Travis E. Sonnett

Review of osteoporosis pharmacotherapy for geriatric patients.

BACKGROUND Fractures are a significant problem in geriatric patients, and understanding the evidence for benefit and possible harm of osteoporosis treatments is critical to appropriate management of this patient population. OBJECTIVE The purpose of this article was to review the evidence and treatment considerations related to use of the approved osteoporosis treatments in the United States across the continuum of ages in the geriatric population. METHODS MEDLINE and the Web of Science were searched to find English-language articles published from 2000 through July 2009. Search terms included: practice guideline, osteoporosis, calcium, vitamin D, pharmacoeconomics, ethnicity, and treatment. The generic names of each of the osteoporosis treatments approved in the United States were searched to find relevant clinical trials and randomized controlled trials (RCTs). Pivotal trials that included fracture data or focused specifically on elderly patients (> or = 60 years of age) were selected. Bibliographies in the identified articles were searched for additional articles, and the prescribing information for each of the approved treatments was reviewed. RESULTS Many osteoporosis studies have a mean patient age >60 years, but data for older patients are limited. Subanalyses of older patient groups have found risedronate to be beneficial for vertebral fractures in patients aged 70 to 79 years (absolute risk reduction [ARR], 8.4%; P < 0.001) and teriparatide to be beneficial for both vertebral (ARR, 6.4%; P < 0.05) and new nonvertebral fragility fractures (ARR, 9.9%; P < 0.05) in women aged > or = 75 years. However, no RCTs of geriatric patients who were either nonambulatory or had multiple comorbidities were identified in the literature. CONCLUSIONS Evidence indicates that the osteoporosis treatments currently available in the United States are beneficial for treating osteoporosis in geriatric patients. However, data are limited for the oldest patients (> or = 80 years) and those with significant comorbidities. Because of the limited availability of data for geriatric patients with significant comorbidities, the properties of the various agents, including efficacy, tolerability, and potential contraindications, should be considered carefully for each geriatric patient.

Diabetes Mellitus, Inflammation, Obesity: Proposed Treatment Pathways for Current and Future Therapies:

Objective To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin. Data sources A literature search using MEDLINE (1966–December 12, 2009), PubMed (1950–December 12, 2009), Science Direct (1994–December 12, 2009), and International Pharmaceutical Abstracts (1970–December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well. Study selection and data extraction Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials. Data synthesis Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies. Conclusions While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.

Pregabalin for the treatment of painful neuropathy

Pregabalin is an α2-δ ligand that binds to and modulates voltage-gated calcium channels, exerting its intended effect to reduce neuropathic pain. Pregabalin is the second of only two medications that are US FDA approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy; it is also the third medication for the treatment of postherpetic neuralgia. Currently, there are three pivotal clinical studies documenting the efficacy and safety of pregabalin for the treatment of painful diabetic neuropathy, and three clinical studies regarding the use of pregabalin for pain associated with postherpetic neuralgia. This article will review each of these studies, as well as provide a clinical review for the use of pregabalin in the treatment of neuropathic pain.

Pharmacology, efficacy and safety of liraglutide in the management of type 2 diabetes

Liraglutide is a glucagon-like peptide-1 analog with pharmacokinetic properties suitable for once-daily administration approved by the Food and Drug Administration for the treatment of patients with type 2 diabetes. Clinical trial data from large, controlled studies demonstrate the safety and efficacy of liraglutide in terms of hemoglobin A1c (HbA1c) reduction, reductions in body weight, and the drug’s low risk for hypoglycemic events when used as monotherapy. Liraglutide has been studied as monotherapy and in combination with metformin, glimepiride, and rosiglitazone for the treatment of type 2 diabetes. Additionally, comparative data with insulin glargine and exenatide therapy are available from Phase III trials. Once-daily administration may provide a therapeutic advantage for liraglutide over twice-daily exenatide, with similar improvements in HbA1c and body weight observed when liraglutide was compared with exenatide. The glucose-dependent mechanism of insulin release with incretin analog therapy holds potential clinical significance in the management of postprandial hyperglycemic excursions, with minimal risk of hypoglycemia when used with non-secretagogue medications. Data to date on patient-reported outcomes with liraglutide treatment are encouraging. The most common adverse events associated with liraglutide therapy are dose-dependent nausea, vomiting, and diarrhea. Diligent postmarketing surveillance to elucidate the risk of pancreatitis and medullary thyroid carcinoma in a heterogeneous population are likely warranted.

Colesevelam Hydrochloride for the Treatment of Type 2 Diabetes Mellitus

BACKGROUND Colesevelam hydrochloride is a bile acid sequestrant approved in January 2008 by the US Food and Drug Administration (FDA) for the treatment of adult patients with type 2 diabetes mellitus (DM) in combination with a sulfonylurea, metformin, and/or insulin therapy. OBJECTIVE The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, adverse effects and tolerability, drug-drug interactions, contraindications/precautions, dosage and administration, pharmacoeconomics, and the overall role of colesevelam in the management of adult patients with type 2 DM. METHODS A literature search using MEDLINE (1966-October 27, 2008), PubMed (1950-October 27, 2008), Science Direct (1994-October 27, 2008), Web of Science (1980-October 27, 2008), American Diabetes Association Scientific Abstracts (2004-2008), and International Pharmaceutical Abstracts (1970-October 27, 2008) was performed using the term colesevelam. English-language, original research and review articles were examined, and citations from these articles were assessed. Manufacturer prescribing information and the FDA review of the new drug application for colesevelam were also examined. RESULTS Colesevelam is a hydrophilic, water-insoluble polymer, with negligible absorption and systemic distribution, that is excreted primarily in the feces. Through a mechanism still under investigation, colesevelam effectively lowers glycosylated hemoglobin (HbA(1c)) when used in combination with a sulfonylurea, metformin, and/or insulin therapy. Three completed, published Phase III clinical trials investigating colesevelam for the treatment of type 2 DM were evaluated for information, data, and conclusions. At dosing of 1.875 g BID or 3.75 g once daily in combination with one of the aforementioned agents versus placebo, reductions in HbA(1c) in all 3 Phase III clinical trials of colesevelam ranged from 0.5% to 0.7% (P < 0.02). In clinical trials, colesevelam was well tolerated, with hypoglycemia occurring in approximately 3% of studied patients. CONCLUSIONS When used in combination with a sulfonylurea, metformin, and/or insulin therapy, colesevelam has been reported to significantly reduce HbA(1c) in adult patients with type 2 DM. Colesevelams role in the management of type 2 DM remains undefined, however; further investigation into its mechanism of action and long-term efficacy and safety should be performed.

Role of colesevelam in managing heterozygous familial hypercholesterolemia in adolescents and children

Background Colesevelam hydrochloride is a synthetic, nonsystemically absorbed polymer that functions as a bile acid sequestrant for the treatment of hypercholesterolemia. Recently, colesevelam was investigated for the treatment of heterozygous familial hypercholesterolemia (HeFH) in the pediatric/adolescent population aged 10–17 years. Objective The purpose of this article is to review the disease state of HeFH in children and adolescents, review the pharmacologic mechanism of action, kinetics, and safety profile of colesevelam, analyze the results of a recent clinical trial of colesevelam in the pediatric/adolescent HeFH population, and discuss the role of colesevelam as a viable treatment option for HeFH. Methods A literature search using Medline (1966–03 May 2010), PubMed (1950–03 May 2010), Science Direct (1994–03 May 2010), and International Pharmaceutical Abstracts (2004–2010) was performed using the search term colesevelam. English language, original research, and review articles were examined, and citations from these articles were also assessed. The manufacturer’s prescribing information and the Food and Drug Administration review of the new drug application for the powder formulation were also examined. Results A 32-week trial was performed investigating the efficacy of colesevelam as monotherapy or combination therapy with a stable statin regimen. Upon completion of the trial, significant benefits were found in regard to the treatment of HeFH and the lowering of low-density lipoprotein cholesterol, total cholesterol, and other secondary measures. Safety and tolerability were also examined throughout the duration of the clinical trial, with adverse drug reactions considered mild in severity. Conclusion Colesevelam has been shown to reduce low-density lipoprotein cholesterol levels significantly in pediatric/adolescent patients with HeFH, while maintaining a mild side effect profile. Although further research would be beneficial for long-term effects in this population, colesevelam should be considered when developing a treatment regimen for HeFH in the pediatric/adolescent population.