Shannon A. Miller

Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Objective: TO review the pharmacology, pharmacokinetics, safety, and efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor in the management of type 2 diabetes mellitus. Data Sources: A MEDLINE search (1966–February 2006) was conducted for English-language articles using the terms dipeptidyl peptidase IV inhibitor, incretin, MK-0431, and sitagliptin. Abstracts from the American Diabetes Association annual meetings in 2004 and 2005 were included as sources of data. Study Selection and Data Extraction: Articles pertaining to the pharmacology of sitagliptin, its pharmacokinetics, safety and efficacy were reviewed. Data Synthesis: Sitagliptin is a potent, competitive, reversible inhibitor of the DPP-IV enzyme. It is eliminated renally, with a terminal half-life of 11.8–14.4 hours. In Phase II clinical trials, sitagliptin was found to be superior to placebo for the treatment of type 2 diabetes mellitus. Results of a small trial comparing sitagliptin with glipizide indicate that both treatments are comparable. The efficacy of sitagliptin has also been demonstrated when used as adjunctive therapy with metformin. Few adverse effects have been reported. Weight gain and hypoglycemia have not been seen with sitagliptin therapy. Conclusions: Based on its unique mechanism of action, sitagliptin will provide practitioners with an additional tool in the treatment of diabetes. Review of the literature to date implies sitagliptin may be effective as monotherapy in type 2 diabetes. In addition, existing evidence supports the use of sitagliptin as adjunct therapy to sulfonylureas and metformin. Another advantage of sitagliptin use is that it appears to be free from the adverse effects of weight gain and hypoglycemia that are associated with currently available treatments.

Albiglutide: a new GLP-1 analog for the treatment of type 2 diabetes

Importance of the field: Despite the wide array of treatments available, a significant number of patients with type 2 diabetes continue to remain uncontrolled. The discovery of the incretin hormones and their role in glucose homeostasis has brought about a new class of medications called the glucagon-like peptide-1 (GLP-1) analogs. This new class of medications provides the benefits of weight loss as well as a lack of hypoglycemia. However, the currently available agents require once or twice daily injections. Areas covered in this review: Relevant literature will be discussed on albiglutide, a new GLP-1 analog in Phase III clinical trials. Several clinical trials examining the use of albiglutide as combination therapy are currently ongoing. What the reader will gain: To date, results of clinical trials suggest that albiglutide may provide a more attractive dosing profile compared with the currently available GLP-1 analogs. Take home message: The results of ongoing trials will help define the role of albiglutide in treating patients with type 2 diabetes.

The Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Treatment of Type 2 Diabetes

PURPOSE Diabetes is a chronic metabolic disorder characterized by hyperglycemia that results from insulin resistance, diminished or absent insulin secretion, or both. Approximately one-half of patients with diabetes fail to achieve acceptable glycemic control. Consequently, morbidity and mortality associated with diabetes is high, resulting from complications such as cardiovascular disease and nephropathy. The sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of medications for the treatment of type 2 diabetes. This article provides an overview of efficacy and safety data for the SGLT2 inhibitors and outlines their role in the management of diabetes. METHODS Relevant articles were identified through searches of PubMed and International Pharmaceutical Abstracts by using the key terms canagliflozin, dapagliflozin, empagliflozin, and sodium-glucose co-transporter 2 inhibitor. A review of bibliographies of retrieved articles was also performed to identify additional references. All identified trials published in English and that involved the efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes were reviewed. FINDINGS The SGLT2 inhibitors improve glucose control by increasing urinary glucose excretion. Effectiveness is decreased in the presence of renal dysfunction. These agents are efficacious as monotherapy and add-on therapy for patients with type 2 diabetes uncontrolled on metformin, sulfonylureas, insulin, and other antihyperglycemic combinations. The SGLT2 inhibitors lower glycosylated hemoglobin by 0.5% to 1% and fasting plasma glucose by ~15 to 35 mg/dL, depending on the agent and the dosage used, and are also associated with modest reductions in weight (-1.5 to -3.5 kg) and systolic blood pressure (-3 to -5 mm Hg). Genital mycotic infections and increased urination, owing to the mechanism of action, are the most common adverse effects. In general, the class is well tolerated, and the risk of hypoglycemia is low. IMPLICATIONS With their unique mechanism of action and good safety and tolerability profiles, the SGLT2 inhibitors are an important addition to existing treatments for type 2 diabetes. Because of the lack of data with this class of drugs when current treatment guidelines for diabetes were published, the SGLT2 inhibitors are recommended as second- or third-line therapies for diabetes. Forthcoming data on the long-term efficacy and safety profile of these agents should help to solidify the role of SGLT2 inhibitors in the management of diabetes.

A review of the treatment of type 2 diabetes in children.

The incidence of type 2 diabetes and obesity in children and adolescents has risen at staggering rates. Studies have shown that treating type 2 diabetes with oral medications in children may be more difficult than treating in adults. Compounding this problem is the fact that most of the medications available for treating type 2 diabetes have not been studied in children. Recently, the American Diabetes Association and the Pediatric Endocrine Society have collaborated to create a guideline for the treatment of type 2 diabetes in children. Similar to the treatment of adults with type 2 diabetes, metformin remains the mainstay of therapy along with diet and exercise. Adjunctive therapy should be based on the limited clinical evidence available as well as on patient preference. In order to avoid detrimental microvascular and macrovascular complications, patients, clinicians, and family members should work together to ensure adequate treatment of type 2 diabetes in children.

Otelixizumab: a novel agent for the prevention of type 1 diabetes mellitus.

Introduction: Type 1 diabetes mellitus is a chronic, progressive autoimmune disorder linked to numerous genetic and environmental factors. Insulin is the only treatment and preventative strategies do not currently exist. An obvious need exists to develop a safe regimen that suppresses the progression of the disease. Areas covered: A MEDLINE search (1966–June 2011) was conducted for English-language articles using the terms ‘otelixizumab’, ‘anti-CD3 antibody’ and ‘prevention of type 1 diabetes mellitus’. Relevant literature on otelixizumab, an anti-CD3 monoclonal antibody, currently in Phase III clinical trials for prevention of T1DM is discussed. Expert opinion: Studies suggest that a monoclonal antibody directed against CD3 mitigates the deterioration in insulin production and decreases the rise in insulin requirement in recent onset T1DM for up to five years. The benefit was most pronounced in younger patients and in those with higher initial β-cell function. Adverse effects were significant but transient. Otelixizumab shows great promise but leaves room for improvement. Results of ongoing trials will help define its role in the prevention of T1DM.

Sodium-glucose cotransporter 2 inhibitors: the new option for diabetes mellitus management.

Abstract Type 2 diabetes mellitus continues to be a challenging disease to manage successfully. Beyond the first-line option metformin, there are a number of classes of medications from which to select. This article reviews the new sodium-glucose cotransporter 2 inhibitors canagliflozin and dapagliflozin, including their benefits, adverse effects, and potential place in therapy. Upon review, the use of these medications has led to an A1c reduction between −0.37% and −1.16%. These medications also have been shown to reduce A1c when used with insulin. Some adverse effects were noted when using canagliflozin and dapagliflozin, with the most frequent being urinary tract infections and genital mycotic infections. We review the sodium-glucose cotransporter 2 inhibitors approved by the US Food and Drug Administration and their potential roles in the management of type 2 diabetes mellitus.

Angiotensin II vaccine: a novel approach in the treatment of hypertension

Background: Hypertension affects approximately 65 million Americans, resulting in 30 million office visits per year. Only about one third of patients have blood pressure below goal. Poor adherence to drug therapy is an important contributor to this statistic. An active immunization, which would induce antibodies against angiotensin, could simplify and improve treatment. An ideal regimen would be a few subcutaneous injections per year, which in turn could vastly improve adherence and subsequent outcomes. Objective: To discuss Cyt006-AngAb, a novel vaccine targeting angiotensin II, which is chemically linked to recombinant virus-like particles. Emphasis is placed on current progress of this vaccines clinical trials. Methods: Relevant literature is discussed. Conclusion: Although advances in hypertension vaccines have faced challenges, the angiotensin II vaccine may provide a promising approach in the control of hypertension.

Novel Approaches to the Treatment of Type 2 Diabetes

The emergence of the glucoregulatory hormone, glucagon-like peptide-1, has expanded our understanding of glucose homeostasis. The glucoregulatory actions of glucagon-like peptide-1 include enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to potentiate the effects of glucagon-like peptide-1 in those with type 2 diabetes. The glucagon-like peptide-1 analogs, such as exenatide, and dipeptidyl peptidase-IV inhibitors, such as sitagliptin, are currently available whereas others are in the final stages of development. These agents effectively reduce hemoglobin A1c while providing the other benefits associated with increased glucagon-like peptide-1. They also offer the potential to preserve the β-cell function. The effects on cardiovascular disease, if any, are unknown. Based on the current evidence, these agents represent viable second-and third-line options in the management of type 2 diabetes.

The role of glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes

Abstract The role of GLP-1 agonists in the treatment of type 2 diabetes have been shown to be viable options for add-on therapy in diabetic patients, as well as potential monotherapy options. With six available GLP-1 agents, and new combination products in the pipeline, they are a promising drug class for type 2 diabetic patients, especially due to their extended dosing interval and potential weight loss benefits.

Quantitative Approaches in Translational Research: An Overview

Cardiometabolic diseases are a group of complex and highly intertwined disorders that contribute significantly to healthcare expenditures. Despite the substantial efforts made for making safe and effective treatment options available to patients, cardiometabolic diseases are still a leading cause of death worldwide. This is in part due to the apparent disconnect between drug development and clinical application of medications. In order to bridge this gap, translational research approaches are needed which allow for integration of available knowledge and transition of drugs from bench to bedside. These translational research approaches further allow to feedback the lessons learned during the development of one drug into the development of next-in-pipeline drugs, which improves their chances to successfully make it to the market. Ultimately, these quantitative approaches can also serve as a knowledge platform for bedside-ready decision support tools that can guide the clinician’s choice of the most appropriate drug and/or dosing regimen.