EPA's pleiotropic mechanisms of action: a narrative review.

Treatment with icosapent ethyl 4 g/day, a highly purified and stable ethyl ester of eicosapentaenoic acid (EPA), demonstrated a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events and death in REDUCE-IT. However, analyses of REDUCE-IT and meta-analyses have suggested that this clinical benefit is greater than can be achieved by triglyceride reduction alone. EPA therefore may have additional pleiotropic effects, including anti-inflammatory and anti-aggregatory mechanisms. EPA competes with arachidonic acid for cyclooxygenase and lipoxygenase, producing anti-inflammatory and anti-aggregatory metabolites rather than the more deleterious metabolites associated with arachidonic acid. Changing the EPA:arachidonic acid ratio may shift metabolic status from pro-inflammatory/pro-aggregatory to anti-inflammatory/anti-aggregatory. EPA also has antioxidant effects and increases synthesis of nitric oxide. Incorporation of EPA into phospholipid bilayers influences membrane structure and may help to prevent cardiac arrhythmias. Clinically, this may translate into improved vascular health, including regression of atherosclerotic plaque. Overall, EPA has a range of pleiotropic effects that contribute to a reduction in ASCVD.

The Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Beyond the Glycemic Benefit.

Type 2 diabetes (T2D) is associated with an increased risk of macro- and microvascular complications, including cardiovascular disease (CVD), heart failure (HF), and chronic kidney disease (CKD). Of the currently available glucose-lowering therapies, sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are the only class to target the pathophysiologic increase in renal glucose reabsorption in patients with T2D. In CV outcomes trials of SGLT-2is in patients with T2D and established CVD or varying levels of CV risk, empagliflozin, canagliflozin, and dapagliflozin were associated with significant improvements in the risk of composite CV and renal outcomes compared with placebo that extended beyond their glycemic effects. Real-world observational studies have also reported improvements in CV outcomes with SGLT-2is compared with other glucose-lowering therapy in routine clinical practice. This review describes the pleiotropic effects of SGLT-2is and discusses the potential mechanisms for these effects as well as how they potentially provide benefits beyond glycemic control in patients with T2D. These favorable nonglycemic effects indicate that SGLT-2is may be of particular benefit in patients with diabetic complications, such as CVD, HF, or CKD. Ongoing large randomized trials in specific patient populations, including those with CVD, HF, or CKD (with or without T2D), may help to confirm the benefits of SGLT-2is in these patients and further elucidate the potential mechanisms of their pleiotropic effects. FUNDING: AstraZeneca.

Differentiating Basal Insulin Preparations: Understanding How They Work Explains Why They Are Different.

Since the introduction of insulin as a life-saving agent for patients with type 1 diabetes, insulin preparations have evolved to approximate physiologic insulin delivery profiles to meet prandial and basal insulin needs. While prandial insulins are designed to have quick time-action profiles that minimize postprandial glucose excursions, basal insulins are designed to have a protracted time-action profile to facilitate basal glucose control over 24 h. Given that all insulins have the same mechanism of action at the target tissue level, the differences in time-action profiles are achieved through different mechanisms of protraction, resulting in different behaviors in the subcutaneous space and different rates of absorption into the circulation. Herein, we evaluate the differences in basal insulin preparations based on their differential mechanisms of protraction, and the resulting clinical action profiles. Multiple randomized control trials and real-world evidence studies have demonstrated that the newer second-generation basal insulin analogs, insulin glargine 300 units/mL and insulin degludec 100 or 200 units/mL, provide stable glycemic control with once-daily dosing and are associated with a reduced risk of hypoglycemia compared with previous-generation basal insulin analogs insulin glargine 100 units/mL and insulin detemir. These advantages can lead to decreased healthcare resource utilization and cost. With this collective knowledge, healthcare providers and payers can make educated and well-informed decisions when determining which treatment regimen best meets the needs of each individual patient.Funding: Sanofi US, Inc.

Pharmacokinetic and pharmacodynamic differences of new generation, longer-acting basal insulins: potential implications for clinical practice in type 2 diabetes.

The treatment of type 2 diabetes (T2D) is often complicated by factors such as patient co-morbidities, complex drug-drug interactions, and management of adverse events. In addition, some of these factors are highly dependent on the nature of the treatment regimen and the molecular and physical properties of the drugs being used to treat patients with this disease. This calls for a better understanding of how the properties of individual drugs affect the overall outcome for patients with diabetes. Clinical pharmacology studies to assess the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of new diabetes drugs play an important role in advancing our understanding of the interactions between a drug and the human body. Specific PK and PD techniques such as the glucose clamp test can be applied to assess the properties of drugs used for the treatment of diabetes. Basal insulin analogs are a common treatment option for the maintenance of glycemic control in patients with T2D. These drugs work by mimicking endogenous insulin secretion within the body and provide stable and prolonged insulin action to achieve optimal glucose levels. Insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg) 100 U/mL and 200 U/mL represent a new generation of longer-acting basal insulins. These drugs demonstrate improved PK and PD properties compared with previous basal insulins, allowing them to more closely mimic physiological basal insulin secretion. Here we review the methods used to evaluate the PK and PD profiles of Gla-300 and IDeg and describe studies that have investigated the PK/PD properties of these drugs in type 1 diabetes. The aim of this review is to inform primary care physicians of the value and limitations of data from clinical pharmacology studies when prescribing these agents for the management of T2D.

Safety and tolerability of new-generation anti-obesity medications: a narrative review.

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk-benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk-benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk-benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk-benefit.

Evaluation of the Use of a Virtual Patient on Student Competence and Confidence in Performing Simulated Clinic Visits.

Objective. To assess the effect of incorporating virtual patient activities in a pharmacy skills lab on student competence and confidence when conducting real-time comprehensive clinic visits with mock patients. Methods. Students were randomly assigned to a control or intervention group. The control group completed the clinic visit prior to completing virtual patient activities. The intervention group completed the virtual patient activities prior to the clinic visit. Student proficiency was evaluated in the mock lab. All students completed additional exercises with the virtual patient and were subsequently assessed. Student impressions were assessed via a pre- and post-experience survey. Results. Student performance conducting clinic visits was higher in the intervention group compared to the control group. Overall student performance continued to improve in the subsequent module. There was no change in student confidence from pre- to post-experience. Student rating of the ease of use and realistic simulation of the virtual patient increased; however, student rating of the helpfulness of the virtual patient decreased. Despite student rating of the helpfulness of the virtual patient program, student performance improved. Conclusion. Virtual patient activities enhanced student performance during mock clinic visits. Students felt the virtual patient realistically simulated a real patient. Virtual patients may provide additional learning opportunities for students.

Antidiabetic agents and cardiovascular outcomes in patients with heart diseases.

INTRODUCTION: This article reviews evidence of the benefits and risk of antidiabetic agents in cardiovascular (CV) outcomes, with a focus on medications approved by the FDA since 2008. STUDY SELECTION: Peer-reviewed articles were identified from MEDLINE and Current Content databases (both 1966 to 1 October 2016) using the search terms insulin, metformin, rosiglitazone, pioglitazone, glyburide, glipizide, glimepiride, acarbose, miglitol, albiglutide, exenatide, liraglutide, lixisenatide, dulaglutide, pramlintide, meglitinide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, colesevalam, bromocriptine, mortality, myocardial infarction (MI), heart failure (HF), and stroke. Trials were included if they were randomized clinical trials evaluating adult patients (≥18 years) with type 2 diabetes; had a period of intervention and follow-up of ≥12 months; and assessed CV outcomes (CV death, fatal/non-fatal MI or HF) as endpoints. Twenty-three randomized trials were included. Antidiabetic agents: Of agents approved prior to 2008, metformin has not been associated with measurable harm in patients with diabetes in terms of mortality and CV events (and has a trend of benefit). Controversial results existed with the use of sulfonylureas and thiazolidinediones (TZDs) for CV outcomes. Among agents approved after 2008, liraglutide and empagliflozin have been shown to be superior to placebo in improving CV outcomes. CONCLUSIONS: The FDA regulatory mandate to demonstrate CV safety in order to approve new diabetes drugs led to an increase in the number of CV outcome trials. However, these trials have placebo-controlled, non-inferiority designs aiming to show absence of CV toxicity. More studies are needed to address other questions, including comparative effectiveness, and longer-term risk versus benefits.

Concentrated Insulins: A Review and Recommendations.

For diabetes mellitus patients who require higher doses of insulin, pen-delivered concentrated insulins offer smaller volumes and potentially a lower risk of dosing errors.

Deoxycholic Acid (ATX-101) for Reduction of Submental Fat.

OBJECTIVE: To review trials evaluating purified synthetic deoxycholic acid (DCA; ATX-101) for the reduction of submental fat (SMF). DATA SOURCES: A literature search was conducted using MEDLINE (1946 to week 4 of April 2016) and Evidence Based Medicine Database (1974 to 6 May, 2016). Keywords searched included deoxycholic acid, ATX-101, and submental fat. STUDY SELECTION AND DATA EXTRACTION: All human studies published in English that addressed the effects of DCA for the reduction of SMF were selected for analysis. DATA SYNTHESIS: Five phase III, multicenter, randomized, double-blinded clinical trials enrolling more than 1700 patients have demonstrated the efficacy of ATX-101 in the reduction of SMF via a variety of validated scales as well as objective measurements. Purified synthetic DCA 2 mg/cm(2) injected monthly for 4 to 6 treatment sessions demonstrated improvement in scales evaluated by both clinicians and patients. Improvement in skin caliper measurements of SMF and Magnetic Resonance Imaging (MRI) provide objective evidence of the efficacy of ATX-101. Adverse events (AEs) are very common but are transient and localized to the treatment area. Pain at the injection site is the most common AE, occurring in more than 80% of patients treated. Other common AEs include swelling, bruising, numbness, and induration. Appropriate injection technique is patient specific and requires detailed knowledge of the submental anatomy to minimize AEs. CONCLUSIONS: ATX-101 is the first pharmacological intervention approved for the reduction of SMF and offers an alternative to invasive measures to improve the submental profile and positively affect patient self-image.

Past, Present, and Future Research Avenues for Metformin: A Literature Review.

Objective: To review why metformin is considered first-line therapy for type 2 diabetes mellitus (T2DM) and review newer avenues of research currently being evaluated. Data Sources: The Cochrane Library and Medline (to January 2014) were searched for case-control and cohort studies, clinical trials, and systematic reviews and meta-analyses involving metformin for any indication. Study Selection and Data Extraction: The literature search found 5 major avenues of research for metformin: reduction in mortality, delayed-onset or prevention of T2DM in the presence of prediabetes, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS), and decreased cancer risk. When available, multi-center, double-blind, controlled clinical trials or meta-analyses thereof were selected for review. If these types of studies did not exist, other types of studies were chosen for review. Data Synthesis: Metformin significantly decreases all-cause and diabetes-related mortality in overweight and obese patients with T2DM. It may also decrease risk of progression to T2DM in patients with prediabetes. Metformin has been studied for the treatment of NAFLD though data are limited. Metformin alone or combined with clomiphene may increase pregnancy and ovulation rates but has not yet been shown to increase live-birth rates in patients with PCOS. Metformin may decrease risk of colorectal cancer but not all-cancer risk. Conclusions: Metformin's clinical role in T2DM and prediabetes is well established. Other avenues of research being evaluated at this time are NAFLD, PCOS, and reduced risk of cancer; more data are needed before it has a clinical role in these indications.

Angiotensin II type 1 receptor blocker-induced immune thrombocytopenia: a case report.

INTRODUCTION: The development of thrombocytopenia after a dose increase in losartan and subsequently after switching the patient to valsartan is reported. CASE PRESENTATION: A 61-year-old Caucasian man presented with epistaxis and gingival bleeding of three weeks duration. Laboratory evaluation revealed a hemoglobin level of 144g/L, a leukocyte count of 16.2×109 cells/L (72.51% neutrophils, 20.1% lymphocytes, 6.8% monocytes, 0.4% eosinophils, 0.2% bands), and a platelet count of 15.0×109 cells/L. Flow cytometry of his peripheral blood showed normal CD4:CD8 ratio and no evidence of any lymphoproliferative disorder. A peripheral smear showed decreased platelets with a few areas of clumping. Four weeks before presentation to the emergency room, his losartan dose was increased to 100mg once daily due to continuously elevated blood pressure readings. He had been maintained on losartan 50mg once daily for five years and previous routine laboratory measurements revealed a baseline platelet count of 248.0×109 cells/L.The patient began receiving an oral prednisone taper and his platelet count returned to a stable value of >200×109 cells/L. Because there was no other probable cause, he was thought to have developed immune thrombocytopenia from the increased losartan dose. Losartan was discontinued and one week later he was switched to valsartan 160mg once daily.Forty-seven days after starting valsartan, the patient presented once again to the emergency room with intermittent epistaxis and gingival bleeding while brushing his teeth of two weeks duration. Laboratory measurement revealed a platelet count of 37×109 cells/L. Valsartan was held and another prednisone taper was initiated. The patient's platelet count recovered upon valsartan discontinuation and in four weeks, his platelet count improved to 214×109 cells/L. CONCLUSIONS: A 61-year-old Caucasian man developed immune thrombocytopenia after an increase in losartan dose and developed immune thrombocytopenia again after he was switched to valsartan.

Insulin degludec: a novel basal insulin analogue.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and potential role in therapy of insulin degludec. DATA SOURCES: Articles were identified using the MEDLINE database (January 1996-December 2012). Abstracts and posters were identified from respective congressional websites and published supplements of the American Diabetes Association, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists (January 2008-December 2012). Clinicaltrials.gov was used to identify any ongoing clinical trials or completed trials whose results had not been presented or published. STUDY SELECTION AND DATA EXTRACTION: All available studies were reviewed for inclusion; pharmacokinetic studies were limited to those reporting human data. DATA SYNTHESIS: Insulin degludec is a novel, ultra-long-acting basal insulin analogue that has a similar safety and efficacy profile when compared with insulin glargine in patients with type 1 or type 2 diabetes. Clinical trials have indicated that there is less hypoglycemia, particularly nocturnal hypoglycemia, associated with this agent. CONCLUSIONS: If insulin degludec is approved, it may offer an alternative basal insulin for patients needing more flexible dosing, having a history of nocturnal hypoglycemia, or those with severe insulin resistance needing a higher concentration of basal insulin.