Pharmacology Watch

Tiotropium for COPD — The New Standard?

In this issue: Anticholinergic drugs for COPD; pioglitazone for diabetes prevention; insulin degludec in Phase 3 trials; and FDA Actions.

Anticholinergic drugs for COPD

Should anticholinergic drugs be first-line agents for preventing exacerbations in patients with chronic obstructive pulmonary disease (COPD)? The answer may be yes, according to a new study in the New England Journal of Medicine. Researchers from Europe compared the anticholinergic drug tiotropium to the beta-agonist salmeterol in more than 7000 patients with moderate-to-very-severe COPD. The study was a randomized, double-blind, double-dummy, parallel-group trial in which tiotropium once a day was compared to salmeterol twice a day. The endpoint was the incidence of moderate or severe exacerbations. Over the 1-year study, tiotropium increased the time to first exacerbation compared to salmeterol (187 days vs 145 days, 17% risk reduction, hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.77 to 0.90; P < 0.001). Tiotropium also increased the time to first severe exacerbation (P < 0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs 0.72; P = 0.002), and reduced the annual number of severe exacerbations (0.09 vs 0.13; P < 0.001). Adverse events were similar in both groups. There were 64 deaths in the tiotropium group (1.7%) and 78 in the salmeterol group (2.1%). The authors conclude that in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations (N Engl J Med 2011;364:1093-1103). This is the first head-to-head study to show benefit for anticholinergics but it must be pointed out that cardiac patients were excluded from the study, and the annual exacerbation rates were lower than has been seen in other trials. The concomitant use of inhaled corticosteroids was evaluated and did not make a difference in the outcomes. The study was sponsored by Boehringer Ingelheim, the manufacturer of tiotropium (Spiriva).

Pioglitazone for diabetes prevention

Pioglitazone reduces the risk of development of diabetes among prediabetic patients, according to a new study. Pioglitazone was compared to placebo in a total of 600 patients with impaired glucose tolerance. After a median follow-up of 2.4 years, the annualized incident rates for type 2 diabetes were 2.1% in the pioglitazone group and 7.6% in the placebo group (HR 0.28, 95% CI, 0.16 to 0.49; P < 0.001). Conversion to normal glucose tolerance occurred in nearly half of the pioglitazone group and in 20% of the placebo group (P < 0.001) and treatment with pioglitazone was associated with significantly lower fasting glucose levels, 2-hour glucose levels, and hemoglobin A1c levels. Pioglitazone also was associated with a decrease in diastolic blood pressure (2.0 mmHg vs 0.0 placebo), reduced rates of carotid intimal-medial thickening (P = 0.047), and an increased level of HDL cholesterol (increase of 7.35 mg/dL vs 4.5 mg/dL; P = 0.008). Pioglitazone caused greater weight gain than placebo (3.9 kg vs 0.77 kg; P < 0.001), as well as edema (12.9% vs 6.4%; P = 0.007). The authors conclude that pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes but was associated with significant weight gain and edema (N Engl J Med 2011;364:1104-1115). Thiazolidinediones have been falling out of favor in recent years for the treatment of type 2 diabetes due to association with edema and heart failure. This new industry-sponsored study suggests that pioglitazone (Actos) is more effective than metformin or lifestyle changes in preventing conversion of prediabetes to diabetes. What is unclear is the effect of these various interventions on long-term diabetic complications.

Insulin degludec in Phase 3 trials

Insulin degludec is an ultralong-acting insulin that is currently in Phase 3 trials. It forms soluble multihexamer assemblies after subcutaneous injection, resulting in a very long half-life of up to 40 hours. A new study suggests that it can be used three times a week, achieving blood sugar control equivalent to daily insulin glargine. In a 16-week randomized, open-label, parallel group trial, 245 type 2 diabetics aged 18-75 were randomized to insulin degludec once a day or three times a week, or insulin glargine once a day, all in combination with metformin. At the end of the study, mean hemoglobin A1c levels were similar across the treatment groups at 7.3%, 7.4%, and 7.2%, respectively. The rate of hypoglycemia was low in all three groups. The authors conclude that insulin degludec provides comparable glycemic control to insulin glargine without additional adverse events and may reduce dosing frequency due to its ultra-long action profile (Lancet 2011;377:924-931). The study was sponsored by its manufacturer, Novo Nordisk.

FDA actions

The FDA has approved the first new drug for lupus (systemic lupus erythematosus) since 1955. Belimumab is a fully human monoclonal antibody the targets human soluble B-lymphocyte receptor stimulator protein. It is indicated for the treatment of adult patients with active, autoantibody-positive lupus who are receiving standard therapy. In two pivotal studies, the drug was found to reduce disease activity compared to placebo plus standard therapy. More deaths and serious infections were reported for belimumab compared to placebo, and it does not appear to be effective in people of African or African American heritage (in whom the disease is three times more common), although more studies are needed to confirm this finding. Belimumab is marketed by GlaxoSmithKline as Benlysta.

The FDA has approved a phosphodiesterase type 4 inhibitor to reduce the number of exacerbations from severe COPD associated with chronic bronchitis. Roflumilast is a once daily oral pill that reduces excess mucus and cough. It does not appear to benefit COPD that involves primarily emphysema. The approval was based on two Phase 3 studies of more than 1500 patients. An accompanying medication guide informs patients of the potential risk of mental health problems including changes in mood, thinking, or behavior, as well as unexplained weight loss. Roflumilast is marketed by Forest Pharmaceuticals as Daliresp.

The FDA has approved a new angiotensin II receptor antagonist, the eighth introduced to the American market. Azilsartan medoxomil is approved for the treatment of hypertension in 40 mg and 80 mg once daily doses. The drug is touted as being more effective in lowering blood pressure than valsartan or olmesartan based on clinical trials. Like other angiotensin II receptor blockers, the drug will carry a box warning regarding pregnancy. Azilsartan is marketed by Takeda Pharmaceuticals as Edarbi.

Zostavax, Merck's vaccine for the prevention of shingles, has been approved for use in individuals ages 50-59. It previously was approved only for those 60 and older. The approval was based on a placebo-controlled trial of more than 20,000 individuals 50-59 years of age. The vaccine reduced the risk of developing shingles in this group by approximately 70%.

The FDA has approved ipilimumab for the treatment of late stage (metastatic) melanoma. The drug is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen (CTLA-4). The approval was based on a single study of 676 patients with melanoma who had stopped responding to other therapies. When compared to an experimental tumor vaccine, those receiving ipilimumab lived an average of 3.5 months longer (10 months vs 6.5 months). Autoimmune reactions were common including fatigue, diarrhea, rash, endocrine deficiencies, and colitis. Severe to fatal autoimmune reactions were seen in 13% of treated patients. Ipilimumab is manufactured by Bristol-Myers Squibb and marketed as Yervoy.

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: