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

Transcription

1 Current Medical Research and Opinion ISSN: (Print) (Online) Journal homepage: Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice Jennifer Goldman, Christoph Kapitza, Jeremy Pettus & Tim Heise To cite this article: Jennifer Goldman, Christoph Kapitza, Jeremy Pettus & Tim Heise (2017): Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice, Current Medical Research and Opinion, DOI: / To link to this article: Accepted author version posted online: 24 May Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [The UC San Diego Library] Date: 26 May 2017, At: 18:27

2 Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice Jennifer Goldman a, Christoph Kapitza b, Jeremy Pettus c, and Tim Heise b a From the School of Pharmacy, MCPHS University, Boston, MA, USA; b Profil, Neuss, Germany; c Division of Endocrinology & Metabolism, University of California San Diego, San Diego, CA, USA. Corresponding author: Jennifer Goldman, Pharmacy Practice, MCPHS University, 179 Longwood Ave Boston MA 02115, jennifer.goldman@mcphs.edu Transparency Declaration of Funding Writing/editorial support funded by Sanofi US Inc. Declaration of Financial/other Relationships JG has acted as a speaker for Novo Nordisk, Glaxo Smith Kline, and Sanofi, and as a consultant for Becton Dickinson. JP is a consultant for Sanofi, Novo Nordisk, Dexcom and Tandem Diabetes. TH is a member of advisory panels for Novo Nordisk and received speaker honoraria and travel grants from Eli Lilly, Mylan and Novo Nordisk. His institution received research funds from Adocia, Astra Zeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Grünenthal, Eli Lilly, Medtronic, Novo Nordisk, Novartis, Sanofi, Senseonics. CK is a member of an advisory board for Sanofi and received speaker honoraria and travel grants from Sanofi. His institution received research funds from Adocia, Astra Zeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Grünenthal, Eli Lilly, Medtronic, Novo Nordisk, Novartis, Sanofi, Senseonics. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Author Contributions The contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. All authors contributed to the writing of this manuscript, including critical review and editing of each draft, and approval of the submitted version. The authors received no honoraria related to the development of this publication. Acknowledgment The authors received writing/editorial support in the preparation of this manuscript provided by Rosalie Gadiot, PhD, of Excerpta Medica, funded by Sanofi US, Inc.

3 Abstract This article reviews pharmacokinetic (PK) and pharmacodynamic (PD) concepts relating to the pharmacology of basal insulin analogs. Understanding the pharmacology of currently available longacting 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. Key words: Insulins, diabetes mellitus, pharmacokinetics, pharmacodynamics Short title: Pharmacokinetic and pharmacodynamic characteristics of basal analog insulins.

4 Introduction In healthy individuals, endogenous insulin secretion by pancreatic β-cells consists of continuous low pulses of basal insulin output between meals and throughout the night that are responsible for maintaining glycemic homeostasis [1,2]. Basal insulin output is augmented by short surges of insulin in response to food ingestion; post-prandial insulin levels peak minutes following a meal, after which the insulin concentrations gradually (within 4 hours) return to baseline levels [3]. Basal insulin analogs, used in the treatment of type 1 (T1D) and type 2 diabetes (T2D), attempt to mimic the physiologic profile of endogenous basal insulin secretion by providing prolonged insulin action to control blood glucose levels in the fasting state that occurs between meals and at night [4]. NPH insulin was the first slow-release insulin preparation to be developed. However, its use is limited by high variation in bioavailability, a high risk of hypoglycemia (particularly nocturnal hypoglycemia), and the intermediate duration of action (12 18 hours) leading to twice-daily (or even more frequent) dosing in many patients [5, 6]. Compared with NPH insulin, modern basal insulin analogs (e.g. insulin glargine, insulin detemir and insulin degludec) aim to provide a pharmacokinetic (PK) and pharmacodynamic (PD) profile that more closely mimics the normal physiologic pattern of basal insulin secretion. This type of profile provides a more evenly distributed, predictable and prolonged time action profile likely to reduce the risk of hypoglycemia and facilitate more flexible dose regimens [4, 6, 7]. While basal insulins such as insulin glargine 100 U/mL and insulin detemir already provided PK/PD profiles mimicking physiologic profiles of endogenous insulin more closesly compared with NPH insulin and are successfully being used to manage blood glucose levels in patients with diabetes, the further improved PK/PD profiles of newer long-acting basal insulin products could offer additional advantages to all patients with diabetes. It should be noted that some patients, usually patients with T1D, show an increase in blood glucose levels in the early morning hours, most likely due to increased endogenous glucose production at this time (dawn phenomenon). For these patients a completely flat and peakless basal insulin profile might not be ideal and could theoretically even lead to hypoglycemia, as an insulin dose adequately suppressing morning hyperglycemia may lead to over-titration during other periods of the day [8]. Nevertheless, insulin glargine 100 U/ml has been shown to improve morning blood glucose levels in comparison with NPH insulin, but some patients will still require a variable basal insulin delivery overnight which can only be achieved with insulin pump therapy [9]. The primary aim of this article is to review PK and PD concepts relating to the pharmacology of the currently available basal insulin analogs. It includes the earlier basal insulins (insulin glargine 100 U/mL [Gla-100] and insulin detemir) and the newer long-acting basal insulin products (insulin glargine 300 U/mL [Gla-300] and insulin degludec 100 U/mL and 200 U/mL). In addition, widely used clinical research methods, such as the euglycemic clamp technique, are explained, as well as the PK and PD characteristics of basal insulins and their observed clinical effects from their respective clinical development program.

5 Determining PK/PD Profiles using the Euglycemic Clamp PK/PD parameters of insulins are usually determined using euglycemic glucose clamp studies. The euglycemic clamp is the gold-standard method used to investigate insulin sensitivity and to evaluate the PK/PD profiles of insulins [10,11]. Table 1 provides an overview of key PK/PD parameters relevant to insulin therapy. In euglycemic clamp studies, insulin is injected into an individual and the anticipated decrease in blood glucose level is prevented by using an exogenous infusion of glucose to maintain blood glucose level at normal ( euglycemic ) levels, typically mg/dl [12] (Figure 1). Clamping glucose levels at a fixed level ensures that all study participants maintain the same level of glucose metabolism; participants are also required to fast before and during the clamp to avoid any confounding effects related to food intake [10]. Euglycemic clamp studies with basal insulins are usually carried out in patients with T1D, because these individuals do not have endogenous insulin secretion that might interfere with the study results when characterizing the basal insulin action profile, particularly with the later part of the PD curve [12]. PK Parameters In general, PK parameters describe what the body does to a drug, explaining the movement of a drug into, through, and out of the body (i.e. the concentration of the drug in the body tissues over time). Adjustable factors, such as dose, dosage form, dose frequency and route of administration, affect PK parameters [10]. Importantly, being able to measure insulin concentrations in a reliable way will help depicting a proper PK profile. In contrast with the measurements for nonalbumin bound insulins, PK studies for acylated insulins (such as insulin detemir and insulin degludec) are limited because of the fact that assays cannot distinguish between bound and free plasma insulin. Important PK parameters reported in studies of insulin analogs are serum insulin concentration (the key PK parameter), area under the curve (AUC) of insulin concentration over time, and the elimination (or terminal) half-life (t 1/2 ) (Table 1). Following administration, the basal insulin analog is absorbed into the circulation and distributed to the tissues. At this point, the elimination of the basal insulin analog begins. In general, the elimination t 1/2 is the time it takes for the amount of insulin in the blood to decrease by 50%. It takes at least four elimination half-lives from the time of maximum concentration for a near-complete elimination of the drug from the body (50% + 25% % % = 93.75% elimination). The t 1/2 is used to establish the dosing interval of a drug and to determine the amount of time needed to reach steady-state concentrations (i.e. it takes approximately 4-5 half-lives to reach steady state) [10]. PD Parameters PD characteristics describe the effect of a drug on the body (i.e. interactions and/or signaling events that occur in cells and organs in response to the drug), that results in intended (and unintended) drug effects, and are presented as parameters over time [10]. The PD parameters of an insulin provide important information on the glucose-lowering effect of insulin therapy and, therefore, information on potential clinical efficacy and safety (with regard to hypoglycemia). For long-acting basal insulins, the PD parameters that have the greatest clinical relevance are the flatness

6 of the glucose infusion rate (GIR)-time curve (distribution of glucose lowering activity over a treatment interval, for basal insulins this is usually 24 hours), duration of action, and within-patient variability (differences in PK/PD profiles derived from a single patient, usually over time) [10]. The GIR expresses the amount of glucose infused over time to maintain blood glucose at the clamped level; it provides a reliable, indirect measure of the PD characteristics of the insulin being studied, including the onset, peak effect and duration of action, as long as blood glucose concentrations are maintained close to the clamp level. Thus, under clamp conditions the GIR reflects the ability of insulin both to suppress endogenous glucose production and to promote glucose utilization [11, 13]. It should be considered, however, that in clamp studies performed in healthy individuals or patients with T2D, duration of action is often overestimated as a result of the contribution of endogenous insulin [12, 13]. Peaks in the GIR curve indicate increased insulin action at a particular time following dosing illustrated by the higher levels of infused glucose required to offset the insulin effect; clinically, such GIR peaks can correspond to an increased risk of hypoglycemia. In order to more closely mimic the profile of endogenous basal insulin secretion, an ideal GIR-time profile for a basal insulin should not feature any significant peak(s) and should show minimal fluctuations[10]. A flatter GIR-time curve reflects a more constant glucose-lowering effect and may translate into a lower risk of hypoglycemia. The duration of action determined from clamp studies as the time interval between injection of insulin and the time point when blood glucose concentration rise from the clamp level to a predefined threshold value [1] is important to help determine the dosing interval (i.e. once- or twicedaily). For clinicians considering prescribing newer long-acting basal insulins, the onset of action is not of high importance. More importantly, the duration of action should be at least 24 hours to achieve steady state basal insulin activity by overlapping action profiles of consecutive once-daily basal insulin administrations. Given that basal insulins are expected to provide consistent daily glycemic control, minimal dayto-day within-patient variability in the glucose-lowering effect is another important PD parameter to consider when making prescribing decisions [3]. Significant within-patient variability in the glucoselowering effect of a basal insulin could result in different insulin responses to the same daily basal insulin dose in the same patient; this lack of predictable response can impede insulin titration and increase the risk of hypoglycemia. Steady State Pharmacokinetics and Insulin Stacking Steady state pharmacokinetics are important for chronically administered long-acting drug products, like basal insulin analogs. These long-acting insulin formulations attempt to mimic the profile of endogenous basal insulin secretion by providing a constant plasma insulin exposure at steady state. To achieve steady state conditions, repeated once-daily injections of a basal insulin analog are required for the drug to accumulate and to reach a state where the rate of absorption equals the rate of elimination. Previous doses of insulin provide a residual therapeutic effect, leading to a decreased peak-to-trough ratio until steady state is reached (Figure 2) [14]. Once steady state is achieved, insulin levels are not expected to increase further unless the dose or dosing interval is changed [1, 3]. The time to reach steady state depends on the t ½ of the drug, and will typically be reached after 4 5 half-lives. Consequently, and compared with shorter-acting basal insulin

7 formulations, the basal insulin analogs with a longer t ½ will take longer to reach steady state [1]. Additionally, when dose adjustments of longer-acting basal insulin analogs are needed, it should be noted that daily dose changes are not recommended because the full effect will only become apparent after a couple of days, when steady state is reached. Insulin stacking is the term used to describe the excessive accumulation of insulin that can occur when additional doses of rapid-acting (prandial) insulin are administered before the previous bolus dose has been completely absorbed; the resulting overlapping insulin effect is associated with an increased risk of hypoglycemia [1]. There is concern among clinicians that once-daily administration of basal insulins with a t ½ of more than 24 hours could contribute to stacking and therefore an increased risk of hypoglycemia. However, the PK for prandial and basal insulins are very different and clinical use has shown that stacking is not an issue with basal insulins because of their relatively flat PK/PD profile [1]. Prandial insulins have been designed to provide a rapid rise and fall in insulin concentrations from a single dose, mimicking the effect of physiologic pulses of insulin at mealtimes. In contrast, basal insulins at steady state aim to provide a flat, peakless insulin action profile over 24-hours. As previously mentioned, once steady state is reached, further basal insulin accumulation will not occur because the rate of insulin absorption equals the rate of uptake and elimination [1]. Consistent with these PK principles, clinical studies have shown that undesirable stacking (and the associated increased risk of hypoglycemia) does not occur when long-acting basal insulins are dosed appropriately and adjusted at appropriate time intervals [1, 15-18]. There might also be concerns that basal insulins with a longer duration of action may make it difficult for patients to adapt their insulin doses in case of physical activity and might therefore increase the risk of hypoglycemia. The few available data on this important topic do not suggest a higher hypoglycemia rate with basal insulin analogs such as insulin detemir or insulin degludec when used with moderate physical activity [19,20]. In general, patients are usually advised to reduce their bolus (rather than basal) insulin with exercise, but there are many individual solutions for optimising insulin therapy in combination with exercise [21]. Athletes or people regularly engaging in highintensity exercise usually prefer insulin pump treatment. Currently Available Basal Insulin Analogs A good understanding of the pharmacology of currently available long-acting basal insulins is essential when considering the efficacy and safety of these agents and when tailoring insulin therapy to the needs of a specific patient. The first slow-release insulin preparation, NPH insulin, was marketed in 1950 and is still used today. NPH insulin has relatively high intra- and interpatient variability in its metabolic effect and high rates of hypoglycemia [5]. To improve upon the PK/PD limitations of NPH insulin, the structure and formulation of newer basal insulin analogs have been modified to delay their release into the blood. This modification results in a flatter GIR-time profile with a less pronounced peak, and a longer glucose-lowering effect. The first long-acting basal insulins with improved PK and PD properties were Gla-100 (approved in the US and the EU in 2000) and insulin detemir 100 U/mL (approved in the EU in 2004 and in the US in 2005). These were followed by the further improved and longer-acting insulin degludec 100 U/mL and 200 U/mL (approved in Europe in 2013 and in the US in 2015) and Gla-300 (approved in the US and Europe in 2015). An overview of PK and PD

8 properties (time to peak concentration, duration of action, t 1/2 ) and dosing frequency of the basal insulins discussed in this article is presented in Table 2. Insulin Detemir 100 U/mL Insulin detemir is an acylated insulin analog in which absorption from the subcutaneous depot is delayed because of self-association into dihexamers and albumin binding via the fatty acid side chain [22]. Further protraction of the action of detemir occurs within the circulation because of albumin binding [23, 24]. As with all insulins, injection of different doses of insulin detemir leads to dose-dependent increases in blood levels of insulin [25, 26]. Insulin detemir is available in vials, or as a prefilled pen. The insulin detemir pen delivers up to 60 units per injection in increments of 1 unit [22]. PK/PD Profile For insulin detemir, maximum insulin concentration is reached 4 6 hours after injection (t max ) [23] and the elimination t 1/2 is 5 7 hours, depending on dose [22]. It should be noted, however, that insulin detemir may not provide full 24-hour duration of glucose-lowering action, and twice-daily rather than once-daily dosing is required in many patients [22, 27]. Indeed, clamp studies in patients with T1D have demonstrated a shorter duration of action of insulin detemir than Gla-100 [13, 28]. Compared with the same dose of NPH insulin, insulin detemir shows less of a peak in the GIR time profile; a glucose clamp study in patients with T1D showed a clear dose response relationship and a flatter (but not completely peak-less), protracted PD profile for insulin detemir [29]. Clinical Implications Insulin Detemir Several studies have investigated the safety and efficacy of insulin detemir in comparison with the conventional NPH insulin formulation. In a 16-week study of patients with T1D treated with twice-daily insulin detemir (administered before breakfast and at bedtime or at a 12-hour intervals), HbA 1c levels were not significantly different with insulin detemir compared with twice-daily NPH insulin (administered before breakfast and at bedtime) in either insulin detemir regimen group, however, fasting plasma glucose was significantly lower as were the rates of minor (in particular nocturnal) hypoglycemia. Insulin detemir also resulted in lower within-patient glycemic variability and had a neutral effect on weight [30]. Similar results were seen in a 20-week and a 26-week trial of patients with T2D comparing insulin detemir with NPH insulin as add-on therapy to OADs. Similar reductions in HbA 1c were observed in patients treated with insulin detemir and NPH insulin, however, insulin detemir achieved this with reduced rates of overall and nocturnal hypoglycemia with less weight gain [31 32]. A basalbolus regimen combining once-daily insulin detemir with meal -time insulin aspart produced comparable HbA 1c results to NPH insulin combined with meal-time regular human insulin in patients with T2D. The insulin detemir plus insulin aspart regimen also resulted in lower within-patient fasting plasma glucose (FPG) variability, lower weight gain and lower (but not statistically significant) nocturnal hypoglycemia risk than the NPH insulin plus regular human insulin regimen [33].

9 Long term safety data are not available for insulin detemir. However, no significant safety concerns have been identified in the 10-year period since it was approved for clinical use. Insulin Glargine 100 U/mL Insulin glargine differs from human insulin by the addition of two specific amino acid residues (arginine at positions B31 and B32) and the substitution of another specific amino acid residue (glycine for asparagine at position A21). These changes alter the isoelectric point of the insulin, making it less soluble at physiologic ph. Upon subcutaneous injection, microprecipitates will form from which insulin glargine is released gradually over time [34]. Enzymatic removal of the two C- terminal arginines upon re-dissolution from the subcutaneous depot yields the M1 insulin metabolite. M1 is the predominant metabolite found in circulation and responsible for the glucose lowering effect. Subsequent loss of threonine at position 30B yields the M2 insulin metabolite [35]. Gla-100 is licensed for once-daily dosing. It is available in vials and in a prefilled pen, which can dose up to 80 U with one injection in increments of 1 unit. Patients requiring higher doses than 80 U need more than 1 injection at the same time of day [36]. PK/PD Profile Gla-100 The administration of Gla-100 results in dose-dependent increases in insulin blood levels. Maximum insulin concentration is reached after 8 12 hours (t max ),[26] and the elimination t ½ is approximately hours [37]. A steady time-action profile over 24 hours after subcutaneaous injection with no pronounced peak has been reported in patients with T1D [28, 38] or T2D [39]. In addition, the high day-to-day reproducibility of serum Gla-100 concentration and time-action profiles due to a uniform release after injection indicate the suitability of Gla-100 as basal insulin supplementation therapy [40]. Based on the time action profile, Gla-100 is licensed for once-daily dosing [36]. Clinical Implications Gla-100 Gla-100 has been extensively studied in comparison with NPH insulin and has been shown to provide benefits in patients with T1D and T2D. Trials of 4, 16 and 28 weeks of duration of patients with T1D have shown that Gla-100 resulted in significantly improved FPG levels compared with NPH, especially in patients who were receiving > 1 injection per day of NPH prior to Gla-100 initiation [41-43]. Patients experienced similar changes in HbA 1c levels when treated with Gla-100 compared with NPH insulin, however, more stable FPG levels were demonstrated [41, 42] with more patients achieving target FPG of <119 mg/dl [42] when treated with Gla-100 compared with NPH insulin. These studies did not report differences in symptomatic or nocturnal hypoglycemia [41-43]. A metaanalysis of trial data of patients with T2D reported similar proportions of patients achieving HbA 1c of 7% with Gla-100 and NPH (30.8 vs. 32.1%, respectively), but with a consistent and significantly reduced risk of overall, nocturnal and severe hypoglycemia [44]. Another study in patients with T2D using a basal bolus regimen found lower HbA 1c levels at endpoint with a lower risk of hypoglycemia and less weight gain when treated with Gla-100 compared with NPH insulin [45].

10 Once-daily Gla-100 has also been compared with insulin detemir in patients with T1D and T2D [27, 46-49]. In patients with T1D, treatment for 26 weeks or 52 weeks with once- or twice-daily insulin detemir provided similar glycemic control to once-daily Gla-100 [48, 49]. Within-patient variability in self-monitored plasma glucose (SMPG) measured before breakfast, before dinner and using 10-point SMPG showed no significant differences between treatments in patients with T1D. There were also no significant differences in risk of hypoglycemia, nocturnal hypoglycemia or severe hypoglycemia between insulin detemir and Gla-100 in the study where patients used insulin detemir once- or twice daily [49]. Another study in patients with T1D demonstrated that, at similar glycemic control, twice-daily insulin detemir resulted in a similar overall risk of hypoglycemia with no differences in confirmed hypoglycemia, but with significant reductions of severe and nocturnal hypoglycemia compared with once-daily Gla-100 [48]. In insulin-naïve patients with T2D, comparison of once-daily Gla-100 and once- or twice-daily insulin detemir showed similar reductions in HbA 1c and FPG levels, and similar rates of overall, nocturnal and severe hypoglycemia [27]. A more recent 26- week study of once-daily Gla-100 and once-daily insulin detemir in patients with T2D, using weekly titration of insulin doses, demonstrated that insulin detemir was inferior to Gla-100 with regard to HbA 1c reduction (estimated treatment difference: 0.30% [95% CI: %]), although patients treated with insulin detemir used higher doses. Rates of total hypoglycemia were significantly lower with insulin detemir compared with Gla-100 (3.19 vs 4.41 events/patient/year, p=0.034). However, it should be considered that these effects may be due to delayed mean FPG reductions with insulin detemir compared with Gla-100, resulting in higher FPG levels with insulin detemir over the course of the study [46]. Gla-100 has an established long-term safety profile, and a long-term multinational clinical study (the ORIGIN trial including 12,537 people with dysglycemia including pre-diabetes and T2D) has reported that Gla-100 has a neutral effect on cardiovascular outcomes and was associated with no increased risk for serious CV events in people with pre-existing CV risk compared with standard of care [50]. Concerns had been raised if insulin glargine could pose an increased risk of developing cancer. However, as demonstrated by the long-term ORIGIN trial, insulin glargine is not associated with an increased risk of cancer and cancer mortality compared with standard care [50]. Another long-term safety study and a meta-analysis also confirmed no link between Gla-100 treatment and increased incidence of cancer [51, 52]. Insulin Glargine 300 U/mL As described for Gla-100, Gla-300 is based on the same active pharmaceutical ingredient, insulin glargine, and has the same metabolism with metabolites M1 and M2, with M1 being the predominant metabolite in circulation [35]. However, the formulation of Gla-300 is different and it provides the same number of units as Gla-100 in one-third of the injection volume. As a result, the subcutaneous depot of Gla-300 has a higher concentration and a smaller volume releasing the insulin more gradually from the subcutaneous tissue than Gla-100 [53]. Like Gla-100, Gla-300 is licensed for once-daily dosing. It is available in a prefilled pen, which can dose up to 80 U with one injection in increments of 1 unit [54].

11 PK/PD Profile Gla-300 Gla-300 is a next-generation basal insulin with a novel formulation of insulin glargine that provides the same number of units of insulin as Gla-100 in one-third of the injection volume [54]. PK/PD studies have shown that, following injection, Gla-300 is released more gradually from the subcutaneous tissue precipitate than Gla-100, without the rise-plateau-fall pattern. Gla-300 has a more constant PK/PD profile with a prolonged duration of action beyond 24 hours [53, 55, 56]. As a result, in a single-dose glucose clamp study blood glucose lowering activity was maintained for up to 36 hours with Gla-300 dosed at 0.4, 0.6 and 0.9 U/kg [56]. The t ½ of Gla-300 when administered subcutaneously is hours and is independent of dose, increased from hours with Gla-100 (0.4 U.kg 1 ) [37, 53]. At steady state, the insulin concentration profile of Gla-300 was more constant and more evenly distributed over 24 hours than Gla-100. Also, the steady state GIR profile of Gla-300 was more constant and more evenly distributed compared with Gla-100 [53]. Another study demonstrated that Gla-300 provides an evenly distributed 24-hour coverage as a result of low fluctuations (within-day variability) and high reproducibility in insulin exposure [55]. Clinical Implications Gla-300 The more constant PK/PD profile of Gla-300 suggests the potential to provide more even glycemic control with less hypoglycemia compared with Gla-100. This potential for reduced hypoglycemia with Gla-300 was confirmed by a meta-analysis of phase 3 trial data, showing that, in patients with T2D, Gla-300 was associated with reduced nocturnal hypoglycemia compared with Gla- 100 with a relative risk of 0.75 (95% CI: 0.68 to 0.83) [57]. In patients with T1D, lower hypoglycemia, especially nocturnal hypoglycemia, has been shown in Japanese patients [58]. In a multi-national study of patients with T1D, hypoglycemia did not differ between patients treated with Gla-100 or Gla-300, apart from the first 8-weeks of treatment when nocturnal confirmed and severe hypoglycemia were lower in Gla-300 treated patients [59]. However, this study might have been insufficiently powered to assess differences in hypoglycemia between Gla-300 and Gla-100 because of the inclusion of 4 different arms investigating morning and evening injections. Additional studies such as the ongoing CGM study in patients with T1D [60] are awaited to provide more information regarding the true benefit of Gla-300 in terms of lower hypoglycemia compared with Gla-100. In six, phase 3, multinational, open-label non-inferiority studies in patients with T1D and T2D, Gla-300 consistently showed comparable glycemic control to Gla-100 [61-68]. A meta-analysis of patient-level data showed a mean change in HbA 1c level of 1.02% with both treatments [69]. A similar meta-analysis of patient-level data from phase 3 clinical trials in patients with T2D also showed that Gla-300 provided comparable glycemic control to Gla-100 [58]. Patients switching to Gla-300 from other basal insulin are advised to use a 1:1 unit conversion to start. It should be noted however that on a unit to unit basis, Gla-300 has a lower glucose lowering effect than Gla-100, meaning that although there is no defined unit-for-unit conversion, a 10 18% higher dose of Gla-300 may be required in order to achieve target blood glucose levels and to achieve equivalent glycemic control [70].To minimize the risk of hyperglycemia during switching, it is recommended that patients monitor glucose daily, titrate Gla-300 according to instructions, and adjust any other glucose lowering therapies according to standard of care [54].

12 Long-term safety data are not yet available for Gla-300. However, as Gla-300 and Gla-100 are based on the same insulin glargine molecule and the same metabolic pathways, and Gla-100 has an established long-term safety profile as demonstrated in the ORIGIN trial [50], the safety of Gla-300 would be expected to be similar. Across the clinical trial program, Gla-300 was generally well tolerated, with similar common adverse events and serious treatment emergent adverse events reported for both Gla-100 and Gla-300. Insulin Degludec 100 U/mL and 200 U/mL Insulin degludec is a novel insulin analog with an added hexadecanoic diacid group attached via a glutamic acid linker; this modification leads to the formation of stable dihexamers in the presence of zinc and phenol at neutral ph. After subcutaneous injection, the phenol dissipates first and the degludec dihexamers interact to form long multihexameric chains, which create a subcutaneous insulin depot [71, 72]. With the subsequent gradual diffusion of the zinc, these chains break up into insulin dimers, which rapidly dissociate into insulin monomers that enter the circulation and bind to plasma albumin [72]. Insulin degludec is available in two formulations for once-daily subcutaneous injection; insulin degludec 100 U/mL and insulin degludec 200 U/mL. Insulin degludec 100 U/mL and insulin degludec 200 U/mL have been shown to be bioequivalent and have similar PD time action profiles [73, 74]. Both are licensed for once-daily dosing. Insulin degludec 100 U/ml is available as a prefilled pen. It is dosed in 1 unit increments and, can be dosed up to 80 U with one injection. Insulin degludec 200 U/mL is available as a prefilled pen. It is dosed in 2 unit increments and can be dosed up to a maximum of 160 U with one injection [75]. PK/PD Profile Insulin Degludec The elimination t ½ of insulin degludec is 25 hours [76], which provides low peak-to-trough variation in plasma concentration throughout the 24-hour dosing interval. At steady state, insulin degludec has a flat, evenly distributed glucose-lowering profile. The duration of action, defined as the time from administration until blood glucose levels were consistently above 150 mg/dl, was shown to exceed 26 hours (in patients with T2D) and 42 hours in patients with T1D, making it suitable for once-daily dosing [76, 77]. A euglycemic clamp study with insulin degludec suggested that insulin degludec100 U/mL had a four-fold lower within-patient variability of PD response compared with Gla-100, which was consistently low over the 24-hour dose interval; the variability of Gla-100 was higher and increased to a maximum at hours post-dosing [78]. Yet, the clinical relevance of these differences in PD parameters between insulin degludec 100 U/mL and Gla-100 have yet to be determined in clinical studies. The PK and PD profiles of insulin degludec 100 U/ml and 200 U/ml are similar, as during development the insulin degludec 200 U/mL formulation was optimised with a slight adjustment of the excipients in order to obtain the same pharmacological properties and effect as insulin degludec 100 U/mL [77]. In contrast, as described above Gla-100 and Gla-300 have different PK and PD profiles. Recently, two different cross-over steady-state studies have explored the PK/PD [79] and PD [80] characteristics of Gla-300 and insulin degludec in patients with T1D. One study examined the within-day GIR variability of Gla-300 and insulin degludec 100 U/mL at 0.4 U/kg/day in patients with T1D and reported a more constant and more evenly distributed insulin concentration profile and a

13 significantly lower within-day GIR variability of Gla-300 versus insulin degludec [79]. The primary outcome of the other study was day-to-day variability (at 3 day intervals) comparing insulin degludec 200 U/mL and Gla-300 at 0.4 U/kg/day in patients with T1D and reporting a lower day-to-day variability of GIR with insulin degludec vs Gla-300 [80]. While the latter study also reported results for within-day variability, the two studies were different in terms of overall study design (within-day vs between-day GIR variability assessments as primary endpoint, PK/PD vs PD only measurements, different degludec products used, and different parameters for assessing within-day variability). Accordingly, a direct comparison of the respective results is difficult. As for all PK/PD studies, the relevance of these findings have to be investigated in appropriately designed clinical trials. To date, there is no published clinical data on head-to-head comparisons of insulin degludec (100 U/mL or 200 U/mL) with Gla-300, but a phase 4 head-to-head trial comparing Gla-300 and insulin degludec in patient with T2D is currently ongoing [81]. Clinical Implications Insulin Degludec 100 U/mL and 200 U/mL Insulin degludec 100 U/mL has a flat glucose-lowering PD profile, with minimal fluctuations, which may translate into a reduced risk of nocturnal hypoglycemia compared with Gla-100 [82-85]. Insulin degludec 200 U/mL, administered with the main meal, was compared with Gla-100, administered once daily at the same time each day, in insulin-naïve patients with T2D in a 26-week open-label trial; a similar reduction in HbA 1c was achieved with both insulins, but insulin degludec 200 U/mL was associated with a greater reduction in FPG levels (an estimated treatment difference of 0.42 mmol/l). However, no significant differences in the rates of overall and nocturnal confirmed hypoglycemia were observed [86]. In a meta-analysis of five randomized studies comparing insulin degludec 100 U/mL (in four studies) and insulin degludec 200 U/mL (in one study) with Gla-100 in patients with T2D, lower FPG values were reported for insulin degludec than Gla-100, but HbA 1c values achieved at study end were similar [87]. Clinical experience and long-term safety data for insulin degludec 100 U/mL and 200 U/mL are still limited, although no safety concerns regarding unexpected adverse events or accumulation of insulin have been identified to date [76, 82, 84, 85]. In response to a supposed signal for an increased risk of major adverse cardiovascular events with insulin degludec, a clinical trial (the DEVOTE study) was conducted at the request of the United States Food and Drug Administration and compares the cardiovascular safety of insulin degludec with that of insulin glargine in patients with T2D at high risk of cardiovascular events. The results of this study are expected to be published in Other Basal Analog Insulins Biosimilars (products that have been designed to have similar properties to an already approved biological reference product) are made using living organisms, and have no clinically meaningful difference from the reference product. However, as insulin is a large molecule and biosimilars are complex mixtures that may be difficult to identify or characterize, simply creating the same amino-acid structure will not necessarily lead to insulins with identical properties. Biosimilar insulins, therefore, have to undergo rigorous clinical testing to demonstrate efficacy and safety prior

14 to approval [88]. A number of insulin glargine biosimilars are currently in development. One insulin glargine biosimilar (100 U/mL) was approved in Europe in September 2014 for the treatment of diabetes in adults, adolescents and children aged 2 years and older; in the USA this product was approved in December 2015 [89, 90]. Glucose clamp studies and two phase 3 clinical trials have shown similar efficacy and safety when comparing the biosimilar insulin glargine with Gla-100 in patients with T1D and T2D [91, 92]. Timing of Basal Insulin Dose Both Gla-100 and insulin detemir are indicated to be administered once daily, meaning once within any 24-hour interval. However, as noted earlier, insulin detemir may not provide full 24-hour duration of glucose-lowering action, and is also indicated to be administered twice daily. Similarly, some patients, especially those with T1D may require 2 injections per day of Gla-100 despite the fact that it is only indicated for once daily dosing [36, 93]. Indeed, although the median duration of action of Gla-100 is 24 hours, this can be as little as 10.8 hours [36]. The extended, flat PD action profiles of the newer longer-acting insulins (Gla-300 and insulin degludec 100 U/mL and 200 U/mL) may allow for greater flexibility in the dosing regimen compared with the older basal insulin products (insulin detemir and Gla-100). Clinical trial data suggests that patients may have a longer window within which to take their dose of basal insulin (if they forget to take the dose at their usual time, for example). Studies in patients with T1D and T2D showed that the injection time of insulin degludec could be varied without compromising either glycemic control or safety compared with same-time administration of insulin degludec [83, 94]. In the 26-week study in patients with T2D, dosing intervals of 8 40 hours resulted in no statistically significant differences in HbA 1c reductions from baseline and comparable hypoglycemia rates between different flexible and fixed dosing schedules [94]. In addition, a subset of patients with T2D treated with Gla-300 in EDITION-1 and EDITION-2 were also instructed to vary the time of daily injection of Gla-300 by up to 3 hours. No differences in efficacy or safety were observed compared with those patients who continued to inject Gla-300 at the same time every 24 hours [95]. Conclusions JUST Compared with NPH insulin and the previous generation of basal insulins (insulin detemir and Gla- 100), the longer-acting basal insulins (insulin degludec 100 U/mL and 200 U/mL, and Gla-300) have improved PK and PD profiles in the sense that these more closely mimic the physiologic profile of endogenous basal insulin. Clamp studies indicate that these insulins have flatter PK/PD profiles without pronounced peak effects and a longer elimination t ½ and duration of action that fully covers 24 hours. They also might have a lower within-patient day-to-day variability in glucose-lowering effect. Although the glucose-lowering efficacy of the various insulins has been discussed in the relevant sections of this article, it is important to note that many of the cited clinical trials were designed to show non-inferiority to comparators. Caution is therefore required when interpreting these results. ACCEPTED

15 Evidence from clinical trials suggest that the improved PK/PD properties of the longer-acting basal insulins translate into important clinical benefits, such as a reduced risk of nocturnal hypoglycemia, and more flexibility in the dosing interval. It is important to note that the insulin degludec 100 U/mL and 200 U/mL formulations are bioequivalent and seem to have similar PK/PD properties. However, Gla-300 has a different PK/PD profile compared with Gla-100 with clinical benefits for Gla-300 that include a prolonged glucose control from a once-daily dose, a more even activity profile and a lower risk of hypoglycemia. Evidence from real life studies are needed to compliment and increase the understanding of the true clinical benefits of the longer-acting basal insulin products. The new generation long-acting basal insulins improve the treatment options for patients requiring insulin therapy. The potential clinical benefits associated with improved pharmacologic characteristics of the new long-acting basal insulins are important to consider when making prescribing decisions, together with issues such as relative cost and individual patient lifestyle factors that may influence adherence.

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19 43. Home PD, Rosskamp R, Forjanic-Klapproth J, et al. A randomized multicentre trial of insulin glargine compared with NPH insulin in people with type 1 diabetes.diabetes Metab Res Rev. 2005;21(6): Rosenstock J, Dailey G, Massi-Benedetti M, et al. Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care. 2005;28(4): Siegmund T, Weber S, Blankenfeld H, et al. Comparison of insulin glargine versus NPH insulin in people with type 2 diabetes mellitus under outpatient-clinic conditions for 18 months using a basal-bolus regimen with a rapid-acting insulin analogue as mealtime insulin. Exp Clin Endocrinol Diabetes. 2007;115(6): Meneghini L, Kesavadev J, Demissie M, et al. P. Once-daily initiation of basal insulin as add-on to metformin: a 26-week, randomized, treat-to-target trial comparing insulin detemir with insulin glargine in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15: Albright ES, Desmond R, Bell DSH. Efficacy of conversion from bedtime NPH insulin injection to once- or twice-daily injections of insulin glargine in type 1 diabetic patients using basal/bolus therapy. Diabetes Care. 2004;27(2): Pieber TR, Treichel HC, Hompesch B, et al. Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy. Diabet Med. 2007;24(6): Heller S, Koenen C, Bode B. Comparison of insulin detemir and insulin glargine in a basal bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: A 52- week, multinational, randomized, open-label, parallel-group, Treat-to-Target noninferiority trial. Clin. Ther. 2009; 31(10): ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4): Fagot JP, Blotière PO, Ricordeau P, Weill A, Alla F, Allemand H. Does insulin glargine increase the risk of cancer compared with other basal insulins? A French nationwide cohort study based on national administrative databases. Diabetes Care Feb 1;36(2): Tang X, Yang L, He Z, Liu J. Insulin glargine and cancer risk in patients with diabetes: a metaanalysis. PloS one Dec 19;7(12):e Becker RH, Dahmen R, Bergmann K, et al. T. New insulin glargine 300 Units ml 1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units ml 1. Diabetes Care. 2015;38(4): Toujeo Prescribing Information. Sanofi website. Available at: [Last accessed May 8, 2017] 55. Becker RH, Nowotny I, Teichert L, et al. Low within- and between-day variability in exposure to new insulin glargine 300 U/ml. Diabetes Obes Metab. 2015;17(3): Shiramoto M, Eto T, Irie S, et al. Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes. Diabetes Obes Metab. 2015;17(3):

20 57. Ritzel R, Roussel R, Bolli GB, et al. Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab. 2015;17(9): Matsuhisa M, Koyama M, Cheng X, Takahashi Y, Riddle MC, Bolli GB, Hirose T. New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1). Diabetes, Obesity and Metabolism. 2016;18(4): Home PD, Bergenstal RM, Bolli GB, Ziemen M, Rojeski M, Espinasse M, Riddle MC. New insulin Glargine 300 units/ml versus Glargine 100 units/ml in people with type 1 diabetes: a randomized, phase 3a, open-label clinical trial (EDITION 4). Diabetes Care. 2015;38(12): ClinicalTrials.gov. (Internet) A Study Comparing the Efficacy and Safety of the Morning Injection of Toujeo Versus Lantus in Patients With Type 1 Diabetes Mellitus Available at: [Last accessed May 8, 2017] 61. Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care. 2014;37: Riddle MC, Yki-Järvinen H, Bolli GB, et al. One year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/mL compared with 100 U/mL in people with type 2 diabetes using basal + meal-time insulin (EDITION 1 12-month randomized trial including 6-month extension). Diabetes Obes Metab. 2015;17: Yki-Järvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care. 2014;37: Yki-Järvinen H, Bergenstal RM, Bolli GB, et al. Less nocturnal hypoglycaemia and weight gain with new insulin glargine 300 U/ml vs 100 U/ml: 1-year results in people with type 2 diabetes using basal insulin and OADs (EDITION 2) [abstract 946]. Diabetologia. 2014;57(suppl 1):S Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17: Matsuhisa M, Koyama M, Cheng X, Sumi M, Riddle MC, Bolli GB, Hirose T; EDITION JP 1 study group.sustained glycaemic control and less nocturnal hypoglycaemia with insulin glargine 300U/mL compared with glargine 100U/mL in Japanese adults with type 1 diabetes (EDITION JP 1 randomised 12-month trial including 6-month extension). Diabetes Res Clin Pract Oct 13;122: Terauchi Y, Koyama M, Cheng X, Shimizu S, Hirose T; On behalf of the EDITION JP 2 Study Group. Glycaemic control and hypoglycaemia in Japanese people with type 2 diabetes mellitus receiving new insulin glargine 300 U/mL in combination with OADs (EDITION JP 2) [abstract 976]. Diabetologia. 2014;57(suppl 1):S401.

21 68. Terauchi Y, Koyama M, Cheng X, Sumi M, Hirose T; On behalf of the EDITION JP 2 study group. New insulin glargine 300 U/mL provides sustained glycemic control and reduced hypoglycemia over 12 months compared with glargine 100 U/mL in Japanese people with T2DM managed with basal insulin plus OAD(s) (EDITION JP 2) [abstract 98-OR]. Diabetes. 2015;64(suppl 1):A Goldman J, White JR Jr. New insulin glargine 300 U/mL for the treatment of type 1 and type 2 diabetes mellitus. Ann Pharmacother. 2015;49(10): Toujeo Summary of Product Characteristics. Website. Available at: _Product_Information/human/000309/WC pdf [Last accessed May 8, 2017] 71. Kurtzhals P, Heise T, Strauss HM, et al. Multi-hexamer formation is the underlying basis for the ultra-long glucose-lowering effect of insulin degludec [abstract]. Diabetologia. 2011;54(suppl 1):S Jonassen I, Havelund S, Hoeg-Jensen T, et al. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29(8): Korsatko S, Deller S, Koehler G, et al. A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec. Clin Drug Investig. 2013;33(7): Bode BW, Chaykin LB, Sussman AM, et al. Efficacy and safety of insulin degludec 200 U/mL and insulin degludec 100 U/mL in patients with type 2 diabetes (Begin: Compare). Endocr Pract. 2014;20(8): Novo Nordisk. Tresiba Prescribing Information. Available at: [Last accessed May 8, 2017] 76. Heise T, Nosek L, Bøttcher SG, et al. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab. 2012;14(10): Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014;53: Heise T, Hermanski L, Nosek L, et al. H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14(9): Bailey T, Dahmen R, Pettus J, et al. Insulin glargine 300 U/mL (Gla-300) provides more stable and more evenly distributed steady-state pharmacodynamic/pharmacokinetic profiles compared with insulin degludec in type 1 diabetes (T1DM). Endocr Pract. 2017;23;1A-48A. 80. Heise T, Nørskov M, Nosek L, Kaplan K, Famulla S, Haahr HL. Insulin degludec: lower day to day and within day variability in pharmacodynamic response compared to insulin glargine U300 in type 1 diabetes. Diabetes, Obesity and Metabolism Mar 14 [epub]. 81. ClinicalTrials.gov. [internet]. Toujeo Tresiba in Insulin-Naive Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Oral Antihyperglycemic Drug(s) ± GLP-1 Receptor Agonist. Available at: [Last accessed May 8, 2017]

22 82.. Heller S, Buse J, Fisher M, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825): Mathieu C, Hollander P, Miranda-Palma B, et al. Efficacy and safety of insulin degludec in a flexible dosing regimen vs Insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab. 2013;98(3): Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin degludec versus insulin glargine in insulinnaive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care. 2012;35(12): Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825): Gough SC, Bhargava A, Jain R, et al. Low-volume insulin degludec 200 units/ml once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulinnaive patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-totarget trial: the BEGIN LOW VOLUME trial. Diabetes Care. 2013;36(9): Rodbard HW, Gough S, Lane W, et al. Y. Reduced risk of hypoglycemia with insulin degludec versus insulin glargine in patients with type 2 diabetes requiring high doses of Basal insulin: a meta-analysis of 5 randomized begin trials. Endocr Pract. 2014;20: United Food and Drug Administration website [internet]. Biosimilars. Available at: ovalapplications/therapeuticbiologicapplications/biosimilars/ucm htm [Last accessed May 8, 2017] 89. Eli Lilly website [internet]. Press release, European Commission grants Lilly and Boehringer Ingelheim s insulin glargine product marketing authorisation in Europe. Available at: [Last accessed May 8, 2017] 90. DeVries JH, Gough SC, Kiljanski J, et al. Biosimilar insulins: a European perspective. Diabetes Obes Metab. 2015;17(5): Linnebjerg H, Lam EC, Seger ME, et al. Comparison of the Pharmacokinetics and Pharmacodynamics of LY Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies. Diabetes Care. 2015;38(15): Rosenstock J, Hollander P, Bhargava A, et al. Similar efficacy and safety of LY insulin glargine and insulin glargine (Lantus) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab. 2015;17(8):

23 93. Ashwell SG, Gebbie J, Home PD. Twice daily compared with once daily insulin glargine in people with Type 1 diabetes using meal time insulin aspart. Diabetic medicine Aug 1;23(8): Meneghini L, Atkin SL, Gough SC, et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care. 2013;36(4): Jeandidier N, Riddle MC, Bolli GB, et al. New insulin glargine 300 U/ml: efficacy and safety of flexible vs fixed dosing intervals in people with type 2 diabetes mellitus [abstract]. Diabetologia. 2014;57(suppl 1):S393 (Abstract 961)

24 Table 1. Definitions of key PK/PD parameters relevant to insulin therapy. Parameter Definition Clinical relevance Area under the curve (insulin concentration) Area under the curve (glucose infusion rate) Duration of action Glucose infusion rate Half-life (elimination) Early glucose infusion rate - t 50% (sometimes used as parameter for onset of action) Calculated from the graph of insulin concentration over time Calculated from the graph of glucose infusion rate over time The time interval between insulin injection and the time point when blood glucose concentrations increases from the clamped glucose level to a predetermined threshold value The amount of glucose infused over time to maintain blood glucose at the clamp level The time necessary for the insulin concentration to decrease by 50% (derived from the slope of decline in insulin concentrations after reaching maximum concentrations). The time to 50% of the maximum glucose infusion rate PK measurement of the total amount of insulin absorbed (allows evaluation of bioavailability) PD measurement of the amount of glucose infused (indicates total daily insulin effect /glucose-lowering effect) and allows evaluation of the cumulative glucodynamic activity Affects number of daily doses (insulins with shorter duration of action require more frequent dosing) Evaluates the glucose-lowering effect of insulin over time (flatter curves suggest a more constant glucose-lowering effect and lower risk of hypoglycemia) Affects number of daily doses (insulins with shorter half-lives require more frequent dosing) Affects dosing interval (insulins with a slower onset of action require closer monitoring of blood glucose levels initially to maintain control) Less relevant for long-acting basal insulins with a duration of action > 24 hours that reach steady state basal insulin activity by overlapping action profiles of consecutive oncedaily basal insulin administrations

25 Table 2. PK/PD characteristics of basal insulin analogs Peak (hours) Duration of action (hours) Half-life (hours) Dosing frequency NPH Insulin Once or twice daily Insulin detemir 100 U/ml Insulin glargine 100 U/ml Insulin glargine 300 U/ml Insulin degludec 4 7 Up to Once or twice daily 8 12 Up to Once daily Close to peakless Close to peakless > Once daily Once daily

26 Figure legends Figure 1. Graphic representation of the hyperinsulinemic-euglycemic clamp procedure. To reach the study target blood glucose level, IV insulin is administered during the feedback period prior to the clamp (A). The euglycemic clamp procedure aims to assess the glucose-disposing effect (B) of the administered study insulin (C). Normally, insulin results in lowering of blood glucose levels; glucagon is then released, leading to hepatic release of glucose (D), which would confound the true glucose-disposing effect of the insulin. This is prevented by regularly monitoring the blood glucose level (E) and keeping it constant by IV glucose infusion (F), a procedure that can be conducted manually or automatically (G). Any residual insulin production by the pancreas (H; eg, patients with T2D) will confound the effect of the study insulin. IV, intravenous ; T2D, type 2 diabetes Figure 2. Example of time-to-reach steady state without inappropriate accumulation of basal insulin using a simplified one-compartment model (10 U, with t ½ ~ 24 hours). Adapted with permission from Heise 2014 [1] the American Association of Clinical Endocrinologists. When dosing frequency is equivalent to the drug half-life, insulin levels will increase until the steady state is reached, at which time the once-daily injected dose is balanced by elimination. s.c. = subcutaneous; U = units of insulin; t ½ = half-life.

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