Sarah L. Anderson

Association of Pancreatitis with Glucagon-Like Peptide-1 Agonist Use

OBJECTIVE: To review the possible association between glucagon-like peptide-1 (GLP-1) agonist use and pancreatitis in patients with type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1950-January 2010) identified key clinical trials delineating adverse effects associated with GLP-1 agonist use. Key search terms included type 2 diabetes mellitus, pancreatitis, incretins, exenatide, liraglutide, albiglutide, and taspoglutide. Review of references listed in the articles identified was also performed. The Food and Drug Administration (FDA) Web site and Amylin Pharmaceuticals file data were utilized to extract case report information and unpublished clinical development data related to GLP-1 agonist use and pancreatitis. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 clinical trials evaluating exenatide, liraglutide, albiglutide, and taspoglutide that discussed treatment-related adverse effects as well as FDA-reviewed case reports of pancreatitis in patients taking these same therapies were included. One study evaluating type 2 diabetes as a risk factor for development of acute pancreatitis was also included. Exenatide case reports and clinical development data were also included. DATA SYNTHESIS: Currently there have been 8 cases during clinical development and 36 postmarketing reports of acute pancreatitis in exenatide-treated patients. Four patients have developed acute (n = 3) or chronic (1) pancreatitis during liraglutide clinical trials. There have been no reports to date of development of acute pancreatitis in patients taking albiglutide or taspoglutide. CONCLUSIONS: Observational reports and clinical trial data suggest an association between GLP-1 agonist use and acute pancreatitis; however, additional clinical trial data and in-depth case report analysis are needed to further evaluate and verify this finding.

Quetiapine for insomnia: A review of the literature

PURPOSE The safety and efficacy of quetiapine for the treatment of insomnia in adults are reviewed. SUMMARY Quetiapine was developed for the treatment of psychiatric disorders, but its antagonism of histamine H1- and serotonin type 2A receptors has the added effect of causing sedation. As such, quetiapine is widely used off-label as a treatment for insomnia. Due to quetiapines potential adverse effects, guidelines for the treatment of insomnia have recommended the drugs use only in patients with specific comorbid psychiatric disorders. The use of quetiapine for the treatment of insomnia in the absence of comorbid conditions has been evaluated in only two clinical trials of 31 patients in total, and very few studies have evaluated quetiapine use in patients with insomnia and other comorbidities. No trials have been conducted comparing quetiapine with an active control (e.g., zolpidem); the data that exist compare quetiapine to a placebo or there is no comparison and all patients are treated with quetiapine. Very few studies have evaluated quetiapines efficacy in the treatment of insomnia using sleep objective testing, another limitation of the available data on quetiapine. CONCLUSION Robust studies evaluating the safety and efficacy of quetiapine for the treatment of insomnia are lacking. Given its limited efficacy data, its adverse-effect profile, and the availability of agents approved by the Food and Drug Administration for the treatment of insomnia, quetiapines benefit in the treatment of insomnia has not been proven to outweigh potential risks, even in patients with a comorbid labeled indication for quetiapine.

Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population

No clinical trials are currently available that demonstrate the effects of marijuana on patients with migraine headache; however, the potential effects of cannabinoids on serotonin in the central nervous system indicate that marijuana may be a therapeutic alternative. Thus, the objective of this study was to describe the effects of medical marijuana on the monthly frequency of migraine headache.

Histamine-1 receptor antagonism for treatment of insomnia

OBJECTIVES To evaluate the literature regarding the use of histamine-1 (H(1)) receptor antagonists and to describe their role in the treatment of insomnia in adult patients, including the elderly. DATA SOURCES Literature was identified via PubMed and Medline through April 1, 2012, using the search terms insomnia and sleep, each individually combined with histamine antagonist, tricyclic antidepressant, trazodone, mirtazapine, doxepin, amitriptyline, nortriptyline, trimipramine, doxylamine, diphenhydramine, and antihistamine. STUDY SELECTION AND DATA EXTRACTION Data included randomized double-blind trials that statistically evaluated H(1) receptor antagonist treatment in patients with insomnia compared with a placebo control or Food and Drug Administration-approved insomnia treatment. Trials selected evaluated sleep latency, wake after sleep onset, total sleep time, number of awakenings, and/or sleep efficiency in a subjective or objective manner. A total of 65 trials were evaluated, and 16 met inclusion criteria. DATA SYNTHESIS With the exception of low-dose doxepin (Silenor-Somaxon), trials evaluating the clinical effectiveness of H(1) receptor antagonists show mixed results and are limited by sample size and generalizability. Large, randomized, appropriately controlled trials are lacking, making it difficult to define the safety and efficacy of these agents. In contrast, low-dose doxepin has been shown to provide consistent sleep benefit compared with placebo. CONCLUSION Over-the-counter antihistamines may have a role for short-term insomnia treatment in younger adults, but tolerance develops rapidly. Mirtazapine should not be used solely for the treatment of insomnia. Sedating antidepressants can be considered after failure of first-line insomnia treatments. Patients taking these agents chronically should be evaluated for continued efficacy and potential harm. Low-dose doxepin may have a unique role in the treatment of insomnia in elderly patients given its tolerability, documented efficacy, and lack of important adverse effects.

Dapagliflozin for the Treatment of Type 2 Diabetes

Objective: To review the literature and describe the pharmacologic, pharmacokinetic, and pharmacodynamic properties; clinical safety; and efficacy of dapagliflozin, a new drug currently under review by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes. Data Sources: A MEDLINE (1995-November 2011) and ClinicalTrials.gov search was conducted using the terms dapagliflozin, sodium-glucose cotransporter 2 inhibitor, and SGLT2 inhibitor. Reference citations from publications identified were also reviewed. Study Selection and Data Extraction: All English-language studies, including abstracts, evaluating dapagliflozin use in humans were included in this review. Data Synthesis: Dapagliflozin is the first-in-class oral sodium-glucose cotransporter 2 (SGLT2) inhibitor that represents a new potential therapeutic option for the treatment of type 2 diabetes mellitus. Its mechanism of action is insulin- and insulin-sensitivity independent. Preliminary data suggest that dapagliflozin decreases hemoglobin A1c, fasting plasma glucose, and postprandial plasma glucose, while also promoting weight loss. In Phase 1, 2, and 3 clinical trials, dapagliflozin has exhibited a safety and tolerability profile similar to that of placebo. Conclusions: Dapagliflozin is a novel oral antihyperglycemic agent that has demonstrated promise as monotherapy and as synergistic combination therapy with currently available agents in Phase 3 clinical trials. On January 19, 2012, the FDA issued a complete response letter to AstraZeneca and Bristol-Myers Squibb regarding the new drug application for dapagliflozin. The FDA is requesting additional clinical data—from ongoing studies and potentially new clinical trials—to better describe the risk-benefit profile of the drug. Both manufacturers remain committed to the development of dapagliflozin, and there are currently 8 Phase 3 trials ongoing. Dapagliflozin has the potential to be the next new oral agent in the diabetes drug armamentarium.

Determining predictors of response to exenatide in type 2 diabetes

OBJECTIVES To determine predictors of glycemic response to exenatide and to assess change in glycosylated hemoglobin (A1C) and whether a correlation exists between weight loss and glycemic response. DESIGN Retrospective observational cohort study. SETTING United States in 2009. PATIENTS 100 adult patients with type 2 diabetes prescribed exenatide. INTERVENTION Retrospective chart review of patients to collect demographic data, weight, serum creatinine, diabetes education, and concurrent diabetes medications. MAIN OUTCOME MEASURES Patients were categorized as responders or nonresponders based on change in A1C. Responders had an A1C decrease of 0.5% or more and nonresponders had an A1C decrease of less than 0.5% from baseline to post-exenatide initiation. Demographic data for each cohort were analyzed. RESULTS 100 patients met inclusion criteria (61 responders and 39 nonresponders). Responders had a mean A1C decrease of 1.57%, whereas nonresponders had a mean A1C increase of 0.23% (P < 0.001). Post hoc linear regression analysis revealed that baseline A1C was a predictor of response to exenatide (P < 0.001). Binary logistic regression analysis demonstrated that no other variables were predictors of response to exenatide (P > 0.05 for all). No correlation was found between weight loss and exenatide and glycemic response (P = 0.99). CONCLUSION Our data indicate that patients with a higher baseline A1C are more likely to have a glycemic response to exenatide than patients with a lower baseline A1C.

Implementation of a Clinical Pharmacy Specialist-Managed Telephonic Hospital Discharge Follow-Up Program in a Patient-Centered Medical Home

The objectives of this retrospective study were to examine the feasibility and characteristics that define successful implementation of a Clinical Pharmacy Specialist (CPS) telephonic hospital discharge follow-up quality improvement initiative, as well as the impact of this initiative. Adult patients who were discharged from a safety-net hospital between July 1, 2010 and June 30, 2011 and who were part of a patient-centered medical home were included in this quality improvement initiative. CPSs attempted to contact 470 patients; of those, 207 received the intervention and 263 did not. Patients in the contacted group were more likely to attend a hospital discharge follow-up appointment (66.2% vs. 44.5%, P<0.01) and had lower rates of 30-day readmission (22 vs. 52, P<0.01) compared to those who were not contacted. Institutions should consider allocating resources for pharmacist-managed posthospital discharge follow-up services because of the potential for positive clinical and financial impact.

Dapagliflozin efficacy and safety: a perspective review

Type 2 diabetes mellitus is a prevalent, progressive disease with a need for innovative therapeutic agents to continue to advance disease management. Dapagliflozin is the second agent in a new class of oral antihyperglycemic drugs: sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is responsible for the majority of renal glucose reuptake; inhibition of the cotransporter allows for increased renal glucose excretion that consequently leads to reduced plasma glucose levels. Because this mechanism does not require the action of insulin, dapagliflozin rarely causes hypoglycemia and is effective in patients both early and late in the course of their disease. Studies of dapagliflozin have demonstrated efficacy both as monotherapy and in combination with oral antihyperglycemic agents and insulin. Dapagliflozin has been shown to decrease hemoglobin A1c (HbA1c) values 6 mmol/mol (0.5%) to 8 mmol/mol (0.7%). The most common adverse reactions observed with dapagliflozin in clinical trials were female genital mycotic infections, urinary tract infections, and nasopharyngitis. Dapagliflozin is a new oral agent for type 2 diabetes with short-term efficacy similar to dipeptidyl peptidase 4 inhibitors; its long-term safety and efficacy are unknown.

Lixisenatide in type 2 diabetes: latest evidence and clinical usefulness:

Type 2 diabetes (T2D) is a highly prevalent disorder that affects millions of people worldwide. The hallmark of T2D is hyperglycemia and, while many treatment modalities exist, achieving and maintaining glycemic control can be challenging. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an appealing treatment option as they improve glycemic control, reduce weight, and limit the risk of hypoglycemia. Lixisenatide is a once-daily GLP-1 RA that has been evaluated in the GetGoal clinical trial program and has demonstrated efficacy and tolerability across a spectrum of patients. The feature that most distinguishes lixisenatide from other GLP-1 RAs is its ability to substantially reduce postprandial glucose (PPG) for the meal immediately following injection. Because of its positive effects on PPG, lixisenatide is being considered as a replacement for prandial insulin, and a fixed dose combination product containing lixisenatide and basal insulin is in development. Lixisenatide is a promising new addition to the antidiabetic armamentarium, but due to the lack of real-world experience with the drug, its exact place in therapy is unknown.

Suvorexant in insomnia: efficacy, safety and place in therapy.

Insomnia is a highly prevalent disorder that can occur in conjunction with other medical or psychiatric conditions or can occur in the absence of a coexisting disorder. Regardless, treatment of insomnia is beneficial to the patient and may benefit comorbidities if they exist. Nonpharmacologic modalities such as sleep hygiene and stimulus controls are important mainstays of insomnia therapy, but may not be sufficient to treat the disorder. Dual orexin receptor antagonists (DORAs) are a new class of insomnia medication that target wakefulness-promoting neuropeptides to regulate the sleep–wake cycle. Suvorexant is the first DORA to be approved and has demonstrated efficacy at decreasing both time to sleep onset and increasing total sleep time compared with placebo. Suvorexant has a novel mechanism of action and may represent an alternative for patients who cannot tolerate or do not receive benefit from traditional sleep agents. Suvorexant is generally effective and well tolerated, but has not been compared head to head with traditional sleep agents and being only newly available, lacks a longer-term ‘real-world’ experience base.