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

Abstract

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 (126, 150)/74.3 (67, 81) mmHg, HbA_1c 7.5 (6.6, 8.6)%, LDL-cholesterol 2.4 (1.9, 3.0) mmol/L, haemoglobin 130 (119, 143) g/L, serum creatinine 115 (91, 137) µmol/L, eGFR 51.7 (42, 65) ml/min per 1.73 m², geometric mean UACR 198.9 (52, 2886) mg/g and frequency of micro/macroalbuminuria 25.7% and 58.2%. ALTITUDE is an event-driven trial to continue until 1628 patients experience a primary cardiovascular-renal event.

Conclusions:

ALTITUDE will determine the potential cardio-renal benefit and safety of aliskiren in combination with ACEi or ARB in high risk patients with type 2 diabetes.

Keywords

Albuminuria aliskiren cardiovascular disease kidney disease

Get full access to this article

View all access options for this article.

References

Parving

H-H

Mauer

Ritz

. Diabetic nephropathy. In: Brenner

(ed.) Brenner & Rector’s The kidney. 8th ed. Boston, USA: WB Saunders, 2008. pp.1265–1298.

Rossing

Hommel

Smidt

. Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment. Diabetologia 1994; 37: 511–516.

De Zeeuw

Remuzzi

Parving

H-H

. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 2004; 65: 2309–2320.

De Zeeuw

Remuzzi

Parving

H-H

. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921–927.

Schmieder

Mann

Schumacher

. Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol 2011; 22: 1353–1364.

Anavekar

McMurray

Velazquez

. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004; 351: 1285–1295.

Chertow

Fan

. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305.

Peti-Peterdi

. High glucose and renin release: The role of succinate and GPR91. Kidney Int 2010; 78: 1214–1217.

Parving

H-H

Lehnert

Bröchner-Mortensen

. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–878.

10.

Parving

H-H

Andersen

Smidt

. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1983; i: 1175–1179.

11.

Brenner

Cooper

de Zeeuw

. Effects of Losartan on Renal and Cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869.

12.

Lewis

Hunsicker

Clarke

. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–860.

13.

Staessen

Richart

. Oral renin inhibitors. Lancet 2006; 368(9545): 1449–1456.

14.

Persson

Rossing

Schjoedt

. Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int 2008; 73: 1419–1425.

15.

Persson

Rossing

Reinhard

. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care 2009; 32: 1873–1879.

16.

Persson

Rossing

Reinhard

. Optimal antiproteinuric dose of aliskiren in type 2 diabetes mellitus: A randomised crossover trial. Diabetologia 2010; 53: 1576–1580.

17.

Parving

H-H

Persson

Lewis

. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 358: 2433–2446.

18.

Parving

H-H

Brenner

McMurray

. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): Rationale and study design. Nephrol Dial Transplant 2009; 24: 1663–1671.

19.

Levey

Bosch

Lewis

. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–470.

20.

Yusuf

Teo

Pogue

. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–1559.

21.

Gaede

Lund-Andersen

Parving

H-H

. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–591.

22.

Preiss

Ray

. Intensive glucose lowering treatment in type 2 diabetes. Br Med J 2011; 343: d4243.

23.

Boussageon

Bejan-Angoulvant

Saadatian-Elahi

. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: Meta-analysis of randomised controlled trials. Br Med J 2011; 343: d4169.

24.

Zoungas

Patel

Chalmers

. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010; 363: 1410–1418.

25.

Reinhard

Hansen

Persson

. Elevated NT-proBNP and coronary calcium score in relation to coronary artery disease in asymptomatic type 2 diabetic patients with elevated urinary albumin excretion rate. Nephrol Dial Transplant 2011; 26: 3242–3249.

26.

Preiss

Sattar

McMurray

. A systematic review of event rates in clinical trials in diabetes mellitus: The importance of quantifying baseline cardiovascular disease history and proteinuria and implications for clinical trial design. Am Heart J 2011; 161: 210–219.

27.

Price

De’Oliveira

Fisher

. The state and responsiveness of the renin-angiotensin-aldosterone system in patients with type II diabetes mellitus. Am J Hypertens 1999; 12: 348–355.

28.

Fisher

NDL

Jan Danser

Nussberger

. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation 2008; 117: 3199–3205.

29.

Feldman

. New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease. Hypertens Res 2010; 33: 279–287.

30.

Stow

Gumz

. The circadian clock in the kidney. J Am Soc Nephrol 2011; 22: 598–604.

31.

Nielsen

Rossing

Bang

. On the mechanisms of blunted nocturnal decline in arterial blood pressure in NIDDM patients with diabetic nephropathy. Diabetes 1995; 44: 783–789.

32.

Sega

Corrao

Bombelli

. Blood pressure variability and organ damage in a general population: results from the PAMELA study (Pressioni Arteriose Monitorate E Loro Associazioni). Hypertension 2002; 39: 710–714.

33.

Solomon

Appelbaum

Manning

. Effect of the direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation 2009; 119: 530–537.

34.

Solomon

Shin

Shah

. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur Heart J 2011; 32: 1227–1234.