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Angiotensin-Receptor Blockade versus Converting-Enzyme Inhibition in Type 2 Diabetes and Nephropathy

Background: This study was conducted to compare the effectiveness of angiotensin receptor blockers (ARBs) to angiotensin-converting enzyme (ACE) inhibitors in a population of patients with type 2 diabetes and nephropathy.

Objective: The purpose of this study was to determine if the ARB (telmisartan) is noninferior to the ACE inhibitor (enalapril) for renoprotection in diabetes patients.

Methods: Prospective, randomized, double-blind, double-dummy, parallel-group study that was conducted at multiple sites in Europe. The inclusion criteria were as follows: male or female, white or Asian, 35 to 80 years old. All patients had to have a diagnosis of type 2 diabetes that was treated by diet, diet plus oral hypoglycemics, or insulin that followed treatment with oral hypoglycemics. If patients were on insulin, the diabetes had to have started after age 40 and their body mass index had to be greater than 25 at the time it was diagnosed. All patients had to have mild to moderate hypertension of less than 180/95 and have been treated with an ACE inhibitor for a minimum of 3 months. Patients had to possess a normal renal morphology, have a urinary albumin excretion rate within a certain range, have a glycosylated hemoglobin of less than 12%, a serum creatinine level of less than 1.6 and a glomerular filtration rate (GFR) greater than 70 ml/minute. Exclusion criteria included any condition that could affect long term survival, allergies to the study drugs, or allergy to the diagnostic drug (iohexol). 250 patients underwent randomization. Drug regimens were telmisartan 40 mg qd or enalapril 10 mg qd for four weeks and then patients were increased to telmisartan 80 mg qd or enalapril 20 mg qd. The dose could be decreased after 2 months but could not be increased. Other medications could be used at the discretion of the investigators. The study duration was planned to be 5 years. 120 patients were randomized to the telmisartan group and 130 patients were randomized to the enalapril group. The primary end point was the change in GFR after 5 years. Secondary end points included the annual change in GFR, urinary albumin excretion, serum creatinine, blood pressure, rates of adverse effects and rates of clinical events, death and lab abnormalities. The power of the study was stated as being 95 percent. The investigators used an intent to treat as well as an on treatment analysis.

Results: Complete data was available for 62 patients in the telmisartan group and 74 patients in the enalapril group. In the intent to treat analysis, patients treated showed a mean change in GFR in the telmisartan group to be -17.9 and in the enalapril to be -14.9. The difference was -3.0 (95% CI, -7.6 to 1.6). These values indicated that telmisartan was noninferior to enalapril. When looking at patients who had complete data for 5 years, the mean GFR change in the telmisartan group was -18.7 compared to -15.8 in the enalapril group (95% CI for the difference, -9.2 to 3.4). These figures also indicated noninferioirity. For secondary end points, the annual change in GFR was similar in both groups. Annual changes in urinary albumin excretion rate was small in both groups. Serum creatinine levels were also not significantly different in the two groups. Telmisartan had a slightly greater influence on systolic pressure. Adverse events occurred in similar number of subjects in both groups. The breakdown of adverse events was also similar in both groups. The authors concluded that telmisartan is noninferior to enalapril when comparing their effects on the parameters looked at in this study.

Strengths: The study compared two agents head to head that both have a place in therapy for the indication. The study was double blinded. There was a lengthy follow up period for those who completed the study. The researchers took many variables into account.

Weaknesses: Possible bias due to funding and author’s affiliations. Some of the results were not reported in a clear and concise manner. It would have been beneficial to have some final data in regards to the diabetes such as the A1C values at the conclusion of the study. The drop out rate was rather high in both groups. Also, some of the results could have favored telmisartan since patients had already been on an ACE inhibitor prior to the study. Additionally, close to 40 sites were utilized so continuity may be a concern.

Conclusion: This study looked at two viable options when dealing with type 2 diabetes and nephropathy. Studies need to be conducted between ARBs and ACE inhibitors. In theory, both classes of drugs should show a benefit due to their mechanisms of action. Both drugs produce a similar net result in this study. ARBs provide a possible alternative to ACE inhibitors; however, due to cost issues, should probably be reserved for patients who fail a trial with an ACE inhibitor. ARBs appear to be beneficial in this population of patients but further work needs to be done in this area to provide further evidence.

Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting enzyme inhibition in type 2 diabetes and nephropathy. NEJM. 2004;351:1952-61.

Tim Miller, Doctor of Pharmacy Candidate