Pharmacology Watch

Statins and the Risk of Diabetes

In this issue: Statins and diabetes risk; new treatment guideline for diabetes; new pertussis vaccine recommendation; antibiotics and rhinosinusitis; fluoroquinolones and cystitis; and FDA actions.

Do statins increase the risk of diabetes?

Studies have suggested that statins may increase the risk of diabetes in the elderly, women, and Asians. A new study reviews data from the 162,000 postmenopausal women enrolled in the Women's Health Initiative to investigate whether the incidence of new onset diabetes mellitus (DM) is associated with statin use among these women. This study reviewed records from women who were enrolled between 1993 and 1998 through 2005. More than 7% of the women in the study reported taking statins. Statin use at baseline was associated with an increased risk of DM (hazard ratio, 1.71; 95% confidence interval, 1.61-1.81). This association remained after adjusting for other potential confounders, including obesity, and was observed for all types of statin medications. The authors conclude that statin medication use in postmenopausal woman is associated with an increased risk for DM and that this may be a medication class effect (Arch Intern Med 2012;172:144-152). As pointed out in a brief comment in the same issue, observational data are potentially susceptible to "bias (confounding) by indication." In other words, women who would be prescribed statins may be inherently at risk for DM. This study did a good job of evaluating women with and without a history of cardiovascular disease and found that there was still an increased risk of DM. This finding "may have important implications for the balance of risk and benefit of statins in the setting of primary prevention in which previous meta-analyses show no benefit on all-cause mortality." The FDA has issued a new warning about statins and the risk of diabetes (see FDA actions).

Oral medications for diabetes

The American College of Physicians has published a new guideline for the "Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus" in the February 21 issue of the Annals of Internal Medicine. The guideline suggests that if diet, exercise, and weight loss fail to improve hyperglycemia, oral drug therapy should be initiated. Most diabetes medicines lower HbA1c levels to a similar degree, and none of the medications have compelling outcomes data to suggest one class is superior to another class with regard to cardiovascular or all-cause mortality. But metformin "was more effective than other medications as monotherapy as well as when used in combination therapy with another agent for reducing HbA1c levels, body weight, and plasma lipid levels (in most cases)." Therefore, the guideline recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy for most patients with type 2 diabetes. Metformin is effective at reducing glycemic levels and is not associated with weight gain. Additionally, the drug helps reduce LDL cholesterol and triglyceride levels. Metformin is contraindicated in patients with impaired kidney function, decreased tissue perfusion or hemodynamic instability, liver disease, alcohol abuse, heart failure, and any conditions that might lead to lactic acidosis. For patients with persistent hyperglycemia despite metformin, a second drug should be added. No good evidence supports one combination over another. Sulfonylureas have a higher risk for hypoglycemia and thiazolidinediones are associated with an increased risk for heart failure. There are no specific recommendations for the use of the glinides (nateglinide or repaglinide) or the DPP-4 inhibitors (linagliptin, saxagliptin, or sitgliptin). The guideline does not make a recommendation for combinations of more than two oral agents. Injectables, such as the various insulins and GLP-1 analogs, were not addressed in the guideline. (Ann Intern Med 2012; 156:218-231).

New recommendation for Tdap vaccine

The Advisory Committee on Immunization Practices, a division of the Centers for Disease Control and Prevention, is recommending that all adults get immunized against pertussis (whooping cough). Previously the committee had recommended that only adults who spend time around infants or young children should be immunized. The goal of the expanded recommendation is to prevent teenagers and adults from spreading the disease to infants. In 2010, California experienced a pertussis outbreak that infected 9000 people and resulted in 10 infant fatalities. The adult vaccine combines tetanus, diphtheria, and acellular pertussis (Tdap). n

Antibiotics not needed for rhinosinusitis

Physicians now have more ammunition for not treating patients with acute rhinosinusitis with antibiotics, based on the results of a new study that shows amoxicillin is of no benefit in these patients. Researchers at Washington University in St. Louis randomized 166 adults with uncomplicated, acute rhinosinusitis to a 10-day course of amoxicillin 500 mg three times a day or matching placebo. The main outcome (change in the Sinonasal Outcome Test) was not significantly different between the two groups at day 3 or day 10. There was a slight improvement in the antibiotic group at day 7. The authors conclude that "treatment with amoxicillin for 10 days offers little clinical benefit for patients clinically diagnosed with uncomplicated acute rhinosinusitis." Patients with symptoms indicative of serious complications were excluded from the trial (JAMA 2012;307:685-692).

Fluoroquinolones for cystitis

Cefpodoxime is inferior to ciprofloxacin for short-course treatment of acute uncomplicated cystitis in women, according to new study. In a randomized, double-blind trial, 300 women ages 18-55 with uncomplicated cystitis were randomized to ciprofloxacin 250 mg orally twice daily for 3 days or cefpodoxime 100 mg twice daily for 3 days. The overall clinical cure rate with the intent-to-treat approach in which patients lost to follow-up were considered as having a clinical cure was 93% for ciprofloxacin compared to 82% for cefpodoxime. For the intent-to-treat approach in which patients lost to follow-up were considered as not having responded to treatment, the clinical cure rate was 83% for ciprofloxacin compared to 71% for cefpodoxime. The microbiological cure rate was 96% for ciprofloxacin compared with 81% for cefpodoxime. At follow-up, 16% of women in the ciprofloxacin group had vaginal Escherichia coli colonization compared with 40% in the cefpodoxime group. The authors conclude that cefpodoxime did not meet criteria for non-inferiority to ciprofloxacin for treating uncomplicated cystitis in women (JAMA 2012;307:583-589). The study is somewhat disappointing given the increasing rates of fluoroquinolone resistance in the community and the need for effective alternatives.

FDA actions

The FDA has issued a new warning and is requiring label changes to all statins regarding the risk of elevated blood sugar and reversible cognitive changes. The agency is making these changes after a comprehensive review of multiple studies that show increases in blood sugar associated with the drugs. A separate labeling change warns that cognitive effects have been reported with statin use, including transient memory loss and confusion — symptoms that are reversible with stopping the medication. There is no evidence that statins are associated with long-term cognitive changes or dementia. Statins affected by these warnings include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In a separate warning, lovastatin is now contraindicated with strong CYP3A4 inhibitors, such as itraconazole and erythromycin. This is a similar warning to that issued for simvastatin in 2011.

In one of the strangest stories of the year, the FDA is warning oncologists that a counterfeit version of bevacizumab (Avastin) may have been purchased and used by some medical practices in the United States. The counterfeit version does not contain any active drug and may have resulted in patients not receiving needed therapy. Counterfeit bevacizumab was purchased from a foreign supplier known as Quality Specialty Products or Montana Health Care Solutions. The FDA is recommending that physicians stop using bevacizumab purchased from the suppliers and call the FDA immediately.

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: