Can a new ultra-long-acting insulin analogue improve patient care? Investigating the potential role of insulin degludec.

The basal-bolus concept of delivering insulin to diabetic patients makes physiological sense, as it mimics normal insulin release in people without diabetes. In line with this concept, a major effort put forth by insulin manufacturers has been to develop the ideal exogenous basal insulin product. The perfect basal insulin product would be injected into subcutaneous tissue without causing irritation, release insulin continuously at a constant rate for at least 24 hours, be stable, not contribute to weight gain, have a low risk of allergic reactions and, very importantly, minimize the risk of hypoglycaemia. While the perfect insulin has not yet been discovered, advancements are still being made. Insulin degludec is an ultra-long-acting basal insulin analogue that possesses a flat, stable glucose-lowering effect in patients with type 1 or type 2 diabetes mellitus. Insulin degludec achieves these pharmacokinetic properties by forming soluble multihexamers upon subcutaneous injection, resulting in the formation of a depot in the subcutaneous tissue that is slowly released and absorbed into circulation. Insulin degludec has been associated with slightly less weight gain and fewer nocturnal hypoglycaemic episodes when compared with insulin glargine in some, but not all, clinical studies. This article briefly reviews current evidence for the use of insulin degludec in patients with type 1 or type 2 diabetes mellitus and discusses the potential impact of this new basal insulin on clinical practice.

Recommendations for improving adherence to type 2 diabetes mellitus therapy--focus on optimizing insulin-based therapy.

Despite its unsurpassed efficacy in the management of diabetes, insulin has been resisted and feared for its risk of side effects (ie, weight gain, hypoglycemia). Many patients and providers have perceived insulin as a last resort therapy given to patients with a poor prognosis, and some patients even as a form of punishment for poor self-management. Also, fear of needles is a constant concern. Fortunately, these challenges to insulin use may be overcome via patient education as well as new developments in insulin therapy. Insulin formulations have been developed that possess pharmacokinetic profiles better adapted to the physiologic needs of patients with type 2 diabetes mellitus (T2DM), including rapid- and long-acting insulin analogues, as well as premixed formulations. Appropriate use of these agents is associated with improved glycemic control, higher levels of adherence to treatment, and lower healthcare costs. A variety of pen delivery systems for insulin delivery are available that allow for easier, more discreet, and more accurately dosed insulin therapy. Patients generally prefer pen delivery systems, and they are associated with greater adherence and better glycemic control as compared with vial and syringe use. In addition to the ever-increasing variety of insulin formulations and delivery systems, educational initiatives are absolutely vital in order to overcome the limited knowledge about diabetes, self-management, and coping skills that can be seen in a large proportion of people with T2DM. Improved adherence to treatment, better outcomes, and reduced costs are contingent upon the appropriate use of, and full access to, appropriate treatment and patient education.

Clinical efficacy of colesevelam in type 2 diabetes mellitus.

PURPOSE: The clinical experience and role in therapy of colesevelam in type 2 diabetes mellitus (T2DM) is discussed. SUMMARY: Colesevelam HCl is a bile acid sequestrant (BAS) with proven efficacy in reducing elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia. Colesevelam HCl gained food and drug administration (FDA) approval in 2008 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. In randomized controlled studies, colesevelam (add-on therapy with metformin, sulfonylureas, and insulin) has shown significant percentage reductions in glycosylated hemoglobin A1c (HbA1c) ranging from 0.5% to 0.54%. Reductions in LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) ranging from -12.8% to -16.7% and -4.0% to -10.3%, respectively, were also observed. Although no direct comparisons have been made, the safety and tolerability profile of this agent appears to be better than other BAS, with the most common side effects being gastrointestinal related. CONCLUSION: Colesevelam is effective as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Due to its effects upon LDL-C and glycemic parameters and favorable safety profile, colesevelam can play a role in an array of T2DM patients.

Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus.

BACKGROUND: Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes. OBJECTIVES: The aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM. METHODS: Relevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data. RESULTS: Pharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited ß-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%-44%), vomiting (13%-17%), and diarrhea (11%-17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%-6% vs 3%-4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo). CONCLUSION: The 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term ß-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined.

Distinguishing among incretin-based therapies. Glucose-lowering effects of incretin-based therapies.

Extensive experience from randomized clinical trials demonstrates the efficacy of GLP-1 agonists and DPP-4 inhibitors as monotherapy and in combination with metformin and other agents, although reductions in FPG and PPG, and consequently A1C, are greater with GLP-1 agonists than with DPP-4 inhibitors. This difference may result from the pharmacologic levels of GLP-1 activity that are achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor. The GLP-1 agonists have attributes that would make either of them an appropriate choice in the management of all 3 patients in our case studies, while either DPP-4 inhibitor would be an appropriate choice for Case 1. Differences in dosing, administration, safety, and tolerability should be considered.

Distinguishing among incretin-based therapies. Patient education and self-management.

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies.

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies.

The multifactorial nature of the pathogenesis of T2DM provides an opportunity to combine treatments that act upon different mechanisms. In addition to improving insulin resistance and pancreatic ß-cell dysfunction, the GLP-1 agonists and DPP-4 inhibitors improve the impaired incretin response, as well as increase insulin secretion and reduce glucagon secretion, both in a glucose-dependent manner. As a result of these multiple actions, the GLP-1 agonists and DPP-4 inhibitors lower both fasting and postprandial glucose levels. The effects of GLP-1 agonists tend to be greater, probably because they produce pharmacologic levels of GLP-1 compared to physiologic levels with the DPP-4 inhibitors. Another difference is that unlike the DPP-4 inhibitors, the GLP-1 agonists also slow gastric emptying and promote satiety.

Distinguishing among incretin-based therapies. Introduction.

The "treat to target" approach is to quickly achieve the target glycosylated hemoglobin (AIC) goal of <7% in most people, and then intensify or change therapy as needed to maintain glycemic control. Results of an online survey demonstrate uncertainty regarding the clinical differences between glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP)-4 inhibitors. The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options.

Saxagliptin: a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus.

PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety, and dosage and administration of saxagliptin are reviewed. SUMMARY: Saxagliptin is a selective, reversible inhibitor of dipeptidyl peptidase-4 (DPP-4) approved for the treatment of type 2 diabetes mellitus in adults. By inhibiting DPP-4, saxagliptin reduces the degradation of endogenous incretin hormones, resulting in increased glucose-dependent insulin release and decreased glucagon secretion from the pancreas. Saxagliptin is rapidly absorbed after oral administration, and its pharmacokinetic profile allows for once-daily oral administration. Clinical trials of saxagliptin as monotherapy and as combination therapy with other oral antidiabetic medications including metformin, glyburide, pioglitazone, and rosiglitazone have demonstrated clinical benefits in various glycemic endpoints, including glycosylated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), and postprandial glucose (PPG) levels over 24 to 102 weeks of therapy. Due to its glucose-dependent mechanism of action, saxagliptin as monotherapy or in combination with metformin results in a low risk for hypoglycemia in patients with type 2 diabetes. Saxagliptin was generally well tolerated in clinical trials, with headache, upper-respiratory-tract infection, and urinary tract infection being the most common adverse events. Saxagliptin has demonstrated a low risk for drug-drug interactions. For patients with moderate or severe renal impairment or end-stage renal disease or patients taking a strong inhibitor of cytochrome P-450 isoenzyme 3A4 or 3A5, the recommended dosage is 2.5 mg once daily. CONCLUSION: Saxagliptin, a DPP-4 inhibitor approved for the treatment of type 2 diabetes, demonstrated safety and efficacy in lowering HbA(1c), FPG, and PPG levels as both monotherapy and in combination with other oral antidiabetic medications.

A review of inhaled technosphere insulin.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and clinical use of Technosphere insulin. DATA SOURCES: A MEDLINE search (1966-March 2010) was conducted for English-language articles using the terms AFREZZA, AFRESA, Technosphere insulin, pulmonary insulin, and inhaled insulin. Abstracts from the American Diabetes Association and European Association for the Study of Diabetes annual meetings, presented in 2004, 2005, 2006, 2007, 2008, and 2009 were also searched for relevant data. STUDY SELECTION AND DATA EXTRACTION: English-language articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of Technosphere insulin were reviewed. DATA SYNTHESIS: Technosphere insulin is an inhaled insulin product with a pharmacokinetic profile suitable to meet prandial insulin needs in patients with diabetes. Technosphere insulin has demonstrated efficacy in terms of postprandial and overall glycemic control, with efficacy and safety outcomes maintained for up to 4 years in one study. The overall tolerability profile for Technosphere insulin in clinical trials published to date has demonstrated a relatively low risk of hypoglycemia and weight gain when compared with subcutaneous mealtime insulins. Clinical trials to date have demonstrated safety in terms of pulmonary function, and the absorption of Technosphere insulin is not significantly altered in patients with chronic obstructive pulmonary disease or in those who smoke. CONCLUSIONS: The Technosphere delivery system allows for the rapid absorption of Technosphere insulin via the lung, making this product a potential option for prandial insulin coverage in both type 1 and type 2 diabetes. The device to administer the insulin is well designed, small, and easy to use. Technosphere inhaled insulin may provide a useful treatment option for patients resistant to or fearful of initiating prandial insulin injections.

Technosphere insulin: an inhaled prandial insulin product.

Given the important role of insulin in the treatment of diabetes mellitus and in light of common barriers to insulin use, new strategies for insulin delivery by routes other than intravenous and subcutaneous injection have been investigated since the discovery of insulin in the 1920s. Most companies researching and developing pulmonary administration systems for the use of insulin announced the termination of product development following the failure of the first US FDA-approved inhaled insulin product, Exubera. One company in particular continued their pursuit of a useful inhaled insulin product. MannKind Corporation has developed a powder formulation of insulin that allows for a high percentage of the administered insulin to be absorbed via the lung. Their product, AFREZZA (Technosphere insulin), is currently under review by the FDA for use in patients with diabetes. Technosphere insulin appears to overcome some of the barriers that contributed to the market withdrawal of Exubera by the manufacturer. Studies with Technosphere insulin have shown it to be a unique insulin formulation in that it is very rapid acting, has a relatively short duration of action, and is efficacious in terms of improved glycemic control without contributing to increased weight gain or the incidence of hypoglycemia when compared with other prandial insulin products. Additionally, Technosphere insulin has demonstrated a favorable safety and tolerability profile in clinical studies to date.

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and beta-cell dysfunction, leading to hyperglycemia and eventual micro- and macrovascular complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP-4 inhibitors-sitagliptin, vildagliptin, saxagliptin, and alogliptin-in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966-July 2009) for pertinent English-language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005-2009 were also searched. As a drug class, the DPP-4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse-effect profile, and once-daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease beta-cell apoptosis and increase beta-cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP-4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP-4 inhibition versus inhibition of other isoenzymes associated with toxicity, comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.

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.

Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus.

The kidney plays a major role in glucose homeostasis because of its role in gluconeogenesis and the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Typically, all of this glucose is reabsorbed with <1% being excreted in the urine. The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose co-transporters (SGLTs). SGLTs encompass a family of membrane proteins that are responsible for the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush-border membrane of proximal renal tubules as well as the intestinal epithelium. SGLT2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney. It accounts for approximately 90% of glucose reabsorption in the kidney and has thus become the focus of a great deal of interest in the field of diabetes mellitus. SGLT2 inhibitors block the reabsorption of filtered glucose leading to glucosuria. This mechanism of action holds potential promise for patients with type 2 diabetes mellitus (T2DM) in terms of improvements in glycaemic control. In addition, the glucosuria associated with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. Dapagliflozin is the SGLT2 inhibitor with the most clinical data available to date, with other SGLT2 inhibitors currently in the developmental pipeline. Dapagliflozin has demonstrated sustained, dose-dependent glucosuria over 24 hours with once-daily dosing in clinical trials. Although long-term safety data are lacking, studies to date have generally found dapagliflozin to be safe and well tolerated. Concerns related to SGLT2 inhibition include the fact that by their very nature they cause glucose elevation in the urine that can theoretically lead to urinary tract and genital infections, electrolyte imbalances and increased urinary frequency. Although studies to date have been promising in terms of these and other concerns, longer-term studies evaluating the usual safety and efficacy outcomes will need to be conducted. Similarly, head-to-head comparator trials are needed to determine the role of SGLT2 inhibitors in relation to the many other therapeutic options available for the treatment of T2DM. If significant reductions in haemoglobin A(1c) are associated with SGLT2 inhibitor therapy, and these agents are determined to be safe and well tolerated in the long term, they could become a major breakthrough in the T2DM treatment armamentarium.

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 A(1c) (HbA(1c)) 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 HbA(1c) 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.

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.

Effective use of paired testing in type 2 diabetes: practical applications in clinical practice.

PURPOSE: The purpose of this article is to discuss practical approaches to the use of self-monitoring of blood glucose (SMBG) in clinical practice using paired glucose testing. A rationale for SMBG use and innovative tools for data collection and analysis are presented. Method Health care professionals from various medical specialties collaborated to review current evidence regarding the value and utility of SMBG and to formulate professional opinions regarding use of SMBG. The literature review included key SMBG studies from 2002 through 2009. Established guidelines, position papers, and other evidence were also reviewed for this report. Reference Manager Software was used to search ISI Web of Science, PubMed, and Z39.50 site databases. RESULTS: Although the utility of SMBG in non-insulin-treated type 2 diabetes remains controversial, a recent report from the International Diabetes Federation recommends SMBG use in this population if it is used to educate/motivate individuals and/or monitor and adjust therapy. Health care providers must develop strategies to use SMBG in ways that address these criteria. CONCLUSIONS: Paired SMBG (testing before/after specific events) promotes diabetes knowledge and self-management skills and facilitates assessment of the impact of behavioral changes, medical nutrition therapy, and pharmacologic interventions on glycemic levels. New tools have been developed to assist in using paired testing in clinical practice.

The chronic burden of diabetes.

Unmanaged diabetes mellitus is a major problem for patients, healthcare providers, and health insurers alike. The incidence of diabetes is growing rapidly and at present approximately 8% of the population is afflicted with this disease. When diabetes goes undiagnosed or untreated, the repercussions can be disastrous physically, as well as economically. In order to improve quality of life and healthcare economics, it is time for managed care systems to identify the barriers to improving the care of diabetes.