Pharmacology Watch

Is This the End of the Road for Calcium Supplementation?

In this issue: Calcium supplementation in women; type 2 diabetes treatments and pancreatitis risk; treating chronic idiopathic urticaria; rivaroxaban and VTE; and FDA actions.

High calcium intakes in women

Another study suggests that calcium supplementation may lead to excess all-cause mortality and cardiovascular disease in otherwise healthy women. Researchers studied more than 61,000 Swedish women for 19 years. Diet and calcium intake, including calcium supplementation, were assessed with the primary outcome being death from all causes and cause-specific cardiovascular disease, ischemic heart disease, and stroke. Higher dietary intake of calcium (> 1400 mg/day) was associated with a higher death rate from all causes compared to intake between 600-1000 mg/day (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.17-1.67). Higher calcium intake was also linked to increased risk of cardiovascular disease (HR, 1.49; CI, 1.09-2.02) and ischemic heart disease (HR, 2.14; CI, 1.48-3.09). There was no higher risk of stroke. Intake of calcium in tablet form > 1400 mg/day was associated with 2.5 times greater risk of death from all causes (HR, 2.57; CI, 1.19-5.55). The authors conclude that higher intakes of calcium in women are associated with higher death rates from all causes as well as increased rates of cardiovascular disease but not stroke (BMJ published online Feb. 13, 2013. DOI: org/10.1136/bmj.f228). Previous studies have focused more on stroke risk associated with calcium showing mixed results. This well-done study, along with previously published data from the Women’s Health Initiative, provides ample evidence to rethink calcium supplementation for the 60% of middle-aged and older American women who are regular users of calcium supplements. The U.S. Preventive Services Task Force came to the same conclusion (even before this study was published) with publication of updated guidelines in February stating that "current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplements for the primary prevention of fractures in postmenopausal women or men." They further state there is no evidence to support use of more than 1000 mg of calcium and 400 mcg of vitamin D per day and recommends against using doses lower than 1000 mg of calcium and 400 mcg of vitamin D. Their rationale is that supplementation does not reduce fracture risk but does increase the risk of renal stones in otherwise healthy women. This does not apply to women with osteoporosis or vitamin D deficiency (Ann Intern Med, published online Feb. 26, 2013).

Diabetes therapies and pancreatitis risk

Glucagonlike peptide 1 (GLP-1) mimetics (e.g., analogs of GLP-1 and dipeptidyl peptidase IV inhibitors) used for the treatment of type 2 diabetes might increase the risk of pancreatitis, according to a recent population-based, case-control study. Using a large population database of type 2 diabetics, 1269 cases of acute pancreatitis were identified and those patients were matched with 1269 controls with similar risk factors (age, sex, diabetes mellitus complications, etc). After adjusting for available confounders, current use of GLP-1 based therapies (exenatide [Byetta] and sitagliptin [Januvia]) more than doubled the risk for acute pancreatitis (adjusted odds ratio 2.24, 95% CI, 1.36-3.68). The authors state that "Our findings suggest a significantly increased risk of hospitalization for acute pancreatitis associated with the use of sitagliptin or exenatide among adult patients with type 2 diabetes mellitus" (JAMA Intern Med published online Feb. 25, 2013. DOI: 10.1001/jamainternmed.2013.2720). Both drugs already carry a boxed warning regarding pancreatitis.

Omalizumab for idiopathic urticaria

Chronic idiopathic urticaria is one of the most frustrating entities to treat as many patients do not respond to antihistamines, even in high doses. Now, a new study suggests that omalizumab (Xolair), an IgE monoclonal antibody used to treat asthma, may be effective in these patients. Patients with moderate-to-severe chronic idiopathic urticaria (n = 323) were randomized to SQ injections of omalizumab every 4 weeks for three total injections at doses of 75 mg, 150 mg, 300 mg, or placebo. The primary outcome was itch-severity score. The 75 mg dose was no better than placebo, but the two higher doses showed significant reductions in itching, with the 300 mg dose being the most effective. The higher dose was also associated with the highest risk of side effects, however, at about 6%. The authors conclude that omalizumab was effective in these patients who were previously symptomatic despite antihistamines. The study was sponsored by the drug manufacturers Genentech and Novartis Pharma (N Engl J Med published online Feb. 24, 2013. DOI: 10.1056/NEJMoa1215372).

Rivaroxaban for VTE prevention

Rivaroxaban, the oral Xa inhibitor, is as effective as enoxaparin in preventing venous thromboembolism (VTE) in patients with acute medical illnesses, but with a higher risk of bleeding, according to a new study. More than 8100 acutely ill hospitalized patients were randomized to 10 days of enoxaparin 40 mg SQ daily or 35 days of rivaroxaban 40 mg orally with matching placebos. The primary outcome of asymptomatic or symptomatic VTE occurred in 2.7% of patients in both groups by day 10. By day 35, the rates were 4.4% for rivaroxaban and 5.7% for enoxaparin (P = 0.02). However, the bleeding rate was more than double in the rivaroxaban group at day 10 (2.8% vs 1.2%, P < 0.001) and even higher at day 35 (4.1% vs 1.7%, P < 0.001). The authors conclude that rivaroxaban was noninferior to enoxaparin for standard duration thromboprophylaxis (10 days) and reduced the risk of VTE at 35 days with an increased risk of bleeding (N Engl J Med 2013;368:513-523).

FDA actions

A new selective estrogen receptor modulator (SERM) has been approved for the treatment of dyspareunia due to vulvar and vaginal atrophy in postmenopausal women. Ospemifene appears to benefit vaginal epithelium without significant effect on the endometrium. The drug’s safety and efficacy was established in three clinical trials of nearly 1900 postmenopausal women with vulvar and vaginal atrophy who were randomly assigned to ospemifene or placebo. After 12 weeks, the first two trials showed statistically significant improvement in dyspareunia while the third trial supported the long-term safety of the drug. The drug is contraindicated in women with genital bleeding, estrogen-dependent cancer, or thromboembolic disease. The risk of stroke and VTE was higher than baseline but lower than the rates seen with estrogen replacement therapy. Ospemifene comes with a boxed warning regarding endometrial hyperplasia and abnormal vaginal bleeding. Common side effects include hot flashes, vaginal discharge, muscle spasms, and sweating. It will be marketed by Shionogi Inc. as Osphena.

The FDA has approved ado-trastuzumab emtansine for use as a single agent in patients with late-stage, HER2-positive breast cancer. The drug is approved for patients who have already been treated with trastuzumab and taxane separately or in combination. Approval was based on a study of nearly 1000 women with metastatic breast cancer in which progression-free survival was about 3 months longer with the drug compared to lapatinib plus capecitabine, and overall survival was about 6 months longer. Ado-trastuzumab emtansine is marketed by Genentech as Kadcyla.

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: