Acta Diabetol (2008) 45:253–268 DOI 10.1007/s00592-008-0052-9

ORIGINAL ARTICLE

The role of new basal insulin analogues in the initiation and optimisation of insulin therapy in type 2 diabetes Mike A. Baxter

Received: 11 November 2007 / Accepted: 25 July 2008 / Published online: 3 September 2008 Ó Springer-Verlag 2008

Abstract Intensive insulin therapy aimed at achieving normoglycaemia is becoming increasingly accepted in the treatment of type 2 diabetes (T2DM) to reduce the risk of diabetes-related complications. Insulin therapy is increasingly combined with oral antidiabetic drugs (OADs) to moderate insulin dosage, reduce weight gain and confer cardiovascular protection. However, traditional insulins are associated with limitations that may act as barriers to initiation, and intensive use of insulin therapy. The advent of newer, longer-acting, basal insulin analogues, such as insulin glargine (glargine) and insulin detemir (detemir), offer improved pharmacokinetic and pharmacodynamic profiles compared with neutral protamine Hagedorn insulin (NPH). This potentially provides concomitant improvements in safety, efficacy and variability of glycaemic control. This paper reviews the properties of these new long-acting, basal insulin analogues and their potential roles in facilitating the initiation and optimisation of insulin therapy. Studies that reported the use of insulin and insulin analogues for the treatment of T2DM were identified using Medline. Key search terms included: ‘insulin glargine’, ‘insulin detemir’, ‘NPH insulin’, ‘basal insulin’, ‘longacting insulin’, ‘insulin analogue’, ‘pharmacokinetics’, ‘pharmacodynamics’, ‘dose titration’, ‘algorithms’ and ‘type 2 diabetes’. Abstracts presented at the American Diabetes Association and the European Association for the Study of Diabetes annual congresses were also searched. The data show that the long-acting insulin analogues glargine and detemir both offer a low risk of hypoglycaemia and improved glycaemic control. Aggressive dose M. A. Baxter (&) Diabetologist, Ashford and Saint Peter’s Hospital NHS Trust, Chertsey, Surrey KT16 0PZ, UK e-mail: [email protected]

titration with glargine and detemir facilitates attainment of glycaemic control targets. The goal of achieving good glycaemic control with a low risk of hypoglycaemia may be more feasible with newer insulin therapies as part of a simple basal insulin regimen with continued OADs. Keywords Insulin glargine
Insulin detemir
NPH insulin
Basal insulin
Type 2 diabetes

Introduction A number of studies in patients with type 2 diabetes (T2DM) have confirmed that maintaining good glycaemic control is important in reducing the risk of developing disease-associated complications that can lead to excessive mortality and morbidity [1–6]. The United Kingdom Prospective Diabetes Study (UKPDS) has shown that a 1% decrease in HbA1c is associated with a 37 and 14% reduction in the risk of microvascular and macrovascular complications, respectively [2]. This observation, supported by consistent data from a number of international trials (for example: Steno-2 [5], STudy tO Prevent NonInsulin Dependent Diabetes Mellitus (STOP-NIDDM) [7], Atherosclerosis Risk in Communities (ARIC) [8], Veteran Affairs Diabetes Trial [9] and the self-monitored blood glucose trial [10]), has led to increasingly tight guidelines defining target levels of glycaemic control aimed at significantly reducing cardiovascular risk. The current American Diabetes Association (ADA) [11] and the International Diabetes Federation [12] guidelines recommend target HbA1c levels of \7.0 and B6.5%, respectively. Meanwhile, the Joint Society Guidelines 2 [13] suggests an ‘auditable’ target of 7.5% but stresses an ‘optimal’ target of 6.5%. The European Society of

123

254

Cardiology (ESC), reflecting the drive to reduce cardiovascular risk, has previously suggested a target of B6.1% [14], although recent combined guidelines from the ESC and the European Association for the Study of Diabetes (EASD) have recommended that an HbA1c target of B6.5% is necessary for reducing cardiovascular risk [15]. Despite widespread recognition of the importance of good glycaemic control, few patients with T2DM meet recommended HbA1c targets. In a retrospective analysis of the United Kingdom General Practice Research database (1998–2002), in 2002, 76% of patients (n = 4,732/6,912) had HbA1c C7.0% [16]. Furthermore, of these patients with inadequate glycaemic control, 52% were taking two or more oral antidiabetic agents (OADs) [16]. Therefore, it is apparent that intensive therapies with insulin are needed to allow more patients to reach recommended targets. This is supported by data from the UKPDS [17], which suggest that [60% of patients with T2DM will require insulin, many within 5 years of diagnosis. Implementation of a logical treatment strategy for T2DM needs to address the early phase of the disease (insulin resistance, macrovascular risk and early b-cell failure) and the progression of the disease (b-cell failure and micro- and macrovascular risk). This strategy would consist of early aggressive treatment with OADs (particularly those addressing insulin resistance and conferring cardiovascular protection), followed by the early introduction of basal insulin therapy for patients with T2DM suboptimally controlled with OADs alone. Further escalation would include the use of preprandial insulin to control postprandial glucose excursions, where required. Insulin therapy is increasingly being initiated earlier [18–21], and progressively more aggressive strategies are being employed in an attempt to attain glycaemic control and reduce the risk of diabetes-related complications [2, 19, 22, 23]. Recently, the ADA and the EASD have proposed a treatment algorithm for T2DM, emphasising the early use of insulin and, in particular, basal insulins for patients inadequately controlled with lifestyle interventions and metformin [24]. However, despite evidence supporting the benefits of the early addition of insulin to OADs [18, 21, 25], there are numerous barriers that prevent or delay the initiation of insulin in patients with T2DM, of which fear of hypoglycaemia, weight gain and injections are key factors [26, 27]. Hypoglycaemia, in particular, is a much feared complication of insulin therapy, the risk of which will undoubtedly increase with more aggressive use and attempts to achieve lower HbA1c. The increased risk of hypoglycaemia has limited both the acceptance and efficacy of traditional insulin preparations, such as neutral protamine Hagedorn insulin (NPH). It is now generally accepted that patient concordance represents a major

123

Acta Diabetol (2008) 45:253–268

problem in the treatment of T2DM. This is a complex response, which depends on multiple interactive factors; however, complexity of treatment regimen, a logical approach to treatment and possible adverse events are all important and have yet to be adequately addressed [28]. The ideal insulin therapy would provide good glycaemic control without an adverse impact on patients’ quality of life, by seeking to replicate physiological insulin secretion, thus controlling baseline glucose (basal insulin) by suppression of hepatic gluconeogenesis and, where appropriate, providing postprandial regulation (bolus insulin) to imitate normal glucose homeostasis. There is evidence demonstrating that fasting blood glucose (FBG) should be the key focus in initial management of patients with poor glycaemic control, while postprandial glycaemia should be targeted in patients with lower HbA1c [29]. A simple and practical approach to implementing basal insulin is to continue OAD therapy and add a single basal insulin dose, titrated according to fasting blood glucose (FBG) [25]. Insulin in combination with OADs has been proven to be effective in a systematic review of 20 randomised clinical trials, which confirmed that basal insulin (NPH) plus OAD therapy provided comparable glycaemic control to insulin monotherapy, and was accompanied by an overall reduction in total daily insulin requirement of 43% [30]. The maintenance of OADs (particularly insulin sensitisers) reduces the dose of insulin required, reduces weight gain and helps stabilise glucose levels by peripheral insulin sensitisation and inhibiting hepatic gluconeogenesis. In addition, OADs may confer glucose-independent reductions in cardiovascular risk [1, 5, 7]. Basal insulin therapy utilises the pharmacokinetic properties of longacting insulin analogues to maintain interprandial and overnight glycaemic control without the need for complex multiple dosing. This strategy also allows titration to be accomplished in a safe and simple manner and is an easy ‘first step’ to progressive insulin therapy. As the disease continues to advance, or if more intensive therapy is required to achieve glycaemic targets, the basal insulin dose may be increased, or treatment may be intensified in a simple, logical, step-wise manner to a basal–bolus regimen, by introducing a preprandial fast-acting insulin analogue to control postprandial blood glucose levels. The most widely used basal insulin is neutral protamine Hagedorn (NPH) insulin, which has a half-life of 8 h, necessitating multiple daily dosing to provide 24-h baseline glucose suppression. In addition, the pharmacokinetic profile of NPH increases the risk of hypoglycaemia, which, in patients taking an evening dose of NPH, manifests itself as an increased risk of nocturnal hypoglycaemia [31]. Newer basal insulin analogues include insulin glargine (glargine) and insulin detemir (detemir). Glargine was the first long-acting basal insulin analogue to be launched and

Acta Diabetol (2008) 45:253–268

mimics normal physiological basal insulin concentrations more closely than traditionally available ‘intermediate’ and ‘long-acting’ insulins, such as NPH and insulin ultralente [32, 33]. Detemir was the second long-acting analogue launched and also offers advantages over NPH for patients with T2DM [34, 35]. Evidence to support the use of basal insulin as opposed to intensification of oral therapy has been collected in several recent studies. In the INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) study, patients with T2DM with HbA1c levels 7.5–11.0% on stable therapy with 0–2 OADs, not including thiazolidinediones, were allocated to either an optimised OAD regimen (with no insulin) or initiation of bedtime glargine (with no increase in the oral therapy) [36]. The decreases in HbA1c and FPG were greater with glargine compared with OAD therapy (P = 0.005 and P = 0.0001, respectively), with no difference in the incidence of hypoglycaemia. Thus, in this study, early addition of glargine to current diabetes therapy (diet or OADs) improved glycaemic control and was more effective compared with optimised diet/oral therapy alone [36]. More recently, the Triple-Therapy Trial [37] compared patients with T2DM failing on dual therapy (metformin and sulfonylurea) who were randomised to additionally receive either rosiglitazone or glargine, the doses of which were increased to optimise control. Although similar improvements in HbA1c were observed with glargine (-1.7%) and rosiglitazone (-1.5%), patients receiving rosiglitazone experienced more hypoglycaemia, peripheral oedema and weight gain, and more patients withdrew from the trial compared with the glargine group. This study demonstrates that single basal insulin regimens offer an effective, acceptable and well tolerated alternative to further drug escalation. Although it is clear that basal insulin analogues provide clinically meaningful improvements in glycaemic control, the theoretical long-term benefits of basal insulin analogues on cardiovascular outcomes have been questioned in a recent meta-analysis of studies comparing glargine or detemir with NPH. This analysis reported that, while the rates of symptomatic, overall and nocturnal hypoglycaemia were significantly lower in the glargine- and detemir-treated patients than in those treated with NPH, there was no evidence for a beneficial effect of long-acting basal insulin analogues on patient-oriented outcomes such as mortality, morbidity or quality of life [38]. However, it must be acknowledged that longer-term studies with glargine or detemir are underway and a number of studies reporting quality of life or treatment satisfaction have emerged after the literature search by Horvath et al. was completed. The present review discusses the properties of the two basal insulin analogues, glargine and detemir, and how

255

these features can enable their effective use in a simple basal insulin plus OAD or basal–bolus regimen in order to optimise glycaemic control in patients with T2DM.

Methods Medline was used to identify studies that reported on the use of insulin and insulin analogues for the treatment of T2DM. Abstracts presented at the ADA and the EASD annual congresses were also searched. Key words used for the search included: ‘insulin glargine’, ‘insulin detemir’, ‘NPH insulin’, ‘basal insulin’, ‘long-acting insulin’, ‘insulin analogue’, ‘pharmacokinetics’, ‘pharmacodynamics’, ‘dose titration’, ‘algorithms’ and ‘type 2 diabetes’.

Structure and pharmacokinetic and pharmacodynamic properties of insulin glargine and insulin detemir Insulin glargine Glargine is an analogue of regular human insulin (RHI) produced by recombinant DNA technology. The primary structure of glargine differs from RHI in two ways [39]: (1) two arginine residues are added to the C-terminus of the B-chain, which alters the isoelectric point (from pH 5.4 to 6.7), making the molecule less soluble at the physiological pH of subcutaneous tissue; and (2) the asparagine residue at position 21 in the A-chain of RHI is replaced with a neutral glycine residue (Fig. 1), which stabilises the molecule, to limit deamidation and dimerisation at the acidic pH of 4.0 at which glargine is formulated. Upon injection into the subcutaneous space (pH 7.4), the acidic glargine solution is neutralised and glargine forms an amorphous suspension, resulting in delayed absorption and an extended duration of action (of up to 24 h) [40]. Glargine exhibits both a slower onset and a longer duration of action compared with NPH [32, 40]. The absorption of glargine is slower than that of NPH in healthy volunteers [33] and in patients with T2DM [40]. NPH demonstrates a peak of concentration 4–6 h after administration, while the absorption of glargine from the injection site is relatively constant with no prominent peak in plasma insulin concentration in healthy male volunteers [33]. These properties mean that glargine mimics normal physiological basal insulin concentrations more closely than traditionally available ‘intermediate’ and ‘long-acting’ insulins, such as NPH and insulin ultralente [32, 33]. The smooth, longacting time–action, 24-h profile of glargine is not dosedependent and offers true once-daily dosing and a reduced incidence of hypoglycaemia compared with NPH in the majority of patients with T2DM [31, 41].

123

256

Acta Diabetol (2008) 45:253–268

Fig. 1 The amino acid structure of insulin glargine showing the key amino acid modifications that result in the protracted duration of action

Insulin detemir Detemir is produced by recombinant DNA technology; the amino acid threonine in position 30 of the B-chain of RHI has been omitted, and myristic fatty acid attached to the eamino group of amino acid lysine B29 in order to obtain long-acting properties (Fig. 2) [42]. The prolonged action of detemir is mediated by the strong self-association of detemir molecules at the injection site and albumin binding via the fatty acid side-chain [43]. Studies in patients with Type 1 diabetes (T1DM) have demonstrated that detemir has a slower, more prolonged absorption over 24 h and a flatter time–action profile compared with NPH [44, 45] and, in clinical practice, detemir is typically administered twice daily. An isoglycaemic clamp study in patients with T1DM showed that the duration of action of detemir is dose-dependent; the mean duration of action ranges from 5.7 to 23.2 h at doses of 0.1–1.6 units/kg [45]. At equipotent doses of detemir and NPH, the duration of action of detemir is estimated to be approximately 4 h longer compared with that of NPH (determined by interpolation of results from two different detemir doses) [45]. The peak of action of detemir is dosedependent. This property has potential implications for detemir titration, as peaks of insulin action may be associated with an increased risk of hypoglycaemia, and is a consideration that should be taken into account when switching from once daily to twice daily administration of detemir (discussed below). In contrast, the smooth, longacting time–action profile of glargine shows no pronounced peak of action and is not dose-dependent, offering true once-daily dosing and a reduced incidence of hypoglycaemia compared with NPH in the majority of patients with T2DM [31, 41].

Fig. 2 The amino acid structure of insulin detemir showing the key modifications that result in the protracted duration of action

123

A direct comparison of the pharmacokinetic and pharmacodynamic properties of glargine and detemir has recently been conducted in a 2-week study of 24 patients with Type 1 diabetes [46]. Findings generally agreed with the once-daily dosage of glargine and twice-daily dosing of detemir commonly used in clinical practice as, while both long-acting insulin analogues had a similar onset of action, the end of action was earlier with detemir. This report is, however, in contrast to another recent study comparing detemir and NN344 (both albumin-bound insulin analogues) with glargine in 27 patients with T2DM [47]. In this instance, detemir was found to have a similar time–action profile and duration of action to glargine, suggesting that detemir may also be well-suited to a oncedaily regimen.

Dosing and titration of insulin glargine and insulin detemir Dosing The 24-h duration of action allows glargine to be administered once-daily. Regarding both the fear of injections and the need for simplistic insulin regimens, once-daily insulin dosing has the potential to improve patient acceptance and compliance compared with more frequent dosing regimens [48, 49], particularly when initiating patients on insulin therapy. In addition, the consistent smooth action profile means that glargine can be administered safely and effectively in either the morning or the evening in patients with T2DM providing that the chosen injection time is maintained consistently each day. The administration of both once- and twice-daily detemir has been investigated in

Acta Diabetol (2008) 45:253–268

257

patients with T2DM. The dose-dependent action profile of detemir [45] means that patients may not reach target glycaemic control with increasing doses of once-daily detemir and may benefit from twice-daily regimens, as demonstrated in the recent 4-T [50] and detemir vs glargine head-to-head [51] studies. Titration Appropriate insulin dose titration is required to achieve optimal glycaemic control with minimal incidence of hypoglycaemia and should be performed immediately following initiation of insulin. There are currently fewer published descriptions of detemir titration algorithms in patients with T2DM than for glargine, reflecting the more recent introduction of detemir. Studies performed using glargine suggest that this insulin can be titrated aggressively, but more safely, than with standard basal insulin regimens [25, 52–55]. Its smooth time-action profile, long duration of action and reduced risk of hypoglycaemia give glargine the potential to facilitate and prolong the use of the evening basal insulin strategy, an approach that was used effectively in the Treat-to-Target study [25]. In the 24-week Treat-to-Target study in overweight patients with inadequately controlled T2DM (HbA1c levels 7.5–10%) on one or two OADs, insulin therapy was initiated with a supplemental evening injection of either glargine or NPH, while continuing the current OAD regimen, to achieve HbA1c levels B7% [25]. A forced titration schedule was used to adjust the insulin dose to achieve target fasting plasma glucose (FPG) levels of B5.5 mmol/L (B100 mg/dL) (Table 1). In this study, approximately 60% of patients achieved HbA1c levels \7%. Furthermore, a high compliance rate ([90%) was observed, suggesting that the forced titration algorithm was not only effective, but simple to initiate and maintain Table 1 The forced weekly titration algorithm utilized in the treatto-target approach to insulin therapy with insulin glargine or neutral protamine Hagedorn insulin in Type 2 diabetes [25] Start with insulin dose of 10 U/day at bedtime Mean FPGa, mmol/L (mg/dL)

Increase in insulin doseb (U/day)

5.5–6.7 (100–120)

2

6.7–7.8 (120–140)

4

7.8–10.0 (140–180)

6

C10.0 (C180)

8

FPG fasting plasma glucose a

Considering mean fasting plasma glucose values over the two preceding days

b

Increase weekly in the absence of severe hypoglycaemia and/or plasma glucose levels \4.0 mmol/L (\72 mg/dL)

[25]. The Treat-to-Target method has also been tested in a study of twice-daily detemir versus NPH [56]. Over 24 weeks, insulin doses were titrated toward an FPG target of B6.0 mmol/L (B108 mg/dL) prebreakfast and predinner (Table 2). In both treatment groups, 70% of patients achieved HbA1c levels B7%, and 90% completed the study per protocol. The treat-to-target method, therefore, represents a simple and practical regimen for the initiation and optimisation of basal insulin therapy in patients with T2DM and has been widely used in clinical practice. The AT.LANTUS (A Trial comparing LANTUS Algorithms to achieve Normal blood glucose Targets in subjects with Uncontrolled blood Sugar) study compared an algorithm based on the treat-to-target algorithm managed by the physician (Algorithm 1: adjusted weekly) with an algorithm managed by the subject (Algorithm 2: adjusted every 3 days) in a large (n = 4,961), multinational (59 countries, 611 centres), 24-week study in a real-world population of patients with T2DM (Table 3) [57]. In this study, significant reductions in HbA1c were observed in both treatment algorithms, with greater reductions in HbA1c and FBG observed with the patient-led algorithm versus the physician-led algorithm (HbA1c: -1.2 vs. -1.1%; FBG: -3.4 vs. -3.2 mmol/L [-62 vs. -57 mg/dL], respectively; P \ 0.001) [57]. The PREDICTIVE 303 (Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation) study has demonstrated that patients with T2DM who self-titrate detemir (303 algorithm; dose titration every 3 days; increase insulin dose by 3 units if the mean FPG was [6.1 mmol/L, no change with FPG 4.4–6.1, decrease by 3 units with FPG \ 4.4 mmol/L) achieved better glycaemic control than patients whose doses were titrated by physicians (standard of care). However, while hypoglycaemic events were significantly reduced (P = 0.0039) from study start in the self-titrating patients, these were still more frequent than in patients receiving standard care [58]. Nevertheless, the AT.LANTUS and PREDICTIVE 303 studies demonstrate that clinically important improvements in glycaemic control can be achieved when patients are given increased responsibility in managing their diabetes treatment. The LANMET study [53] of 110 patients with suboptimally controlled T2DM (mean HbA1c 9.5%), placed on twice-daily metformin (1 g), used a patient self-titration treat-to-target algorithm to compare bedtime glargine with NPH and used a modem to transfer home blood glucose values to the treatment centre in conjunction with less frequent (3-monthly) physician contact. The regimen used in this study involved self-titration of 2 U of glargine every 3–7 days if FPG levels exceeded 4.0–5.5 mmol/L (72–100 mg/dL), provided hypoglycaemia did not occur.

123

258

Acta Diabetol (2008) 45:253–268

This regimen offers patients an alternative to the standard treat-to-target algorithm (discussed above) according to clinical circumstances and patient preferences. The LANMET study demonstrated large decreases in HbA1c (glargine: 9.1% at week 0 to 7.1% at week 36; NPH: 9.3% at week 0 to 7.2% at week 36). Although both glargine and NPH regimens were equally effective, the glargine group achieved the reduction in HbA1c with significantly less hypoglycaemia during the first 12 weeks (4.1 vs. 9.0 Table 2 The forced weekly titration algorithm utilized in the treatto-target approach to insulin therapy with insulin detemir or neutral protamine Hagedorn insulin in Type 2 diabetes [56] Criteria for titration

Insulin dose adjustment (units or IU) Responders

Non-responders

A single prebreakfast plasma glucose \3.1 mmol/L (\56 mg/dL) -4

-4

3.1–4.0 mmol/L (56–72 mg/dL)

-2

-2

Average prebreakfast/predinner plasma glucosea 6.1–7.0 mmol/L (109–126 mg/dL)

?2

?2

7.1–8.0 mmol/L (127–144 mg/dL)

?2

?4

8.1–9.0 mmol/L (144–162 mg/dL)

?4

?6

9.1–10.0 mmol/L (163–180 mg/dL)

?6

?8

?10

?10

[10.0 mmol/L ([180 mg/dL) a

Plasma glucose categories are based on the average of three consecutive self-measurements immediately preceding each contact; responders = patients in whom the average plasma glucose value was reduced to a lower category following the previous adjustment; nonresponders = patients in whom the average plasma glucose value remained in the same category or increased following the last adjustment

episodes/patient–year; P \ 0.05), after which the frequency of hypoglycaemia episodes became similar in the two treatment groups and with less weight gain compared with NPH. Further data regarding the efficacy of glargine versus NPH insulin were obtained in the LAPTOP (LANTUS plus Amaryl plus metformin versus Premixed insulin in patients with T2DM after failing Oral treatment Pathways) study [59], which compared once-daily glargine plus glimepiride with twice-daily 30% RHI/70% NPH (premix) in insulin-naı¨ve patients with suboptimally controlled T2DM (HbA1c 7.5–10.5%) on a sulfonylurea plus metformin. A forced insulin titration to target FBG B5.5 mmol/L (B100 mg/dL) was used in this study for both insulins, with an additional pre-dinner blood glucose target B5.5 mmol/L (B100 mg/dL) for the premix. Patients in the glargine plus OADs regimen had greater reductions in HbA1c (-1.64 vs. -1.17%; P = 0.0003) and FBG levels (9.5–6.4 mmol/L [171–115 mg/dL] versus 9.6–7.4 mmol/L [172–133 mg/dL]; adjusted mean between treatment difference: -0.9 mmol/L [-17 mg/dL]; P \ 0.0001), and more patients achieved HbA1c B7% without confirmed nocturnal hypoglycaemia compared with the premix regimen (45.5 vs. 28.6%; P = 0.0013) [59]. The LAPTOP study has been criticised owing to the fact that, unlike the glargine group, patients treated with premix did not receive OADs. However, it should be noted that this trial was designed to compare an innovative new therapy with the previously accepted escalation from oral to insulin therapy through a simple conversion to twice-daily premix without OADs.

Table 3 Summary of the two treatment titration regimens for insulin glargine in the AT.LANTUS study in patients with Type 2 diabetes [57] Mean FBG for the previous 3 consecutive days

Increase in daily basal glargine dose (U)a Treat-to-target algorithmb: titration at every visit; managed by physician

Patient self-titration algorithmb: titration every 3 days; managed by subject

C5.5 mmol/L and \6.7 mmol/L

0–2c

0–2c

2

2

4

2

6–8c

2

(C100 mg/dL and \120 mg/dL) C6.7 mmol/L and \7.8 mmol/L (C120 mg/dL and \140 mg/dL) C7.8 mmol/L and \10 mmol/L (C140 mg/dL and \180 mg/dL) C10 mmol/L (C180 mg/dL)

AT.LANTUS A Trial comparing LANTUS Algorithms to achieve Normal blood glucose Targets in subjects with Uncontrolled blood Sugar; FBG fasting blood glucose a

Target fasting blood glucose B5.5 mmol/L (B100 mg/dL)

b

Reviewed by physician at each visit, either in person or over the telephone; titration occurred only in the absence of blood glucose levels \4.0 mmol/L (\72 mg/dL)

c

Magnitude of daily insulin glargine dose was at the discretion of the investigator.

123

Acta Diabetol (2008) 45:253–268

These studies demonstrate the safety and efficacy of simple glargine treatment algorithms that allow patient involvement and empowerment in the titration of the insulin dose, and may offer patients with T2DM flexibility with respect to the choice of treatment regimen.

Glycaemic control To date, only one study has directly compared glargine with detemir in patients with T2DM [51]. In this study, 582 insulin-naı¨ve patients with T2DM who were taking one or more OADs were randomised to receive either glargine or detemir for 52 weeks. Evening insulin (glargine or detemir) was initiated at 12 U and titrated to achieve target FPG \6.0 mmol/L (108 mg/dL). At 52 weeks, improvements in HbA1c (from 8.6% at baseline to 7.2 vs. 7.1% for detemir and glargine, respectively) and FPG (from 10.8 mmol/L [195 mg/dL] at baseline to 7.1 vs. 7.0 mmol/ L [128 vs. 126 mg/dL] for detemir and glargine, respectively) were similar in both treatment arms. In the detemir arm of the study, if pre-dinner plasma glucose exceeded 7.0 mmol/L (126 mg/dL) escalation of therapy was allowed, with the introduction of a morning dose of detemir. At the end of the study, 45% of patients remained on once-daily detemir while 55% received twice-daily detemir. Both glargine and detemir have been extensively studied using NPH as the comparator of choice, thus, these data can be discussed. Insulin glargine versus neutral protamine Hagedorn insulin for glycaemic control The results of key studies comparing glargine and NPH treatment in patients with T2DM are summarised in Table 4. Several studies have compared glargine with NPH as the supplemental basal insulin to oral therapy, in which glargine typically showed equivalent or improved glycaemic control compared with NPH [25, 31, 55, 60, 61]. For example, in the Treat-to-Target study in patients with T2DM on OAD therapy, mean HbA1c and FPG levels improved with both glargine and NPH treatment and approximately 60% of patients achieved HbA1c levels B7%. Significantly more patients achieved HbA1c levels B7% without documented nocturnal hypoglycaemia with glargine versus NPH (33.2 vs. 26.7%; P \ 0.05) [25]. In a 24-week, randomized study in 695 patients with T2DM comparing morning or bedtime glargine plus glimepiride treatment with bedtime NPH plus glimepiride, morning glargine provided better glycaemic control compared with either bedtime NPH or bedtime glargine [60] (Table 4).

259

In a recent meta-analysis of four trials comparing glargine and NPH (plus OADs or prandial insulin) in patients with T2DM, HbA1c levels at endpoint were comparable with glargine versus NPH (7.8 ± 1.3 vs. 7.7 ± 1.2%) and a similar proportion of patients achieved target HbA1c levels B7% (30.8 vs. 32.1%). Endpoint FPG levels were significantly lower with glargine versus NPH (P = 0.023) [41]. Insulin detemir versus neutral protamine Hagedorn insulin for glycaemic control In the three studies that have been published in full using detemir in patients with T2DM, detemir provided equivalent glycaemic control to NPH (Table 5) [34, 35, 56]. Two studies investigated the use of detemir as part of a basal– bolus regimen in combination with insulin aspart (aspart) [34, 35]. The first study, by Raslova et al. [34] compared detemir (once or twice daily) plus aspart with NPH (once or twice daily) plus RHI over 22 weeks in 395 patients with T2DM. Comparable reductions in HbA1c levels were observed with the detemir and NPH regimens (detemir: from 8.2 to 7.5%; NPH: from 8.1 to 7.5%). At endpoint, FPG levels (mean ± standard deviation [SD]) were also comparable (both 7.3 ± 0.1 mmol/L [132 ± 2 mg/dL]). In the second study, by Haak et al., in 505 patients with T2DM previously receiving insulin therapy, patients received aspart plus detemir or NPH (both once daily or twice daily according to their prior regimen) for 26 weeks [35]. HbA1c levels decreased in both groups, with no between-group differences (detemir: from 7.9 to 7.6%; NPH: from 7.8 to 7.5%). Similarly, there was no difference in the decrease in FPG levels with detemir versus NPH (-0.5 vs. -0.6 mmol/L [-9 vs. -11 mg/dL]) [35]. In the third study, by Hermansen et al., which was a 24week study of 475 patients with T2DM inadequately controlled on OAD therapy and who switched to detemir or NPH (both twice-daily) [56], baseline to endpoint decreases in HbA1c (detemir: from 8.6 to 6.8%; NPH: from 8.5 to 6.6%) and FBG (11.1 to 6.9 mmol/L [200 to 124 mg/dL] vs 10.8 to 6.6 mmol/L [194 to 119 mg/dL]) were similar for both detemir and NPH. The proportion of patients who reached target HbA1c (B7.0%) was similar in both groups (70 vs 74%), however, more patients reached target HbA1c without experiencing hypoglycaemia with detemir (26 vs. 16%) [56]. The uncertainty about the most appropriate, and effective, insulin regimen in patients with T2DM, particularly those in whom insulin is initiated early in the disease process is further underlined by a recent study [50]. The Treating-To-Target in T2DM (4-T) study) compared fixed mixed insulins, premeal fast-acting insulin and once-daily dosing with detemir. The basal arm of this study was undermined by the unspecified conversion to twice daily

123

123

Eliaschewitz et al. [52]

231 250

Bedtime NPH ? morning glimepiride

389

Bedtime glargine ? morning glimepiride

Bedtime NPH ? prestudy OADs

367

9.2

9.0

8.6

8.6

9.1

Bedtime NPH ? glimepiride Bedtime glargine ? pre-study OADs

Riddle et al. [25]

9.1

Bedtime 227 glargine ? glimepiride 232

8.9 9.1

Bedtime NPH ? OADs 281 Fritsche et al. Morning 236 [60] glargine ? glimepiride

9.5 9.1

Bedtime glargine ? OADs

68

9.7

72 289

MassiBenedetti et al. [61]

NPH ? OADs

9.8

9.3

9.1

64

208

Bedtime NPH ? OADs

HOE Study Glargine 30 ? OADs Group [55] Glargine 80 ? OADs

214

Bedtime glargine ? OADs

Yki-Ja¨rvinen et al. [31]

7.8 (-1.4)

7.6 (-1.4)

7.0 (-1.6)

7.0 (-1.7)

6.9 (-5.3)

6.8 (-5.2)

7.4 (-2.6) 7.0 (-5.1)

10.8

11.2

6.6 (-4.1)

6.4 (-4.8)

FPG: 10.8 FPG: 6.7 (-4.1)

FPG: 11.0 FPG: 6.5 (-4.5)

8.3 (-0.84) 12.2

8.1 (-0.96) 12.0

8.5 (-0.38) 9.9 7.8 (-1.24) 12.1

7.2 (-2.7)

FPG: 11.7 FPG: 8.6 (-3.1)

FPG: 12.2 FPG: 8.7 (-3.5)

FPG: 12.6 FPG: 9.2 (-3.4)

FPG: 11.0 FPG: 6.0 (-5.0)

?0.68

Events/pt–yr:

NA

BG B3.1 mmol/L: 1.3

2.6% 4.4%

52.8% 62.8%e

BG B3.1 mmol/L: 5.1

34.8%e

20.4%

BG B3.1 mmol/L: 2.5e

BG B4.0 mmol/L: 5.5e

BG B4.0 mmol/L: 12.9e e

Nocturnal: 6.9

Symptomatic: 17.7e

Events/pt–yr:

BG B3.1 mmol/L: 3.0 NA

BG B4.0 mmol/L: 3.1 BG B4.0 mmol/L: 9.2 Events/pt–yr:

Nocturnal: 4.0

Symptomatic: 13.9

Events/pt–yr:

38%f, 2.6%

58%f

23%

1.8%

NA

NA

?2.8 ± 0.2

?3.0 ± 0.2

NA

NA

?1.88 NA

24%d 17%

43%g

?2.01

12%

h

?0.64 19.1%d

?0.31

?3.5 ± 0.7

?2.6 ± 0.6

Change in weight (kg)

8.3%

6.3%

NA

NA

Nocturnal

c

NA 2.1%

NA

NA

NA

NA

0

0

Severe

b

41% 56%

35%

32.4%

25.0%

18.8%

8.0 episodes/pt

5.4 episodes/pt

a

Incidence of hypoglycaemia

Endpoint (Change) Symptomatic

FPG: 11.3 FPG: 5.7 (-5.6)

Baseline

FBG (mmol/L)

8.6 (-0.46) 9.9

8.7 (-0.8)

8.8 (-0.9)

9.0 (-0.8)

7.2 (-2.1)

7.1 (-2.0)

Baseline Endpoint (Change)

No. of Outcome measure patients HbA1c (%)

Insulin regimen

Study

Table 4 Key trials and recent studies in patients with Type 2 diabetes comparing once-daily insulin glargine with once- or twice-daily neutral protamine Hagedorn insulin when insulin is initiated to patients on oral antidiabetic therapy

260 Acta Diabetol (2008) 45:253–268

291

8.6

9.6

9.5

7.1 (-1.5)

7.2 (-2.4)

7.1 (-2.4)

FPG: 10.8 FPG: 7.0 (-3.8)

FPG: 12.9 FPG: 6.0 (-6.9)f

Major: 0.0 1.3 episodes/ episodes/pt–yr pt–yr

Nocturnalc

?3.9

?3.5

?2.6

Change in weight (kg)

Typically defined as clinical symptoms that could be confirmed by blood glucose values \2.8 mmol/L

h

g

f

e

d

c

P = 0.001 morning insulin glargine versus bedtime neutral protamine Hagedorn insulin

P = 0.004 morning versus evening insulin glargine

P B 0.001 bedtime insulin glargine versus bedtime neutral protamine Hagedorn insulin

P \ 0.05 between treatments

Typically defined as an event occurring while the patient was asleep between administration of bedtime insulin and determination of blood glucose the next morning P = 0.012 combined insulin glargine groups versus neutral protamine Hagedorn insulin

Typically defined as a symptomatic hypoglycaemic event requiring assistance associated with blood glucose values \2.0–3.1 mmol/L or prompt recovery after administration of oral carbohydrate or intravenous glucose or glucagon

b

a

FBG fasting blood glucose, glargine insulin glargine, glargine 30 insulin glargine with 30 lg/mL zinc, glargine 80 insulin glargine with 80 lg/mL zinc, OAD oral antidiabetic drug, BG blood glucose, FPG fasting plasma glucose, NA not available, wks = weeks, yr year, pt patients, NPH NPH insulin

3.2 episodes/pt–yr

Overall: 8.0

First 12 weeks: 9.0e

Confirmed symptomatic hypoglycaemia (events/pt–yr)

First 12 weeks: 4.1 Overall: 5.4

Confirmed symptomatic hypoglycaemia (events/pt–yr)

Severeb

Incidence of hypoglycaemia

Endpoint (Change) Symptomatica

FPG: 13.0 FPG: 5.8 (-7.2)

Baseline

FBG (mmol/L)

Changes from endpoint to baseline may not be exact owing to rounding of significant digits

Evening glargine

49

Bedtime NPH ? pre-study metformin

Rosenstock et al. [51]

61

Bedtime glargine ? pre-study metformin

Yki-Ja¨rvinen et al. [53]

Baseline Endpoint (Change)

No. of Outcome measure patients HbA1c (%)

Insulin regimen

Study

Table 4 continued

Acta Diabetol (2008) 45:253–268 261

123

123 7.9 7.8

199 341 164

(Once- or twice- Bedtime or morning and bedtime daily insulin) NPH ? mealtime RHI

Haak et al. [35]

Morning and bedtime NPH plus OADs

Once or twice daily detemir

(Twice-daily insulin)

Rosenstock et al. [51]

8.6

8.5

8.6

8.1

8.2

7.2 (-1.4) 10.8

6.6 (-1.9) 10.8

6.8 (-1.8) 11.1

7.5 (-0.4) 10.4

7.6 (-0.2) 10.1

7.5 (-0.6) NA

7.5 (-0.7) NA 25.3

23.9

Symptomatica

NA

Major: 0.0 1.3 episodes/ episodes/ pt–yr pt–yr

NA

?3.9

Less weight gain with detemir versus NPH regardless of baseline BMI

?1.8e

?1.0

?1.13 ± 0.21d

?0.51 ± 0.22

Change in weight (kg)

e

d

c

b

a

P = 0.038 between groups P = 0.017 between groups

Defined as any episode between 23:00 and 06:00 hours

Defined as when the individual was unable to treat themselves

Defined as an event that was not confirmed by plasma glucose measurement or with a plasma glucose level C3.1 mmol/L (C56 mg/dL)

HbA1c haemoglobin A1c, detemir insulin detemir, NPH neutral protamine Hagedorn insulin, FPG fasting plasma glucose, RHI regular human insulin, OAD oral antidiabetic drug, BMI body mass index, End study endpoint, NA not available

7.1 (-3.7) 3.0 episodes/pt–yr

6.6 (-4.2) NA

55% lower risk

23.6

\2

6.9 (-4.2) 47% lower risk (any NA hypoglycaemia)

9.6 (-0.6) NA

15.8

17.5

14.9

Nocturnalc

\2

0.5

1.1

Majorb

Incidence of hypoglycaemia (%)

9.7 (-0.5) NA

End: 7.3

End: 7.3

Baseline Endpoint (Change)

FPG (mmol/L)

Changes from endpoint to baseline may not be exact owing to rounding of significant digits

291

225

Morning and bedtime detemir plus 227 OADs

Hermansen et al. [56]

Bedtime or morning and bedtime detemir ? mealtime aspart (Once- or twicedaily insulin) Bedtime or morning and bedtime NPH ? mealtime aspart

195

Bedtime or morning and bedtime detemir ? mealtime aspart

Raslova et al. [34]

Baseline Endpoint (Change)

No of Outcome measure patients HbA1c (%)

Insulin regimen

Study

Table 5 Key trials and recent studies in patients with type 2 diabetes comparing once- or twice-daily insulin detemir with once-or twice-daily neutral protamine Hagedorn insulin

262 Acta Diabetol (2008) 45:253–268

Acta Diabetol (2008) 45:253–268

detemir ‘where required’ on the basis of poor (non-target) glycaemic control. This study demonstrated disappointing levels of glycaemic control with small numbers (9–23%) of patients achieving HbA1c of B6.5% on the three regimens. The regimen that appeared most effective was premeal fast-acting insulin, which may reflect the stage of development of the disease. The basal regimen did not include a glargine arm and, as indicated by the requirement of the detemir to be escalated to twice daily, may not reflect an optimal basal insulin regimen. However, taken at face value, the data in that trial suggest that the most effective regimen may be detemir in combination with preprandial dosing (multidosing). This multidose regimen is under investigation in the next phase of the study. The findings of the 4-T study are in some contrast with some of the findings from the 44-week APOLLO study, in which once-daily glargine was compared with three-timesdaily insulin lispro (at mealtimes) [62]. In the APOLLO study, the mean change in HbA1c was -1.7% with glargine and -1.9% with insulin lispro, showing non-inferiority of glargine (difference: 0.157; 95% confidence interval: -0.008, 0.322), with 30 and 38% of subjects, respectively, reaching HbA1c B6.5% at endpoint (58 and 68% reached A1c B7.0%). Consistent with the 4-T study, subjects treated with glargine showed significantly greater improvements in FBG (P \ 0.001) and at 03:00 h (P = 0.0041), while subjects in the insulin lispro group showed significantly greater improvements after lunch and after dinner (P \ 0.001 for both) and after breakfast (P = 0.0137). Nevertheless, the incidence of hypoglycaemia was significantly lower with glargine (5.21 vs. 24.00 episodes per patient per year; P \ 0.0001).

Hypoglycaemia Traditionally, patients with T2DM have received less vigorous insulin treatment compared with patients with T1DM and are, therefore, at a lower risk of experiencing insulininduced hypoglycaemia. The physiological differences between T1DM and T2DM may also mean that patients with T2DM are not generally at risk of hypoglycaemia until the baseline levels of glucose are reduced to near normoglycaemia by aggressive use of glucose-lowering therapies. New treatment algorithms for T2DM advocate the early introduction of insulin therapy [24], recognising b-cell failure, the inevitable requirement for insulin therapy and the quest to reduce the risk of diabetes-associated complications by improved glycaemic control [18, 19]. The changing treatment paradigms in T2DM carry the risk of a large increase in the prevalence of severe hypoglycaemia in this patient population. Ultimately, this problem may limit the scope of aggressive glycaemic management.

263

Since T2DM accounts for up to 95% of diabetes patients, a substantial number of patients are potentially at a high risk of severe hypoglycaemia. Without intervention, hypoglycaemia can cause considerable morbidity and mortality. Prolonged hypoglycaemia can cause cerebral damage, seizure, coma or death [63, 64]. In addition, prior hypoglycaemia can result in a reduced response to subsequent episodes, leading to a cycle of recurrent hypoglycaemia [65]. Fear of hypoglycaemia represents a major barrier to insulin therapy [66] and very often prevents the initiation of insulin therapy or the appropriate titration of insulin required to achieve good glycaemic control [66, 67]. While the risk of hypoglycaemia increases with improving glycaemic control, this risk is linked to the pharmacokinetic profile of the insulin in use [32, 68–70]. For example, the peak in activity observed 4–6 h after the administration of NPH increases the risk of hypoglycaemia between meals and overnight. While insulin ultralente is subject to considerable variation in dosing, with erratic peaks in activity that can lead to variations in glucose levels and unpredictable hypoglycaemia [71]. In contrast, the flat action profile with little or no pronounced peak observed with glargine offers a reduced risk of hypoglycaemia. In the study by Rosenstock et al., the incidence rate of hypoglycaemia was comparable with glargine and detemir (all: 6.2 vs. 5.8 episodes/patient–year; nocturnal: 1.3 vs. 1.3 episodes/patient–year; symptomatic: 3.2 vs. 3.0 episodes/ patient–year, respectively) [51]. Insulin glargine versus neutral protamine Hagedorn insulin for hypoglycaemia In patients with T2DM, glargine is associated with a significant reduction in the risk of overall hypoglycaemia, particularly nocturnal hypoglycaemia, versus NPH, with similar improvements in HbA1c [25, 31, 53, 55, 60, 61] (Table 4). The recent meta-analysis, which compared glargine with NPH in patients with T2DM showed that while glycaemic control was equivalent in both groups, glargine was associated with a lower risk of both overall hypoglycaemia (11% relative risk [RR] reduction) and, clinically more important, severe hypoglycaemia (46% RR reduction) [41]. Insulin detemir versus neutral protamine Hagedorn insulin for hypoglycaemia In two trials with detemir as part of a basal–bolus regimen in patients with T2DM, detemir was associated with comparable [34, 35] risk of hypoglycaemia versus NPH with similar improvements in HbA1c (Table 5). In the study by Haak et al. [35], the risk of nocturnal hypoglycaemia

123

264

(RR: 1.02; 95% CI: 0.55, 1.89; P = 0.95) and total hypoglycaemia (RR: 0.84; 95% CI: 0.52, 1.36; P = 0.48) was similar with detemir and NPH insulin. In the study by Raslova et al., the proportion of patients who experienced any (34.6 vs. 36.1%; RR: 0.89; 95% CI: 0.54, 1.45; P = 0.65) or nocturnal hypoglycaemia (14.9 vs. 17.5%; RR: 0.62; 95% CI: 0.32, 1.17; P = 0.14) was similar with detemir and NPH insulin [34]. However, in the study by Hermansen et al., detemir was associated with a lower risk of hypoglycaemia compared with NPH, when added to existing OAD therapy [56]. Thus, the insulin analogues glargine and detemir may offer advantages over NPH in terms of hypoglycaemia and may, therefore, help patients to overcome this significant barrier to both initiation and appropriate titration of insulin.

Body weight Insulin therapy is generally associated with some weight gain [72, 73], and achieving good glycaemic control in the absence of excessive weight gain is an important challenge for insulin therapy in patients with T2DM. Although one study has shown less weight gain with glargine compared with NPH [54], the majority of studies have shown little difference in weight gain between the two insulin treatments [25, 31, 60] (Table 4). Detemir has also been associated with reduced weight gain when compared with NPH at equivalent levels of glycaemic control [34, 35, 56] (Table 5). Moreover, the reduced levels of weight gain with detemir versus NPH in patients with T2DM has been shown to occur irrespective of patient BMI [56]. In the study comparing glargine with detemir [51], both insulins were associated with weight gain, although the magnitude of weight gain was significantly less with detemir (detemir, 3.0 kg; glargine, 3.9 kg; P \ 0.012). Patients with T2DM are typically overweight or obese and excessive adiposity is associated with increased risk of cardiovascular disease [74]. Therefore, weight management is an important aspect of diabetes therapy. However, in studies of obese patients with T2DM, the weight gain associated with insulin therapy was not sufficient to adversely influence cardiovascular risk factors and parameters including blood pressure and lipid profiles actually improved [75, 76]. Thus, the long-term clinical benefits of insulin therapy with respect to glycaemic control appear to outweigh any risk from insulin-related weight gain.

Within-subject variability The issue of within-subject variability with respect to pharmacokinetic and pharmacodynamic properties of

123

Acta Diabetol (2008) 45:253–268

different insulin preparations is one that is receiving increasing attention. Variability and unpredictability in insulin action contribute to variable glycaemic control, which increases the risk of hypoglycaemia and is also an independent risk factor for mortality [77, 78]. Glargine and detemir are soluble insulin preparations and should, therefore, show less variability in their action compared with the insoluble NPH. However, the studies that have been conducted to date describing variability need to be interpreted with some caution. The only reliable way to obtain appropriate quantitative information regarding the pharmacokinetic and pharmacodynamic properties of an insulin preparation is to use a euglycaemic clamp [79]. There are a number of comparative euglycaemic clamp studies but these can all be criticised on basic technical reasons. Bearing in mind these challenges and limitations, clamp studies and clinical studies have suggested that both glargine and detemir are associated with less within-subject variability of action compared with NPH in patients with T1DM [32, 44, 80– 83] and T2DM [25, 34, 35]. Glargine is also associated with less variability of action in healthy volunteers [71]. However, it should also be noted that care must be taken in extrapolating data regarding glycaemic control from these highly controlled experimental conditions to everyday clinical practice. The Treat-to-Target study, comparing glargine with NPH in patients with T2DM, showed less within-subject variability between seven sequential FPG measurements over the course of the 24-week treatment phase with glargine versus NPH [25]. The mean deviation from the median of the FPG values for individual subjects was significantly lower with glargine versus NPH (1.0 vs. 1.1 mmol/L [18 vs. 20 mg/dL]; baseline-adjusted P = 0.013) [25]. The study by Haak et al. demonstrated that treatment with detemir (plus aspart) for 26 weeks was associated with significantly less within-subject day-to-day variation in FBG compared with NPH (plus aspart; 1.3 vs. 1.4 mmol/ L [23 vs. 25 mg/dL]; P = 0.021) [35]. A similar observation was reported with detemir plus aspart compared with NPH plus RHI; within-subject day-to-day variation in FPG levels was significantly lower with detemir (SD: 1.2 vs. 1.5 mmol/L [22 vs, 28 mg/dL]; P \ 0.001) [34]. In contrast, in the study by Hermansen et al. [56], there was no difference in within-patient variability between detemir and NPH (0.9 vs. 0.9 mmol/L [16 vs. 16 mg/dL]) [56]. In the direct comparison between detemir and glargine in patients with T2DM, Rosenstock et al., reported that within-patient variability was similar in terms of prebreakfast blood glucose (glargine vs. detemir; 1.03 vs. 1.06 mmol/L, respectively; P = 0.45) and predinner blood glucose (1.55 vs. 1.60 mmol/L, respectively; P = 0.41) [51].

Acta Diabetol (2008) 45:253–268

Insulin dose At the end of the glargine Treat-to-Target trial, mean insulin dose was higher with glargine than with NPH (47.2 U vs. 41.8 IU; P \ 0.005), from a starting dose of 10 U/IU per day (once-daily injections). In the comparable detemir Treat-toTarget trial, insulin dose was also greater at endpoint with detemir than with NPH (detemir: morning and evening, 36.1 and 29.5 units [total: 65.6 units]; NPH: 25.3 and 19.7 IU [45.0 IU]). However, in this study, the starting dose of insulin was 10 units/IU per injection (twice-daily injections), although this was reduced to 6 units/IU if the initial prebreakfast or predinner plasma glucose was\7.0 mmol/L (126 mg/dL). This was also found to be the case in the study by Rosenstock et al., which directly compared detemir with glargine (0.78 units/kg) vs. 0.44 U/kg) [51]. The formulation of an insulin unit differs between glargine and detemir. One insulin unit contains 0.0364 mg of glargine compared with 0.142 mg of detemir. This is necessary, as acylated insulin analogues (including detemir) have a low affinity for the insulin receptor but high affinity for albumin [43, 84]. In the two Treat-to-Target studies, the mean daily insulin dose tended to be greater with detemir than with glargine, which may reflect the need to overcome the low affinity of detemir for the insulin receptor. Taking into account the more concentrated formulation of detemir, patients will thus be exposed to greater levels of insulin with detemir than with glargine. Further studies will help to clarify whether this is clinically relevant.

265

once-daily in the evening is inadequate to optimise glycaemic control and in particular FBG, necessitating the addition of a second dose in the morning. Nevertheless, the goal of achieving good glycaemic control with a low risk of hypoglycaemia may be more feasible with the use of newer insulin therapies as part of a simple basal insulin regimen with continued OAD therapy [85]. The pharmacokinetic properties of glargine and detemir permit the safe and effective use of insulin analogues as early insulin therapy for T2DM, as reported in the clinical studies discussed here. The lower risk of hypoglycaemia with glargine compared with NPH facilitates more aggressive dose titration in the treatment of diabetes, enabling glycaemic control targets to be reached with a reduced risk of hypoglycaemia. The time–action profile of detemir is smoother than that of NPH with low risk of hypoglycaemia. The dose-dependent action of detemir may have implications on dose titration, such that patients may benefit from twice-daily dosing. Long-term cardiovascular outcome data following the improvements in glycaemic control and the low incidence of hypoglycaemia observed with both glargine and detemir are not yet available and are eagerly anticipated. Basal insulins are recommended by the ADA and EASD as an early therapeutic option for patients with T2DM [24]. The insulin analogues glargine and detemir offer significant advantages in therapy compared with NPH insulin. Data regarding the optimal titration regimen for detemir are of interest for future studies and would be beneficial for interpretation of balanced comparative studies with glargine.

Conclusions The insulin analogues, glargine and detemir, offer improved pharmacokinetic and pharmacodynamic profiles compared with NPH and, therefore, offer advantages with respect to safety, efficacy and variability. These advantages may help patients with T2DM to overcome some of the barriers associated with insulin initiation and therapy, such as fear of hypoglycaemia, injections and weight gain. The consistent 24-h profile of glargine offers reliability and predictability, and the lower risk of hypoglycaemia with glargine compared with NPH facilitates more aggressive dose titration, enabling glycaemic control targets to be reached with a reduced risk of hypoglycaemia with once-daily dosing. Detemir is associated with equivalent glycaemic control, less risk of hypoglycaemia, and lower within-subject dayto-day FPG variability compared with NPH. In some studies, detemir is associated with less weight gain compared with NPH. For many patients, detemir administered

Acknowledgment This review was supported by the Global Publications group of sanofi-aventis.

References 1. United Kingdom Prospective Diabetes Study Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865 2. United Kingdom Prospective Diabetes Study Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853 3. Ohkubo Y, Kishikawa H, Araki E et al (1995) Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 28:103–117 4. Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405–412

123

266 5. Gaede P, Vedel P, Larsen N et al (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383–393 6. Genuth S, Eastman R, Kahn R et al (2003) Implications of the United kingdom prospective diabetes study. Diabetes Care 26:S28–S32 7. Chiasson JL (2006) Acarbose for the prevention of diabetes, hypertension, and cardiovascular disease in subjects with impaired glucose tolerance: the Study to Prevent Non-InsulinDependent Diabetes Mellitus (STOP-NIDDM) Trial. Endocr Pract 12:25–30 8. Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett AR (2006) HbA1c and peripheral arterial disease in diabetes: the atherosclerosis risk in communities study. Diabetes Care 29:877– 882 9. Kirkman MS, McCarren M, Shah J, Duckworth W, Abraira C (2006) The association between metabolic control and prevalent macrovascular disease in Type 2 diabetes: the VA Cooperative Study in diabetes. J Diabetes Complications 20:75–80 10. Martin S, Schneider B, Heinemann L et al (2006) Self-monitoring of blood glucose in type 2 diabetes and long-term outcome: an epidemiological cohort study. Diabetologia 49:271–278 11. American Diabetes Association (2003) Standards of medical care for patients with diabetes mellitus. Diabetes Care 26:S33–S50 12. European Diabetes Policy Group (1999) A desktop guide to Type 2 diabetes mellitus. Diabet Med 16:716–730 13. British Cardiac Society, British Hypertension Society, Diabetes UK, et al. (2005) JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 91:v1–v52 14. De Backer G, Ambrosioni E, Borch-Johnsen K et al (2003) European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 24:1601–1610 15. Ryden L, Standl E, Bartnik M et al (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 28:88–136 16. Fox KM, Gerber RA, Bolinder B, Chen J, Kumar S (2006) Prevalence of inadequate glycemic control among patients with type 2 diabetes in the United Kingdom general practice research database: a series of retrospective analyses of data from 1998 through 2002. Clin Ther 28:388–395 17. United Kingdom Prospective Diabetes Study Group (1995) Overview of 6 years’ therapy of type II diabetes: a progressive disease. (UKPDS 16). Diabetes 44:1249–1258 18. Wright A, Burden AC, Paisey RB, Cull CA, Holman RR (2002) Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 25:330–336 19. Riddle MC (2002) Timely addition of insulin to oral therapy for type 2 diabetes. Diabetes Care 25:395–396 20. Chan JL, Abrahamson MJ (2003) Pharmacological management of type 2 diabetes mellitus: rationale for rational use of insulin. Mayo Clin Proc 78:459–467 21. Riddle MC (2004) Timely initiation of basal insulin. Am J Med 116:3S–9S 22. Boyne MS, Saudek CD (1999) Effect of insulin therapy on macrovascular risk factors in type 2 diabetes. Diabetes Care 22:C45–C53 23. Cerveny JD, Leder RD, Weart CW (1998) Issues surrounding tight glycemic control in people with type 2 diabetes mellitus. Ann Pharmacother 32:896–905

123

Acta Diabetol (2008) 45:253–268 24. Nathan DM, Buse JB, Davidson MB et al (2006) Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 29:1963–1972 25. Riddle MC, Rosenstock J, Gerich J (2003) The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 26:3080– 3086 26. Cryer PE (2002) Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. Diabetologia 45:937–948 27. Korytkowski M (2002) When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord 26:S18–S24 28. Rubin RR (2005) Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med 118:27S–34S 29. Monnier L, Lapinski H, Colette C (2003) Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26:881–885 30. Goudswaard AN, Furlong NJ, Rutten GE, Stolk RP, Valk GD (2004) Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 4:CD003418 31. Yki-Jarvinen H, Dressler A, Ziemen M (2000) 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 23:1130–1136 32. Lepore M, Pampanelli S, Fanelli C et al (2000) Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 49:2142–2148 33. Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R (2000) Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care 23:813–819 34. Raslova K, Bogoev M, Raz I et al (2004) Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract 66:193–201 35. Haak T, Tiengo A, Draeger E, Suntum M, Waldhausl W (2005) Lower within-subject 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 7:56–64 36. Gerstein HC, Yale JF, Harris SB et al (2006) A randomized trial of adding insulin glargine vs. avoidance of insulin in people with Type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. Diabet Med 23:736–742 37. Rosenstock J, Sugimoto D, Strange P et al (2006) Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulinnaive patients. Diabetes Care 29:554–559 38. Horvath K, Jeitler K, Berghold A et al (2007) Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2:CD005613 39. Dunn CJ, Plosker GL, Keating GM, McKeage K, Scott LJ (2003) Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs 63:1743–1778 40. Luzio SD, Beck P, Owens DR (2003) Comparison of the subcutaneous absorption of insulin glargine (Lantus) and NPH

Acta Diabetol (2008) 45:253–268

41.

42. 43.

44.

45.

46.

47.

48. 49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

insulin in patients with Type 2 diabetes. Horm Metab Res 35:434–438 Rosenstock J, Dailey G, Massi-Benedetti M et al (2005) Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 28:950–955 Barlocco D (2003) Insulin detemir. Novo Nordisk. Curr Opin Investig Drugs 4:449–454 Havelund S, Plum A, Ribel U et al (2004) The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res 21:1498–1504 Heise T, Nosek L, Ronn BB et al (2004) Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 53:1614–1620 Plank J, Bodenlenz M, Sinner F et al (2005) A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care 28:1107–1112 Porcellati F, Rossetti P, Busciantella NR et al (2007) Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study. Diabetes Care 30:2447–2452 Klein O, Lynge J, Endahl L et al (2007) Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable timeaction profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab 9:290–299 Paes AH, Bakker A, Soe-Agnie CJ (1997) Impact of dosage frequency on patient compliance. Diabetes Care 20:1512–1517 Claxton AJ, Cramer J, Pierce C (2001) A systematic review of the associations between dose regimens and medication compliance. Clin Ther 23:1296–1310 Holman RR, Thorne KI, Farmer AJ et al (2007) Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 357:1716–1730 Rosenstock J, Davies M, Home PD et al (2008) 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 51:408–416 Eliaschewitz FG, Calvo C, Valbuena H et al (2006) Therapy in type 2 diabetes: insulin glargine vs. NPH insulin both in combination with glimepiride. Arch Med Res 37:495–501 Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M et al (2006) Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia 49:442–451 Rosenstock J, Schwartz SL, Clark CM Jr et al (2001) Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 24:631–636 HOE901/2004 Study Investigators Group (2003) Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients. Diabet Med 20:545–551 Hermansen K, Davies M, Derezinski T et al (2006) A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care 29:1269–1274 Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R (2005) Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care 28:1282–1288 Meneghini L, Koenen C, Weng W, Selam JL (2007) The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes—results of the

267

59.

60.

61.

62.

63.

64. 65. 66. 67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

randomized, controlled PREDICTIVE 303 study. Diabetes Obes Metab 9:902–913 Janka HU, Plewe G, Riddle MC et al (2005) Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care 28:254–259 Fritsche A, Schweitzer MA, Haring HU (2003) Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med 138:952–959 Massi-Benedetti M, Humburg E, Dressler A, Ziemen M (2003) A one-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes. Horm Metab Res 35:189–196 Bretzel RG, Nuber U, Landgraf W et al (2008) Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet 371:1073–1084 Gossain VV, Carella MJ, Rovner DR (1994) Management of diabetes in the elderly: a clinical perspective. J Assoc Acad Minor Phys 5:22–31 Gerich JE (2000) Physiology of glucose homeostasis. Diabetes Obes Metab 2:345–350 Cryer PE (2004) Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 350:2272–2279 Cryer PE (1999) Hypoglycemia is the limiting factor in the management of diabetes. Diabetes Metab Res Rev 15:42–46 McCrimmon RJ, Frier BM (1994) Hypoglycaemia, the most feared complication of insulin therapy. Diabete Metab 20:503– 512 Home PD, Barriocanal L, Lindholm A (1999) Comparative pharmacokinetics and pharmacodynamics of the novel rapidacting insulin analogue, insulin aspart, in healthy volunteers. Eur J Clin Pharmacol 55:199–203 Heinemann L, Linkeschova R, Rave K et al (2000) Time–action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 23:644–649 Lindholm A, Jacobsen LV (2001) Clinical pharmacokinetics and pharmacodynamics of insulin aspart. Clin Pharmacokinet 40:641–659 Scholtz HE, Pretorius SG, Wessels DH, Becker RH (2005) Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 48:1988–1995 de Boer H, Jansen M, Koerts J, Verschoor L (2004) Prevention of weight gain in type 2 diabetes requiring insulin treatment. Diabetes Obes Metab 6:114–119 DeWitt DE, Hirsch IB (2003) Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 289:2254– 2264 Lee M, Aronne LJ (2007) Weight management for type 2 diabetes mellitus: global cardiovascular risk reduction. Am J Cardiol 99:68–79 Cusi K, Cunningham GR, Comstock JP (1995) Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care 18:843–851 Emanuele N, Azad N, Abraira C et al (1998) Effect of intensive glycemic control on fibrinogen, lipids, and lipoproteins: Veterans Affairs Cooperative Study in Type II Diabetes Mellitus. Arch Intern Med 158:2485–2490 Heinemann L (2002) Variability of insulin absorption and insulin action. Diabetes Technol Ther 4:673–682

123

268 78. Russell-Jones D (2004) Insulin detemir: improving the predictability of glycaemic control. Int J Obes Relat Metab Disord 28:S29–S34 79. Heinemann L, Anderson JH Jr (2004) Measurement of insulin absorption and insulin action. Diabetes Technol Ther 6:698–718 80. Hermansen K, Fontaine P, Kukolja KK et al (2004) Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basalbolus therapy for patients with type 1 diabetes. Diabetologia 47:622–629 81. Hermansen K, Madsbad S, Perrild H, Kristensen A, Axelsen M (2001) Comparison of the soluble basal insulin analog insulin detemir with NPH insulin: a randomized open crossover trial in type 1 diabetic subjects on basal-bolus therapy. Diabetes Care 24:296–301 82. Danne T, Lupke K, Walte K, Von Schuetz W, Gall MA (2003) Insulin detemir is characterized by a consistent pharmacokinetic

123

Acta Diabetol (2008) 45:253–268 profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 26:3087–3092 83. Vague P, Selam JL, Skeie S et al (2003) Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 26:590–596 84. Kurtzhals P, Schaffer L, Sorensen A et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005 85. Johnson R, Hauber B, Bolinder B (2003) Trade-offs between glucose control and hypoglycemia in different patient types: results of a 5-country physician survey. Diabetes 52:A264 (Abstract 1134)