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The first head-to-head comparison study of an ACE inhibitor and an angiotensin receptor blocker, to assess renoprotective effects in type 2 diabetes, has shown that the drugs are comparable in their benefit. It has been known for more than a decade that ACE inhibitors prevent progression of microalbuminuria in type 2 diabetes, out of proportion to their blood pressure lowering effects. It has also been shown that angiotensin receptor blockers are renoprotective, but it has not been shown that the drug classes are equivalent in their benefit. The Diabetics Exposed to Telmisartan and Enalapril Study Group (DETAIL study) was designed in 1996 to compare the 2 drugs in 250 patients with type 2 diabetes and early nephropathy. Patients were randomized to 80 mg of telmisartan or 20 mg enalapril daily. The primary end point was the change in Glomerular Filtration Rate (GFR) during 5 years of the study. Secondary end points included annual changes in GFR, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of end stage renal disease and cardiovascular events; and all-cause mortality. After 5 years, the change in GFR was -17.9 mL/min with telmisartan and -14.9 mL/min with enalapril (the 95% CI, -7.6- 1.6 mL/min). The data suggest that telmisartan is not inferior to enalapril in providing long-term renotection in patients with type 2 diabetes (N Engl J Med. 2004;351:1952-1961). In the same issue of the Journal, researchers in Italy compared the ACE inhibitor trandolapril plus verapamil, trandolapril alone, verapamil alone, or placebo in patients with hypertension and type 2 diabetes, and normal urinary albumin excretion. The end point was the development of persistent microalbuminuria. Over 3 years of treatment, the percentage of those patients developing microalbuminuria were: trandolapril 6%, trandolapril plus verapamil 5.7%, verapamil alone 11.9%, and placebo 10%. The authors conclude that trandolapril plus verapamil and trandolapril alone decrease the incidence of microalbuminuria to similar extent, whereas the effectiveness of verapamil alone was similar to that of placebo (N Engl J Med. 2004; 351:1941-1951).
The Infection Risk of Acid-Suppressing Drugs
Ever since cimetadine was first marketed in 1977, physicians have been concerned about the risk of infection associated with acid-suppressing drugs. Now researchers from the Netherlands have shown that concern is warranted, by demonstrating a link between acid-suppressing drugs and community-acquired pneumonia (CAP). Utilizing the Integrated Primary Care Information database in the Netherlands between 1995 and 2002, incidence rates for pneumonia were calculated for those exposed to acid-suppressive drugs and those who were unexposed. A case control analysis was conducted, nested in a cohort of incident users of acid-suppressive drugs, with up to 10 controls matched to each case for practice, year of birth, sex, and index date. The main outcome was CAP. The incidence rates for pneumonia in non-acid-suppressive drug users and acid-suppressive drug users were 0.6 in 2.45 per hundred person-years, respectively. The adjusted relative risk for pneumonia among persons currently using a proton pump inhibitor (PPI), compared with those who stopped using a PPI, was 1.89 (95% CI, 1.36-2.62). The risk for current users of H2 antagonists was 1.63 (95% CI, 1.07-2.48). The authors conclude that acid-suppressive drugs, especially proton pump inhibitors (PPIs), are associated with an increased risk of pneumonia, and suggest that these drugs should be used with caution, and at the lowest possible doses in patients who are at risk for pneumonia (JAMA. 2004;292:1955-1960). An accompanying editorial points out the biological plausibility of the findings and suggest that, while acid-suppressive drugs are indicated for a wide variety GI conditions, long-term, chronic use of these drugs should always be balanced with patient safety (JAMA. 2004;292:2012-2013).
Is Rosuvastatin As Safe As Other Statins?
Rosuvastatin (Crestor), AstraZeneca’s entry into the high potency statin market, has not achieved marketshare comparable to Pfizer’s atorvastatin (Lipitor) or Merck’s simvastatin (Zocor). This, despite the facts that the drug is very potent and AstraZeneca has priced the drug 15-20% lower than Lipitor. Some physicians remember the cerivistatin (Baycol) withdrawal from the market, and may be concerned regarding the highest doses of rosuvastatin, especially since European regulators issued a warning earlier this year about the drug. New postmarketing data suggest, however, that rosuvastatin is as safe and well-tolerated as other statins. The records of 12,400 patients who received 5-40 mg/day were reviewed, representing 12,212 continuous patient years. In fixed dose trials with comparator statins, 5-40 mg of rosuvastatin showed an adverse event profile similar to those for 10-80 mg of atorvastatin, 10-80 mg of simvastatin, and 10-40 mg of pravastatin. Clinically significant increases in liver transaminases were uncommon (< 0.2%) in all groups. Myopathy with creatine kinase increases > 10 times the upper limit of normal, with muscle symptoms occurring in < 0.03 % of patients who took rosuvastatin at doses of 40 mg or less. Proteinuria, at the same doses, was comparable to the rate seen with other statins as well. There were no deaths and no cases of rhabdomyolysis in patients on 40 mg or less of rosuvastatin. The authors conclude that rosuvastatin was well-tolerated, and out of safety profile similar to other commonly statins (Am J Cardiol. 2004;94:882-888).
Which Estrogen Preparation is the Safest?
Is esterified estrogen safer than conjugated equine estrogen? At least with regard to venous thrombosis, the answer may be yes, according to a recent study. Group Health Cooperative in Washington State, a large HMO, switched their patients from conjugated equine estrogen (CEE) to esterified estrogens (EE) in 1999. Records of perimenopausal and postmenopausal women were studied between January 1995 and the end of 2001. The primary outcome was the risk of first venous thrombosis, in relation to current use of either estrogen with or without a progestin. There were 586 cases of venous thrombosis identified. Compared with women not currently using hormones, current users of EE had no increase in venous thrombotic risk (odds ratio, 0.92; 95% CI, 0.69-1.22). Women taking CEE however, had an elevated risk (OR, 1.65; 95% CI, 1.24-2.19). Comparing users of the 2 estrogens, current users of CEE had an odds ratio of 1.78 for venous thrombosis, compared to users of EE (95% CI, 1.11-2.84), and higher doses of CEE were associated with a higher risk. Among all estrogen users, concomitant use of progestin was associated with an increased risk, compared to use with estrogen alone (OR, 1.60; 95% CI, 1.13-2.26). The authors conclude that conjugated equine estrogen, but not esterified estrogen, is associated with an increased risk of venous thrombosis (JAMA. 2004; 292:1581-1587). While the authors acknowledge that these data need to be replicated, the study raises the interesting question of the differences between various estrogen preparations and the potential risks associated with them, especially when noting that conjugated equine estrogen was the only estrogen preparation used in the Women’s Health Initiative.
FDA Actions
Serono has been given approval to market recombinant human luteinizing hormone (Luveris) for the treatment of infertility in women. The drug, which was granted orphan status, has been available in more than 60 countries for several years.
The FDA and Centocor have issued a warning to health care professionals about the increase risk of lymphoma associated with inflixamab (Remicade) in patients with rheumatoid arthritis and Crohn’s disease. The warning applies to all tumor necrosis factor blocking agents. The drugs are associated with a 1 in 1400 risk of lymphoma, according to MedWatch, the FDA’s safety information program.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: [email protected].
The first head-to-head comparison study of an ACE inhibitor and an angiotensin receptor blocker, to assess renoprotective effects in type 2 diabetes, has shown that the drugs are comparable in their benefit.
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