Jennifer Goldman

New Insulin Glargine 300 U/mL for the Treatment of Type 1 and Type 2 Diabetes Mellitus:

Objective: To describe the studies evaluating the efficacy and safety of new insulin glargine 300 U/mL (Gla-300) as a basal insulin in the treatment of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Data Sources: A literature search of MEDLINE was conducted (January 2008-June 2015) using the terms U300, Gla-300, and insulin glargine 300 units/mL and supplemented with congress abstracts published in 2014 and 2015. Study Selection and Data Extraction: All English language studies assessing the efficacy and/or safety of Gla-300 were evaluated. Data Synthesis: The efficacy and safety of once-daily Gla-300 has been compared with insulin glargine 100 U/mL (Gla-100) in the EDITION trials, 6 phase-3, multinational, open-label studies in T1DM and T2DM. Across these studies, Gla-300 consistently demonstrated glycemic control comparable to Gla-100; a mean (standard error) change in glycated hemoglobin A1c of −1.02% (0.03) with both Gla-100 (n = 1235) and Gla-300 (n = 1239) was seen in a patient-level meta-analysis. Gla-300 was associated with comparable or reduced nocturnal hypoglycemia compared with Gla-100; the relative risk for nocturnal hypoglycemia with Gla-300 versus Gla-100 was 0.75 (95% CI = 0.68 to 0.83) in a patient-level meta-analysis. There is also some evidence for less weight gain with Gla-300 compared with Gla-100, despite a higher insulin dose. Gla-300 was well tolerated, with the number of adverse events being comparable to that with Gla-100. Conclusions: These results suggest that Gla-300 may have a place as an alternative, long-acting basal insulin for patients with T1DM or T2DM, with the possibility for improved tolerability.

Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice

Abstract This article reviews pharmacokinetic (PK) and pharmacodynamic (PD) concepts relating to the pharmacology of basal insulin analogs. Understanding the pharmacology of currently available long-acting basal insulins and the techniques used to assess PK and PD parameters (e.g. the euglycemic clamp method) is important when considering the efficacy and safety of these agents, and can help in understanding the rationale for specific dosing strategies when tailoring therapy for a specific patient. Basal insulins such as insulin glargine 100 units (U)/mL and insulin detemir show improved PK/PD characteristics compared with the intermediate-acting NPH insulin, with a longer duration of action, a more consistent glucose-lowering effect and less prominent concentration peaks. However, more recently developed basal insulins (insulin glargine 300 U/mL, and insulin degludec 100 U/mL and 200 U/mL) have PK/PD profiles closer to the physiologic profile of endogenous basal insulin owing to a more evenly distributed, predictable and prolonged time–action profile that exceeds 24 hours and improved within-patient variability in glucose-lowering effect. The clinical implications and relevance of these PK/PD profiles is explored, including the potential effect of PK/PD parameters on glycemic control and hypoglycemia, and the timing of dosing. The improved PK/PD properties of newer longer-acting basal insulins may translate into clinical benefits for patients with type 1 and type 2 diabetes, such as more consistent insulin levels in the blood over 24 hours, lower intra-patient variability, a reduced risk of nocturnal hypoglycemia, and more flexibility in dosing time, all of which are important to consider when choosing a basal insulin regimen.

Students’ Attitudes, Academic Performance and Preferences for Content Delivery in a Very Large Self-Care Course Redesign

Objective. To evaluate students’ performance/attitudes toward a flipped team-based learning (TBL) format in a “very large” self-care course based on student content delivery preference. Design. Third-year students enrolled in the course were surveyed regarding elements of redesign and homework completion. Additionally, their performance and incoming grade point average were evaluated. Assessment. A survey was completed by 286 of 305 students. Nineteen percent of respondents preferred traditional content delivery, whereas 30% preferred flipped TBL, 48% preferred a mixed format, and 3% had no preference. The grades achieved in the course were: A (49%), B (48%), C (3%) and D (0%). The majority completed “all” or “most” of the homework, appreciated attributes of course redesign, felt home preparation and in-class activities engaged them, and reported improved communication/evaluation skills. Content delivery preference significantly affected attitudes. Conclusion. Students positively received a flipped team-based learning classroom format, especially those who preferred flipped TBL or mixed content delivery. A minority with preference for traditional teaching style did not enjoy the new format; however, their academic performance did not differ significantly from those who did.

Rationale for, Initiation and Titration of the Basal Insulin/GLP-1RA Fixed-Ratio Combination Products, IDegLira and IGlarLixi, for the Management of Type 2 Diabetes

Type 2 diabetes (T2D) is a progressive disease affecting glucose regulation and a major cause of morbidity and mortality globally. Many patients are not escalated up the treatment ladder appropriately despite failing to achieve glycemic control, with barriers such as fear of hypoglycemia, weight gain, and treatment burden recognized as factors. Exogenous basal insulin is titrated to address control of fasting plasma glucose and may preserve residual β-cell function, thus promoting a greater endogenous prandial insulin response. Native glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the gut in response to nutrient ingestion; it increases insulin secretion, inhibits glucagon secretion, and prolongs gastric emptying, thereby lowering overall food intake. As its glucose-lowering action is glucose dependent, a GLP-1 receptor agonist (GLP-1RA) achieves these benefits with a lower risk of hypoglycemia compared with other diabetes therapies. Two products, an insulin degludec/liraglutide combination (IDegLira) and an insulin glargine/lixisenatide combination (IGlarLixi), were approved for use in adults with T2D by the US Food and Drug Administration in 2016. The efficacy and safety of these two basal insulin/GLP-1RA combination products were studied in the DUAL program (NCTs 01336023, 01392573, 01676116, 01618162, 01952145, and 02298192) and the LixiLan program (NCTs 02058160 and 02058147). Compared with basal insulin, insulin/GLP-1RA fixed-ratio combinations are superior at reducing HbA1c with weight neutrality or weight loss rather than weight gain, as well as reduced hypoglycemia rates, and reduced insulin-dose requirement with IDegLira. A combination of different medications may often be required to achieve glycemic control, and fixed-ratio combination products allow such therapies to be given in simple regimens. Clinical trial data for these products highlight the great potential of these agents, not merely their efficacy and safety but also their ease of use and decreased injection burden for patients.

Lixisenatide, a Once-Daily Prandial Glucagon-Like Peptide-1 Receptor Agonist for the Treatment of Adults with Type 2 Diabetes

Lixisenatide, a short‐acting glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA), has been available in Europe since 2013 and was recently approved in the United States for the treatment of type 2 diabetes (T2D) as an adjunct to diet and exercise. The objective of this systematic review is to describe the pharmacology, pharmacokinetics, safety, and efficacy of lixisenatide in patients with T2D. We conducted a search of the EMBASE database, limited to human studies with abstracts available in English. Published conference abstracts, limited to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes meetings in 2015, as well as abstracts presented at the ADA meeting in 2016, were also screened. The abstracts retrieved were assessed for relevance; review articles and meta‐analyses focusing on GLP‐1 RAs as a class were excluded. Lixisenatide induced mean reductions of 0.46–0.99% in glycated hemoglobin A1c (HbA1c), 55.86–143.43 mg/dl in 2‐hour postprandial glucose (PPG) levels, and 56.58–127.75 mg/dl in mealtime glucose level variations. Changes in fasting plasma glucose (FPG) levels and weight ranged from −21.98 to +5.41 mg/dl and from −2.96 to +0.3 kg, respectively, in patients with T2D enrolled in the GetGoal clinical program (a program of clinical trials that established the efficacy and safety profile of lixisenatide 20 μg once/day across patients with T2D with differing background therapies). Lixisenatide was well tolerated, demonstrating rates of symptomatic hypoglycemia of 0.8–42.9% and a very low rate of severe hypoglycemia (< 1.5%) as well as no increased risk of cardiovascular events. The most common adverse events were gastrointestinal in nature, mainly transient nausea and vomiting of mild‐to‐moderate severity. Lixisenatide effectively lowers HbA1c levels in patients with T2D through a mechanism of action complementary to that of agents that mainly target FPG, with the additional benefit of weight loss. Its once‐daily administration schedule and effect on PPG levels make it an attractive option as add‐on treatment to basal insulin therapy or oral antidiabetic agents.

Comparison of long-term knowledge retention in lecture-based versus flipped team-based learning course delivery

OBJECTIVES To determine whether team based learning (TBL) is superior to traditional lecture -based learning in confidence and knowledge retention one year later. DESIGN A survey was administered 17 months after a completion of a required over-the-counter /self-care (OTC) course to two different cohorts of students. The survey assessed confidence and knowledge related to OTC topics. The lecture group had a traditional lecture based classroom experience; the intervention group experienced a TBL format throughout the entire course. ASSESSMENT One hundred forty-seven students of 283 enrolled (51.9%) in the lecture group and 222 of 305 (72.8%) students in the TBL group participated in the knowledge assessment and survey. Demographic data including student grade point averages (GPA) and confidence were similar in both groups. Mean assessment scores (±SD) on OTC knowledge was significantly higher in the traditional lecture based group versus the TBL group; 62.9±19.3 vs. 54.9±15.7 (p=0.001). CONCLUSION Although TBL is thought to improve student engagement and mastery of material, after an initial implementation of TBL, knowledge retention in the long term appears to be lower than lecture based learning.

iGlarLixi: A Fixed-Ratio Combination of Insulin Glargine 100 U/mL and Lixisenatide for the Treatment of Type 2 Diabetes:

Objective: To review the safety and efficacy of iGlarLixi, a titratable fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide, a glucagon-like peptide-1 receptor agonist. Data Sources: A literature search of MEDLINE for all English-language primary articles through June 2016, using the terms LixiLan, iGlarLixi and insulin glargine and lixisenatide, and a search of abstracts presented at the 2016 Scientific Sessions of the American Diabetes Association were performed. Study Selection and Data Extraction: All studies assessing the efficacy and/or safety of iGlarLixi were evaluated. Data Synthesis: iGlarLixi has been approved in the United States for glycemic control in people with type 2 diabetes (T2D) inadequately controlled with basal insulin (<60 U/d) or lixisenatide. In clinical trials, iGlarLixi was associated with significantly greater reductions from baseline in glycated hemoglobin A1C (A1C) than iGlar or lixisenatide alone. Reductions in postprandial glucose were also greater with iGlarLixi than with iGlar or lixisenatide. iGlarLixi was weight neutral compared with the weight gain with iGlar and loss with lixisenatide alone, and there was no increase in hypoglycemia with iGlarLixi compared with iGlar despite the greater A1C reduction. Gastrointestinal events, frequently associated with lixisenatide, were less common with iGlarLixi. Potential drawbacks of iGlarLixi include reduced flexibility in dosing and the absence of long-term efficacy and safety data. Conclusions: iGlarLixi is a titratable fixed-ratio combination that shows improved efficacy and comparable or improved safety outcomes relative to its separate constituents, offering an alternative approach to intensification of therapy in T2D.

Commentary: Why Was Inhaled Insulin a Failure in the Market?

Just a few years shy of a century ago, a group of Canadian researchers discovered a viable method of extracting insulin, filling a large and critical gap in the therapeutic treatment of diabetes (1). Since then, insulin and its associated delivery devices have become an integral part of the care and management of patients living with diabetes. Shortly after the first insulin injection was successfully delivered, vials of insulin became available commercially. At this time, large glass syringes were used to administer insulin, and each injection required sterilization of the syringe, as well as sharpening of the syringe needle with a pumice stone. Through the years, insulin syringes modernized, but it was not until the 1970s that an alternate delivery system—the insulin pump, used in continuous subcutaneous insulin infusion (CSII) regimens—became available. Fifteen years later, the first insulin pen was introduced to the marketplace, providing evidence that, as time progresses, there is no shortage of innovation in the diabetes arena. The first two rapid-acting inhaled insulins on the market—Exubera in 2006 and Afrezza in 2014—represented yet another innovation milestone. In theory, inhaled insulin completely eliminated the psychological barriers associated with subcutaneous insulin delivery, such as needle phobia and incorrect injection technique. However, in October 2007, Pfizer withdrew Exubera from the market, and in January 2016, Sanofi withdrew from a

Biosimilar and Follow-on Insulin: The Ins, Outs, and Interchangeability:

925 million marketing agreement with MannKind for Afrezza; both removals were due to poor sales volume. Although patients and providers have been searching for years for alternatives to injecting insulin, Exubera has already failed, and Afrezza’s destiny is uncertain. In 2006, Exubera was the first inhaled insulin approved by the U.S. Food and Drug Administration (FDA). It showed noninferiority in efficacy with regard to A1C lowering in both type 1 diabetes (2) and type 2 diabetes (3) compared to mixed regular/NPH …

Combination of Empagliflozin and Metformin Therapy: A Consideration of its Place in Type 2 Diabetes Therapy:

Objective: To provide an overview of the differences between biosimilars and generics, and to summarize regulatory requirements and outstanding issues related to biosimilar insulins in the United States, including the issue of interchangeability. Data Sources: References were obtained using MEDLINE searches, the bibliographies of articles identified during the searches, review articles, and general Internet searches. Key words included the following: diabetes, insulin, biosimilar, regulatory, follow-on, and interchangeability. Study Selection and Data Extraction: Articles, studies, regulatory documents, and opinion pieces that addressed issues around biosimilar/follow-on insulins and interchangeability of insulins in people with diabetes were selected for inclusion in this narrative review. Data Synthesis: There is understandable interest in the potential for new copies of existing insulins—termed biosimilar insulins or follow-on insulins—to reduce the substantial and growing costs associated with managing the diabetes epidemic and to improve access, as has been achieved with conventional generic drugs. However, biosimilars or follow-on insulins are not generics. There are critical differences between biologic products and conventional chemical drugs, which present specific challenges to manufacturers, regulators, and clinicians. Conclusions: Health care providers and payers need to be aware of the issues surrounding biosimilar and follow-on insulins as they become more widely available in the coming years. In particular, in the face of limited data on comparative safety and efficacy, careful consideration needs to be given when interchanging between originator and biosimilar drugs, when switching patients from one biosimilar drug to the other.