Pharmacology Watch

Statins and Cognition — More to the Story?

In this issue: Side effects of statins; effects of cannabis use; antihypertensives and lip cancer; and FDA actions.

Review challenges FDA warning

Do statins cause changes in cognition? In February, the FDA added warnings to statin labels regarding the risk of reversible memory loss and confusion. But a new review from the Journal of the American College of Cardiology reviews the evidence given to the FDA and concludes "that there is no increased risk of cognitive decline" with statin use. The State-of-the-Art Paper was a comprehensive review of case reports, observational research, and randomized, controlled trials of statins and cognitive change, as well as risk of cancer and diabetes. Most of the evidence for cognitive changes came from individual case reports, many of which were self-reported by consumers to the FDA. Observational studies gave mixed results on cognition with four of nine studies showing statins improved cognition, while three showed no change, and two studies found an increased risk of cognitive impairment. The authors suggest that these studies are inconclusive and prone to selection bias. Two large, randomized, controlled clinical trials specifically looked at the effect of statins on cognitive function as the major secondary endpoint. In both, no significant differences were seen between the study and control groups with regard to cognitive decline. Twelve smaller studies showed mixed results with the majority showing no change and only one in 12 showing a detrimental effect of statins on cognitive function, while two studies showed a benefit. Along with lack of evidence to suggest statins lead to cognitive decline, the authors also found no evidence that statins increase the risk of cancer. They did, however, find a small risk for development of diabetes, which they felt was "outweighed by the cardiovascular benefits in patients for whom statin therapy is recommended" (J Am Coll Cardiol published online August 15, 2012).

Cannabis use and cognitive decline

Persistent cannabis use — particularly in adolescence — may lead to permanent cognitive decline, according to a new study. Researchers looked at a birth cohort of 1037 healthy individuals in New Zealand who underwent neuropsychological testing in the mid 1980s before the onset of cannabis use, and then again in 2010-2012 after some had developed a persistent pattern of cannabis use. Persistent cannabis use over 20 years (at least 4 days per week) was associated with neuropsychological decline, with greater decline evidence for more persistent users. This effect was only seen in adolescent-onset cannabis users and was associated with an average 8 point loss in IQ by age 38. The effect persisted after controlling for education, other drugs, or tobacco. The effects were not seen among adult-onset cannabis users. The authors conclude that increasing efforts should be directed toward delaying the onset of cannabis use by young people, "particularly given the recent trend of younger ages of cannabis use initiation in the United States and evidence that fewer adolescents believe that cannabis use is associated with serious health risk." (Proc Natl Acad Sci U S A published online August 27, 2012). This study and others are increasingly important as cannabis, the most widely used illicit drug in the world, is being considered for more medicinal uses as well as legalization.

Antihypertensives and lip cancer

Two photosensitizing antihypertensives, hydrochlorothiazide and nifedipine, may increase the risk for lip cancer in non-Hispanic white patients, according to a new study from Kaiser Permanente in California. From a large cohort of patients, 712 were identified with lip cancer along with nearly 23,000 matched controls. At least a 5-year supply of the drug resulted in the following odds ratios for lip cancer (95% confidence intervals) — hydrochlorothiazide 4.22 (2.82-6.31), hydrochlorothiazide-triamterene 2.82 (1.74-4.55), nifedipine 2.50 (1.29-4.84), and lisinopril 1.42 (0.95-2.13). When atenolol was given without other hypertensives, the odds ratio for lip cancer was 0.54 (0.07-4.08). The authors suggest that while antihypertensive therapy outweighs the risk of lip cancer, preventive measures should be taken for those at increased risk because of fair skin and long-term sun exposure (Arch Intern Med published online August 06, 2012).

FDA actions

The FDA has approved a delayed-release form of prednisone for the treatment of endocrine, inflammatory, and neoplastic conditions. Delayed-release prednisone should be taken once a day with timing to be determined by the disease being treated. For example, 10 p.m. dosing is recommended for rheumatoid arthritis, as it is more effective than immediate-release prednisone taken in the morning for treating morning stiffness associated with the disease. Dosing is based on the theory that both cytokines and endogenous cortisol follow a circadian rhythm, and that dosing the drug based on the condition being treated may afford more effective treatment than immediate-release prednisone. The new product delays the release of prednisone by approximately 4 hours. Side effects are the same as short-acting prednisone. Delayed-release prednisone will be marketed as RAYOS by Horizon Pharma.

The FDA has approved a new chlorofluorocarbon (CFC)-free, over-the-counter inhaled racepinephrine product for the treatment of asthma. The new product takes the place of the banned Primatene Mist, which was taken off the market at the end of 2011 because it contained CFCs. Inhaled epinephrine has been used for the treatment of asthma for more than 100 years. Marketed as Asthmanefrin, the new product will be sold as a starter kit and refill package. The starter kit will include 10 vials of racepinephrine along with the EZ Breathe Atomizer. The refill kit will include 30 vials of the drug. The drug is not without controversy, however, with many asthma experts feeling that the side effects of epinephrine are serious and well-documented, and over-the-counter use goes against published guidelines for treating asthma. Asthmanefrin will be marketed by Nephron Pharmaceuticals.

The FDA has approved linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. The drug is the first guanylate cyclase (GC-C) agonist that acts locally in the gut with minimal systemic exposure. The drug is taken once daily on an empty stomach at least 30 minutes before the first meal of the day. Safety and efficacy in the management of irritable bowel syndrome with constipation was established in two double-blind studies of nearly 1300 patients who were randomly assigned to linaclotide or placebo for 12 weeks. Patients taking the drug experienced more complete spontaneous bowel movements than those taking placebo. The drug should not be used in patients 17 years or younger. Linaclotide will be jointly marketed by Ironwood Pharmaceuticals and Forest Pharmaceuticals as Linzess.

Montelukast (Singulair), Merck's popular asthma and allergy medication, will soon be available as a generic. The leukotriene receptor antagonist will be manufactured by 10 generic companies in tablet form, oral granules, and chewable tablets. The FDA warns that montelukast should not be used for relief of sudden asthma attacks and further warns that patients should contact a clinic immediately if they are experiencing behavior and mood-related changes such as aggression, depression, or hallucinations.

The FDA has approved the first generic version of pioglitazone (Actos). The drug is approved along with diet and exercise to improve blood sugar control in adults with type 2 diabetes. This happens as thiazolidinediones have generally fallen out of favor for use in type 2 diabetes due to side effects including worsening heart failure and edema. The FDA also recently issued a warning for pioglitazone regarding increased risk of bladder cancer if the drug is taken for more than 1 year. The first generic pioglitazone will be manufactured by Mylan Pharmaceuticals.

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: