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Drug Evaluation
10.1517/17425255.2.5.793 © 2006 Informa UK Ltd ISSN 1742-5255 793
Insulin aspart: a reviewDavid Owens† & Jiten Vora†Llandough Hospital, Diabetes Research Unit, First Floor, Academic Centre, Penlarn Road, Penarth, South Glamorgan, CF64 2FX, Wales, UK
Insulin aspart, an analogue of human insulin, which is approved for use inpeople with diabetes, is more rapidly absorbed and achieves higher plasmaconcentrations than human soluble insulin following subcutaneous injection.Hence, it has a faster and more effective glucose-lowering action, with supe-rior control of postprandial hyperglycaemia compared with human solubleinsulin. Its shorter duration of action makes interprandial and nocturnalhypoglycaemia less of a problem than with human soluble insulin. Insulinaspart is approved for use in continuous subcutaneous infusion and offers avaluable treatment option during pregnancy.
Keywords: diabetes, insulin analogues, insulin aspart, pharmacodynamics, pharmacokinetics, therapeutic use
Expert Opin. Drug Metab. Toxicol. (2006) 2(5):793-804
1. Overview
In 2003, the worldwide prevalence of diabetes in adults (20 – 79 years of age) wasestimated to be 5.1% [101]. This figure is predicted to increase to 6.3% by 2025 dueto an increased prevalence in factors such as obesity and physical inactivity com-monly associated with urbanisation. Diabetes mellitus directly and indirectly poses amajor threat to health worldwide [1].
In healthy persons, endogenous insulin is normally secreted by the pancreaticβ-cells at a low rate that is relatively constant throughout the day (basal insulin secre-tion), and is punctuated by insulin peaks (bolus or prandial insulin secretion) pro-duced in response to a nutrient challenge. Type 1 diabetes results from a state ofnear-absolute insulin deficiency. In Type 2 diabetes, an initial decline in the prandialinsulin response leads to an elevated and prolonged postprandial hyperglycaemia. Thisis associated with a compensatory increase in insulin secretion during the late post-prandial period, which may in turn lead to a state of insulin resistance. As pancreaticfunction declines with disease progression, postprandial and fasting hyperglycaemiaensues. If not addressed, hyperglycaemia results in microvascular complications and,in association with other risk factors, macrovascular complications, leading to excessmorbidity and mortality in people with diabetes.
Landmark studies, such as the Diabetes Control and Complications Trial(DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), clearlydemonstrate the benefits of striving towards normalisation of blood glucose controlin people with Types 1 and 2 diabetes, respectively [2,3]. These studies showed thatimprovement in glycaemic control can delay the onset and retard the progression ofmicrovascular complications and, to a lesser extent, cardiovascular disease [4]. Therequirement for controlling postprandial glucose levels in addition to fasting hyper-glycaemia has recently been acknowledged as a result of compelling epidemiologicaland pathophysiological evidence linking postprandial hyperglycaemia with adversecardiovascular outcomes [5].
In people with Type 1 diabetes, treatment with exogenous insulin is mandatoryfrom the onset, whereas for many people with Type 2 diabetes, exogenous insulin isinstigated after a variable number of years in order to regain and maintain glycaemiccontrol [6].
1. Overview
2. Introduction
3. Overview of pharmacodynamic
properties
4. Pharmacokinetic properties
5. Safety and tolerability
6. Therapeutic use including dose
and administration
7. Conclusion
8. Expert opinion
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Insulin aspart
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Figure 1. Structure of insulin aspart.
Asp
B30
A1
B1
A21
B28Thr
Pro
Gly
Ile
Glu
GlnCys Cys Thr Ser Ile Cys Ser
Leu
Gln
Leu
Glu
Asn
CysAsn
AspThr
Phe Phe GlyArg
GluGly
Cys
Leu
Leu
Ala
Glu
Leu
HisSer
GlyCysLeuHisGlnAsnPhe
Tyr
Val
Tyr
Val
Val
ValTyr
Tyr
Lys
Recent treatment goals for diabetes from the InternationalDiabetes Federation (IDF) [7], American Diabetes Association(ADA) [8] and American Association of Clinical Endocrino-logists (AACE) [9] specify glycosylated haemoglobin (HbA1c)targets ranging from < 7% for all patients and < 6.5% in thepresence of cardiovascular disease. Furthermore, the IDF,AACE and ADA also recommend 2-h postprandial glucoselevels of < 8.0 mmol/l (1.45 mg/ml), < 7.8 mmol/l(1.40 mg/ml) and < 10 mmol/l (1.80 mg/ml), respectively, inan effort to achieve near-normal glycaemia.
2. Introduction
Insulin aspart is an analogue of human insulin prepared byrecombinant DNA technology. It is specifically designed toovercome some of the limitations of human soluble insulinwith regard to absorption pharmacokinetics when deliveredby subcutaneous injection. In particular, absorption of humansoluble insulin is too slow and the duration of action is toolong, resulting in a delayed effect and increased risk ofhypoglycaemia after the meal.
Endogenous human insulin is a 51-amino acid proteincomprising two peptide chains linked by disulfide bonds [10].Under physiological conditions (below 10-9 mol/l), insulinmolecules are present as monomers. At higher concentrations,a spontaneous, reversible self-association of monomers toform dimers occurs while in the presence of zinc ions; three ofthese dimers aggregate into a hexamer [11]. Due to the highinsulin concentration in commercially available insulin prepa-rations (≥ 10-4 mol/l), hexamers predominate (> 75% of themolecules). Due to their size, hexamers, in contrast to
monomers, are poorly permeable through the capillary wall.The dissociation rate of hexamers into dimers and eventuallymonomers is responsible for the observed lag in the absorptionof human soluble insulin into the circulation after subcuta-neous injection [12]. However, few people with diabetes treatedwith human soluble insulin follow this advice and, thus, arelikely to experience suboptimal prandial glucose control [13].There is also an associated increased risk of hypoglycaemiaduring the subsequent interprandial period, as insulin levelsmay remain elevated. Therefore, plasma insulin profilesachieved with subcutaneous human soluble insulin are limitedin normalising meal-related glucose concentrations [14].
Therefore, one way to achieve a faster rate of absorption ofinsulin from the subcutaneous tissue is to increase the rate ofdisassociation of the insulin hexamers. This can be achievedby modifying the primary structure of the insulin molecule,particularly in the side chains of single amino acids at theC-terminal end of the B-chain that play an important role inself-association. In insulin lispro (the first insulin analogueapproved for clinical use), the amino acids proline and lysineare reversed at positions 28 and 29 of the B-chain. In insulinaspart, the proline at position B28 in the human insulinmolecule is substituted by the negatively charged aspartic acid[15]; in all other respects, it is structurally identical to humaninsulin (Figure 1). The result of this substitution is to removethe normal interaction between proline B28 and glycine B23in the peptide chains, thereby reducing the tendency for insu-lin molecules to self-associate [15]. Thus, although insulinaspart exists predominantly as hexamers in the pharmaceuticalformulation, it rapidly dissociates into dimers and monomersafter subcutaneous injection [15]. Therefore, insulin aspart is
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absorbed faster into the systemic circulation than human sol-uble insulin after subcutaneous injection, allowing a moreprompt onset of its glucose-lowering action [15-17]. Accord-ingly, insulin aspart can be injected immediately before, oreven shortly after, meals [18-20], thereby increasing treatmentflexibility and patient satisfaction [21].
Insulin aspart is primarily used as a meal-related insulin,usually in combination with an intermediate- or long-actinginsulin. Alternatively, it may be combined with an inter-mediate-acting insulin in a premixed formulation for twice-or three times-daily administration. Insulin aspart can also beused in continuous subcutaneous insulin infusion (CSII)devices [22,23].
3. Overview of pharmacodynamic properties
In preclinical studies, the kinetics of insulin aspart in relationto the insulin and IGF-1 receptors was demonstrated to besimilar to those of human soluble insulin [24].
Euglycaemic glucose clamp and infusion studies show amore rapid onset of action of insulin aspart compared withthat of human insulin, as well as a shorter time to peak activ-ity and a shorter duration of action [16,17,25-27]. The time tomaximum decrease in plasma glucose levels was shorter afterinsulin aspart injection (65 – 145 min) than after human sol-uble insulin injection (148 – 201 min) and peak effect wasstatistically significantly higher for insulin aspart than humansoluble insulin (Figure 2) [16,17,25,26]. Thus, the time–actionprofile of insulin aspart more closely mimics the normalmeal-related insulin secretory pattern [28].
Variability of the metabolic effects of human soluble insu-lin between individuals and within individuals limits the abi-lity to achieve optimal glycaemic control [29]. In a euglycaemicclamp study in 20 healthy subjects, insulin aspart exhibitedless intrasubject variability in time to maximum effect and inpeak glucose-lowering effect than human soluble insulin [26],suggesting a more predictable timing of the glucose-loweringeffect with insulin aspart.
Figure 2. Insulin remaining at the injection site (A) and change in blood glucose (B). The more rapid absorption of insulin aspartthan human soluble insulin is reflected in the faster onset of glucose-lowering effect. Data are shown as mean ± 2 SEM. Copyright © 1991 American Diabetes Association. From Kang S et al. Diabetes Care 1991 14(7):571-577 [17]. Reproduced with permission from the AmericanDiabetes Association.SEM: Standard error of the mean.
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)40
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The pharmacodynamic properties and clinical efficacy ofinsulin aspart have been studied over a range of doses and atequimolar doses human soluble insulin and insulin aspart areequipotent [25]. However, although subcutaneous human solu-ble insulin exhibits a considerable prolongation in its durationof action at high doses (12 and 24 IU subcutaneously), expos-ing patients to an increased risk of postprandial hypoglycaemia,insulin aspart shows only a moderate, nonsignificant increase induration of action at the same doses [30].
Pharmacodynamic studies of the rapid-acting analogue,insulin lispro, have shown comparable results to insulin aspartwhen compared to human soluble insulin [31]. Comparison ofthe two short-acting insulin analogues using the clamp tech-nique in people with Type 1 diabetes demonstrated equiva-lence of the blood glucose infusion rates for insulin aspart andinsulin lispro during the first 6 h after injection, suggestingthat both insulin analogues are equally effective for control ofpostprandial blood glucose excursions [32].
4. Pharmacokinetic properties
4.1 Absorption and distributionInsulin aspart is absorbed twice as fast as human soluble insu-lin and achieves maximum plasma concentrations that aretwice as high and occur earlier (Figure 3) [17,26,28,33]. The fasterabsorption has been observed in healthy individuals [25], aswell as in people with diabetes [17,26,28,33]. In healthy men aftera single subcutaneous dose of insulin aspart (0.1 U/kg),maximum serum insulin concentrations were achieved after52 min, compared with 145 min for human soluble insulin(p < 0.001), and peak insulin levels were 41 versus 18 mU/l,respectively (p < 0.001) [18]. Overall, bioavailability of insulin
aspart and human soluble insulin were not significantlydifferent [16]. The pharmacokinetic properties of insulinaspart and insulin lispro are reported to be similar in healthyvolunteers [34], as well as in people with Type 1 diabetes [32,35].In two single-dose studies in people with diabetes, Cmax weresimilar with the two insulins [32,35] and Tmax as well as AUC at4 and 6 h after injection were comparable in one study [32].However, Cmax for insulin aspart was significantly higher thanfor insulin lispro in healthy volunteers [34], whereas Tmax andAUC at 40 min were higher for insulin lispro than for insulinaspart in people with diabetes [35].
The absorption profile of insulin aspart exhibits dose line-arity over the 0.06 – 0.2 U/kg dose range [26]. Similar tohuman insulin, insulin aspart is only minimally (5 – 10%)bound to circulating plasma proteins [36].
4.2 Metabolism and eliminationThe plasma clearance rates of insulin aspart and humansoluble insulin are similar [18], but insulin aspart’s lowermean residence time at the insulin receptor explains thepharmacokinetic differences between the two insulins [37].
As insulin aspart differs from human soluble insulin solelyby the substitution of a single amino acid, it is likely thatdegradation of the insulin aspart molecule is similarlyachieved by insulin protease or insulin-degrading enzyme [21].None of the metabolites formed after cleavage aremetabolically active [38].
4.3 Food interactionsInsulin aspart is injected subcutaneously as a meal-timeinsulin to help to control the prandial blood glucose levels.No interactions with food have been reported. Due to its
Figure 3. Insulin aspart reaches its maximum concentration more rapidly than human soluble insulin, reaches a highermaximum concentration and levels return faster to baseline values (mean ± 2 SEM). Copyright © 1999, Springer Verlag, reproduced with permission from Home PD et al., Eur. J. Clin. Pharmacol. 1999 55(3):199-203 [16].SEM: Standard error of the mean.
0 120 240 360 480
Insulin aspartHuman soluble insulin40
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rapid onset of action, insulin aspart may be administeredshortly before or immediately after a meal [18,19].
4.4 Drug interactionsDrugs that affect either the action of insulin or blood sugarlevels will interfere with the action of insulin aspart; however,there are no reasons to expect that insulin aspart will behavedifferently to human soluble insulin in this respect. In clinicalpractice, rapid-acting insulins are frequently admixed withintermediate- or long-acting insulin immediately before injec-tion. When insulin aspart and human neutral protein Hage-dorn (NPH) insulin are mixed, this results in a blunting anddelayed release of insulin aspart [39]. A premixed formulationof insulin aspart, consisting of 30% insulin aspart and 70%protamine-retarded insulin aspart, is available. The rapidactivity of insulin aspart is retained within the insulin aspartpremixture, allowing injection just prior to a meal andimproved postprandial glucose control with a reduced risk fornocturnal hypoglycaemia, as compared with premixed humaninsulin [40]. Insulin aspart cannot be mixed with either insulindetemir or insulin glargine.
4.5 Demographic interactions4.5.1 AgeAlthough age is recognised to have a profound effect on drugmetabolism [39], data indicate no difference in insulin aspart’spharmacodynamic profile between adults, children andadolescents with Type 1 diabetes [41].
4.5.2 Gender and raceSimilar pharmacodynamic responses to insulin aspart havebeen reported in healthy males and females [42]. Furthermore,the pharmacodynamic response in healthy Japanese men didnot differ from that observed in Caucasians, suggesting thatthere is no marked effect of race on response to insulin aspartresponse [43].
4.6 Special populations4.6.1 Hepatic diseaseThe liver is the major site of metabolism of circulatinginsulin [44]. Insulin aspart’s pharmacokinetics might thereforebe expected to be altered in patients with liver disease. In astudy involving 18 nondiabetic patients with mild-to-severehepatic impairment, insulin aspart pharmacokinetic para-meters (Cmax, AUC0 – 24 h) were not different from those insubjects (n = 6) with normal hepatic function [45].
4.6.2 Renal diseaseRenal impairment can alter insulin pharmacokinetics byreducing insulin clearance [46]. However, in a single-dosestudy in 12 patients with Type 1 diabetes and varying degreesof renal impairment (mild creatinine clearance [CLCR]> 50 – 80 ml/min, n = 7; moderate CLCR 30 – 50 ml/min,n = 3; and severe CLCR < 30 ml/min, n = 2), no significantinteractions were detected between any pharmacokinetic
parameter of insulin aspart relative to CLCR [46]. Theseresults suggest that adjustment of insulin aspart dose isunlikely to be necessary in patients with mild-to-moderaterenal disease. However, a reduction of insulin aspart dose maybe necessary in patients with severe renal disease.
4.6.3 ObesityThere is a strong link between obesity and Type 2 diabetes. Esti-mates suggest that, compared with persons with a body massindex (BMI) between 18.5 and 24.9 kg/m2, those with a BMI> 30 kg/m2 are ∼ 20-times more likely to develop diabetes [47].Indeed, 80% of people with Type 2 diabetes are overweight atdiagnosis [47]. In diabetic subjects with a range of BMI values(19 – 32 kg/m2, n = 23), increasing obesity was associated witha reduction in apparent clearance of insulin aspart per body-weight (kg), resulting in an increased half-life and increased areaunder the plasma concentration–time curve [47]. Although thelatter observation might suggest that the starting dose of insulinaspart should be reduced in subjects with high BMI values, thedegree of individual variation in these parameters is too large tosuggest dose adjustment based on BMI [45].
4.6.4 PregnancyPregnancy complicated by Type 1 diabetes or gestational dia-betes has been associated with increased risk of both maternaland neonatal complications. Normal or near-normal glycaemiccontrol prior to and during pregnancy reduces many of theserisks to levels observed in the general population. In a para-llel-group, randomised, controlled, multi-centre study in322 pregnant women with Type 1 diabetes, treatment withinsulin aspart was associated with a lower rate of major hypo-glycaemia and similar overall glycaemic control to human solu-ble insulin [48,49]. Similar numbers of live births, fetal losses andcongenital malformations were reported between treatments.The occurrence of perinatal complications was also comparablebetween insulin aspart and human soluble insulin. Furthermore,in women with insulin-requiring gestational diabetes, insulinaspart was more effective than human soluble insulin in reduc-ing the peak postprandial glucose concentration [50] and pro-vided overall similar glycaemic control to human soluble insulin[51]. As increased postprandial glucose concentrations have beenassociated with an elevated risk for macrosomia [52], reductionsin postprandial glucose concentrations with insulin aspart mayresult in improved infant birthweight and thus fewer birth com-plications. By comparison, mean fasting, postprandial glucoseconcentrations and end point HbA1c levels in pregnant womenwith Type 1 or gestational diabetes on insulin lispro were similarto those with human soluble insulin, although women oninsulin lispro had fewer hypoglycaemic episodes [53,54].
5. Safety and tolerability
5.1 HypoglycaemiaThe most significant barrier to optimising glycaemic control isthe increasing risk of hypoglycaemia associated with reduction
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in HbA1c. However, the more rapid action of insulin aspartmakes postabsorptive and nocturnal hypoglycaemia less of aproblem than is found with human soluble insulin [55]. Thefear of hypoglycaemia and its associated morbidity make manyinsulin-treated patients more reluctant to pursuerecommended targets for glycaemic control [56].
In long-term clinical studies, overall incidences of major orminor hypoglycaemic episodes with insulin aspart were lowerthan [57] or similar to those with human soluble insulin[55,58-60] in patients with Type 1 and 2 diabetes. Consistentwith these results, a large meta-analysis of 7933 participantsfrom 42 clinical trials reported a weighted mean reduction ofoverall mean hypoglycaemic episodes per patient per month of-0.2, for insulin lispro and insulin aspart versus human solubleinsulin in patients with Type 1 and 2 diabetes, and a lowerincidence of major hypoglycaemia for patients with Type 1 or2 diabetes on insulin analogues (median 20.3 and 0.6 epi-sodes/100 person-years, respectively) than on human solubleinsulin (median 37.2 and 2.8 episodes/100 person-years,respectively) [61].
The prolonged duration of action of human soluble insulincan lead to an overlap with that of the evening basal (NPH)insulin, increasing the likelihood of nocturnal hypoglycaemia.The more rapid onset and shorter duration of action of insu-lin aspart, with waning of insulin activity by bedtime, resultsin lower nocturnal plasma insulin concentrations and, there-fore, higher blood glucose levels through the night, which, inturn, results in a significant reduction in incidence of noc-turnal hypoglycaemia in comparison with human solubleinsulin [55,62,63]. A 6-week, double-blind, randomised studyinvolving 155 patients with Type 1 diabetes reported a 72%reduction in the risk of experiencing a major nocturnalhypoglycaemic episode with insulin aspart plus NPH insulinthan with human soluble insulin plus NPH insulin [62]. Whenused in combination with the long-acting insulin analogue,insulin detemir, the risk of major nocturnal hypoglycaemiawas 83% lower than with a combination of human solubleinsulin plus NPH insulin [63]. These results are consistentwith those reported for the other rapid-acting analogue, insu-lin lispro, although in a head-to-head comparison, fewerpatients on CSII insulin aspart than on CSII human insulinor insulin lispro experienced nocturnal hypoglycaemic events(59 versus 75 or 80%, respectively) during the last 3 monthsof a 6-month study [60].
5.2 Immunogenicity and toxicityModifications of the human insulin molecule may increase itsimmunogenicity, potentially leading to increased formation ofcirculating insulin-binding antibodies. Such antibodies canpotentially interfere with the pharmacokinetics of insulin,thereby causing delayed insulin peaks, prolongation of action,increased risk of hypoglycaemia and varying bioavailability [64].In 23 patients with Type 1 diabetes, levels of circulating insu-lin-binding antibodies were assessed following 12 weeks ofmultiple daily injections of biphasic insulin aspart (30%
fast-acting insulin aspart, 70% protamine-crystallised insulinaspart) [65]. Patients were stratified into two groups accordingto the level of insulin binding to insulin antibodies. Total insu-lin aspart profiles were significantly higher in patients withhigh versus low-to-moderate antibody levels. The free insulinaspart pharmacokinetics, pharmacodynamics and HbA1c weresimilar between patients with moderate and high levels of insu-lin antibodies [65] and the total daily insulin dosage was signifi-cantly lower in patients with high rather than moderate levelsof insulin antibodies. In longer-term studies (6 – 12 months),most patients with Type 1 [57,58] or 2 [66] diabetes were free ofinsulin aspart-specific and human insulin-specific bindingantibodies throughout the study period [67]. Furthermore,although levels of crossreacting antibodies were detected in64 – 68% of patients on study entry, which increased duringthe first 3 months of treatment, these subsequently declined tobaseline levels by 6 – 12 months [67]. The weak immuno-genicity of insulin aspart evidenced is comparable to thatshown for insulin lispro [68].
Few potentially allergic events and no anaphylactic reactionshave been reported in patients using insulin aspart or insulin lis-pro, and severe dermal reactions at the injection site are infre-quent with insulin analogues, occurring in < 1% of patients [69].Indeed, immune response to human soluble insulin can be obvi-ated by the use of either analogue [70,71]. Although the mainimmunogenic insulin epitopes remain unchanged in the insulinaspart molecule, immunogenicity appears to be reduced,possibly because of the rapid dissociation into monomers [70].
5.3 MitogenicityNative human insulin has a weak mitogenic effect. Potentially,structural modifications of the insulin molecule could increasethe mitogenic potency, possibly resulting in proliferativeand/or mitogenic signalling [72]. For example, the monomericinsulin analogue, Asp B-10, in which aspartic acid replaces thenaturally occurring histidine at residue 10 of the B-chain of theinsulin molecule, increased insulin and IGF-1 receptor bind-ing, tyrosine kinase activation and DNA synthesis [24,72] and,at high doses, induced tumours in the mammary glands offemale rats [24]. Further clinical studies with this analoguewere, therefore, halted. However, data from long-term animalstudies shows insulin aspart to be safe in terms of toxicity andcarcinogenic potency [72,73]. In in vivo cell model experiments,insulin aspart showed similar on-and-off rates to the insulinand IGF-1 receptor to those of human insulin [72,73]. Impor-tantly, insulin aspart’s lower residence time at the insulin recep-tor and reduced affinity for the IGF-1 receptor does not resultin enhanced mitogenic potency [72]. The mitogenic effect ofinsulin aspart is similar to that of insulin lispro [72].
6. Therapeutic use including dose and administration
The rapid-acting insulin analogues, insulin aspart and insulinlispro, can be used in intensified insulin treatment with or
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without insulin infusion pumps, for prandial insulin supple-mentation, and in premixed insulin preparations for peoplewith Types 1 and 2 diabetes. The more physiologicaltime–action profile of the analogues means that they mimicthe rapid physiological rise of serum insulin in response to ameal much better than human soluble insulin [55] and, in mostcases, the injection can be given immediately prior to, or evenimmediately after, the meal. Thus, patients treated with insulinaspart have significantly better postprandial glycaemic controlthan patients treated with human soluble insulin [37,55,27,58],both when given at the beginning of meals and 30 min before[67]. For example, in a 4-week, double-blind, crossover study inpeople with Type 1 diabetes, postprandial glucose values weresignificantly (p < 0.01) lower with insulin aspart than withhuman soluble insulin, whereas premeal glucose levels weresimilar [55]. Furthermore, in two long-term (> 6 months) stud-ies in Europe [57] and the US [58] involving > 1900 people withType 1 diabetes, baseline-adjusted peak postmeal blood glu-cose excursions were significantly lower with insulin aspartthan with human soluble insulin (European study, 0.54 versus1.69 mmol/l, respectively, p < 0.0001; US study, 0.12 versus1.58 mmol/l, respectively, p < 0.001). These results are consist-ent with those reported for insulin lispro, but evidence suggeststhat improved postprandial control with insulin aspart isachieved without deterioration in late postprandial glucoseconcentrations [55]. Improved meal-time glycaemic controlwith insulin aspart has also been demonstrated in both nor-mal-weight and overweight people with Type 2 diabetes[59,74,75]. In a study involving 231 patients with Type 2diabetes, postprandial blood glucose values were lower by0.44 – 1.67 mmol/l for patients on insulin aspart comparedwith those on human soluble insulin [59]. As a decrease in theprandial insulin response is one of the first abnormalities ofβ-cell decline in Type 2 diabetes, there is a strong physiologicalbasis for supplementation with prandial rapid-acting insulin.Indeed, in poorly controlled, long-term diabetic subjects withsevere insulin resistance with impaired insulin response, theinitiation of insulin therapy with rapid-acting insulin ana-logues in combination with existing oral antidiabetic drugs isan effective means of optimising glycaemic control, withoutincreasing the risk for hypoglycaemia [76,77].
Improvements in postprandial glycaemic control withinsulin aspart have been associated with statistically signifi-cant, albeit minor, falls in HbA1c of ∼ ≤ 0.3% [57,58]. In thelargest trial [57], this effect was sustained in a 2.5-year trialextension (n = 753) in which patients receiving insulin asparthad a mean HbA1c that was 0.16% lower than those receivinghuman soluble insulin (p = 0.035) [78]. In this open-labelstudy, insulin aspart was given subcutaneously immediatelybefore the main meals and human soluble insulin recom-mended to be given 30 min before meals. When insulin aspartand human soluble insulin were injected 0 – 5 min beforemeals, mean HbA1c was similar on both treatments [62]. Insubjects with Type 2 diabetes, similar preprandial doses ofinsulin aspart and human soluble insulin reduced HbA1c by
0.91 and 0.73%, respectively [59]. No adverse impacts of insu-lin aspart treatment on the rate of major hypoglycaemia wereseen in any of these trials. On the contrary, in the dou-ble-blind study reported by Heller et al. [62], substitution ofinsulin aspart as part of a ‘basal-bolus’ regimen in tightly con-trolled patients significantly reduced the risk of major noctur-nal hypoglycaemia compared with human soluble insulin.Improvements in glycaemic control without increasing therisk for hypoglycaemia requires optimal basal insulin replace-ment, either by multiple daily injections of NPH insulin or byCSII. Evidence suggests that the short-acting insulin ana-logues would be better matched by a more predictable basalinsulin analogue, such as insulin detemir, than the erraticallyabsorbed and shorter-acting NPH insulin [55]. In this respect,it is of interest to note that patients on insulin aspart plusinsulin detemir experienced a significantly lower mean HbA1c
at 18 weeks than those on insulin aspart plus NPH insulin, aswell as significantly better postprandial control, lower weightgain and a lower risk of nocturnal hypoglycaemia [63,79].
Studies have demonstrated that the rapid-acting insulin ana-logues are superior to human soluble insulin for loweringHbA1c levels in patients who receive insulin by CSII [80].Indeed, insulin aspart was at least as effective (similar or greaterreductions in HbA1c) and well tolerated, showing a similar rateof hypoglycaemia, as human soluble insulin and insulin lisproin patients with Type 1 diabetes, and was considered as suita-ble insulin for CSII using external pumps [60,81]. Insulin asparthas also been shown to be effective in Type 2 diabetes [22].
Many people with diabetes are recognised to have a reducedquality of life, which may negatively impact on their diabetesself-management. Insulin aspart compared well with humansoluble insulin in studies examining treatment satisfactionand health-related quality of life [85-87] and, when used inCSII, was associated with a significantly greater improvementin treatment satisfaction than intensive insulin therapy [22].
For patients with Type 2 diabetes, insulin initiation is oftenassociated with weight gain and improving glycaemic controlaccompanied by a reduction in glycosuria. However, in a3-month study, no weight gain was observed in patients start-ing with insulin aspart, whereas patients on human solubleinsulin gained a median of 0.5 kg [59]. Furthermore, inpatients with Type 1 diabetes, the bodyweight of patientsreceiving insulin aspart with insulin detemir was 1 kg lowerthan that of patients receiving human soluble insulin plusNPH insulin over an 18-week trial period (p < 0.001) [63].
As for other insulin products, dosage requirements ofinsulin aspart vary among patients and are individualisedaccording to the patient’s specific metabolic needs, eatinghabits and lifestyle. The usual total daily insulin require-ment ranges 0.5 – 1.0 U/kg/day, whereby 50 – 70% of thetotal dose may be provided by meal-related injections ofinsulin aspart and the remainder by a basal insulin. Whenused in combination with oral hypoglycaemic agents(OHAs) the dose of insulin aspart is generally lower than inbasal-bolus regimens [76,77].
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Furthermore, as the faster action of the rapid-acting ana-logues may increase the risk for exercise-induced hypo-glycaemia, patients who exercise early in the postprandialperiod (within 1 – 3 h of eating) may need to reduce theirinsulin dose or take extra carbohydrates prior to exercise.Conversely, those who exercise later will require a smaller orno change in insulin aspart dose.
7. Conclusion
Extensive preclinical and clinical data are available characteris-ing the pharmacokinetic, pharmacodynamic and safety/toler-ability profile of insulin aspart. Accumulated evidencesupports that insulin aspart is safe and effective for use inpatients with Types 1 and 2 diabetes. Its rapid onset of actionprovides better postprandial glucose control than solublehuman soluble insulin and its shorter duration of actionreduces the risk of interprandial and nocturnal hypo-glycaemia. The impact on postprandial hyperglycaemia isimportant for reducing the risk of cardiovascular morbidityand mortality associated with exaggerated postprandial glu-cose excursions. When used in combination with inter-mediate- or long-acting insulin, insulin aspart helps toprovide 24-h control of blood glucose. Furthermore, datafrom long-term studies also show that insulin aspart helps toachieve good metabolic control with continued use, withoutincreasing the risk of major hypoglycaemia. It is also suitablefor use in CSII delivery systems.
8. Expert opinion
Insulin therapy aims to recreate the normal physiological insu-lin profile, thereby limiting meal-time glucose excursions andproviding adequate basal insulin requirements to normalisethe fasting plasma glucose. The pharmacokinetic properties ofthe rapid-acting insulin analogues, insulin aspart and insulinlispro, demonstrate a more rapid absorption after subcuta-neous injection than for human soluble insulin [26]. Thismeans that, similar to insulin lispro, insulin aspart provides amore physiological action profile in relation to the ingestion ofnutrients than does human soluble insulin [17,26] and, hence,achieves better postprandial glucose control [33,58]. In patientswith Type 2 diabetes, the rapid time–action profile of insulinaspart in contrast to regular human soluble insulin effectivelycurtails postprandial hepatic glucose production, which con-tributes to lower postprandial glucose peaks [82]. Suchimprovements in postprandial hyperglycaemia and the relatedglycaemic variability may play an important role in forestallingthe development of diabetes-related complications.
As is the case for insulin lispro, the reduction in post-prandial glucose levels associated with insulin aspart has notbeen associated with a significant reduction in HbA1c levelswhen compared to human soluble insulin [32]. This lack ofdifference may reflect the inadequacy of the basal insulinreplacement, as good basal interprandial coverage with at least
two doses of NPH insulin or a long-acting insulin analogue,such as insulin detemir, are required for effective glycaemiccontrol. Certainly, when used in insulin infusion pumps,HbA1c levels are lower than with human soluble insulin, pro-vided basal insulin supply is adequately adjusted [81]. Further-more, combined use of insulin aspart and the long-actinganalogue, insulin detemir, permits improved glycaemic con-trol compared with a human insulin regimen, as well as highlyflexible control of glycaemia, including variable meal times ormissing meals, with little overlap of the short and prolongedinsulin action [57,58]. Such regimens are associated with a lowrisk of hypoglycaemia, as well as limiting weight gain, as lesssnacking is required [59,63,77]. Insulin aspart, when used incombination with OHAs, improves glycaemic control inType 2 diabetes patients who have failed to achieve glycaemictargets on maximal OHA therapy [76,77].
Although better glycaemic control decreases the risk oflong-term diabetic complications, it is often associated with anelevated incidence of hypoglycaemia. Rapid-acting insulin ana-logues, due to their shorter duration of effect, were expected toreduce the incidence of hypoglycaemia between meals. A con-sistent decrease in the incidence of hypoglycaemia comparedwith human soluble insulin has not been demonstrated.Nevertheless, insulin aspart is reported to significantly reducethe occurrence of major nocturnal hypoglycaemia, the mostunwanted side effect of insulin therapy [62]. In pregnantwomen with Type 1 diabetes, insulin aspart is associated with alower incidence of major hypoglycaemia, especially nocturnalevents, at a comparable level of glycaemic control comparedwith human soluble insulin [48,49]. The avoidance of hyper-glycaemia is recognised to be essential in optimising pregnancyoutcome in Type 1 diabetes; however, the price to pay is oftena striking increase in major maternal hypoglycaemia [83]. Treat-ment satisfaction in terms of flexibility and convenience isgreater with insulin aspart compared with human solubleinsulin [84]. This is of particular benefit to those patients whocannot adhere to a 30-min premeal injection interval asrecommended for human soluble insulin.
The use of rapid-acting insulin analogues in Europe israpidly expanding, with almost 75% of persons with insu-lin-treated diabetes using insulin analogues for theirmeal-time insulin supplementation. Their usage wouldappear set to increase, as growing evidence suggests potentialclinical advantages [85]. Despite the fact that studies haveshown similar or superior efficacy and safety outcomes withthe rapid-acting insulin analogues compared with humansoluble insulin that may directly or indirectly reduce costs oftreating people with diabetes, few pharmacoeconomic stu-dies have compared treatment costs in clinical practice. Acost–benefit analysis for insulin lispro, which has a similarefficacy and safety profile to that of insulin aspart, revealedcost neutrality compared with human soluble insulin, whichwas mainly due to significantly lower in-patient andhypoglycaemia-related hospitalisations, despite a higherpharmacy price [86].
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In common with all new pharmacological therapies,long-term experience is required to ensure both safety and effi-cacy of insulin aspart. However, despite initial concerns aboutincreased mitogenic capacity of insulin analogues seen withprototype insulin analogues [87], there is no evidence to suggestthat insulin aspart is associated with increased toxicity or carci-nogenic potency and its insulin receptor interaction profileappears identical to that of human insulin. Recent data showthat insulin aspart is as safe and human soluble insulin for useduring pregnancy in women with Type 1 diabetes [48,49].
In summary, insulin aspart offers a promising alternativefor meal-related human soluble insulin therapy in patients
with Types 1 and 2 diabetes. Its hypoglycaemic potency issimilar for all age groups, ranging from children and adoles-cents to the elderly. Although its ability to lower HbA1c levelsto a greater extent than that achieved by human soluble insu-lin cannot always be demonstrated, the advantages of bettercontrol of postprandial glucose, more flexible dosing andlower associated rates of severe nocturnal hypoglycaemia makeit an attractive alternative option to human soluble insulin formany patients. Long-term follow up of patients who use insu-lin aspart will provide further clinical data on the safety andefficacy of this analogue in various clinical situationsinvolving insulin-requiring persons with diabetes.
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Website
101. http://www.eatlas.idf.orgIDF Diabetes Atlas, 2nd edn (2005). Accessed 27 March 2006.
AffiliationDavid Owens†1 MD, FRCP, CBiol, FIBiol, CBE & Jiten Vora2 BA, MB, BChir, MA, MRCP, MD, FRCP†Author for correspondence1Llandough Hospital, Diabetes Research Unit, First Floor, Academic Centre, Penlarn Road, Penarth, South Glamorgan, CF64 2FX, Wales, UKTel: +44 29 2071 6298; Fax: +44 29 0235 0147;E-mail: owens [email protected] Liverpool University Hospitals Link, Liverpool, UKTel: +44 151 706 3470; Fax: +44 151 706 5871;E-mail: [email protected]
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