Correspondence
Telmisartan vs. Enalapril in Type 2 Diabetes
N Engl J Med 2005; 352:835-836February 24, 2005
- Article
To the Editor:
Barnett et al. (Nov. 4 issue)1 compared telmisartan and enalapril in type 2 diabetic nephropathy, without reporting or adjusting for certain major risk factors associated with diabetic nephropathy: glycemic control and hyperlipidemia. They assessed blood-pressure changes as a secondary end point, but their results indicate important issues regarding the extent to which their study can be generalized.
It is not clear why the target blood pressure was initially less than 160/90 mm Hg and what the subsequent, lower targets were during the study. The currently recommended blood-pressure goal for antihypertensive therapy in patients with diabetic nephropathy is 130/80 mm Hg; even lower blood pressures are the goal for patients with macroalbuminuria.2 According to the results, 58 percent of the patients had systolic pressures higher than 140 mm Hg, and most had diastolic pressures above the currently recommended target. Since a lack of blood-pressure control is an important factor in the progression of diabetic nephropathy, the results of the current study best apply to patients with poorly controlled blood pressure and should be interpreted with caution with respect to patients whose blood pressure is well controlled.
2 ReferencesAli Ali Asgari, M.D.
Farzaneh Sarvghadi, M.D.
Nargessadat Zahed, M.D.
Shahid Beheshti University of Medical Sciences, 1333635445 Tehran, Iran
aasgari@ams.ac. ir 1
Barnett AH ,Bain SC ,Bouter P , et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952-1961
Full Text | Web of Science | Medline2
Rose BD, Bakris GL. Treatment of diabetic nephropathy. Wellesley, Mass: UpToDate, 2004. (Accessed February 3, 2005, at http://www.uptodate.com.)
To the Editor:
Barnett et al. report that telmisartan is not inferior to enalapril in providing long-term renoprotection in type 2 diabetes and nephropathy. The primary end point was the change in the glomerular filtration rate from baseline to five years and was assessed in only 54 percent of the randomly assigned patients because of dropouts. Equivalence of the two drugs was to be claimed if the difference in the change in the glomerular filtration rate was less than 10 ml per minute per 1.73 m2 of body-surface area — a large difference in a heterogeneous group of patients, 82 percent of whom had normoalbuminuria or microalbuminuria. Five studies in patients with type 2 diabetes and microalbuminuria, published before the design of the Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study in 1996, showed declines in the glomerular filtration rate ranging from 0 to 4 ml per minute per year per 1.73 m2 (median, <2).1 Furthermore, the major part of the initial drop in the glomerular filtration rate with angiotensin-receptor blockade is hemodynamic and completely reversible when treatment is discontinued.2 The observed difference between the two agents in the decline in the glomerular filtration rate (0.6 ml per minute per year per 1.73 m2) is regarded as trivial by Barnett et al., despite the important study by Brenner et al.3 The latter included 1513 patients with type 2 diabetes and nephropathy and demonstrated a difference of only 0.8 ml per minute per year per 1.73 m2 (P=0.01).
Barnett et al. do not mention or discuss optimal renoprotective dosages of the two drugs. We suggest that the conclusions of the DETAIL study be interpreted with caution owing to the heterogeneous patient groups, small sample, potentially suboptimal dosages, and use of an end point that may have been improperly evaluated.
3 ReferencesHans-Henrik Parving, M.D.
Peter Hovind, M.D.
Peter Rossing, M.D.
Steno Diabetes Center, DK-2820 Gentofte, Denmark1
Parving H-H ,Lehnert H ,Brochner-Mortensen J ,Gomis R ,Andersen S ,Arner P . The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-878
Full Text | Web of Science | Medline2
Andersen S ,Brochner-Mortensen J ,Parving H-H . Kidney function during and after withdrawal of long term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care 2003;26:3296-3302
CrossRef | Web of Science | Medline3
Brenner BM ,Cooper ME ,De Zeeuw D , et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869
Full Text | Web of Science | Medline
To the Editor:
Barnett et al. conclude that 80 mg of telmisartan daily was “not inferior” to 10 mg of enalapril daily in preventing a decrease in the glomerular filtration rate in patients with type 2 diabetes. The cost of generic enalapril is about 1/10th the cost of telmisartan. Would the authors comment on this fact?
Joseph E. Loewenstein, M.D.
4 Saddle Club Dr., Midland, TX 79705Author/Editor Response
Ali Asgari et al. question the effects of hyperlipidemia and glycemic control on our results. There was no significant difference between the groups in these variables at the start of the study (Table 1 of our article) or at the end of the study (low-density lipoprotein cholesterol, 193 mg per deciliter in the telmisartan group and 196 mg per deciliter in the enalapril group; high-density lipoprotein cholesterol, 50 mg per deciliter and 52 mg per deciliter, respectively; and glycosylated hemoglobin, 8.2 percent and 8.4 percent, respectively). These data are consistent with the almost identical use of statins, aspirin, and other cardiovascular therapies in the two groups (Table 2 of our article). Ali Asgari et al. emphasize that blood-pressure targets are more stringent now than they were when the study was designed. The choice of 160/90 mm Hg was based on the widely adopted World Health Organization–International Society of Hypertension guidelines published in 1993,1 but we allowed participating centers to lower their targets over time. However, the Bergamo Nephrologic Diabetes Complications Trial2 (reported in the same issue of the Journal as our study) used a stringent blood-pressure target (systolic pressure, 120 mm Hg) and a formal stepped-care treatment protocol but achieved systolic pressures of only about 140 mm Hg. Furthermore, there is no a priori reason why the effects of angiotensin-converting–enzyme inhibition and angiotensin II blockade should differ according to blood-pressure levels.
Parving and colleagues note the small number of subjects who completed our study and suggest that the predefined margin of change in the glomerular filtration rate — a decrement of 10 ml per minute per 1.73 m2 over a five-year period — was too large for a cohort of patients with microalbuminuria. However, our inclusion criteria allowed a mean albumin excretion rate of up to 999 μg per minute, which is well within the range of macroalbuminuria. Rossing et al. recently reported a yearly rate of decline of 5.2 ml per minute per 1.73 m2 in such patients.3 Moreover, Brenner et al. used calculated values for the glomerular filtration rate, not measured values as in the DETAIL study, and their study was much shorter (mean follow-up, 3.4 years).4 We highlighted that telmisartan was used at a high dose in more than 90 percent of the subjects, since a suboptimal dose of the angiotensin II receptor blocker has previously been cited as a reason for the lack of benefit as compared with the effect of angiotensin-converting–enzyme inhibition.5,6 We cannot comment about whether further increases in the doses of telmisartan and enalapril above the usual maintenance doses given for hypertension would have exposed a difference in the effect on the glomerular filtration rate (although again, we cannot think of an obvious reason why it should).
Finally, Dr. Loewenstein highlights the issue of drug costs. We did not design this study as a health-technology assessment, and cost issues would have been very different at the onset of the study, when enalapril was still under patent protection. Readers will, no doubt, take costs into account when prescribing medications for their patients with diabetes and hypertension.
6 ReferencesStephen C. Bain, M.D.
Anthony Barnett, M.D.
Birmingham Heartlands and Solihull National Health Service Trust (Teaching), Birmingham B9 5SS, United Kingdom
anthony.barnett@heartsol. wmids. nhs. uk 1
Summary of 1993 World Health Organisation-International Society of Hypertension guidelines for the management of mild hypertension. BMJ 1993;307:1541-1546[Erratum, BMJ 1994;308:45.]
CrossRef | Web of Science2
Ruggenenti P ,Fassi A ,Ilieva AP , et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-1951
Full Text | Web of Science | Medline3
Rossing K ,Christensen PK ,Hovind P ,Tarnow L ,Rossing P ,Parving HH . Progression of nephropathy in type 2 diabetic patients. Kidney Int 2004;66:1596-1605
CrossRef | Web of Science | Medline4
Brenner BM ,Cooper ME ,De Zeeuw D , et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869
Full Text | Web of Science | Medline5
Pitt B ,Poole-Wilson PA ,Segal R , et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial -- the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-1587
CrossRef | Web of Science | Medline6
Dickstein K ,Kjekshus J . Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-760
CrossRef | Web of Science | Medline
