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aliskiren combined with losartan in type 2 diabetes and nephropathy

Aliskiren Combined with Losartan in Type 2 Diabetesand Nephropathy

N Engl J Med 2008;358:2433-46.

The discovery 110 years ago that crude kidney extract elicited a pressor reaction provided the first evidence of the existence of the renin–angiotensin– aldosterone system, a major vasoactive system,
  • the complex actions and interactions of this important cascade are still unfolding.
A reactive increase in the activity of renin, widely considered the rate-limiting component of the system, occurs when either ACE inhibitors or angiotensin-receptor blockers are used for long periods
  • It was anticipated that the ability to inhibit renin would improve blood-pressure control and might modify other actions and interactions of this important vasoactive system.
renin exerts additional actions through a renin receptor, distinct from its actions that lead to the production of angiotensin and aldosterone
  • The recent approval of aliskiren, an oral renin inhibitor, by the Food and Drug Administration and the European Medicines Agency is permitting new clinical questions to be examined.
renin and prorenin
Renin and prorenin
  • 75% to 85% of measured plasma renin is in the form of Prorenin which is inactive and needs to be activated to become Renin
renin has separate enzymatic and receptor mediated effects

Cell membrane

Cellular effects

Renin has separate enzymatic and receptor-mediated effects

Enzymatic effects

Receptor-mediated effects


Ang II effects


Ang I

activation mapk cell signalling pathways by renin


Cell membrane

(Pro)renin receptor








Activation MAPK cell signalling pathways by renin

MAPK, mitogen-activated protein kinasePAI-1, plasminogen activator inhibitor-1

1 Nguyen et al. 2002; 2 Nguyen et al. 1996; 3 Ichihara et al. 2006a; 4 Saris et al. 2006.

Whether this drug is superior to other available medications that block the renin–angiotensin–aldosterone system is, as yet, unclear.
  • whether aliskiren in combination with ACE inhibitors, angiotensin-receptor blockers, or aldosterone- receptor antagonists would be superior to combinations of these latter classes of drugs?
aliskiren generally decreases plasma renin activity, although renin concentration is measured as increased, in part because most direct assays also measure prorenin, which is inactive.
  • When both an ACE inhibitor and an angiotensin-receptor blocker are used, the increase in plasma renin is marked.
Might using a direct inhibitor in combination with either an ACE inhibitor or an angiotensin-receptor blocker be more beneficial?
some evidence
Some evidence
  • In 2007, Oparil et al. reported a study in which patients with mild-to-moderate hypertension received aliskiren (150 mg), valsartan (160 mg), both, or a placebo for 4 weeks, followed by a doubling of the agents in all groups for another 4 weeks.
  • At the end of the study period, dual blockade lowered both systolic and diastolic blood pressure (in the range of 4 to 4.5 mm Hg systolic and 2.5 to 3 mm Hg diastolic) more than either agent alone.
Uresin et al.recently examined the efficacy and safety of aliskiren and the ACE inhibitor ramipril, alone or in combination, in patients with type 1 or type 2 diabetes and hypertension.
  • The decreases in blood pressure that were seen after treatment with aliskiren in combination with other blockers of the renin-angiotensin-aldosterone system were similar in magnitude no matter which ACE inhibitor or angiotensin-receptor blocker was used.
None of these studies, however, examined the effect of aliskiren on proteinuria or other intermediate end points, leaving open the question of whether aliskiren is renoprotective?
  • In a rat model of diabetic nephropathy,aliskiren reduced albuminuria and interstitial fibrosis, as well as blood pressure, and was more effective than perindopr

N Engl J Med 2008;358:2433-46.

Original ArticleAliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

Hans-Henrik Parving, M.D., D.M.Sc., Frederik Persson, M.D., Julia B. Lewis, M.D., Edmund J. Lewis, M.D., Norman K. Hollenberg, M.D., Ph.D., for the AVOID Study Investigators

N Engl J Med

Volume 358(23):2433-2446

June 5, 2008

what is known
What is known?
  • The pathogenesis of diabetic nephropathy is multifactorial, and the renin- angiotensin−aldosterone system plays an important role.
  • Persistent proteinuria is causes a progressive rise in blood pressure, a declining glomerular filtration rate, and a high risk of fatal or nonfatal cardiovascular events.
The degree of proteinuria is closely associated with the rates of renal and cardiovascular events.
  • Furthermore, a reduction in proteinuria is associated with a slowing of both the decline in the glomerular filtration rate and the progression to end-stage renal disease.
In addition, decreasing proteinuria is associated with improved cardiovascular outcomes in patients with diabetic nephropathy and arterial hypertension.
  • As a result, a reduction in proteinuria has been widely used as a surrogate end point for renoprotection.
there is still a large, unmet need to develop strategies for the prevention of diabetic nephropathy and its progression to end-stage renal disease.
  • Diabetic nephropathy remains the leading cause of end-stage renal disease in the developed world.
The aim of this trial was to evaluate the potential renoprotective capacity of direct renin inhibition with aliskiren in patients with hypertension, type 2 diabetes, and proteinuria
  • who were already receiving the maximal recommended renoprotective treatment with losartan (100 mg daily) and optimal treatment for hypertension
inclusion criteria
Inclusion criteria
  • patients with hypertension who were 18 to 85 years of age and who had type 2 diabetes and nephropathy
  • defined by an early-morning urinary albumin-to-creatinine ratio of >300 mg per gram, or >200 mg per gram in patients receiving therapy targeted at blockade of the renin−angiotensin−aldosterone system
  • nondiabetic kidney disease, a urinary albumin-to-creatinine ratio of more than 3500 mg per gram,
  • an estimated glomerular filtration rate of less than 30 ml per minute per 1.73 m2 of body-surface area,
  • chronic urinary- tract infection,
  • a serum potassium level greater than 5.1 mmol per liter at the time of randomization,
  • severe hypertension, or major cardiovascular
  • disease within the previous 6 months.
randomized, double-blind, placebo-controlled study that was conducted in 15 countries and 150 centers worldwide

Numbers of Patients Who Were Screened for the Study, Who Underwent Randomization, and Who Completed the Study

Parving HH et al. N Engl J Med 2008;358:2433-2446

The study was overseen by a steering committee that included nonvoting members from the sponsor, Novartis
  • The steering committee oversaw the design of the study, the conduct of the trial, and the management and analysis of all data.
  • The sponsor was also involved in the design of the study and in the collection and analysis of the data.
  • All authors had access to all study data and vouch for the accuracy and completeness ofthe data reported.
The patients were examined 13, 12, 8, 4, and 2 weeks before randomization; at the time of randomization; and 1, 4, 8, 11, 12, 16, and 24 weeks after randomization.
  • the baseline urinary albumin-to-creatinine ratio, which was based on the median values in three early-morning urine collections, was calculated 2 weeks before randomization.

Blood pressure and pulse, adverse events, concomitant medications, and adherence to medication regimens were assessed at each visit.

Three early-morning spot urine specimens were collected on 3 sequential days 13 weeks and 2 weeks before randomization and 4, 8, 12,16, and 24 weeks after randomization.
  • Three overnight urine specimens were obtained on 3 sequential nights 2 weeks before randomization (baseline) and 12 and 24 weeks after randomization
Three measurements were obtained, 2 minutes apart at each time point, and the average of the three was used for the calculation of the 24-hour trough level (i.e., the level 24 hours after administration of the drug).
  • The target blood pressure during the open-label and double-blind periods was less than 130/80 mm Hg for both groups.
The primary efficacy measure was the percentage reduction in the early-morning urinary albumin-tocreatinine ratio from baseline to the end of the study (24 weeks) among patients who received aliskiren, as compared with patients who received placebo.
Changes in the log-transformed urinary albumin-to-creatinine ratio from baseline (2 weeks before randomization) to weeks 4, 12, and 16 and to week 24 (end point)
  • were assessed for the intention- to-treat population with the use of an analysis of covariance (ANCOVA) model,.
For patients with missing albumin-to-creatinine ratio values for week 24 (13% and 9.7% in the aliskiren and placebo groups, respectively),
  • the last post-baseline urinary albuminto-creatinine ratio was carried forward for the week-24 end-point analysis
Treatment comparisons between the patients who received aliskiren and those who received placebo were performed with the use of
  • a two-sided test with a significance level of 0.05.
mean differences between the groups (aliskiren vs. placebo) for the change from baseline in the urinary albumin-to-creatinine ratio (and associated 95% confidence intervals) were
  • back-transformed to provide aliskiren-to-placebo ratios.
Correlations between changes from baseline in blood pressure and changes from baseline in the urinary albumin-to-creatinine ratio were assessed by linear regression analysis.
  • Well powered to detect differences
  • target sample size for patients completing the study was approximately 396 patients (198 per treatment group).
  • Assuming a dropout rate of 20%, 496 patients were required.
  • This sample size would have provided 90% power to detect, a treatment difference of 18% in the primary end point
  • With 599 patients enrolled, and with the same assumptions as stated above, the power was approximately 94%.

Baseline Characteristics of the Randomized Population

Parving HH et al. N Engl J Med 2008;358:2433-2446


Concomitant Antihypertensive Therapies Received at Baseline and during the Double-Blind Period among Patients with Type 2 Diabetes and Nephropathy

Parving HH et al. N Engl J Med 2008;358:2433-2446


Changes from Baseline in the Urinary Albumin-to-Creatinine Ratio, Urinary Albumin Excretion Rate, and Blood Pressure According to Study Group

Parving HH et al. N Engl J Med 2008;358:2433-2446

By the end of the study period, treatment with aliskiren (150 mg daily for 3 months, followed by 300 mg daily for another 3 months) had reduced
  • the mean urinary albumin-to-creatinine ratio by 20%, as compared with placebo (95% confidence interval [CI], 9 to 30; P<0.001)
After adjustment for the change from baseline in systolic blood pressure,
  • the reduction was 18% (95% CI, 7 to 28; P = 0.002)
  • By week 12, 150 mg of aliskiren daily,as compared with placebo, had decreased the urinary albumin-to-creatinine ratio by 11% (95% CI, 2 to 20; P = 0.02)
At week 24, the overnight urinary albumin excretion rate showed a similar pattern, with a reduction of 18% in the aliskiren group(95% CI, 5 to 30; P = 0.009 for the comparison with the placebo group)
By the end of the study period (week 24), the mean blood pressure in the aliskiren group was 2/1 mm Hg lower than that in the placebo group (P=0.07 for systolic pressure, P = 0.08 for diastolic pressure)
  • A reduction of 50% or more in albuminuria was seen in 24.7% of the patients who received aliskiren, as compared with 12.5% of the patients who received placebo (P<0.001).
  • A comparison of baseline characteristics between patients who had a heightened response (a reduction of 50% or more in albuminuria) and those who had a normal response (a reduction of less than 50% in albuminuria) did not reveal any significant differences.
Even though aliskiren appeared to have a beneficial effect or trend in all subgroups, the effect was not always significant.
  • The mean rate of decline in the estimated glomerular filtration rate during the 24-week study period was 2.4 ml per minute per 1.73 m2 (95% CI, 1.1 to 3.7) in the aliskiren group and 3.8 ml per minute per 1.73 m2 (95% CI, 2.5 to 5.1) in the placebo group (P = 0.07).


  • Aliskiren may have renoprotective effects that are independent of its blood-pressure−lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment

one cannot completely rule out the possibility that changes in antihypertensive medications after randomization might have confounded the results of the study.

many of the patients in both of in the study received three or more antihypertensive agents,
  • systolic blood-pressure goal of 130 mm Hg was reached in less than half the patients, whereas our diastolic blood-pressure goal of 80 mm Hg was reached in the majority of patients in both groups.
  • Previous studies among patients with diabetic nephropathy have also shown that ideal control of systolic blood pressure is very difficult to attain in patients with diabetes,
The number of patients with a serum potassium level of 6.0 mmol per liter or more was higher with the combined drugs than with placebo,
  • Although the occurrence of such cases, after adjustment for the nine patients who were mistakenly enrolled in the trial, was low.
  • Concerns about dual-agent blockade of the renin– angiotensin–aldosterone system have been raised, with particular concern expressed about the potential increase in the incidence of hyperkalemia
  • and decrease in the glomerular filtration rate
The dual therapy in the AVOID trial achieved the goal of reducing albuminuria; however, it is not known how the patients would have fared if they had taken the medications for a longer period of time.
  • Although adverse events were not marked, participating patients were chosen carefully — patients with glomerular filtration rates of less than 30 ml per minute or potassium levels greater than 5.1 mmol per liter were excluded.