [95% CI 1.38, 1.68]) and all-cause mortality (1.41 [1.22, 1.60]) unadjusted and after adjustment for traditional risk factors (CVD 1.50 [1.27, 1.65] and all-cause mortality 1.37 [1.01, 1.60]). Lower ABI was a determinant of CVD (1.49 [1.32, 1.61]) and a...

Research paper thumbnail of Symmetric and asymmetric dimethylarginine as risk markers of cardiovascular disease, all-cause mortality and deterioration in kidney function in persons with type 2 diabetes and microalbuminuria

Cardiovascular diabetology, Jan 11, 2017

To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk mark... more To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model's improved ability to discriminate events from n...

Research paper thumbnail of Intensified multifactorial intervention in type 2 diabetics with microalbuminuria leads to long-term renal benefits

Kidney International, 2017

In the present post hoc analyses we studied the impact of intensified, multifactorial treatment o... more In the present post hoc analyses we studied the impact of intensified, multifactorial treatment on renal outcomes in patients with type 2 diabetes and microalbuminuria enrolled in the Steno-2 Study. Outcome measures were progression to macroalbuminuria, decline in the glomerular filtration rate (GFR), and development of end stage renal disease (ESRD). In total, 160 patients with type 2 diabetes and microalbuminuria were recruited and assigned to conventional or intensified therapy targeting multiple risk factors. The mean duration of the intervention was 7.8 years after which all patients were offered intensified therapy over a total follow-up up to 21 years on albuminuria, GFR, ESRD and mortality. Progression to macroalbuminuria was significantly reduced in the intensive-therapy group with hazard ratio of 0.48 [95% confidence interval 0.31, 0.84]. The decline in GFR was significantly different with 3.1 ml/min/year in the intensivetherapy group compared to 4.0 in the conventionaltherapy group. Progression to ESRD trended towards a decreased hazard with an adjusted ratio in the intensive group of 0.36 [0.12, 1.05]. ESRD combined with death had a significantly reduced hazard ratio of 0.53 [0.35, 0.8]. Thus, intensified, multifactorial treatment slowed progression in nephropathy and renal function loss reducing the risk of ESRD.

Research paper thumbnail of Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study

Scandinavian Journal of Clinical and Laboratory Investigation, 2008

To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy... more To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides). IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n = 269, 68 %). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-beta) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information. In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28 % increase ( = 1 SD) in Z-score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75 % increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p = 0.038). Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915.

Research paper thumbnail of Aliskiren Combined with Losartan in Diabetes and Nephropathy

New England Journal of Medicine, 2008

To the Editor: In the report on the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID... more To the Editor: In the report on the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study by Parving et al. (June 5 issue),1 there is convincing evidence that aliskiren, in addition to losartan, has a significant antiproteinuric effect, which supports the potential therapeutic role of a renin inhibitor in diabetic nephropathy. However, the authors do not indicate specifically the type of calcium-channel blocker the patients were concomitantly taking. Non-dihydropyridine calcium-channel blockers, such as diltiazem, have been shown to have antiproteinuric and renoprotective properties.2 Since more than 50% of the patients were taking a calcium-channel blocker, this may have partially contributed to the observed decrease in proteinuria. Furthermore, the superiority of telmisartan over losartan in reducing proteinuria in patients with diabetes was recently reported.3 We question whether aliskiren would have resulted in the same magnitude of reduction in proteinuria had telmisartan been used instead of losartan. Mandip Panesar, M.D. Amar Damodar, M.D.

Research paper thumbnail of Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria

Diabetes Care, 2009

OBJECTIVE We investigated whether the antiproteinuric effect of the direct renin inhibitor aliski... more OBJECTIVE We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS Placebo geometric mean albuminuria was 258 mg/day (range 84–2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m2. Aliskiren treatment reduced albuminuria by 48% (95% CI 27...

Research paper thumbnail of Aliskiren in Combination with Losartan Reduces Albuminuria Independent of Baseline Blood Pressure in Patients with Type 2 Diabetes and Nephropathy

Clinical Journal of the American Society of Nephrology, 2011

Background and objectives Elevated BP contributes to development and progression of proteinuria a... more Background and objectives Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study. Design, setting, participants, & measurements In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), Ͻ130/80 mmHg (n ϭ 159); Group B, Ͻ140/90 mmHg but Ն130/80 mmHg (n ϭ 189); and Group C (insufficient BP control), Ն140/90 mmHg (n ϭ 251). Results Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P ϭ 0.013). Conclusions Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control.

Research paper thumbnail of Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

New England Journal of Medicine, 2012

Background This study was undertaken to determine whether use of the direct renin inhibitor alisk... more Background This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. Methods In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. Results The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = 0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). Conclusions The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful.

Research paper thumbnail of Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

New England Journal of Medicine, 2008

Background Diabetic nephropathy is the leading cause of end-stage renal disease in developed coun... more Background Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin−angiotensin−aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. Methods We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an earlymorning urine sample, at 6 months. Results The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-tocreatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P = 0.07] and diastolic, 1 mm Hg lower [P = 0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. Conclusions Aliskiren may have renoprotective effects that are independent of its bloodpressure−lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955.

Research paper thumbnail of Baseline characteristics in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)

Journal of the Renin-Angiotensin-Aldosterone System, 2012

Introduction: Patients with type 2 diabetes are at enhanced risk for macro- and microvascular com... more Introduction: Patients with type 2 diabetes are at enhanced risk for macro- and microvascular complications. Albuminuria and/or reduced kidney function further enhances the vascular risk. We initiated the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Aliskiren, a novel direct renin inhibitor, which lowers plasma renin activity, may thereby provide greater cardio-renal protection compared with angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) alone. Materials and methods: ALTITUDE is a randomized, double-blind, placebo-controlled study in high risk type 2 diabetic patients receiving aliskiren 300 mg once daily or placebo added to recommended cardio-renal protective treatment including ACEi or ARB, but not both. The number of patients randomized was 8606. Results: Baseline characteristics (median, IQR) are: age 65 (58, 72) years, male 68%, BMI 29.1 (25.7, 32.2) kg/m2, cardiovascular disease 47.9%, blood pressure 134.7 (1...

Research paper thumbnail of Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes

Kidney International, 2008

Background. Blockade of the renin-angiotensin system is the primary target in the treatment of di... more Background. Blockade of the renin-angiotensin system is the primary target in the treatment of diabetic kidney disease. Angiotensin II subtype 1 (AT1) receptor antagonists reduce albuminuria and lower blood pressure, but the initial time course of these effects after initiation of treatment is unknown. We evaluated the time course of the antihypertensive and antialbuminuric effect after initiation of AT1 receptor blockade by losartan in diabetic nephropathy. Methods. Ten hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, patients received losartan 100 mg once daily for 28 days. Every morning, one urine sample was collected for daily determination of albuminucreatinine ratio. Twentyfour hour blood pressure (Takeda TM2420), plasma renin and plasma creatinine were measured at baseline and days 7, 14 and 28. Results. Baseline levels of urinary albuminucreatinine ratio and 24 h mean arterial blood pressure were 676 (402-1136) mgug (geometric mean and 95% CI, respectively) and 100"3 mmHg (mean"SEM). Albuminucreatinine ratio was significantly reduced after 7 days of treatment by 29% (15-41) (95% CI) without significant further reductions during the 28 day study period (P-0.01 vs baseline). Mean arterial blood pressure was significantly lowered by 7 mmHg after 7 days of treatment and remained unchanged throughout the study (P-0.01 vs baseline). Plasma renin was significantly increased from baseline after initiation of losartan treatment and stabilized after 7 days (P-0.01). We found no changes in plasma creatinine during the study. Conclusions. The initial time course of the reduction in arterial blood pressure and albuminuria are concordant, which suggests that systemic and renal haemodynamic mechanisms are of primary importance in the reduction of albuminuria.

Research paper thumbnail of The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy

Journal of the American Society of Nephrology, 2014

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with typ... more Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m 2 in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria$30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Research paper thumbnail of Urinary proteomics predict onset of microalbuminuria in a cohort of normoalbuminuric type 1 diabetic patients in the DIRECT 1 study

Early prevention of diabetic nephropathy is not successful as early interventions have shown conf... more Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria. We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics. Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273-classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4-4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75-0.84; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043). In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273-classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy.

Research paper thumbnail of Number and Frequency of Albuminuria Measurements in Clinical Trials in Diabetic Nephropathy

Background and objectives Albuminuria change is often used to assess drug efficacy in interventio... more Background and objectives Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-today variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits. Design, setting, participants, & measurements This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements. Results Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4-to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone. Conclusions Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Research paper thumbnail of Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

New England Journal of Medicine, 2008

A nefropatia diabética é a principal causa de doença renal terminal no mundo desenvolvido. O fato... more A nefropatia diabética é a principal causa de doença renal terminal no mundo desenvolvido. O fator marcante dessa condição é a proteinúria persistente, situação associada a aumento dos níveis pressóricos, diminuição da taxa de filtração glomerular e elevado risco de desenvolvimento de eventos cardiovasculares. O grau de proteinúria está diretamente associado às taxas de eventos cardiovasculares e renais. A redução do grau de proteinúria tem sido usada, com freqüência, como desfecho substituto para proteção renal.