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 $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 …

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 HbA_1c 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.

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.

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 A _1c 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.

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.