Diabetes, Obesity and Metabolism 16: 695–706, 2014. © 2014 John Wiley & Sons Ltd

Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice P. Rossetti1 , F. J. Ampudia-Blasco2 & J. F. Ascaso2 1 Department of Internal Medicine, Sant Francesc de Borja Hospital, Gandia, Spain 2 Department of Medicine, Division of Endocrinology and Nutrition, Clinic University Hospital of Valencia – Fundacion ´ INCLIVA, University of Valencia, Valencia, Spain

Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients’ individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care. Keywords: insulin analogues, insulin therapy, pharmacodynamics Date submitted 14 May 2013; date of first decision 5 July 2013; date of final acceptance 20 December 2013

Introduction The market value of antihyperglycaemic drugs amounted to US$39.2 billion [1,2] in 2011 and is predicted to increase to US$43–48 billion in 2015 [3]. Insulin formulations represent about 50% of the drug expenses for people with diabetes. It is expected that over the next 20 years insulin sales will continue growing worldwide and even faster in China and India [4,5]. The insulin market can be broken into two product classes, i.e. recombinant human insulins (HI) and insulin analogues. In the last 10 years, the use of HI has declined being displaced by insulin analogues [4,5]. Indeed, analogues constitute approximately 50–60% of the insulin market volume representing more than 80% of its total value [4–6]. Basal formulations are leading this market transformation, with long-acting analogues approaching 80% of global market penetration [4]. This happened despite the still controversial clinical evidence in favour of analogues’ superiority [7,8] and some unfavourable cost/effectiveness analysis [9,10], in both type 1 (T1DM) and type 2 diabetes (T2DM), especially when hypoglycaemia is not considered in the economic models. Evidence from clinical trials can hardly cover the whole spectrum of clinical conditions and is exposed sometimes Correspondence to: Paolo Rossetti, MD, Department of Internal Medicine, Sant Francesc de Borja Hospital, Gandia, Spain. E-mail: [email protected]

to publication bias [11], which in turn may hamper evidence-based clinical practice. As a result, we are convinced that looking back into the classical pharmacokinetic and pharmacodynamic (PK/PD) data may be helpful for better insulin prescription. PK/PD data can help in predicting and interpreting the results from clinical trials and in translating their balanced benefits into clinical practice particularly when there is a lack of definitive clinical evidence [12]. In this article, we review first the concepts behind PK/PD studies, giving some key clues for the interpretation of PD parameters. We then analyse PD results focusing on those studies comparing basal insulin analogues with HI and, when available, first-generation with second-generation formulations in subjects with diabetes. Finally, we try to interpret clinical evidence from the perspective of PK/PD studies, giving emphasis to those aspects that may help the physician in selecting the more appropriate basal insulin replacement in a specific clinical context.

Comparison of PK/PD Profiles of Basal Insulin Formulations The success of any insulin replacement strategy in patients with diabetes depends on its ability to reproduce the physiology of insulin secretion [13]. Achievement of a ‘physiological’ pattern characterized by flat and nearly constant insulin concentrations in the fasting and postabsorptive state (as well as by timely

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Figure 1. A schematic representation of the euglycaemic or isoglycaemic clamp technique, for the assessment of pharmacodynamics (PD) parameters of insulin formulations. Before the injection of the study drug, insulin is infused i.v. (if needed) to standardize and stabilize preinjection plasma glucose (PG), usually at euglycaemic levels. Following the injection of the study insulin, i.v. insulin infusion is tapered to 0. Glucose is then infused at variable rate (GIR), if needed, to maintain PG at target. The area under the GIR curve (AUC-GIRstudy period , in mg/kg or umol/kg) represents the global insulin effect over a specific period. The maximal glucose infusion rate GIRmax represents the peak insulin action and the time to GIRmax (GIR T max ) is time to peak activity. Regarding the onset and the end of action, both can be defined based on GIR: the former as the time at which i.v. glucose was initiated after s.c. insulin injection (t 2 ) [17] and the latter as the time at which the infusion was stopped (t 4 ). However, when subjects with DM are studied (especially T1DM), onset of action can be defined as the time at which the rate of IV insulin consistently decreased compared with the preinjection time period (t 1 < t onset < t 2 ) [23,31]. Similarly, end of action is frequently defined as the time t at which PG consistently increased above a predefined threshold [17,23,31] (t 4 < tend < t 5 ). Notably, heterogeneity of definitions can significantly affect the estimation of PD parameters [18].

plasma insulin elevations following nutrient ingestion) remains essential to optimize glucose control minimizing the risks for hypoglycaemia [14,15]. For this reason research has focused on basal insulin formulations with ‘flat’ profile, low interand intra-subject variability, prolonged (≥24 h) and ideally also with hepatoselective action. After more than 50 years of NPH dominance, in the last 10–15 years four insulin analogues [glargine, detemir, neutral protamine lispro (NPL) and degludec] have been introduced whereas two others are still in development (glargine U300 and LY2605541). Understanding the differences between the available insulin formulations is relevant for the optimization of insulin replacement in clinical practice. However, as detailed below, appropriate interpretation of data from PK/PD studies requires some specific considerations.

Interpreting Correctly PK/PD Studies The euglycaemic clamp technique [16], which was originally developed for quantifying insulin secretion and resistance, remains the gold standard for evaluating the PK/PD characteristics of insulin formulations. Insulin PK refers to

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the time course of plasma insulin concentration following its administration in another compartment (usually the SC tissue). Under clamp conditions, the blood glucose-lowering effects of a study insulin formulation (PD) are assessed in the context of individual insulin sensitivity. Basically, following insulin injection, glucose is infused intravenously (GIR, glucose infusion rate expressed in mg/kg/min or μmol/kg/min) to maintain a selected glycaemic target, usually at near-normal or at euglycaemia. Then, PD parameters are obtained through the analysis of the plasma glucose (PG) and the GIR profiles (Figure 1). In order to interpret PK/PD data correctly, the following aspects of clamp studies should be considered: GIR Data Should Be Analysed Preferably Considering PG Data. In subjects with impaired/absent endogenous insulin secretion, GIR gives only a partial picture of the PD of the injected insulin. This should be completed with the PG information during the clamp procedure in order to correctly define and interpret all PD parameters (Figure 2) and to assess the quality of the glucose clamp. In fact, in case of major PG deviations from the study target, GIR does not really reflect insulin action.

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Figure 2. These cartoons show the importance of looking at both glucose infusion rate (GIR) and plasma glucose (PG) when interpreting pharmacokinetic and pharmacodynamic (PK/PD) clamp studies. Ideally, basal insulin at the ‘perfect’ dose should maintain PG at euglycaemia during the inter-injections interval (for example, 24 h) without any need for exogenous glucose [i.e. restraining hepatic glucose production as to exactly match fasting glucose uptake (GU)]. In this ideal case, GIR would be 0 and PG constant during the considered period. Now, imagine that the above results are from three different basal insulin preparations, A-B-C, injected into subjects with type 1 diabetes (T1DM). If one looks only at GIR (panel 1), she/he might conclude that insulin A has the longest duration of action whereas insulin C has the shortest. However, if the concomitant PG is that shown in panel 2 we see that all of the three insulins maintain PG constant during the study period and hence have the same duration of action when it is measured based on PG criteria (although insulin A would still have higher potency, and likely greater duration of action than the others). On the contrary, if PG is that shown in panel 3, insulin A will exhibit the longest duration of action and the greatest potency as compared to B and C.

This is particularly true for basal insulin formulations when looking at the duration of action [12,17–19]. In clamp studies of long-acting insulin formulations, the end of action may not be reached because the duration of action is greater than the preplanned duration of the study. In such studies, the end of action is the duration of the clamp itself, hindering the possibility of detecting differences between insulins. Ideally, individual GIR and PG profiles should be published to give information about the sometimes large intra- and inter-subject PD variability of insulin formulations [20]. Study Subjects. Most PK/PD studies have been performed in healthy subjects. However, as has been noted by others [17], these study results may be confusing due to existing endogenous insulin secretion and the effect of prolonged fasting that interfere with the determination of some PD parameters, namely onset, overall activity and especially duration of action. This is particularly true when long-acting preparations are studied. To overcome these limitations in healthy subjects, a constant low dose i.v. insulin infusion (e.g. 0.15–0.2 mU/kg/min) has been proposed by some authors to suppress endogenous insulin secretion during the clamp [21]. The metabolic effect of the i.v. insulin, however, may anticipate the onset of action and delay the end of action of the insulin formulation under study, resulting in an observed PD which is the sum of the s.c. plus the i.v. insulin action [18]. For these reasons, we and others consider that subjects with T1DM represent the cleanest model for PK/PD studies [17], especially for long-acting insulin formulations where the end of action parameter is of particular relevance. Owing to the

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absence of any endogenous insulin secretion in these subjects, waning of insulin action during the clamp study will be sensitively reflected initially by a decrease in the GIR (Figure 1, last part of the t 3 –t 4 period), followed by the rise of PG concentrations (Figure 1, at some point following t 4 ), free fatty acids (FFA) and β-OH-butyrate (BOH) [17,22]. A more precise definition of PD parameters is therefore possible in T1DM as compared to both healthy subjects and patients with T2DM. Indeed, T2DM represents a very heterogeneous population, in which the endogenous insulin secretion might be impaired to a variable extent (from mild defects in prandial insulin secretion to absolute insulin deficiency), making the interpretation of clamp studies a difficult task. Remaining endogenous insulin may be additive to the action of exogenous insulin and this may explain why both PD and clinical studies in T2DM found smaller differences between insulins as compared with studies in T1DM (see below). Although PD data from T1DM patients cannot directly be transferred to the whole T2DM population, a substantial part of patients with T2DM will eventually develop almost absolute insulin deficiency with increased risk of hypoglycaemia. In this context understanding the differences between insulin formulations becomes relevant to clinical practice. Insulin Dose. PD parameters are dose-dependent either with basal [23,24] or prandial insulin formulations [25]. As a general rule, the greater the dose the higher the peak (GIRmax ), the time to peak (GIR T max ) and the duration of action. Depending on the prevailing plasma insulin concentrations, the insulin effect will result from (i) restraint of hepatic glucose production (HGP) (fasting and postabsorptive state) or (ii)

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Table 1. Main pharmacodynamic parameters of currently available basal insulin formulations.

NPH [20,23,24,31] NPL [35,36,93] Glargine [20,22,31,42] Detemir [20,22,23,37] Degludec [42,43]

Onset of action* (hours)

End of action* (hours)

Duration of action* (hours)

GIR T max (time of peak)

Within-subject variability*,† (CV% of AUC-GIR)

1–2 1–2 1–2 1–2 NR (studied at steady state)

14–15 17–23 22–27 19–23 >42

13–16 16–22 21–27 16–23 >42

5–7 4–7 4–12 7–9 Virtually none

68 48 48–99 27 20

Whenever possible, the data presented here are from studies in subjects with T1DM (the ‘best model’ for the study of the PK/PD of long-acting insulins), which are referenced in the first column. Glargine U300 and LY2605541 are not included because still not available in the market. AUC-GIR, area under the GIR curve; NR, not reported; PK/PD, pharmacokinetic and pharmacodynamic; PG, plasma glucose; T1DM, type 1 diabetes. *The definition may vary among studies (see Figure 1). Additionally, specific clamp conditions such as the target PG (iso- or euglycaemic) may influence these PD parameters. We have reported data of clamp studies where clinically significant doses were injected (0.3–0.4 U/kg). †Within-subject variability (day-to-day variability) is expressed as the coefficient of variation of the AUC-GIRstudy period from clamp studies where each subject received the same insulin dose in repeated occasions.

both suppression of HGP and the increase in peripheral glucose uptake (GU) (postprandial state) [26]. In ideal conditions, basal insulins should regulate PG concentrations by only matching HGP to GU. Therefore, in euglycaemic clamp studies GIR is always expected to be substantially lower than approximately 2.5 mg/kg/min (i.e. the basal HGP in the fasting state under conditions of euglycaemia [27,28]) when a basal formulation is injected at a clinically relevant dose (relevant with regard to the population object of the PD clamp study). This should be considered when comparing GIR profiles from different studies, in order to avoid over- or underestimation of PD parameters (particularly end of action and GIRmax ) [23,24,29]. Owing to the above considerations, we will review mainly the results from clamp studies performed in subjects with diabetes, although relevant aspects of studies in healthy subjects will also be mentioned when appropriate. Similarly, analysis of PD parameters like duration of action or peak activity will be performed only for clinically relevant insulin doses.

Results from Clamp Studies Comparisons Between NPH and First-Generation Long-Acting Analogues. The PK/PD of first-generation basal insulin formulations has been reviewed previously [12,17,19]. Longer duration of the insulin effect and smoother action profile appear to be the main benefits of long-acting insulin analogues over NPH insulin, although this aspect is still somewhat controversial [30]. Findings from glucose clamp studies indicate that at clinically relevant doses (0.3–0.5 U/kg), glargine and detemir (Table 1 and Table S1, Supporting Information) show: 1 Approximately 20–35% greater median duration of action (glargine > detemir > NPH) (Table 1). 2 Smoother mean peak effect (GIRmax ), especially at lower doses in some studies [23,31,32] but not in others [20,24,33,34]. 3 Almost similar equipotency to NPH (as shown by AUCGIRstudy period ) (Table S1). (Although detemir might be less potent than glargine, at least in T1DM). However, as shown below, differences between NPH and analogues are sometimes subtle, especially in T2DM.

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In clamp studies with T1DM, differences between detemir and NPH insulin tend to disappear at higher doses. Indeed, in the study by Wutte et al. [24] detemir had a 26% greater duration of action at 0.3 U/kg dose. However, GIRmax was not different at any dose and both formulations showed a clear peak effect at higher doses [23,24]. A quick summary of the mean peak effect of detemir in comparison with NPH suggests no significant differences in T1DM (Table S1). In contrast, glargine exhibited consistently longer duration of action and lower peak activity than did NPH (Tables 1 and S1) [20,31], but the difference was not always statistically significant. Of note, NPL resembles the PD profile of NPH and does not seem to offer any advantage other than, perhaps, reduced variability [35,36] (Tables 1 and S1). Recent experiments have confirmed lower duration of action and significantly greater peak activity of NPL as compared with either glargine [35] or detemir [36]. Nevertheless, in T1DM glargine and detemir show a more ‘physiologic’ profile as its action (expressed as AUC-GIRperiod ) is more smoothly distributed. In contrast, both NPH and NPL exert most of their action during the first 12 h following injection, as shown by a high AUC-GIR0–12h /AUC-GIR12–24h ratio [22,31,36]. In addition, analogues show lower withinsubject variability (detemir < glargine < NPH) (Table 1) which may be translated into lower probability of large deviations from mean insulin activity reducing the risk of both hyper- and hypoglycaemia [20]. As already mentioned, results from studies in subjects with T2DM are difficult to interpret. The existing differences among insulin formulations are subtle and can be easily masked by residual endogenous insulin secretion and/or by the heterogeneity of the studied population. In fact, the differences observed in T1DM in terms of duration of action and peak activity tend to disappear when subjects with T2DM are studied. Lucidi et al. published a three-way, crossover, 32-h euglycaemic clamp study comparing 0.4 U/kg of NPH, detemir and glargine [33], showing that all of the insulin formulations maintained PG at target during at least 24 h. Additionally, no clear peak effect was observed with any of the study drugs. The only meaningful difference was the increase in the morning PG with NPH insulin, which was not observed with the analogues, suggesting their greater efficacy in coping

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with the dawn phenomenon. Detemir showed lower potency than NPH and both showed lower potency than glargine (detemir < NPH < glargine) [22]. Comparisons Between Glargine and Detemir. Comparisons between these two first-generation analogues have been an object of controversy, especially regarding its duration of action [17,19]. Although with some discrepancy in absolute numbers, data suggest that glargine has longer duration of action and possibly greater potency than detemir (at least in T1DM), but also significantly higher variability (Tables 1 and S1). When detemir was compared with glargine in T1DM in a study with crossover design, it showed significantly lower AUCGIRperiod and median duration of action [17.5 (range 13–24) vs. 24 h (range 22–24)] [22]. Interestingly, a recent parallel group study of glargine and detemir confirmed significantly longer duration of action of glargine at steady state (27.1 ± 7.7 vs. 23.3 ± 4.9 h) and its greater potency (a 30% greater AUCGIR0–30h ) [37]. In contrast to Porcellati et al. [22], detemir exhibited a duration of action close to 24 h, as already shown by others [19]. However, distribution of hypoglycaemic activity was smoother with glargine (AUC-GIR0–12h /AUC-GIR12–30h ratio of 0.86), whereas detemir exerted most of its activity during the first 12 h (AUC-GIR0–12h /AUC-GIR12–30h ratio of 3.32) [37]. As mentioned before, Lucidi et al. also demonstrated longer duration of action and greater potency of glargine as compared with detemir in T2DM [33]. In contrast, a dose–response study comparing glargine with detemir showed similar potency, peak activity and duration of action at all doses [38]. The latter finding has been recently confirmed in another 24-h euglycaemic clamp study [39]. However, the short duration of these studies as compared to the study by Lucidi et al. (24 vs. 32 h) was probably inadequate to find a difference. Second-Generation Formulations. Among second generation of long-acting analogues, insulin degludec is currently the only available in some countries (UK, Denmark, Japan, Mexico and Switzerland), whereas glargine U300 and PEGylated insulin lyspro (LY2605541) are expected to be marketed in the next years. PD studies with degludec have used glargine as a comparator and have reported longer duration of action, smoother profiles and possibly lower intra-subject variability as compared to first-generation formulations (glargine, detemir) [30,40,41]. However, the real clinical impact of these differences remains largely unknown, as only few direct comparisons in T1DM or healthy subjects have been published (mostly as abstracts). Direct comparisons of the PD properties between second- and first-generation long-acting analogues in T2DM are not available. Among the newest analogues, degludec has been studied more extensively. It has a half-life of approximately 25 h, twice as long as glargine, and a blood glucose (BG)-lowering action extending beyond 42 h at steady state, being virtually peakless and with very low intra-subject variability (Table 1) [42–45]. Degludec was compared with glargine in T1DM, demonstrating four times lower day-to-day variability [42] and a more uniform distribution of glucose-lowering effect [44,46]. However, due to its prolonged activity it is difficult to estimate exactly the end

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review article of action (in 42h-clamp studies there was a persistent on-going insulin activity at the end of the clamp) [46]. Additionally, some aspects of degludec PK/PD remain unknown as several parameters such as onset of action and time to peak have not been published. Few PD data on glargine U300 are available [47–49]. When compared to glargine U100 in subjects with T1DM, glargine U300 showed flatter profiles with less fluctuation in individual GIRs and longer duration of action [47,50]. In a 36-h clamp study, 0.4 U/kg of glargine U100 was compared with three different doses of glargine U300 (0.4, 0.6 and 0.9 U/kg) [47,50]. After 20 h, mean PG levels for glargine U100 gradually increased until clamp end. In contrast, increasing doses of glargine U300 resulted in PG more tightly to the clamp level (around 5.5 mmol/l) at the end of study (36 h). Consistent with these findings, the T50%-AUC-GIR0–36h median values were around 18 [17,23,31] hours for glargine U300, but only 12 h for glargine U100. AUC-GIR0–36h increased with glargine U300 doses, but the overall potency was reduced as compared with glargine U100. No formal analyses of peak activity, time to peak and intra-subject variability of glargine U300 have been reported to date. The second-generation analogue PEGylated insulin lyspro (LY2605541) has been studied in a 24-h clamp study in T2DM. Four groups of insulin-treated subjects (8 patients per group) received each one a different dose of LY2605541 (3, 4.5, 6 and 9 nmol/kg), showing duration of action apparently greater than 24 h and an even distribution of the insulin effect over the study period [51]. However, a clear dose–response relationship could not be demonstrated likely due to the small number of the subjects and the study design [51]. When compared with glargine in healthy subjects in a dose–response clamp with crossover design, LY2605541 showed sustained GIR for at least 36 h without a clear peak effect. In contrast, glargine waned at 24 h and showed a smoothed peak effect at 12–14 h that increased with dose. A clamp study with crossover design in subjects with T1DM showed lower mean GIR (normalized to unit of insulin) for LY2605541 than glargine [52]. Glucose infusion persisted over 24 h with LY2605541 whereas with glargine it started to decline at approximately 20 h. Although a flatter GIR profile with LY2605541 has been suggested, the distribution of the hypoglycaemic effect of both insulins over the study period was quite uniform. Indeed, the ratio between the mean GIR of the first/last 6 h of study was 0.75 with LY2605541 and 1.17 with glargine. In summary, first generation of basal insulin analogues offer overall modest but consistent PK/PD benefits over NPH insulin. Differences between glargine and detemir are subtle but do exist [22,37] and, as explained below, may have some clinical implications (Table 2), especially in T1DM. Preliminary PD data of second-generation analogues suggest a further step toward the ‘ideal’ basal insulin, i.e. flat, consistent and protracted duration of action of more than 24 h. Owing to the paucity of available data (especially for glargine U300 and LY2605541), these findings must be confirmed particularly with regard to the issues of peak action (all formulations), potency, variability and distribution of activity (glargine U300 and LY2605541).

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Table 2. Summary of the main PD characteristics and findings of clinical studies of currently available basal insulin formulations and its implications for clinical practice. Glargine U300 and LY2605541 are not included because still not available in the market. PK/PD main results

Results from clinical trials

Special considerations

Translation into clinical practice

Duration of action NPH < detemir < glargine < degludec Peak activity NPH: significant* 3–7 h following injection Detemir and glargine: smooth Degludec: apparently peakless† Potency NPH = detemir ≤ glargine ≤ degludec Variability NPH < glargine < detemir < degludec

Same HbA1c but lower incidence of hypoglycaemia with the analogues. As compared to glargine, detemir may require twice-daily administration (in 30–50% of patients) and a greater dose (up to 50%) to achieve similar metabolic control Degludec appears to further reduce the risk of hypoglycaemia as compared with first-generation analogues. Ultra-long duration of action allows for between-injections interval of up to 48 h without deterioration of metabolic control

The absolute incidence of hypoglycaemia is very low in early T2DM, making it difficult to appreciate differences between insulin formulations in clinical practice Differences between analogues become apparent with absolute insulin deficiency (T1 and advanced T2DM)

NPH may be used in insulinization of short-duration T2DM with a low absolute risk of hypoglycaemia When insulin deficiency is present and in patients at risk from hypoglycaemia (frail patients), the use of analogues should be preferred whenever possible: Glargine can be successfully administered once daily in most patients Detemir may require twice-daily administration in a significant proportion of patients. This may allow a better tuning of day- and night-time basal insulin replacement when high glycaemic variability is an issue Flexibility in degludec timing of injection may represent an advantage, especially in people with less predictable lifestyle (delayed/missed doses)

NPH, neutral protamine Hagedorn; PD, pharmacodynamic; T2DM, type 2 diabetes. *At a clinically relevant dose (i.e. achieving fasting blood glucose euglycaemia), it may induce complete suppression of hepatic glucose production and/or stimulate glucose uptake causing hypoglycaemia. †At steady state.

The most critical remaining question is whether new basal insulin formulations with better PD profiles will result in improved metabolic control.

How Results from PK/PD Studies Can Help in Predicting Results from Clinical Trials NPH Insulin and First-Generation Long-Acting Analogues Patients with T1DM. A recent meta-analysis reported that in patients with T1DM, long-acting insulin analogues (glargine, detemir) are as effective as NPH insulin, except for detemir twice daily which resulted in a slightly higher decrease of HbA1c [−0.14% or 1.3 mmol/mol, 95% confidence interval (CI) −0.21 to −0.08] [53]. Alternatively, another meta-analysis found small but statistically significant improvement in HbA1c with glargine (−0.11% or 0.97 mmol/mol, 95% CI −0.21 to −0.02%) with a non-significant 10–20% difference in the risk of any type of hypoglycaemia [7]. In contrast, no significant reductions in HbA1c were found with detemir, although there were slight diminutions in severe hypoglycaemia and nocturnal hypoglycaemia in T1DM [7]. Direct comparisons between glargine and detemir in T1DM did not show major differences in reducing HbA1c or in rates of hypoglycaemia between them [53].

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The finding of substantial equivalence in terms of HbA1c reduction between human insulin and analogues [7,10] is not surprising at all. Indeed, these are the expected results of the ‘treat to target’ strategies implemented in the vast majority of randomized, controlled clinical trials. Some differences, however, can be noticed. When a combined analysis of HbA1c and hypoglycaemia is performed [54,55], it becomes evident that when NPH is used the same metabolic control can be achieved but at the expense of an overall approximately 20–30% greater incidence of hypoglycaemia (particularly nocturnal episodes) [7,10]. The latter is the expected result of greater GIRmax and variability with protaminated formulations [20,31,35,36], which at some time after its injection (usually 3–7 h) may result in over-insulinization. Owing to its shorter duration of action (Table 1), NPH must be administered at least twice daily in a very fixed regimen for optimal insulin replacement (Table 2). For example, early administration of NPH at dinner was demonstrated to increase the risk of nocturnal hypoglycaemia as compared with bedtime administration at 23 h [56]. In contrast, PD of insulin analogues allow for a more convenient once-daily injection in most patients. Together with the lower risk of hypoglycaemia, this explains why detemir and glargine have also been shown to be associated with improved quality of life, and higher treatment satisfaction compared with NPH [57,58]. However, the latter

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finding should be interpreted with caution as it has been shown in studies with an open design potentially prone to bias. When detemir is compared with glargine, differences are subtle but do exist and explain at least some of the clinical findings. As pointed out by others [30,41], detemir appears to be slightly less potent and to have marginally shorter duration of action than glargine, requiring approximately 20–30% greater dose and twice-daily administration in a high proportion of patients to achieve similar HbA1c targets [59,60]. Interestingly, this observation could be predicted from the results of PK/PD studies with crossover design (which rules out the large inter-individual variability), which showed lower AUC-GIRtot , shorter duration of action and greater AUCGIR0–12h /AUC-GIRtot with once-daily detemir as compared with glargine [22,37]. On the other hand, from a clinical point of view it is likely that the lower PD variability observed with detemir [20] contributes significantly to the lower incidence of hypoglycaemia, especially nocturnal and severe episodes [59]. Patients with T2DM. A large number of studies have been published comparing first-generation long-acting analogues with NPH insulin in patients with T2DM. In combination with oral agents, both glargine and detemir (once or twice daily) were as effective as NPH insulin in lowering HbA1c. In addition, detemir was associated with less weight gain than either NPH insulin or glargine [55,61,62]. Under basal-bolus therapy, no significant differences between detemir and NPH insulin were found in terms of HbA1c reduction (0.10, 95% CI −0.18 to 0.38%) [7]. Regarding hypoglycaemia, first-generation analogues are also associated with less hypoglycaemic risk in patients with T2DM, especially for nocturnal episodes, with reductions between 46 and 61% [55,61,63,64]. One meta-analysis did not find any difference in reduction of severe hypoglycaemia with long-acting insulin analogues in combination with oral agents, although there was a high degree of heterogeneity between studies [7]. Similar results have been found in comparisons using basal-bolus therapy: less risk of nocturnal hypoglycaemia (∼45%), less risk of overall hypoglycaemia but the same risk for severe hypoglycaemia [7]. As pointed out earlier in connection with T1DM, the finding of equivalent metabolic control in patients with T2DM is largely the result of the treat-to-target strategies [7,10,55,61,63,64]. However, higher reduction of fasting blood glucose (FBG) was observed with the analogues when following a previously established titration algorithm. This is in line with the greater suppression of morning hepatic glucose production with detemir and glargine than with NPH [33], and with the longer duration of action of analogues observed in T1DM [23,31]. Although in T2DM NPH duration of action was not different from that of detemir and glargine, [33], as previously explained, this could be due to residual endogenous insulin secretion of the study subjects. A few studies compared glargine with detemir in patients with T2DM [65–69]. When detemir was administered twice daily in combination with oral agents, no significant differences were found regarding HbA1c reduction or nocturnal hypoglycaemia [68]. The same result was found when detemir could be injected either once or twice daily, although 55% patients on detemir required twice-daily administration

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review article [65]. In both studies [65,68], the mean detemir dose was 50–75% greater than glargine. When both insulins were administered once daily [69], detemir resulted in higher HbA1c, 14% greater dose and slightly lower overall rate of hypoglycaemia (but not nocturnal hypoglycaemia). In a basalbolus regimen with aspart as the prandial insulin, there were either no differences [65] or a minor reduction in HbA1c [66] (0.21% or 1.7 mmol/mol, 95% CI 0.0149–0.3995), and no differences in overall hypoglycaemia risk [66]. Further, approximately 88% of patients in the detemir group remained on a once-daily regimen and the total daily insulin dose was only marginally greater (0.81 ± 0.456 and 0.75 ± 0.324 U/kg for the detemir and glargine groups, respectively – p = 0.100) [66]. These findings are in line with the similar PD profiles observed in subjects with T2DM [38]. Indeed, the limited differences observed in T1DM are likely to be compensated by the residual endogenous insulin secretion [33] frequently observed in clinical practice. Nevertheless, according to the findings of clamp studies in T1DM [22,37], the shorter duration of action of detemir, its time profile and potency explain why a subset of patients with T2DM will need twice-daily administration and greater doses as compared with glargine.

Second-Generation Analogues Second-generation analogues have recently been the object of a detailed review [41], with special focus on degludec clinical trials. Although with some inconsistencies [41], findings demonstrate that once-daily degludec is not inferior to comparators and suggest a minimal reduction in overall hypoglycaemia (∼10%) and a lower rate of confirmed nocturnal hypoglycaemia episodes (∼25%) [46]. Very preliminary results with glargine U300 and LY2605541 suggest similar reductions in the rate of nocturnal hypoglycaemia [70–72]. Patients with T1DM. Clinical data suggest that degludec reduces the incidence of nocturnal hypoglycaemia by ∼25% and achieves better fasting plasma glucose (FPG) as compared with glargine [73–75], whereas achieving comparable results in terms of HbA1c reduction. Interestingly, one study shows that this can be obtained by administrating degludec either in a fixed (every 24 h) or flexible regimen allowing variations in the daily injection times [74]. However, rates of overall confirmed hypoglycaemia were numerically (although not significantly) worse for degludec than glargine [73,75]. This finding in patients with T1DM was confirmed by a separate analysis by the Food and Drug Administration (FDA) [46]. Results in term of reduction of hypoglycaemia are somewhat inconsistent as they are sensitive to changes in the definition of hypoglycaemia [41]. Nevertheless, whatever the magnitude of the phenomenon, a reduction in the incidence of nocturnal hypoglycaemia (along with lower FPG) is the expected result of the flat PD profile and very low intra-patient variability of degludec (Tables 1 and 2) [42]. The fact that this reduction was also obtained when intervals between injections were significantly different from 24 h [74] is an indirect confirmation of the positive effects of degludec’s ultra-long duration of action and reduced intra-subject variability.

doi:10.1111/dom.12256 701

review article Very few data on the use of LY2605541 are available in T1DM. Actually only one short open label, phase II, crossover study (8 weeks, followed by crossover to the comparator treatment for a further 8 weeks) compared PEGylated insulin lyspro with glargine, both administered once daily in the morning, in a basal-bolus regimen with prandial insulin [70]. LY2605541 achieved better glycaemic control as shown by lower mean daily blood glucose (8.0 vs 8.4 mmol/l, p < 0.001) and a greater improvement in HbA1c from baseline (−0.59% or −4.1 mmol/mol vs. −0.43% or −2.3 mmol/mol, p < 0.001). Nocturnal hypoglycaemia was slightly but significantly less frequent with LY2605541 than glargine (0.88 ± 1.22 vs. 1.13 ± 1.42, p = 0.012), apparently confirming the flatter PD profile of LY2605541 [52]. However, the overall rate of hypoglycaemia was higher for LY2605541 than glargine (8.74 ± 7.70 vs. 7.36 ± 6.80 events/30 days, p = 0.04). Additionally, FBG levels were not different, indicating similar suppression of hepatic glucose production in the morning, despite glargine is theoretically supposed to be at the end of action. The latter findings (greater overall rate of hypoglycaemia and similar FBG), combined with approximately 24% lower meal-time insulin requirement during LY2605541 treatment, suggest greater activity than glargine at some point in the 12-h period following injection. These findings, however, are in contrast with the few available PD data and need further investigation with clamp and clinical studies. No data are available on the use of glargine U300 in comparison with glargine U100 in T1DM. Patients with T2DM. Recent trials have compared degludec with glargine either in basal only (‘BEGIN ONCE LONG’ and ‘BEGIN FLEX’ trials) [76,77] or basal-bolus regimens [78]. Results proved that degludec is not inferior to glargine in terms of metabolic control. The overall confirmed hypoglycaemia rate was not significantly different in the basal-only trials, with rate ratios (RR) degludec/glargine of 0.82 (95% CI 0.64–1.04) [76] and 1.03 (95% CI 0.75–1.40) [77], whereas it was lower in the basal-bolus regimen (RR 0.82, 95% CI 0.69–0.99) [78]. Confirmed nocturnal hypoglycaemia was reduced by 25–30% in all studies (RR between 0.64 and 0.77) [76–78], but in one case the reduction did not achieve statistical significance (RR 0.77, 95% CI 0.44–1.35) [77]. Similarly, once-daily degludec in a premixed formulation with aspart (respectively 70 and 30%), administered with a main meal, yielded a 37% reduction in nocturnal hypoglycaemia when compared with detemir once daily at the evening meal or at bedtime [79]. Only one open label, phase II study compared LY2605541 with glargine in previously basal insulin + OADS treatment [72]. As in T1DM, LY2605541 achieved lower mean daily blood glucose (least square mean difference −8.8 in favour of study drug, 90% CI −15.0, −2.7), lower intra-day blood glucose variability and a 48% rate reduction in nocturnal hypoglycaemia than glargine (the latter after adjusting for baseline hypoglycaemia). However, the mean rates (±s.e.) (number of events/30 days) of nocturnal hypoglycaemia were not different (0.25 ± 0.07 vs. 0.39 ± 0.12, p = 0.178). At variance with T1DM, mean rates of total hypoglycaemia were similar with both insulins (1.34 ± 0.26 vs. 1.52 ± 0.34,

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LY2605541 vs. glargine, p = 0.804). This could be due to the very low absolute incidence of hypoglycaemia and the small sample size, and requires confirmation in further studies. To date, only very limited data on glargine U300 are available from the EDITION programme [71]. The EDITION I compared U300 with glargine in a basal-bolus regimen. The main finding was the lower occurrence of any nocturnal hypoglycaemic event (% of people with at least one event) during the 6-month study period with U300 as opposed to glargine (45.3 vs. 59.7%; RR 0.76; 95% CI 0.66–0.87). Sanofi claims similar results in patients treated with basal insulin plus oral antidiabetic agents (EDITION II) [71].

Basal Insulin Replacement in Clinical Practice Patients with T1DM Patients with T1DM unequivocally benefit from early attainment of good metabolic control [80]. PK/PD studies show that long-acting analogues mimic the physiology of insulin secretion better than NPH (see above) and thus are better suited for insulin replacement. Hypoglycaemia (especially nocturnal episodes) remains the major barrier for optimization of FBG with NPH insulin [81]. The peak action of NPH (5–7 h following its injection) often results in an over-insulinization during the postaborptive and fasting states and thus greater incidence of hypoglycaemia, especially during the night [56] due to reduced counterregulatory responses to and awareness of hypoglycaemia [82]. Significantly, the greatest clinical benefits are expected when both long-acting and short-acting insulin analogues are used in combination. In the few clinical trials where analogue-based was compared with HI-based basalbolus regimen, analogues demonstrated superiority at least regarding reduction of nocturnal hypoglycaemia [7,54,83–85]. The same finding has been shown in recently published trials comparing the newest analogues degludec and LY2605541 with glargine, highlighting the positive clinical effects of a ‘flat’ profile and reduced PD variability [70,73–75,79,86]. As patients with T1DM are at high risk for and from hypoglycaemia [87] and considering that exposure to repeated hypoglycaemia is burdensome [88], we believe that all patients with T1DM should benefit from the widespread use of analogue-based basal-bolus regimens [or continuous subcutaneous insulin infusion (CSII) when indicated]. In addition, patients with hypoglycaemia unawareness, who usually are excluded from clinical trials, may expect to have particular benefit from the favourable PK/PD characteristics of insulin analogues [81]. Following this concept, a further benefit may be obtained by the use of degludec (and perhaps also from the other second-generation analogues) based on PK/PD data [42,44,46]. These advantages seem to be confirmed by the findings from Phase III clinical trials [73–75]. However, degludec did not reduce overall hypoglycaemia consistently across clinical trials [41]. Additionally, some concern has been raised regarding its cardiovascular safety [89]. For these reasons, although ultra-long duration and low variability of action of degludec may represent an advance over first-generation analogues

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(compensating for missing injections or unpredictable lifestyle in some people), its superiority must be still demonstrated in clinical practice. On the other hand, NPH at lower doses exhibits only a modest peak effect. Therefore, when long-acting insulin analogues are not affordable, splitting NPH into 2–4 daily injections is still an effective and safe strategy for basal insulin replacement in patients with T1DM [81,90].

Patients with T2DM The addition of basal insulin to previous oral agents has achieved wide acceptance as an easy and effective way of starting insulin treatment in T2DM when optimization of metabolic control is needed [91]. The same metabolic control can be obtained with any of the basal insulin formulations, especially if titration strategies are implemented [92]. But clearly, lower incidence of hypoglycaemia is expected with long-acting insulin analogues due to their generally smoother distribution of activity over 24 h and lower variability. The fact that the mean reduction of hypoglycaemia is ‘only’ 20–30% reflects the small differences observed in terms of GIR Cmax in patients with T2DM [33] (residual endogenous insulin secretion protects against hypoglycaemia). For the same reason, differences are more evident during the night because subtle PD dissimilarities are more likely to be observed in the fasting state without the glycaemic perturbations and variability induced by meals (and, in the case of basal-plus and basal-bolus, by prandial insulin). Interestingly, the recently published trials comparing secondgeneration with first-generation long-acting analogues showed lower incidence of nocturnal hypoglycaemia [71,72,76–78], confirming the favourable effect of reduced PD variability and a flat GIR profile on glucose control also in T2DM [42,43]. However, in the basal-only trials, the incidence of nocturnal hypoglycaemia was very low in absolute numbers (less than 1.5 episodes/patient/year with all insulin analogues and even lower in the most recent trials), making a 20–30% reduction undetectable in clinical practice. Thus, insulinization of people with T2DM may be safely initiated with NPH, at least in the early stages of T2DM that exhibit low risk for hypoglycaemia [87]. Notably, due to its PD profile [35,36] NPL is not expected to offer any advantage over NPH [93] and at greater cost (about 30%) in countries where it is commercially available (Spain, Italy and Japan). Nevertheless, patients with longstanding T2DM requiring full insulin replacement show an increased risk for (and from) hypoglycaemia [87]. As a result, the prescribing physician should carefully balance between the need for strict metabolic control and the risk of hypoglycaemia for her/his patients and then use longacting insulin analogues for those at higher risk. In this regard, the use of second-generation analogues may represent a small additional advantage, especially for those patients with high glycaemic variability. This theoretical benefit must be confirmed in further clinical studies.

Conclusions In conclusion, scientific evidence alone frequently is not enough for helping physicians in tailoring insulin treatment

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to individual patient needs. Results from clinical trials do not strongly support any of the current available basal insulins over the others, and frequently generate confusion and uncertainty among physicians. Certainly, insulin marketing might have played a major role in switching from NPH to long-acting insulin analogues. However, the use of long-acting insulin analogues remains justified for many patients due partially to their favourable PD characteristics resulting in reduced risk of hypoglycaemia and greater convenience as compared to NPH. Nevertheless, considering that the PD differences between long-acting insulin analogues and NPH are subtle and the clinical evidence in favour of the analogues is still controversial, we should not overestimate the expected benefits. A rational approach to the prescription of insulin should always balance the individual patient’s risk for/from hypoglycaemia and the projected glycaemic goal. Keeping these aspects in mind may help in optimizing the anticipated benefits of long-acting insulin analogues and their cost-effectiveness.

Acknowledgements This work has been partially funded by the European Union through the Seventh Framework Programme (FP7/2007/2013) under the grant agreement 252085 (Marie Curie Actions, IEF).

Conflict of Interest When he started writing the manuscript, P. R. was a recipient of a Marie Curie IEF fellowship (grant agreement #252085). He does not have any conflict of interest to declare. F. J. A.-B. has received honoraria as speaker and/or consultant from Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, LifeScan, Lilly, Madaus, MannKind Corp., Medtronic, Menarini, Merck Farma y Qu´ımica, SA, MSD, Novartis, Novo Nordisk, Pfizer, Roche, sanofi-aventis, Schering-Plough and Solvay. In addition, F. J. A.-B. has participated in clinical trials supported totally or partially by AstraZeneca, GlaxoSmithKline, LifeScan, Lilly, MSD, Novo Nordisk, Pfizer, sanofi-aventis and Servier. J. F. A. has no potential conflicts of interest to declare. P. R. designed the study, performed data collection and analysis, wrote and revised the manuscript. F. J. A.-B. performed data collection, wrote and revised the manuscript. J. F. A. contributed to study design and revised the manuscript.

Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Potency as expressed by AUC_GIRtot and peak activity (GIR Cmax ) of commercially available basal insulin formulations, as reported in comparative pharmacokinetic and pharmacodynamic (PK/PD) clamp studies in subjects with diabetes.

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39. Luzio SD, Dunseath GJ, Atkinson MD, Owens DR. A comparison of the pharmacodynamic profiles of insulin detemir and insulin glargine: a single dose clamp study in people with type 2 diabetes. Diabetes Metab. 2013; 39: 537–542. 40. Zinman B. Newer insulin analogs: advances in basal insulin replacement. Diabetes Obes Metab 2013; 15(Suppl 1): 6–10. 41. Owens DR, Matfin G, Monnier L. Basal insulin analogues in the management of diabetes mellitus: what progress have we made? Diabetes Metab Res Rev 2014; 30: 104–119. 42. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab 2012; 14: 859–864. 43. Kurtzhals P, Heise T, Strauss HM. Multi-hexamer formation is the underlying mechanism behind the ultra-long glucose-lowering effect of insulin degludec. Diabetes 2011; 60(Suppl 1A): 42-LB. 44. Heise T, Hovelmann U, Nosek L, Bøttcher SG. Heise: insulin degludec has a two-fold longer half-life and a more consistent pharmacokinetic profile than insulin glargine. Diabetologia 2011; 54: S425. 45. Heise T, Nosek L, Bøttcher SG, Hastrup H, Haahr H. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab 2012; 14: 944–950. 46. fda.gov. Insulin Degludec and Insulin Degludec/Insulin Aspart Treatment to Improve Glycemic Control in Patients with Diabetes Mellitus. NDAs 203314 and 203313. Briefing Document. Available from URL: http:// www.fda.gov/downloads/advisorycommittees/committeesmeetingma terials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm 327017.pdf. Accessed 23 September 2013. 47. Tillner J, Bergmann K, Teichert L, Dahmen R, Heise T, Becker RHA. Euglycemic clamp profile of new insulin glargine U300 formulation in patients with type 1 Diabetes (T1DM) is different from glargine U100. Diabetes 2013; 62(Suppl 1): A234. 48. Dahmen R, Bergmann K, Lehmann A et al. New insulin glargine U300 formulation evens and prolongs steady state PK and PD profiles during euglycemic clamp in patients with type 1 diabetes (T1DM). Diabetes 2013; 62(Suppl 1): A29. 49. Jax T, Heise T, Dahmen R, et al. New insulin glargine formulation has a flat and prolonged steady state profile in subjects with type 1 diabetes (ePoster 1029). 49th EASD Annual Meeting, 23–27 September 2013, Barcelona, Spain. 50. sanofi.com. Available from URL: http://en.sanofi.com/img/content/stu dy/PKD11627_summary.pdf. Accessed 19 September 2013. 51. Sinha VP, Howey DC, Choi SL, Mace KF, Heise T. Steady-state pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 dosed once-daily in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2014; 16: 344–350. 52. Morrow LA, Hompesch M, Jacober SJ, Choi SL, Qu Y, Sinha VP. LY2605541 (LY) exhibits a flatter glucodynamic profile than insulin glargine (GL) at steady state in subjects with type 1 diabetes (T1D). Diabetes 2013; 62(Suppl 1): 917-P. 53. Sanches ACC, Correr CJ, Venson R, Pontarolo R. Revisiting the efficacy of long-acting insulin analogues on adults with type 1 diabetes using mixed-treatment comparisons. Diabetes Res Clin Pract 2011; 94: 333–339. 54. Mullins P, Sharplin P, Yki-Jarvinen H, Riddle MC, Haring H-U. Negative binomial meta-regression analysis of combined glycosylated hemoglobin and hypoglycemia outcomes across eleven Phase III and IV studies of insulin glargine compared with neutral protamine Hagedorn insulin in type 1 and type 2 diabetes mellitus. Clin Ther 2007; 29: 1607–1619. 55. Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering

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review article drugs in insulin-naive people with type 2 diabetes. Diabetes Care 2006; 29: 1269–1274. 56. Fanelli CG, Pampanelli S, Porcellati F, Rossetti P, Brunetti P, Bolli GB. Administration of neutral protamine Hagedorn insulin at bedtime versus with dinner in type 1 diabetes mellitus to avoid nocturnal hypoglycemia and improve control. A randomized, controlled trial. Ann Intern Med 2002; 136: 504–514. 57. Witthaus E, Stewart J, Bradley C. Treatment satisfaction and psychological well-being with insulin glargine compared with NPH in patients with type 1 diabetes. Diabet Med 2001; 18: 619–625. 58. Suh DC, Aagren M. Cost-effectiveness of insulin detemir: a systematic review. Expert Rev Pharmacoecon Outcomes Res 2011; 11: 641–655. 59. Pieber TR, Treichel H-C, 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: 635–642. 60. 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: 2086–2097. 61. Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006; 28: 1569–1581. ¨ 62. Haak T, Tiengo A, Draeger E, Suntum M, Waldhausl W. Lower withinsubject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab 2005; 7: 56–64. ¨ 63. Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care 2000; 23: 1130–1136. 64. Riddle MC, Rosenstock J, Gerich J. The Treat-to-Target Trial: Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26: 3080–3086. 65. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008; 51: 408–416. 66. Raskin P, Gylvin T, Weng W, Chaykin L. Comparison of insulin detemir and insulin glargine using a basal-bolus regimen in a randomized, controlled clinical study in patients with type 2 diabetes. Diabetes Metab Res Rev 2009; 25: 542–548. 67. Hollander P, Cooper J, Bregnhøj J, Pedersen CB. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther 2008; 30: 1976–1987. 68. Swinnen SG, Dain M-P, Aronson R et al. A 24-week, randomized, treatto-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs. Diabetes Care 2010; 33: 1176–1178. 69. Meneghini L, Kesavadev J, Demissie M, Nazeri A, Hollander 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: 729–736. 70. Rosenstock J, Bergenstal RM, Blevins TC et al. Better glycemic control and weight loss with the novel long-acting basal insulin LY2605541 compared

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