Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Preventing Renal Complications in Type 2 Diabetes: Results of the Diabetics Exposed to Telmisartan and Enalapril Trial
Anthony Barnett
Undergraduate Centre, Birmingham Heartlands Hospital, Birmingham, United Kingdom
Address correspondence to: Prof. Anthony Barnett, Undergraduate Centre, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK. Phone: +44-121-424-3587; Fax: +44-121-424-0593; E-mail: anthony.barnett{at}heartofengland.nhs.uk
Patients with type 2 diabetes are prone to hypertension andpersistent protein leakage from the kidney (microalbuminuriaor macroalbuminuria). A progressive decline in renal functioncan lead to overt diabetic nephropathy and ESRD. The likelihoodof cardiovascular disease also is increased. Control of hypertensionis paramount to prevent these life-threatening complications.Agents that target the renin-angiotensin system—angiotensin-convertingenzyme inhibitors and angiotensin II receptor blockers—havebeen shown to be renoprotective. The groundbreaking DiabeticsExposed to Telmisartan And enalaprIL (DETAIL) trial was designedto address the absence of comparative data on the long-termeffects of an angiotensin II receptor blocker versus an angiotensin-convertingenzyme inhibitor on renoprotection and survival in 250 patientswith hypertension and early type 2 diabetic nephropathy. Theprimary purpose of the 5-yr double-blind, double-dummy, randomizedstudy was to establish whether 40 to 80 mg of telmisartan conferredsimilar (i.e., noninferior) renoprotection to 10 to 20 mg ofenalapril as determined by the change from baseline in GFR,measured by the plasma clearance of iohexol. Secondary end pointsincluded the emergence of ESRD and all-cause mortality. Telmisartanwas not inferior to enalapril in reducing the decline in GFR:Mean annual declines in GFR were 3.7 and 3.3 ml/min per 1.73m2 with telmisartan and enalapril, respectively. During the5-yr study period, no patient developed a serum creatinine >200µmol/L, and none required dialysis. There were only sixdeaths in each treatment group during the study, with half beingdue to cardiovascular events.
The prevalence of type 2 diabetes has escalated in recent years,mainly as a result of changes in lifestyle and increasing obesity(1). This has serious public health implications: Life expectancyof men and women who receive a diagnosis of type 2 diabetesat age 40 is reduced by 11.6 and 14.3 yr, respectively (2).Death is usually due to cardiovascular disease, especially ifnephropathy is already present (3). In type 2 diabetes, hypertensionis a frequent comorbidity, often being present when diabetesis diagnosed (4). Hypertension is associated with thickeningof the glomerular basement membrane and glomerulosclerosis,leading to albuminuria (5). Up to 30% of patients with type2 diabetes develop macroalbuminuria (6).
Aggressive BP control to prevent the onset of nephropathy, orits progression if already present, is emphasized in recentguidelines (7,8). Many classes of antihypertensive agents areavailable, and their use will overcome the GFR decline and developmentof ESRD (9). In particular, angiotensin-converting enzyme (ACE)inhibitors and angiotensin II receptor blockers (ARB), bothof which target the renin-angiotensin system, have been shownto be renoprotective (10).
Although ACE inhibitors are the agents of choice for renoprotectionin type 1 diabetes, their efficacy in type 2 diabetes varies.This may be due partly to the generation of angiotensin II byrenal non-ACE pathways, which are not susceptible to ACE inhibitors(11). In patients with diabetes, these alternative pathwaysproduce approximately 40% of angiotensin II, possibly explainingthe findings of a recent meta-analysis that showed that ACEinhibitors did not prevent ESRD or doubling of serum creatinine(12). By contrast, ARB act by preventing binding of angiotensinII to type 1 (AT1) receptors (13), which are implicated in angiotensinII’s pathologic effects. Therefore, ARB may provide morecomplete renin-angiotensin system blockade. Furthermore, angiotensinII is available to stimulate AT2 receptors, which may counteractthe harmful effects of AT1 stimulation (14).
Before the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL)trial (15), six studies had evaluated ARB in type 2 diabeticnephropathy. Their duration differed, with none lasting morethan 3.4 yr. Four were performed in patients with microalbuminuria(16–19), and two were performed in patients with overtnephropathy (20,21). IRbesartan in patients with type 2 diabetesand MicroalbuminuriA (IRMA 2) (18) provides the most conclusiveevidence for ARB use in incipient nephropathy. The 2-yr studyshowed that irbesartan significantly improved albumin excretionrate compared with placebo and slowed progression to overt nephropathy.For established nephropathy, Irbesartan in Diabetic NephropathyTrial (IDNT) (20) and Reduction of Endpoints in NIDDM with theAngiotensin II Receptor Antagonist Losartan (RENAAL) (21) demonstratedbenefits.
The primary purpose of the 5-yr, double-blind, double-dummy,randomized DETAIL study was to establish whether telmisartanconferred similar (i.e., noninferior) renoprotection to enalapril(15). Until DETAIL, only the 1-yr study by Lacourcièreet al. (16) had compared the effects of an ACE inhibitor versusan ARB. It is known that enalapril has a long-term stabilizingeffect on plasma creatinine and proteinuria in normotensivepatients with type 2 diabetes (22). Of the available ARB, telmisartanhas the highest lipophilicity (23), which assists in tissuepenetration; has the longest half-life of approximately 24 h(24); and is almost exclusively excreted in feces (25). Telmisartanhas well-documented antihypertensive efficacy (26) and reducesBP and proteinuria as effectively as enalapril in hypertensivepatients with moderate renal failure (27).
Enrolled patients were mild to moderately hypertensive (restingsystolic/diastolic BP <180/95 mmHg) and had type 2 diabetestreated by diet and/or oral hypoglycemics or insulin (providedthat diabetes had been diagnosed after 40 yr of age and oralhypoglycemics had been given for at least 1 yr before startinginsulin). All patients had to have been treated with an ACEinhibitor to eliminate anyone who was intolerant of these agents.Patients with an albumin excretion rate of 11 to 999 µg/minand normal gross renal morphology were eligible, but those withserum creatinine >140 µmol/L and/or GFR <70 ml/minper 1.73 m2 were excluded.
The 250 eligible patients received their current antihypertensivetherapy for 1 mo before being randomly assigned to 40 mg oftelmisartan or 10 mg of enalapril for 1 mo. Thereafter, thedose of the assigned drug was doubled, but it could be reducedagain after an additional 3 mo if hypotension occurred. Additionalantihypertensive agents were allowed if hypertension persisted.The primary end point was change from baseline in GFR, determinedby plasma clearance of iohexol (28), after 5 yr. Noninferioritywas established when the upper boundary of the 95% confidenceinterval (CI) for the difference between telmisartan and enalaprilin the 5-yr cumulative reduction in GFR was less than –10ml/min per 1.73 m2. Secondary end points included emergenceof ESRD and incidences of cardiovascular and all-cause mortality.
There was no significant difference in GFR or in change in GFRaccording to treatment after 5 yr (Figure 1) (15). The differencebetween telmisartan and enalapril in GFR was –3.1 ml/minper 1.73 m2 (95% CI –7.6 to 1.6). The 95% CI of the differencebetween treatments was less than –10 ml/min per 1.73 m2;therefore, telmisartan was noninferior to enalapril. The GFRdecline was steepest for year 1 (Figure 2). This may be dueto the hemodynamic effect associated with systemic BP loweringand consequent intraglomerular pressure reduction (29). Afteryear 1, annual rate of decline was markedly reduced with a consistent,year-on-year effect. In telmisartan patients, mean annual GFRdecline was 3.7 ml/min per 1.73 m2 for those who completed thestudy and 3.6 ml/min per 1.73 m2 in the last observation carriedforward data set. In enalapril-treated patients, respectivemean annual declines were 3.3 and 3.1 ml/min per 1.73 m2. Duringthe study, no patient had serum creatinine >200 µmol/L,and none required dialysis.
Figure 2. Annual changes in GFR in patients who were treated with telmisartan or enalapril (15).
The annual GFR decline is approximately 10 to 12 ml/min per1.73 m2 in patients with type 2 diabetes and untreated nephropathy(30), compared with approximately 1 ml/min per 1.73 m2 in normalindividuals (31). In DETAIL, the initial steep decline stabilizedafter 3 yr; thereafter, both telmisartan and enalapril resultedin an annual GFR decline of approximately 2 ml/min per 1.73m2 (Figure 2), which is close to the target annual decline of<2 ml/min per 1.73 m2 (32). The annual decline in DETAILis comparable to that in IRMA 2 (18), IDNT (20), and RENAAL(21) of 4.9, 5.5, and 4.4 ml/min per 1.73 m2, respectively (allof which calculated GFR from serum creatinine). Furthermore,the annual GFR decline of 3.7 ml/min per 1.73 m2 compares veryfavorably with the annual decline of 5.2 ml/min per 1.73 m2achieved with best-practice care in early diabetic nephropathy(33).
There were only six deaths in each treatment group during thestudy, representing a mortality rate of approximately 5%; onlyhalf were due to cardiovascular events (15). By comparison,a population study found that the mortality rate over 5 yr wasapproximately 35% in older patients with type 2 diabetes andmicroalbuminuria and approximately 50% when macroalbuminuriawas present (34). Although ARB have been shown to reduce ESRDsignificantly (18,20,21), until now, there has been no evidencethat they have a positive impact on mortality in type 2 diabeticnephropathy (12).
DETAIL is a groundbreaking study, being the first long-termhead-to-head comparison of an ARB and an ACE inhibitor in patientswith hypertension and early type 2 diabetic nephropathy (15).Determination of GFR using iohexol, a safe and accurate methodof evaluating renal function (35), distinguishes it from previousARB studies (16–21). Pharmacologic intervention is essentialto prevent the inevitable decline in renal function and to minimizethe likelihood of early death (10). DETAIL shows that telmisartanis comparable to enalapril in reducing GFR decline and thatit provides renoprotection in type 2 diabetic nephropathy. BeforeDETAIL, there were no direct comparisons of relative survivaladvantages of ARB versus ACE inhibitors (12). In DETAIL, telmisartanand enalapril were associated with similar, low rates of all-causemortality.
Mensah GA, Mokdad AH, Ford E, Narayan KM, Giles WH, Vinicor F, Deedwania PC: Obesity, metabolic syndrome, and type 2 diabetes: Emerging epidemics and their cardiovascular implications.
Cardiol Clin 22
: 485
–504, 2004[CrossRef][Medline]
Narayan KMV, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF: Lifetime risk for diabetes mellitus in the United States.
JAMA 290
: 1884
–1890, 2003[Abstract/Free Full Text]
Folan LA, Tuttle KR: Diabetic nephropathy: Implications for renal and cardiovascular outcomes.
Minerva Med 95
: 385
–394, 2004[Medline]
American Diabetes Association: Hypertension management in adults with diabetes.
Diabetes Care 27
[Suppl 1]: S65
–S67, 2004[CrossRef][Medline]
Kimmelstiel P, Wilson C: Intercapillary lesions in the glomeruli of the kidney.
Am J Pathol 12
: 83
–92, 1987
Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J: Preserving renal function in adults with hypertension and diabetes: A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group.
Am J Kidney Dis 36
: 646
–661, 2000[Medline]
Guidelines Committee: 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension.
J Hypertens 21
: 1011
–1153, 2003[CrossRef][Medline]
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
JAMA 289
: 2560
–2572, 2003[Abstract/Free Full Text]
Hovind P, Tarnow L, Parving HH: Remission and regression of diabetic nephropathy.
Curr Hypertens Rep 6
: 377
–382, 2004[Medline]
de Zeeuw D: Should albuminuria be a therapeutic target in patients with hypertension and diabetes?
Am J Hypertens 17
: 11S
–15S, 2004[Medline]
Dullaart RP, Roelse H, Sluiter WJ, Doorenbos H: Variability of albumin excretion in diabetes.
Neth J Med 34
: 287
–296, 1989[Medline]
Strippoli GFM, Craig M, Deeks JJ, Schena FP, Craig JC: Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: Systematic review.
BMJ 329
: 828
–838, 2004[Abstract/Free Full Text]
Toto R: Angiotensin II subtype 1 receptor blockers and renal function.
Arch Intern Med 161
: 1492
–1499, 2001[Abstract/Free Full Text]
Siragy HM: AT1 and AT2 receptor in the kidney: Role in health and disease.
Semin Nephrol 24
: 93
–100, 2004[CrossRef][Medline]
Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J: Diabetics exposed to telmisartan and enalapril study group: Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.
N Engl J Med 351
: 1952
–1961, 2004[Abstract/Free Full Text]
Lacourciere Y, Belanger A, Godin C, Halle J-P. Ross S, Wright N, Marion J: Long-term comparison of losartan and enalapril on kidney function in hypertensive type diabetics with early nephropathy.
Kidney Int 58
: 762
–769, 2000[CrossRef][Medline]
Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study.
BMJ 321
: 1440
–1444, 2000[Abstract/Free Full Text]
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
N Engl J Med 345
: 870
–878, 2001[Abstract/Free Full Text]
Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators: Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: A blood pressure-independent effect.
Circulation 106
: 672
–678, 2002[Abstract/Free Full Text]
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
N Engl J Med 345
: 851
–860, 2001[Abstract/Free Full Text]
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
N Engl J Med 345
: 861
–869, 2001[Abstract/Free Full Text]
Deferrari G, Ravera M, Berruti V, Leoncini G, Deferrari L: Optimizing therapy in the diabetic patient with renal disease: Antihypertensive treatment.
J Am Soc Nephrol 15
[Suppl 1]: S6
–S11, 2004
Wienen W, Entzeroth M, van Meel JCA, Stangier J, Busch U, Ebner T, Schmid, J, Lehmann H, Matzek K, Kempthorne-Rawson J, Gladigau V, Hauel NH: A review on telmisartan: A novel, long-acting angiotensin II-receptor antagonist.
Cardiovasc Drug Rev 18
: 127
–156, 2000
Neutel JM, Smith DHG: Dose response and antihypertensive efficacy of the AT1 receptor antagonist telmisartan in patients with mild to moderate hypertension.
Adv Ther 15
: 206
–217, 1998
Stangier J, Schmid J, Turck D, Switek H, Verhagen A, Peeters PA, van Marle SP, Tamminga WJ, Sollie FAE, Jonkman JHG: Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers.
J Clin Pharmacol 40
: 1312
–1322, 2000[Abstract]
Battershill AJ, Scott LJ: Telmisartan: A review of its use in hypertension.
Drugs 66
: 51
–83, 2006[CrossRef][Medline]
Hannedouche T, Chanard J, Baumelou B, French Collaborative Telmisartan Study Group: Evaluation of the safety and efficacy of telmisartan and enalapril, with the potential addition of frusemide, in moderate-renal failure patients with mild-to-moderate hypertension.
J Renin Angiotensin Aldosterone Syst 2
: 246
–254, 2001[Abstract/Free Full Text]
Krutzen E, Back SE, Nilsson-Ehle I, Nilsson-Ehle P: Plasma clearance of a new contrast agent, iohexol: A method for the assessment of glomerular filtration rate.
J Lab Clin Med 1984
: 955
–961, 1992
Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE: Short-term effects of protein intake, blood pressure, and antihypertensive therapy on glomerular filtration rate in the Modification of Diet in Renal Disease Study.
J Am Soc Nephrol 7
: 2097
–2109, 1996[Abstract]
Brenner BM: AMGEN International Prize: The history and future of renoprotection.
Kidney Int 64
: 1163
–1168, 2003[CrossRef][Medline]
National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification.
Am J Kidney Dis 39
[Suppl 1]: S1
–S266, 2002[CrossRef][Medline]
Rossing K, Christensen PK, Hovind P, Tarnow L, Rossing P, Parving HH: Progression of nephropathy in type 2 diabetic patients.
Kidney Int 66
: 1596
–1605, 2004[CrossRef][Medline]
Valmadrid CT, Klein R, Moss SE, Klein BE: The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus.
Arch Intern Med 160
: 1093
–1100, 2002
Chowdhury TA, Dyer PH, Bartlett WA, Legge ES, Durbin SM, Barnett AH, Bain SC: Glomerular filtration rate determination in diabetic patients using iohexol clearance: Comparison of single and multiple plasma sampling methods.
Clin Chim Acta 277
: 153
–158, 1998[Medline]
This article has been cited by other articles:
M. J. Crespo, N. Cruz, P. I. Altieri, and N. Escobales Enalapril and Losartan Are More Effective Than Carvedilol in Preventing Dilated Cardiomyopathy in the Syrian Cardiomyopathic Hamster
Journal of Cardiovascular Pharmacology and Therapeutics,
September 1, 2008;
13(3):
199 - 206.
[Abstract][PDF]
A. Remuzzi and G. Remuzzi Review: Potential protective effects of telmisartan on renal function deterioration
Journal of Renin-Angiotensin-Aldosterone System,
December 1, 2006;
7(4):
185 - 191.
[Abstract][PDF]
Top
Abstract
Introduction
