Jennifer N. Clements

Liraglutide An Injectable Option for the Management of Obesity

OBJECTIVE To review the efficacy and safety of liraglutide, marketed as Saxenda, a glucagon-like peptide-1 analog for obesity management. DATA SOURCES A MEDLINE search (1970 to March 2015) was conducted for English-language articles using the terms glucagon-like peptide 1, liraglutide, and obesity. STUDY SELECTION AND DATA EXTRACTION Published articles pertinent to the efficacy and safety of liraglutide for short- and long-term obesity management among overweight or obese patients and special populations were reviewed and summarized. DATA SYNTHESIS Based on randomized placebo-controlled and active-comparator studies, liraglutide can increase weight loss among overweight and obese patients in a dose-dependent manner with once-daily doses of 1.2 to 3.0 mg. It has been shown that a higher proportion of patients experienced 5% and 10% weight loss from baseline compared with placebo and orlistat. Data support the potential benefit of liraglutide among overweight and obese patients with prediabetes, as well as women with polycystic ovary syndrome (PCOS) with an inadequate response to metformin. Larger and more robust studies are needed to determine the clinical significance of liraglutide among other agents for obesity in diverse populations. CONCLUSIONS Liraglutide is an adjunct to lifestyle modifications to improve success rates among overweight or obese individuals without diabetes. It may have a potential role in special populations, such as in those with prediabetes and women with PCOS. Based on its clinical evidence, liraglutide can result in more weight loss from baseline compared with orlistat and placebo. Adverse events associated with liraglutide are primarily gastrointestinal and usually dose dependent.Objective: To review the efficacy and safety of liraglutide, marketed as Saxenda, a glucagon-like peptide-1 analog for obesity management. Data Sources: A MEDLINE search (1970 to March 2015) was conducted for English-language articles using the terms glucagon-like peptide 1, liraglutide, and obesity. Study Selection and Data Extraction: Published articles pertinent to the efficacy and safety of liraglutide for short- and long-term obesity management among overweight or obese patients and special populations were reviewed and summarized. Data Synthesis: Based on randomized placebo-controlled and active-comparator studies, liraglutide can increase weight loss among overweight and obese patients in a dose-dependent manner with once-daily doses of 1.2 to 3.0 mg. It has been shown that a higher proportion of patients experienced 5% and 10% weight loss from baseline compared with placebo and orlistat. Data support the potential benefit of liraglutide among overweight and obese patients with prediabetes, as well as women with polycystic ovary syndrome (PCOS) with an inadequate response to metformin. Larger and more robust studies are needed to determine the clinical significance of liraglutide among other agents for obesity in diverse populations. Conclusions: Liraglutide is an adjunct to lifestyle modifications to improve success rates among overweight or obese individuals without diabetes. It may have a potential role in special populations, such as in those with prediabetes and women with PCOS. Based on its clinical evidence, liraglutide can result in more weight loss from baseline compared with orlistat and placebo. Adverse events associated with liraglutide are primarily gastrointestinal and usually dose dependent.

Drug-Induced Vitamin B12 Deficiency: A Focus on Proton Pump Inhibitors and Histamine-2 Antagonists:

Objective: To review primary literature of gastric acid suppressive agents and vitamin B12 deficiency. Data Synthesis: From the published articles, proton pump inhibitors (PPIs) are associated with a higher risk of inducing vitamin B12 deficiency than histamine-2 receptor antagonists (H2RAs). Literature suggests that there is an increased risk of developing vitamin B12 deficiency in patients who are exposed to extended durations of therapy with PPIs. There are, however, some conflicting data in elderly patients suggesting that the PPI use for more than 3 years does not increase the risk of vitamin B12 deficiency. No evidence was found to support the extended use of H2RA monotherapy causing vitamin B12 deficiency. The inconsistency of results reported could be due to the differing patient populations studied, such as Zollinger-Ellison syndrome (ZES) and elderly patients. Overall, the lack of consistent evidence shows the need for more research in this area. Conclusion: To investigate the clinical significance of vitamin B12 deficiency caused by acid suppression with PPIs and H2RAs, longer prospective studies are needed. These studies should focus on patient-centered outcomes to accurately determine the extended usage of PPI and H2RA and the true effects on vitamin B12 deficiency.

Dalfampridine: A new agent for symptomatic management of multiple sclerosis

PURPOSE The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, and place in therapy of dalfampridine are reviewed. SUMMARY Dalfampridine is a novel drug with a unique mechanism for the symptomatic management of multiple sclerosis (MS) among all classifications. Dalfampridine was approved in January 2010 to improve walking for patients with MS. Dalfampridine blocks potassium channels on demyelinated neurons and allows normal electrical conduction, thus improving locomotor difficulty. Dalfampridine is rapidly absorbed after oral administration, reaching its peak plasma concentration in 1.3 hours. Approximately 95.9% of dalfampridine and its metabolites (3-hydroxy-4-aminopyridine and 3- hydroxy-4-aminopyridine sulfate) is excreted in the urine. Dalfampridine is not an inhibitor or inducer of a major cytochrome P-450 isoenzyme; therefore, the potential for drug-drug interactions is minimal. Clinical studies have shown dalfampridine to improve walking speed. The dosage of dalfampridine varied in clinical trials, but the recommended dosage is 10 mg orally twice daily. Dalfampridine is not appropriate for patients with seizures or moderate-to-severe renal impairment. Phase III studies found that extended-release fampridine 10 mg twice daily is well tolerated. The most frequent adverse events reported in dalfampridine clinical trials were insomnia, dizziness, headache, nausea, and weakness. The Food and Drug Administration has required the manufacturer to have a risk evaluation and mitigation strategy for dalfampridine. Ongoing trials will determine the long-term benefit of dalfampridine. CONCLUSION Dalfampridine is a potassium channel blocker that has demonstrated efficacy for improving the symptoms of MS. Several studies have demonstrated increased walking speed in patients, though high doses should be avoided due to the risk of seizures.

Insulin glargine 300 units/mL: A new basal insulin product for diabetes mellitus

PURPOSE The pharmacokinetics, efficacy, and safety of U-300 insulin glargine for the management of diabetes are reviewed. SUMMARY U-300 (300 units/mL) insulin glargine is a long-acting basal insulin with low within-day variability, high day-to-day reproducibility, longer duration, and constant pharmacokinetic profile compared with U-100 (100 units/mL) insulin glargine. U-300 was evaluated in six randomized, active-comparator, open-label, Phase III clinical studies (EDITION trials) among patients with type 1 or 2 diabetes. The primary endpoint for all EDITION studies was the reduction in glycosylated hemoglobin from baseline to six months. Safety endpoints included confirmed or nocturnal hypoglycemia between week 9 and month 6 and the change in weight from baseline. For hypoglycemic episodes, U-300 insulin glargine was superior to U-100 insulin glargine when comparing the risk of hypoglycemia. U-300 insulin glargine is supplied in a prefilled device (for safety purposes) and packaged in boxes of three or five pens. It is still early to determine the role of U-300 insulin glargine in diabetes management. When compared with U-100 insulin glargine, U-300 insulin glargine appeared to be associated with a lower risk of hypoglycemia and nocturnal hypoglycemia, most likely due to its pharmacokinetics. The wholesale average cost of U-300 insulin glargine is

A Practical Guide to Concentrated Insulin for Pharmacists

335.48 per box of three pens. CONCLUSION The efficacy outcomes of U-300 insulin glargine were similar to those of U-100 insulin glargine, but the constant pharmacokinetic profile and longer duration of action of U-300 insulin glargine may help certain patients with type 1 or type 2 diabetes achieve better glycemic control.

Exenatide extended-release: a once-weekly option for patients with type 2 diabetes.

Purpose: Insulin improves glycemic control in several ways, for example, by stimulating glucose uptake in the muscle and inhibiting hepatic glucose production. It has other mechanisms of action for correcting the abnormal metabolism of proteins, fats, and carbohydrates. The formulation of concentrated insulin (U-500) is a higher potency of insulin than the U-100 regular formulation. It is indicated for children and adults with type 1 and type 2 diabetes who have not achieved adequate glycemic control with exercise and proper dietary habits. However, the unique characteristics of concentrated insulin require that a patient be educated on its use. This article provides a practical guide for pharmacists on the use of concentrated insulin in both inpatient and outpatient settings and highlights specific concerns and management strategies. Conclusion: Concentrated insulin works in the same mechanism as U-100 insulin formulations for treating type 1 and type 2 diabetes. Pharmacists are knowledgeable about managing the disease and can identify patients who will benefit with treatment of concentrated insulin. They can provide recommendations to prevent and resolve situations, such as dosing errors, which arise in patients on concentrated insulin and can educate patients and health care professionals on dosing conversions and titration.

Lesinurad, a Selective URAT-1 Inhibitor With a Novel Mechanism in Combination With a Xanthine Oxidase Inhibitor, for Hyperuricemia Associated With Gout:

Exenatide extended-release is a new long-acting glucagon-like peptide-1 agonist that may be an attractive option for patients desiring to lose weight, who are prone to hypoglycemic episodes, and who have not achieved desired glycemic control with current therapy.

Obesity management among patients with type 2 diabetes and prediabetes: a focus on lifestyle modifications and evidence of antiobesity medications

Objective: To review the pharmacokinetics, clinical efficacy, safety, and role of lesinurad for the management of hyperuricemia associated with gout. Data Selection: A MEDLINE search (2000 to April 2017) was conducted using the terms hyperuricemia, gout, URAT-1, URAT-1 transporter, and lesinurad. Published articles and scientific posters relevant to the efficacy and safety of lesinurad were reviewed and summarized. Data Synthesis: Lesinurad was evaluated in 3 randomized, phase 3 clinical trials (CRYSTAL, CLEAR 1 and 2). The primary endpoint for CRYSTAL trial was the percentage of patients achieving serum uric acid (SUA) concentration ≤ 5 mg/dL. The CLEAR 1 and 2 trials had a primary endpoint of percentage of patients achieving SUA concentration ≤ 6 mg/dL. Lesinurad at either 200 or 400 mg/d was superior to xanthine oxidase inhibitor (XOI) monotherapy in reducing the SUA concentration to 5 or 6 mg/dL, when added to either allopurinol or febuxostat. Conclusion: Data from phase 3 clinical studies suggest the addition of lesinurad to allopurinol or febuxostat is superior to XOI monotherapy alone in reducing SUA concentrations while increasing the risk of renal-related adverse events. Lesinurad, 200 mg orally per day, would be a safe recommendation, in combination with an XOI, among patients with adequate renal function (i.e., above 45 mL/min) who need additional therapy for inadequately controlled hyperuricemia associated with gout.

Role of Bupropion Plus Naltrexone for the Management of Obesity

ABSTRACT Introduction: The prevalence of obesity has increased over the past three decades in the United States and worldwide. This article reviews landmark trials for lifestyle modifications as well as clinical evidence and implications for locaserin, phentermine with topiramate, buproprion with naltrexone, and liraglutide in patients with type 2 diabetes and obesity. Areas covered: A MEDLINE search, from 1970 to May 2017, was conducted using key search terms - lifestyle modifications, antiobesity medication, obesity and diabetes. Published clinical trials, in the English language, with the adult patient population of type 2 diabetes or prediabetes, were reviewed and critiqued. Expert commentary: Lifestyle modifications have shown to prevent the progression to type 2 diabetes mellitus. Pharmacologically, each medication has proven effect on both type 2 diabetes mellitus and obesity, specifically reducing weight from baseline by 4.7 kg, 10.2 kg, 5.0 kg, and 6.4 kg with lorcaserin, phentermine with topiramate, bupropion with naltrexone, and liraglutide, respectively. The most efficacious medication is phentermine with topiramate, but liraglutide has long-term evidence, up to 3 years, particularly in patient with prediabetes. A risk-benefit analysis should be completed to determine which specific medication should be initiated for a patient with type 2 diabetes and obesity.

Liraglutide, GLP-1 receptor agonist, for chronic weight loss

Objective. The pharmacology, pharmacokinetics, efficacy, and safety of bupropion plus naltrexone for weight loss were reviewed. Data Sources. A MEDLINE search (1970 to November 2015) was conducted for English-language articles using specific MESH terms. Study Selection and Data Extraction. Published Phase 3 clinical trials with primary endpoints related to weight loss were included and critiqued in this review. Study Selection and Data Extraction. Five trials were retrieved and reviewed regarding the efficacy and safety of bupropion plus naltrexone among obese and overweight patients. Data Synthesis. Bupropion is a dopamine/norepinephrine reuptake inhibitor, and naltrexone is an opioid receptor antagonist. The combination of these agents has led to increased weight loss, compared to placebo, among overweight and obese patients with a body mass index (BMI) at or above 30 or BMI at or above 27 with a comorbid condition. The combination of bupropion and naltrexone can produce an average placebo-subtracted weight loss of 4.25% over 56 weeks. Gastrointestinal (ie, nausea, vomiting, constipation) and central nervous system adverse events (ie, headache, dizziness) were commonly reported, and there was a high dropout rate among participants. Conclusions. Bupropion plus naltrexone has demonstrated effective weight loss, in conjunction with lifestyle modifications, among overweight and obese patients with and without comorbidities. Bupropion plus naltrexone has not been studied among special patient populations, such as those with sleep apnea, osteoarthritis, or extreme BMIs. Additional clinical trials and postmarketing data will provide a better understanding of this medication for weight loss.