1. Insulin Therapy
Insulin supplementation is essential for subjects with type 1 diabetes mellitus and is eventually required by the majority of subjects with type 2 diabetes in order to successfully control blood glucose and prevent micro- and macrovascular complications. The outcomes of large interventional trials have highlighted the importance of achieving tight glycaemic control in the treatment of diabetes, and the current focus on tighter postprandial control further extends the debate beyond glycosylated haemoglobin and fasting blood glucose.[1-3] To this end, replacement of physiological insulin secretion is the goal of insulin therapy.
However, replacement of physiological insulin secretion with injectable or, more recently, inhaled insulin products has proven difficult to emulate since endogenous insulin is released into the portal vein prior to reaching peripheral sites.[4] This limits exogenous insulin administration to mimicking physiological insulin concentration profiles as closely as possible, with peaks in insulin activity at mealtimes that complement a continuous 24-hour basal insulin supply.[5-7]
Regular human insulin has traditionally been used to complement or substitute for endogenous mealtime insulin. However, regular human insulin has a slow onset of action (30-45 minutes after administration) and a long duration of action (6-8 hours) compared with meal-related endogenous insulin profiles.[6] This reduces patient flexibility with regard to the size and timing of a meal, and carries the risk of late hypoglycaemia.
Protein engineering and recombinant DNA technology have enabled the production of human insulin analogues with improved physicochemical properties that increase absorption. An insulin glulisine solution for injection in vial (Apidra® Cited Here...; sanofi-aventis Deutschland GmbH, Frankfurt, Germany) is the most recent rapid-acting insulin product. This review focuses on the pharmacokinetic and pharmacodynamic actions of insulin glulisine.
1.1 Rapidly Absorbed Insulin Analogues
The rate and extent of absorption of insulin molecules from subcutaneous tissue into the bloodstream are two of the main factors for the rate and extent of the metabolic activity (glucodynamic action). The rate-limiting factor for the absorption of regular human insulin is the degree and strength of self-association of insulin molecules in injectable and, presumably, inhaled insulin products. Human insulin is biologically active and best absorbed as a monomer. At a physiological pH, human insulin exists only as monomers at low concentrations (≤1 × 10-9 mol/L); at higher concentrations and at a neutral pH (for example, in pharmaceutical preparations of 0.6 × 10-3 mol/L [100 U/mL]), it exists in equilibrium between higher-order aggregates and, in the presence of zinc, assembles mainly as hexamers.[8]
The functional importance of each amino acid residue in the human insulin molecule for biological activity and/or higher-order assembly was revealed through the study of modified human insulins. This demonstrated that amino acid residues at positions B26-B30 are not needed for full biological activity, whereas the proline in position B28 and, to a lesser degree, those in its immediate vicinity (e.g. lysine at B29) are pivotal for dimer formation.[9] Similarly, amino acid residues at positions B1-B8 (e.g. asparagine at B3) have a role in hexamer formation. Notably, exchange of histidine at B10 for any other amino acid completely prevents hexamer formation since this impedes the docking of the zinc ion.
Insulin lispro injection (Humalog®; Eli Lilly and Company, Indianapolis, USA) and insulin aspart injection (Novolog®; Novo Nordisk A/S, Copenhagen, Denmark) were the first and second insulin analogue products, respectively, to be introduced for mealtime use.[10,11] Insulin aspart differs from human insulin by the exchange of proline at position 28 of the B chain for aspartic acid, whereas insulin lispro is generated by inverting amino acids at positions B28 and B29 (28B-Pro, 28B-Lys → 29B-Lys, 29B-Pro). In the absence of ligands, both of these insulin analogues remain in the monomeric state even at high concentrations when compared with human insulin. However, while monomers are perfect for rapid absorption, they possess a more solvent-exposed, unprotected surface area that is more vulnerable to unfolding and denaturation than dimers and hexamers.[12] Consequently, like regular human insulin, both insulin lispro and insulin aspart products contain zinc as a stabilizing ligand which, as outlined above, promotes hexamer formation. The hexamers are further strengthened by a conformational change induced by antimicrobiological agents (phenol, m-cresol), which are essential in all insulin products.[11,13] This conformational change effectively reduces the rapid absorption associated with the monomeric state.[14] Nevertheless, more rapid deployment of monomers from hexamers is attained for both insulin analogue products when compared with regular human insulin.
2. Insulin Glulisine
2.1 Primary Structure
Apidra® (insulin glulisine solution for injection in vial) is the newest rapid-acting insulin product[15] to receive approval from the US FDA and the European Agency for the Evaluation of Medicinal Products for the treatment of diabetes.[16,17]
Insulin glulisine differs from regular human insulin by the substitution of amino acid residues at positions 3 and 29 of the B chain (3B-Asp → 3B-Lys and 29B-Lys → 29B-Glu) [figure 1]. The exchange of 29B-Lys for 29B-Glu simultaneously weakens self-association of monomers while still allowing the formation of dimers, and constrains the flexibility of the C-terminal β-strand by bridging to 1A-Gly.[18] Together, these render insulin glulisine in solution less sensitive to denaturation, which occurs when insulin monomers unfold.[19] Like other rapid-acting insulin analogues, insulin glulisine forms higher-order aggregates up to T6-hexamers in the presence of zinc but shows no further conformational change to the tighter R6-hexamers induced by phenolic excipients (phenol, m-cresol) because of the substitution of 3B-Asp to 3B-Lys.[20] In addition, the isoelectric point (pI) is lowered to 5.1,[21] enhancing solubility at a physiological pH, similarly to pure insulin aspart.[22] In contrast, both pure human insulin and pure insulin lispro possess identical pIs (5.5) because of identical amino acid compositions.[11,23-26]
2.2 Developmental Studies
The modifications in insulin glulisine have significant consequences for the viability of the commercial insulin glulisine product. The tendency to exist as more stable dimers at pharmaceutical concentrations and the inherently more stable monomer allow the insulin glulisine product to meet pharmaceutical specifications without the addition of zinc.[12,17,27] The addition of the detergent polysorbate 20 to the product composition further prevents irreversible formation of aggregates (fibrils) from monomers and, thus, enhances the physical stability.[12]
Developmental and exploratory in vitro, animal and human studies of different formulations of insulin glulisine have confirmed tighter self-association of insulin glulisine in the presence of zinc and corresponding pharmacological consequences,[20] while the addition of polysorbate 20 did not change the absorption and action profile of insulin glulisine formulated without zinc.[15]
For example, randomized, double-blind, four-way crossover studies comparing zinc-free insulin glulisine with half-stochiometric zinc-containing insulin glulisine (7.5 µg/mL or about one Zn2+ ion per hexamer) or stochiometric zinc-containing insulin glulisine (15 µg/mL or about two Zn2+ ions per hexamer) in healthy volunteers showed that the absorption of zinc-stabilized insulin glulisine was progressively and significantly delayed, and approached the profile obtained for regular human insulin (figure 2).[28] In contrast, solely adding polysorbate 20 did not change the absorption and action profiles. This is in accordance with in vitro circular dichroism studies, which assessed the self-association states of insulin glulisine in the absence and presence of zinc.[20]
3. Pharmacokinetics and Pharmacodynamics
3.1 Principle of the Euglycaemic Clamp Method
Characterization of the concentration-time and action-time profiles of any insulin product is fundamental in understanding the clinical implication for therapy. An established method of simultaneously assessing pharmacokinetic characteristics and quantifying pharmacodynamic characteristics of insulin products is the euglycaemic clamp technique.[8,29,30] In the experimental paradigm, the decrease in the blood glucose level in response to the injected insulin is prevented by an intravenous glucose infusion, which can be manually or automatically adjusted (by a Biostator), while conventional pharmacokinetic variables are derived from concentration profiles obtained from samples taken at defined times after injection. The rate and duration of the glucose infusion (the glucose infusion rate [GIR]) required to maintain the blood glucose concentration at or slightly below the fasting level reflects the metabolic activity of the injected insulin.
Insulin glulisine concentrations were quantified with a radioimmunoassay specific for insulin glulisine, at a lower limit of quantification of 5 µU/mL, with a working range of 5-200 µU/mL (Linco Research Inc., St Charles, MO, USA). Similarly, insulin lispro concentrations were quantified with a radioimmunoassay specific for insulin lispro or with a non-specific insulin radioimmunoassay (Linco Research Inc.). Therefore, quantitative comparisons of volume parameters are restricted by the use of different RIAs (see section 3.2).
3.2 Potency, Distribution and Metabolism
Insulin glulisine displays equipotent glucodynamic efficacy to regular human insulin on a molar base. This was shown in a single-centre, randomized, open-label, two-way crossover study in 16 healthy male subjects infused with regular human insulin using the manual euglycaemic clamp technique.[31] The subjects received insulin glulisine or regular human insulin for 2 hours at 0.8 mU/min/kg, which established steady-state concentrations similar to those observed after meals. Glucose disposal at steady state (the area under the GIR curves [GIR-AUCss]) - insulin glulisine versus regular human insulin 209 versus 214 mg/kg; point estimate 97.6% (90% CI 88.4, 107.6) - demonstrated equipotency of insulin glulisine and human insulin on a molar base. By contrast, the apparent exposure to insulin glulisine and regular human insulin was different because of the different insulin assays.[31]
The distribution and elimination of insulin glulisine and regular human insulin are similar and reflect low binding to plasma protein (approximately 11%) and rapid elimination from the systemic circulation after intravenous administration (geometric means [range] for insulin glulisine versus regular human insulin for the volume of distribution at steady state 13 L [9-17 L] vs 22 L [13-31 L]; elimination half-life (t½) 13 min [9-26 min] vs 17 min [9-26 min]; total clearance 927 mL/min [785-1046 mL/min] vs 1084 mL/min [864-1606 mL/min]; mean residence time [MRT] 14 min [9-17 min] vs 19 min [12-18 min]).[16,32]
However, this is different after subcutaneous administration since elimination is determined by the rate of absorption, which is more rapid for insulin glulisine, with a t½ of 42 minutes compared with 86 minutes for regular human insulin.[15,17]
Biodegradation of human insulin by insulin protease is well known from the literature.[33] Modifications of the primary insulin structure in insulin glulisine do not involve the peptide bonds that are sensitive to insulin protease degradation. Therefore, it is unlikely that the metabolism of insulin glulisine is different from that of regular human insulin.
Furthermore, insulin glulisine is not known to be subject to pharmacokinetic drug-drug interactions.
3.3 Concentration-Time and Action-Time Profiles
Numerous pharmacokinetic studies performed in healthy volunteers,[15,34-36] subjects with type 1 diabetes,[37-39] including children and adolescents,[40,41] and subjects with type 2 diabetes[42] have demonstrated that subcutaneous injections of insulin glulisine have concentration-time and action-time profiles of a rapidly absorbed and acting insulin analogue. This was shown in a randomized, six-way crossover, euglycaemic clamp study that investigated the dose-exposure and dose-response relationships between 0.075, 0.15 and 0.3 U/kg doses of both insulin glulisine and regular human insulin in 18 patients with type 1 diabetes (table I[39] and figure 3 a).[43]
At equivalent total insulin exposure (INS-AUCtotal) with each dose, insulin glulisine reached twice the early insulin exposure (at 2 hours post-injection) [INS-AUC2], reached twice the peak insulin concentration (INS-Cmax) and had a time to peak concentration (INS-tmax) approximately twice as fast as that of regular human insulin (figure 3 a). Similarly, the time to 10% of total exposure (reflecting the onset of exposure) was about 30 minutes for insulin glulisine 0.15 U/kg and about 55 minutes for regular human insulin. The time to 90% of total exposure (reflecting completion of absorption) was about 3.5 and 6 hours for insulin glulisine and regular human insulin, respectively.[39]
Correspondingly, early glucose disposition (at 2 hours) for insulin glulisine (GIR-AUC2) was twice as great at otherwise equivalent total glucose disposition (GIR-AUCtotal), and greater peak insulin activity (GIRmax) was reached earlier (figure 3 b). Also, the times to 10% of total disposal (reflecting the onset of activity) were about 45 minutes for insulin glulisine 0.15 U/kg and about 90 minutes for regular human insulin, while the times to 90% of total disposal (reflecting completion of activity) were assessed to be about 4 and 5.5 hours, respectively. The difference of up to 45 minutes in the time to 10% disposal corresponds to the approximate interval between the injection and commencement of the meal recommended for regular human insulin.[46]
Dose proportionality for the INS-AUC2, INS-AUCtotal and INS-Cmax was seen for insulin glulisine over the dose range of 0.075, 0.15 and 0.3 U/kg, which corresponds to 6, 12 and 24 U for an 80-kg person. This was similar for regular human insulin. Closer inspection of these data reveals that insulin exposure may tend to increase more than proportionally with large doses. However, dose-proportional metabolic activity was observed only with insulin glulisine for the dose range of 0.075-0.15 U/kg, and not with regular human insulin at any dose escalation. Together with the attenuated increase in total glucose disposition and the GIRmax, this is in line with the concept of a saturable receptor-mediated biological response and clearance, regardless of the insulin molecule, and indicates a general limitation in insulin efficacy.
3.3.1 Comparison with Rapid-Acting Analogues
Some studies in healthy volunteers[15] and subjects with type 1[37] and type 2[42] diabetes have included insulin lispro as a rapid-acting insulin analogue comparator alongside regular human insulin (table II). The study in 16 healthy volunteers compared 0.3 U/kg of insulin glulisine with 0.3 U/kg of regular human insulin and insulin lispro in a randomized, three-way crossover trial.[15] The studies in subjects with type 1 or type 2 diabetes followed an incomplete, randomized, double-blind, four-way crossover design with replication of single 0.2 U/kg doses of insulin glulisine, insulin lispro or regular human insulin.[37,42] Moreover, the studies in subjects with diabetes also allowed comparative assessment of intrasubject variability of insulin exposure and action.
Table II. Pharmacoki...Image Tools
These early studies demonstrated that the absorption profiles of the two rapidly absorbed insulin analogues were essentially similar and distinct from that of regular human insulin.
Furthermore, the action-time profiles of the rapidly absorbed insulin analogues were almost superimposable and distinctly different from that of regular human insulin. Again, comparable amounts of total glucose disposal (GIR-AUCtotal) at the same doses for all insulins proved their equipotency in vivo.[37]
In subjects with type 2 diabetes, the concentration-time profiles of both insulin analogues were slightly attenuated and retarded compared with those in lean, healthy volunteers and subjects with type 1 diabetes (table III, figure 3 b). Similarly, the action-time profiles were slightly attenuated but only modestly delayed for both insulin analogues, while regular human insulin was more affected in this study. The modest delay in absorption can be explained by the greater skin thickness (subcutaneous fat layer) commonly associated with type 2 diabetes, with the injected insulin requiring more dilution and diffusion time. By contrast, the reduced insulin sensitivity seen in subjects with type 2 diabetes is associated with a greater visceral fat mass and is common to all insulins.
Table III. Pharmacok...Image Tools
Importantly, these comparative studies in subjects with type 1 or type 2 diabetes also demonstrated that the reproducibility of both the pharmacokinetic and pharmacodynamic profiles was high and similar for all three insulin treatments, as indicated by similar small coefficients of variation (CVs) for all parameters (derived from the mean square error terms of ANOVA; average CV% of insulin glulisine for the INS-AUC2 ~10%, INS-AUCtotal ~7%, INS-Cmax ~13%, INS-tmax ~27%).[37,42] The variability in glucodynamics was larger but the same for all insulins (average CV% of insulin glulisine for GIR-AUC2 ~25%, GIR-AUCtotal ~18%, GIRmax ~23%, GIR-tmax ~35%). Interestingly, individual variability in exposure was not correlated to individual variability in activity, indicating that day-to-day variability in insulin sensitivity dominates the response, confirming previous observations.[42] Nonetheless, both insulin analogues confer the consistent day-to-day insulin exposure required for optimal dosing.[8]
3.4 Absolute Bioavailability and Site of Injection
The exposure and action after intravenous administration of insulin glulisine were compared with those after subcutaneous injection at various sites (femoral, deltoid or abdominal) in healthy individuals.[34] The total exposure and, therefore, absolute bioavailability were the same (around 70%), had low intrasubject variability (CV 11%)[16,17] and were independent of the injection site.[34] Slightly faster absorption and action, as determined by shorter INS-tmax and GIR-tmax, were observed for the abdominal injection site compared with the femoral and deltoid sites; however, total metabolic activity was similar for all injection sites (table IV). Similar observations have been made for insulin lispro,[47] insulin aspart[48] and regular human insulin.[26]
Table IV. Pharmacoki...Image Tools
3.5 Pre-Mixing with Intermediate-Acting Insulin
Pre-mixing of rapid-acting insulin analogues with intermediate-acting insulin (such as neutral protamine Hagedorn [NPH] insulin) is not recommended, although it is practiced particularly in paediatric and sometimes in adult patients. A randomized, open-label, two-way crossover study compared the effects of injecting a single 0.1 U/kg dose of insulin glulisine immediately after pre-mixing with a single 0.2 U/kg dose of NPH insulin, with separate but simultaneous administration of a 0.1 U/kg dose of insulin glulisine and 0.2 U/kg NPH insulin in 32 healthy male subjects.[50] At similar total exposure (INS-AUCtotal), pre-mixing attenuated the INS-Cmax by approximately 27% compared with separate injections, without a significant shift in the INS-tmax consistent with the previous data[15] (figure 3 c). Moreover, the GIR-AUCtotal and GIRmax were unaffected by pre-mixing. This study, therefore, showed that pre-mixing with NPH insulin immediately prior to use did not significantly change the rapid absorption and action of insulin glulisine. In general, similar findings have been reported for insulin lispro.[51]
4. Special Populations
4.1 Subjects of Japanese Ethnicity
Ethnicity did not unduly influence the pharmacokinetic and pharmacodynamic profiles of insulin glulisine. A euglycaemic clamp study with single 0.2 U/kg doses of insulin glulisine, insulin lispro or regular human insulin confirmed faster absorption and action compared with regular human insulin in Japanese and body mass index (BMI)-matched Caucasian men.[52]
Interestingly, although not significantly different, the Japanese population demonstrated slightly faster absorption, higher exposure and corresponding action-time characteristics compared with the Caucasian population for either insulin. This may be explained by the leanness of Japanese men, which is reflected in lower body weight rather than in the BMI. Indeed, matching different ethnic groups according to BMI does not properly and accurately reflect body composition (for example, it fails to distinguish between fat and muscle mass). When considering fat deposition, the Japanese group showed a greater proportion of median fat-free mass than the Caucasian group (median 84.5% vs 80.9%).[32] Therefore, the anthropometric nature, rather than any particular ethnic trait, may explain the differences in pharmacokinetics and pharmacodynamics between insulins in different ethnic groups.
4.2 Patients with Renal Impairment
The metabolism of insulin may be altered in patients with renal impairment.[53] This prompted an investigation into the pharmacokinetics of a single 0.15 U/kg dose of either insulin glulisine or regular human insulin in a crossover study in 24 subjects without diabetes, matched for age and BMI, but with different degrees of renal impairment.[54] Renal dysfunction in this study was defined by creatinine clearance: normal renal function (>80 mL/min); moderate renal impairment (30-50 mL/min); and severe renal impairment (<30 mL/min but not requiring haemodialysis). The concentration-time profiles (INS-AUC2, INS-Cmax and INS-tmax) for both insulin glulisine and regular human insulin were similar across subjects with or without renal impairment (figure 3 d). This was corroborated by similar blood glucose excursions after a standardized meal, independent of renal function, which were, however, consistently lower[54] with insulin glulisine than with regular human insulin.
4.3 Children and Adolescents
The delayed action-time characteristics of regular human insulin are particularly disadvantageous to children and adolescents, who may have difficulty in adapting to prandial insulin administration regimens. Rapid-acting insulin analogues can be used much closer to mealtimes and offer a good alternative to regular human insulin. Consequently, the rapid-acting properties of insulin glulisine in children and adolescents have been characterized. The pharmacokinetics of a single 0.15 U/kg dose of insulin glulisine were compared with those of regular human insulin in 10 children (aged 5-11 years) and 10 adolescents (aged 12-17 years) with type 1 diabetes.[40,41]
Insulin glulisine was more rapidly absorbed than regular human insulin in both children and adolescents with type 1 diabetes. Initial insulin exposure (INS-AUC2) was 69% higher and the INS-Cmax was 71% higher (with an earlier INS-tmax) following administration of insulin glulisine compared with regular human insulin. Furthermore, insulin glulisine was eliminated in less time, as evidenced by a reduced MRT (88 vs 137 minutes; point estimate [95% CI] for geometric means of insulin glulisine/regular human insulin 64% [59, 70]). Interestingly, equivalent pharmacokinetic profiles were seen for insulin glulisine in children and adolescents (point estimates [95% CI] for geometric means adolescents/children: INS-AUC2 112% [72, 174]; INS-AUCtotal 111% [73, 169]; INS-Cmax 112% [73, 172]).[41] In contrast, regular human insulin demonstrated a 64% higher overall insulin concentration and a 77% higher INS-Cmax in adolescents compared with children.[41] The reason for this difference is not known.
As demonstrated in adults with type 1 diabetes,[38] postprandial blood glucose excursions after insulin glulisine administration, assessed as the area under the baseline-subtracted blood glucose concentration-time curve (BG-AUC), were lower compared with regular human insulin (BG-AUC6 641 mg · h/dL for insulin glulisine vs 801 mg · h/dL for regular human insulin).[41]
This study replicated the pharmacokinetic characteristics observed in healthy adult volunteers and adults with type 1 diabetes. Although insulin glulisine is currently indicated for adult patients, its use is expected to be extended to the paediatric population on the basis of recently completed, large-scale, confirmatory clinical studies.
4.4 Lean to Obese Subjects without Diabetes Mellitus
Obesity is frequently associated with type 2 diabetes, and decreased insulin sensitivity associated with obesity is a hallmark of type 2 diabetes. At otherwise little affected total exposure, slower absorption is observed with an increasing subcutaneous fat layer, while decreased insulin sensitivity is due to the lipid burden related to increased visceral fat and requires larger doses to achieve sufficient glucodynamic efficacy with increasing obesity.[55] Therefore, obesity affects exposure profiles and inevitably decreases the efficacy of insulins, while any insulin molecule is equipotent and equally rapid and active after entering the systemic circulation (with the exception of albumin-bound insulin detemir).[36]
A randomized, double-blind, three-way crossover, euglycaemic clamp study of 18 fasting, moderately to severely obese, but otherwise healthy volunteers (BMI 30-40 kg/m2) was performed using single 0.3 U/kg doses of insulin glulisine, regular human insulin or insulin lispro.[36] In agreement with data from healthy, non-obese subjects, both insulin glulisine and insulin lispro demonstrated more rapid pharmacokinetic profiles (a shorter INS-tmax and MRT at a higher INS-Cmax) than regular human insulin. Both insulin glulisine and insulin lispro retained rapid action-time profiles compared with regular human insulin, as demonstrated by a greater GIR-AUC2 and a higher and earlier GIRmax.[36]
Of note, insulin glulisine consistently exhibited faster absorption (time to 20% of total insulin exposure [INS-t20%]) and faster elimination with greater early glucose utilization (GIR-AUC1 and GIR-AUC2) and a significantly shorter time to 20% of total glucose disposal (GIR-t20%; p = 0.025 at 2 hours) than insulin lispro.[36]
In this study, the GIR-tmax for both insulin lispro and regular human insulin was positive correlated with skin thickness and also with the BMI. This represented a shift in action profiles with increasing subcutaneous fat thickness for insulin lispro and regular human insulin. There was no significant correlation with insulin glulisine for either measure.[36]
Whether the faster early exposure and action compared with insulin lispro was restricted only to obese subjects was the subject of a follow-up, randomized, four-way crossover study that compared insulin glulisine and insulin lispro at two different doses (0.2 and 0.4 U/kg) in a population with a wider range of BMIs (<25, ≥25-<30, ≥30-<35 and ≥35 kg/m2) and without diabetes.[56]
Across the range of BMI groups, early absorption of insulin glulisine was significantly faster than that of insulin lispro, as demonstrated by a significantly reduced time to 10% of total insulin exposure (INS-t10%) of approximately 5-6 minutes (p < 0.05)[56] and significantly greater exposure within the first hour after injection ([INS-AUC1 : INS-AUCtotal] ratio). Consequently, insulin glulisine displayed a significantly more rapid onset of action (i.e. glucose-lowering activity) for either dose, with a shorter time to 10% of total glucose disposal (GIR-t10%), a higher GIR-AUC1 and a higher GIR-AUC1 : GIR-AUCtotal ratio at an otherwise similar GIR-AUCtotal compared with insulin lispro (table V). Moreover, dose proportionality was observed for insulin exposure with either insulin regardless of the BMI.
Table V. Pharmacokin...Image Tools
Interestingly, the INS-AUCtotal increased with both rapid-acting insulin analogues as total dosing increased with the BMI, whereas the GIR-AUCtotal decreased. Additionally, the INS-tmax and GIR-tmax increased moderately with an increasing BMI. These observations are in line with slightly reduced, but overall unaffected, availability of either insulin analogue with an increasing subcutaneous fat layer, increasing insulin resistance and abdominal fat and, thus, an increasing BMI.
While the difference between the insulin analogues in early absorption and action appear inconsequential, it is in line with the different self-association in solution, outlined above, and may add to the genuine benefits of rapid-acting insulin products in terms of injection time flexibility.
4.5 Meal Test Studies with Insulin Glulisine
4.5.1 Subjects with Type 1 Diabetes
Pre-meal insulin dosing is recommended; however, administration of prandial insulin post-meal is not an uncommon practice.[2,46] The more rapid absorption and action of insulin glulisine should translate into better postprandial glucose control when compared with regular human insulin. This was tested in a randomized, four-way, crossover study of 59 patients with type 1 diabetes using single 0.15 U/kg doses of insulin glulisine or regular human insulin.[38] Subjects were administered subcutaneous injections of insulin glulisine immediately prior to or 15 minutes after the start of a standardized meal, or regular human insulin 30 minutes prior to or immediately before a standardized meal.
As expected, insulin glulisine administered immediately pre-meal provided tighter postprandial glucose control than regular human insulin given immediately before the meal. Lower total blood glucose excursion, maximum blood glucose concentration and time-to-maximum blood glucose excursion were observed with insulin glulisine compared with regular human insulin (figure 4). Furthermore, insulin glulisine injected immediately pre-meal showed equivalent efficacy to that of regular human insulin given 30 minutes pre-meal (i.e. following recommended practice).[38] Post-meal dosing of insulin glulisine provided glucose control similar to that provided by pre-meal regular human insulin. Total glucose disposal was unaffected by the time of administration and was equivalent for both insulin glulisine and regular human insulin.
This study confirmed that insulin glulisine administered either pre- or post-meal was absorbed and eliminated more rapidly and reached almost double the peak insulin concentration in approximately half the time compared with regular human insulin at either injection time. Total insulin exposure was consistent with previous studies in healthy volunteers and demonstrated similar INS-AUCtotal values for both insulin glulisine and regular human insulin. The time of administration, pre- or post-meal, had no effect on absorption or elimination for either insulin.
Together with the observations in children and adolescents discussed earlier, this study provides further evidence that insulin glulisine could be used in a more flexible dosing regimen, which gives at least equivalent postprandial glucose control compared with regular human insulin.
4.5.2 Obese Subjects with Type 2 Diabetes
A randomized, open-label, two-arm, crossover meal study of obese (BMI >30 kg/m2) patients with type 2 diabetes evaluated the efficacy of single 0.15 U/kg doses of insulin glulisine or insulin lispro administered immediately prior to standardized meals at breakfast, lunch and dinner.[58]
In agreement with the slightly faster absorption of insulin glulisine, small between-treatment differences were observed, which accumulated to approximately 12% (p < 0.01) lower diurnal postprandial blood glucose excursions following dosing of insulin glulisine compared with insulin lispro.[58]
Therefore, taken with the data outlined earlier, insulin glulisine dosing in both type 1 and type 2 diabetes provided improved postprandial glucose control compared with regular human insulin or insulin lispro.[38,58]
4.6 Continuous Subcutaneous Insulin Infusion
The fast onset and short duration of action of rapid-acting insulin analogues are also advantageous for use in continuous subcutaneous insulin infusion (CSII) to achieve effective glycaemic control with a lowered risk of severe hypoglycaemia.[59-62]
The safety and efficacy of insulin glulisine compared with insulin aspart in CSII, delivered via an external pump, have been established in a multicentre, open-label, randomized, controlled study of 59 patients with type 1 diabetes,[63] which demonstrated comparable hypoglycaemia between the two insulin treatments.
Of note, there was a tendency for fewer catheter occlusions with insulin glulisine (13.8% of the study population) compared with insulin aspart (26.7% of the study population). As outlined earlier, this is probably attributable to the primary structure of insulin glulisine, which confers reduced flexibility of the C-terminus, which is otherwise associated with unfolding and denaturation (fibril formation). In addition, the detergent polysorbate 20 reduces the initiation of unfolding caused by interaction of monomers with the solvent.[12] However, an in vitro study comparing different experimental formulations assigned a greater sensitivity for precipitation with increasing acidification to insulin glulisine compared with insulin aspart, despite similar pIs.[22] A similar observation was made for insulin aspart when compared with insulin lispro;[24] however, the clinical relevance of these findings is debated.[64]
This notwithstanding, the above study confirmed that insulin glulisine can also be used in CSII and further provides potential benefits derived from the difference between its formulation and those of other insulin analogues.
5. Conclusions
Rapidly absorbed and acting insulin analogues are increasingly favoured for prandial insulin substitution and are displacing regular human insulin. Insulin glulisine is the newest rapidly absorbed and rapidly acting insulin analogue, and more closely mimics physiological insulin than regular human insulin. The amino acid substitution of lysine to glutamic acid at position B29 allows insulin glulisine molecules to exist at pharmaceutical concentrations in dimeric states, while avoiding zinc-promoted hexameric (and higher-order) forms, to achieve a practical shelf-life.
The pharmacokinetic profile of subcutaneously injected insulin glulisine has been confirmed as consistent and predictable in lean to obese healthy subjects of different ethnicities, in subjects with type 1 diabetes (including children and adolescents), in subjects with type 2 diabetes and in subjects with renal dysfunction. Moreover, the approved formulation provides for consistent, more rapid early absorption and action compared with insulin lispro across a wide range of lean to severely obese subjects.
Therefore, the structure and unique formulation of insulin glulisine results in a well balanced compromise in achieving both immediate availability of monomeric and dimeric insulin molecules for absorption upon subcutaneous injection and a practical shelf-life for a viable product. Consequently, it offers the convenience of pre- or post-meal administration in managing postprandial glucose control and, thus, provides not only greater flexibility for dosing regimens and meal size but also a closer approach to physiological replacement for the prevention of micro- and macrovascular complications associated with diabetes.
Acknowledgements
This work was sponsored by sanofi-aventis. Editorial support was provided by the Global Publication Group of sanofi-aventis. Both authors are employees of sanofi-aventis.
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