A review of exenatide as adjunctive therapy in patients with type 2 diabetes.

BACKGROUND: Incretin glucagon-like peptide-1 (GLP-1) is a hormone released from cells in the gastrointestinal tract (GI), leading to glucose-dependent insulin release from the pancreas. It also suppresses postprandial hyperglycemia, glucagon secretion and slows gastric emptying. Exenatide (EXE), a functional analog of human GLP-1, was approved by the US FDA in April 2005. OBJECTIVE: This article reviews current primary literature on the clinical efficacy and safety of EXE in the treatment of type 2 diabetes mellitus (DM) and describes the pharmacokinetics, pharmacodynamics, dosing and administration of EXE. METHODS: English-language articles were identified through a search of MEDLINE (1966 to March 2009), International Pharmaceutical Abstracts (1970 to present), and Cochrane Database of Systemic Reviews (1995 to March 2009). Search terms included EXE, diabetes mellitus, postprandial hyperglycemia, gastric emptying, glucagon, pharmacokinetics and pharmacodynamics. Articles were selected for review if their designs were randomized, blinded and of controlled design that focused on clinical outcomes of patients with type 2 DM. RESULTS: EXE is administered subcutaneously in the thigh, abdomen or upper arm within the 60-minute period before the morning and evening meals. Its C(max) is reached within 2.1 hours, and its T(1/2) in 2.4 hours. EXE's metabolism is primarily through the kidneys. For the patients who received EXE 10 microg SC BID in three, 30-week, placebo-controlled studies with background sulfonylureas (SUs), metformin (MET), or SU + MET, there were significant reductions in HbA(1c) (0.77 to 0.86%), fasting plasma glucose (0.6 mmol/L) and body weight (1.6 to 2.8 kg) (P < or = 0.05 vs PCB) that were sustained in patients who completed two open-label phase trials with an additional 52 weeks of therapy. The use of thiazolidinediones was associated with a slight advantage over EXE in improving HbA(1c) along with increased weight gain; those who received EXE lost weight, but experienced more GI adverse effects. Patients who received EXE lost significant body weight while patients who received insulin gained weight. Patients receiving insulin had lower fasting, prelunch and predinner glucose excursions while patients in the EXE groups had lower postprandial glucose levels. Nausea was most frequently (>20%) reported in patients receiving the highest dose of EXE (10 microg SC BID vs 5 microg SC BID). CONCLUSIONS: EXE at the dose of 10 microg SC BID has been proven to decrease HbA(lc) by 1.3% +/- 0.1% and decrease body weight by up to 5.3 +/- 0.8 kg at week 82. Nausea was the most frequently reported adverse event (>20%) especially in patients being treated with EXE 10 microg SC BID. EXE can be safely added to MET therapy, SU therapy or MET + SU combination to effectively target glycemic goals in patients with type 2 DM. Long-term, head-to-head studies assessing the effect of the EXE +/- oral agents/insulins in patients with HbA(lc) > or = 10% are still needed to fully clarify the role of EXE in poorly controlled patients with type 2 DM.

Levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children.

BACKGROUND: Levocetirizine (LCZ) is a second-generation antihistamine that was approved in January 2008 for the relief of symptoms of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), and chronic idiopathic urticaria (CIU) in adults and children aged > or = 6 years. OBJECTIVES: This article reviews the available literature on the pharmacokinetics and pharmacodynamics, clinical efficacy and tolerability, and effect on quality of life (QoL) of LCZ. METHODS: A search of the English-language literature was performed using the following databases: MEDLINE (1966-February 2009), International Pharmaceutical Abstracts (19 70-February 2009), Database of Abstracts of Reviews of Effectiveness, Cochrane Database of Systematic Reviews, EMBASE Drugs & Pharmacology (1991-February 2009), Blackwell Synergy, CINAHL Plus with Full Text, EBSCOhost, ScienceDirect, and Wiley Interscience. The search terms were levocetirizine, allergic rhinitis, chronic idiopathic urticaria, antihistamine, pharmacokinetics, quality of life, drug interactions, case reports, and cost. Publications describing studies of > or = 2 weeks' duration that concerned the efficacy, tolerability, pharmacoeconomics, and/or QoL effects of LCZ were included in the review. RESULTS: In 4 studies in adult patients with moderate to severe PAR, LCZ 5 mg/d was associated with significant improvements in symptom scores for sneezing, rhinorrhea, and ocular/nasal pruritus at 4 to 6 weeks compared with placebo (P < or = 0.05). In 3 studies, nasal congestion scores were significantly improved within 4 to 6 weeks compared with placebo (P < 0.001). LCZ 5 mg/d was associated with improvements compared with placebo in scores for the ability to do housework, complete work activities, and engage in outdoor activities at 6 months (P < or = 0.011). In a 6-week study in children with moderate to severe SAR, LCZ 5 mg/d was associated with significant improvements compared with placebo in sneezing, rhin-orrhea, and itchy nose (P < 0.004); significant improvements in symptoms from baseline were also seen in a 4-week study in adults with SAR (P < 0.001). One study in patients with SAR reported no significant difference between LCZ and fluticasone compared with fluticasone monotherapy in terms of improvement in QoL, nasal airflow obstruction, sneezing, or pruritus. In a 6-week study in patients with moderate to severe CIU, LCZ 5 mg/d was significantly more effective than placebo in reducing overall CIU symptoms (P < 0.05). In two 4-week studies, one comparing LCZ 5 mg/d with placebo and the other comparing it with desloratadine (DSL), LCZ was significantly more effective than either comparator in terms of improvement in scores for pruritus severity (P < or = 0.001 vs placebo; P < 0.004 vs DSL) and duration (P < or = 0.001 vs placebo; P = 0.009 vs DSL). LCZ was significantly more effective than placebo (but not DSL) in reducing the number and size of wheals (both, P = 0.001). In a 12-week, open-label, crossover study, patients reported significantly longer symptom relief with cetirizine than LCZ (P < 0.005). The most commonly reported adverse events in two 6-month studies in adults with PAR treated with LCZ 5 mg/d included headache (23.8%), pharyngitis (19.4%), influenza (14.6%), fatigue (8.3%), and somnolence (8.3%). There is serious concern about the possibility of febrile seizures in infants treated with LCZ. Three pharmacoeconomic studies of LCZ 5 mg/d were identified, one comparing it with placebo in patients with PAR, one comparing it with placebo in patients with CIU, and another comparing it with second-generation antihistamines and montelukast in patients with PAR. Because of design limitations and differences in comparators in these studies, it was not possible to determine the cost-effectiveness of LCZ in the treatment of PAR or CIU. CONCLUSIONS: In the studies reviewed, LCZ 5 mg/d was effective in reducing symptoms of PAR, SAR, and CIU and improving QoL, with an acceptable tolerabili-ty profile. There is a need for studies of longer durations, head-to-head comparisons against other anti-histamines, drug-interaction studies, safety studies in infants, and cost-effectiveness analyses.

A review of the efficacy of smoking-cessation pharmacotherapies in nonwhite populations.

BACKGROUND: Cigarette smoking continues to be the leading cause of preventable morbidity and mortality in the United States. Research suggests that behavioral support strategies and pharmacotherapy can improve abstinence rates. However, both approaches, especially pharmacotherapy, have been understudied in nonwhite US populations. OBJECTIVE: The aim of this review was to evaluate the efficacy of smoking-cessation pharmacotherapy in nonwhite US populations. METHODS: Using search terms smoking cessation, nicotine replacement therapy, bupropion SR, varenicline, minority, ethnicity, African American, black, Hispanic, American Indian, and Alaska Native, a literature search was conducted to identify English-language studies that evaluated the use of smoking-cessation pharmacotherapies in nonwhite patients in MEDLINE (1966\2-December 2007), International Pharmaceutical Abstracts (1980\2-January 2008), Database of Abstracts of Reviews of Effectiveness (1990\2-December 2007), and EMBASE Drugs & Pharmacology (1991\2-third quarter 2007). RESULTS: Nine studies were identified and assessed. Six studies looked at smoking-cessation pharmacotherapy in black smokers, 1 in Hispanic smokers, 1 in Native American smokers, and 1 in white and nonwhite smokers. In black smokers (N = 410; mean cigarettes per day [cpd], 20.4) who received the nicotine patch versus placebo, the 30-day self-reported abstinence rates were 21.5% versus 13.7% (P = 0.03) at 10 weeks and 17.1% versus 11.7% (P = NS) at 6 months. In black smokers (N = 600; mean [SD] cpd, 16.1 [7.5]) who received sustained-release (SR) bupropion 150 mg BID versus placebo for 7 weeks, the 7-day biochemically verified abstinence rates at weeks 6 and 26 were 36.0% versus 19.0% (Delta, 17%; 95% CI, 9.7\2-24.4; P < 0.001) and 21.0% versus 13.7% (Delta, 7.3%; 95% CI, 1.0\2-13.7; P = 0.02). Predictors of smoking cessation included use of bupropion SR (abstinence rate, 41.5% vs 21.1%; P<0.001); smoking nonmentholated cigarettes (abstinence rate, 28.3% in mentholated smokers [n = 417] vs 41.5% in nonmentholated smokers [n = 118]; P = 0.006); not smoking within 30 minutes of awakening (abstinence rate, 26.4% [n = 420] in those who did vs 48.7% [n = 115] in those who did not; P < 0.001); and lower baseline salivary cotinine levels (256.8 [137.0] ng/mL in those who became abstinent vs 305.6 [143.4] ng/mL in those who remained smokers; P < 0.001). In black light (or=7 consecutive days (odds ratio, 0.20; 95% CI, 0.05-0.77; P = 0.02). CONCLUSIONS: Data from the studies in this review support the use of smoking-cessation pharmacotherapy (nicotine patch and bupropion SR) in nonwhite patients. Black patients, who smoked within 30 minutes of awakening, smoked mentholated cigarettes, and had high salivary cotinine levels may have difficulty quitting regardless of the number of cigarettes smoked per day; therefore, determining the type of cigarettes smoked (mentholated vs nonmentholated) and salivary cotinine levels may be helpful in assessing the severity of smoking addiction and guide pharmacotherapy (eg, starting at higher doses of nicotine-replacement therapy in a light smoker). Other than smoking-cessation behavioral studies, there is a lack of congruent smoking-cessation pharmacotherapy studies in American Indian/Alaska Native, Hispanic, and other ethnic populations.

Comparing hyperlipidemia control with daily versus twice-weekly simvastatin.

BACKGROUND: Costs associated with the use of hydroxymethylglutaryl coenzyme A reductase inhibitors are increasing. Finding ways to manage hyperlipidemia at lower costs is critical to all healthcare systems. OBJECTIVE: To assess effectiveness, safety, cost, and patients' satisfaction when converting hyperlipemic patients taking simvastatin daily to simvastatin twice weekly. METHODS: This nonrandomized, open-label, proof-of-concept study converted patients treated with simvastatin 10 or 20 mg daily to 40 or 80 mg twice weekly, respectively, for 12 weeks. The lipid profiles at enrollment, week 6, and week 12 were compared using repeated-measures ANOVA. The percentage of patients attaining the appropriate low-density lipoprotein cholesterol (LDL-C) goal was determined. RESULTS: Thirty-one patients completed the study. The proportion of patients at the LDL-C goal was not statistically different between enrollment and week 12 (87% vs 68%; p = 0.068). The mean LDL-C value +/- SD at weeks 6 and 12 increased compared with enrollment (112 +/-20, 111 +/-17, and 97 +/- 17 mg/dL, respectively; p < 0.001). Three (10%) patients reported nonadherence to the twice-weekly regimen. Seventeen (55%) patients reported that both regimens were equally convenient or preferred the twice-weekly regimen. Estimated cost-savings at our institution associated with this regimen would be $32 000 per 1000 patients per year. CONCLUSIONS: The twice-weekly regimen safely maintained most of the patients at their LDL-C goal level, and over half the patients found this regimen to be the same or easier to follow than a daily regimen. Large outcome studies evaluating this approach are needed.