Pharmacology Watch

Do Benzodiazepines Cause Dementia in the Elderly?

In this issue: Dementia and benzodiazepines; effectiveness of omega-3 fatty acid and Ginkgo biloba supplements; and FDA actions.

Benzodiazepines and dementia

Can benzodiazepines increase the risk for dementia? Researchers in France studied 1063 men and women with an average age of 78 who were free of dementia and did not start taking benzodiazepines until they had been followed for at least 3 years. During a 15-year follow-up, 253 cases of dementia were confirmed. New use of benzodiazepines occurred in 9% of the study population and was associated with an increased risk of dementia (32% benzodiazepine group vs 23%, adjusted hazard ratio 1.60, 95% confidence interval [CI] 1.08-2.38). After correcting for the existence of depressive symptoms as well as age and diabetes, the hazard ratio was unchanged. A secondary analysis looking at participants who started benzodiazepines at different times during follow-up also showed an elevated risk of dementia. Results of the complementary, nested, case-control study showed that ever use of benzodiazepines was associated with an approximate 50% increased risk of dementia compared with never users. The authors conclude that in this prospective, population-based study new use of benzodiazepines was associated with a significantly increased risk of dementia. They further conclude that "indiscriminate widespread use should be cautioned against" (BMJ 2012;345:e6231). The obvious criticism of the study was the presence of confounders — whether use of benzodiazepines was a marker for early onset dementia rather than a cause. While the authors feel the study was carefully controlled, selection bias cannot be completely ruled out. They further state that the research should be done on younger patients to see if starting benzodiazepines at ages younger than 65 may have deleterious effects. They also recommend that "physicians and regulatory agencies should consider the increasing evidence of potential adverse effects of this drug class for the general population."

Popular supplements’ use questioned

Two popular supplements — omega-3 fatty acids and Ginkgo biloba — may be of limited value, according to two recent studies. Omega-3 fatty acids are thought to have a number of benefits, including lowering triglyceride levels, preventing arrhythmias, decreasing platelet aggregation, and lowering blood pressure. But the fish oil supplement’s ability to prevent major cardiovascular events has been debated in the literature. Twenty studies of nearly 67,000 patients were included in a meta-analysis looking at the effect of omega-3 on all-cause mortality, cardiac death, sudden death, myocardial infarction, and stroke. After correcting for dose and comorbidities, there was no difference in the absolute or relative risk of any of the outcomes associated with omega-3 supplementation. The authors concluded that marine-derived omega-3 polyunsaturated fatty acid supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke (JAMA 2012;308:1024-1033).

Ginkgo biloba for the prevention of Alzheimer’s disease (AD) was studied in a randomized, parallel group, double-blind, placebo-controlled trial of adults age 70 years or older who spontaneously reported memory complaints to their primary care physician in France. Patients were randomized to a twice per day 120 mg standardized Ginkgo biloba extract or matching placebo and followed for 5 years. The primary outcome was conversion to probable AD. More than 2800 patients were enrolled with about 1400 patients in each group. By 5 years, 61 participants in the ginkgo group were diagnosed with AD vs 73 in the placebo group (hazard ratio 0.84, 95% CI 0.60-1.18; P = 0.306). Adverse events were the same between both groups and mortality was roughly the same as well. Sixty-five participants in the ginkgo group had a stroke compared to 60 in the placebo group (P = 0.57). The authors conclude that long-term use of standardized Ginkgo biloba extract did not reduce the risk of progression to AD compared to placebo (Lancet Neurology 2012;11:851-859).

FDA actions

The FDA has approved teriflunomide for the treatment of relapsing forms of multiple sclerosis (MS). The approval was based on a 2-year study in which the drug reduced relapses by nearly a third compared to placebo — results that are about the same as other MS drugs and no better than Merck’s popular injectable interferon beta 1a (Rebif). Side effects include diarrhea, abnormal liver function tests, nausea, and hair loss. It should not be used during pregnancy. Teriflunomide has the advantage of being a once-daily oral medication, the second oral MS medication after Novartis’ fingolimod (Gilenya). Teriflunomide will be marketed by Sanofi Aventis as Aubagio. A third oral MS medication, Biogen Idec’s BG-12, was recently found to reduce MS relapses by about 50% (N Engl J Med 2012;367:1087-1097; 1098-1107). BG-12 is not yet approved by the FDA, but a decision is expected before the end of the year.

The FDA has delayed the approval of apixaban (Eliquis) once again. Pfizer and Bristol-Myers Squibb’s novel oral anticoagulant (NOAC) was expected to be approved last spring after publication of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, which showed that the drug was effective in preventing strokes in patients with non-valvular atrial fibrillation — data that suggested that the drug was perhaps even more effective than the two other NOACs, dabigatran (Pradaxa) and rivaroxaban (Xarelto). In June, the FDA told the manufacturers they needed "additional information on data management and verification from the ARISTOTLE trial." Now, the agency says that the review date will be March 17, 2013. No reason was given by the FDA for the delay.

About 25% of Internet consumers have purchased prescription medications online, while at the same time, the prevalence of fraudulent Internet pharmacies has grown. The FDA has now launched a national campaign to raise public awareness called BeSafeRx – Know Your Online Pharmacy, a resource that provides patients and caregivers with a better understanding of who they are buying from, and makes sure the medication they buy matches what their doctor prescribed. The FDA recommends that patients only buy medications from online pharmacies that require a prescription, are located in the United States, have a licensed pharmacist available for consultation, and are licensed by the patient’s state board of pharmacy. More information can be found at

The FDA has approved enzalutamide to treat men with late-stage, castration-resistant prostate cancer under the agency’s priority review program. The drug was approved based on a study of nearly 2000 men with metastatic prostate cancer who had been previously treated with docetaxel. Men treated with enzalutamide lived an average of 18.4 months vs 13.6 months for men treated with placebo. Enzalutamide is co-marketed by Astellas and Medivation as Xtandi.

The FDA has also approved a new agent for the treatment of advanced colorectal cancer. Regorafenib is a multi-kinase inhibitor that was also approved under the FDA’s priority review program. In a study of 760 patients with previously treated metastatic colorectal cancer, regorafenib extended survival about 45 days to 6.4 months from 5 months for placebo as well as progression-free survival of 2 months vs 1.7 months for placebo. Regorafenib is marketed by Bayer as Stivarga.

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) 262-5404. E-mail: