Insulin aspart: a novel rapid-acting human insulin analogue

In order to improve therapy and increase the quality of life for diabetic patients, it has been of significant interest to develop rapid-acting insulin preparations that mimic the physiological meal-time profile of insulin more closely than soluble human insulin. Insulin aspart (B28Asp human insulin) is a novel rapid-acting insulin analogue that fulfils this criterion. The B28Asp modification weakens the self-association of the insulin molecule and provides a more rapid absorption from the sc. injection site. The preclinical evaluation in vitro and in vivo demonstrates that apart from the more rapid absorption, insulin aspart is equivalent to human insulin. Thus, insulin aspart is equivalent to human insulin on key in vitro parameters such as insulin receptor affinity, insulin receptor dissociation rate, insulin receptor tyrosine kinase activation, IGF-I receptor binding affinity, metabolic and mitogenic potency. In accordance with the equivalent in vitro profiles, the toxico-pharmacological properties of insulin aspart and human insulin are also identical. The available data for insulin aspart and other rapid-acting insulin analogues supports that in vitro assays are sensitive and valuable in the preclinical evaluation of insulin analogues. Clinical studies demonstrate that insulin aspart has a pharmacokinetic and pharmacodynamic profile superior to that of soluble human insulin. In Type 1 diabetic patients on a basal-bolus injection regimen, insulin aspart given immediately before the meals provides an improved postprandial glycaemic control and an improved long-term metabolic control, as compared to soluble human insulin given 30 min before the meals, without increasing the risk of hypoglycaemia. Taken together, the data support the hope that insulin aspart will allow the diabetic patient to combine a more flexible lifestyle with better glycaemic control, without any increased safety risk.     

Clinical pharmacokinetics and pharmacodynamics of insulin aspart

Insulin aspart is a novel rapid-acting insulin analogue with improved subcutaneous absorption properties when compared with soluble human insulin. Pharmacokinetic studies show an absorption profile with a time to reach peak concentration (t(max)) about half that of human insulin, a peak plasma drug concentration (Cmax) approximately twice as high and shorter residence time. The potency and bioavailability of insulin aspart are similar to those of human insulin. The pharmacokinetics of insulin aspart have been studied in healthy Caucasian and Asian-Japanese volunteers, in patients with type 1 and 2 diabetes mellitus, and in children with diabetes, with both pre- and postprandial administration and during continuous subcutaneous insulin infusion (CSII). The pharmacokinetic profile was similar to that of another rapid-acting insulin analogue, insulin lispro, on the basis of published information for that agent. Pharmacodynamic studies show a smaller excursion of postprandial glucose with insulin aspart injected subcutaneously just before the meal compared with soluble human insulin injected 30 minutes before the meal in patients with type 1 diabetes mellitus, and an equivalent control in patients with type 2 diabetes displaying residual insulin production. In a treatment study, glucose excursions evaluated from 24-hour glucose profiles showed less variability with insulin aspart compared with human insulin. Adverse events, including hypoglycaemia-induced ventricular repolarisation and hypoglycaemic threshold and awareness, did not differ between insulin aspart and human insulin. The available data suggest that subcutaneous injections of insulin aspart just before meals better mimic the endogenous insulin profile in blood compared with human insulin, resulting in improved glucose control in a meal-related insulin regimen. This review summarises the clinical pharmacokinetics and pharmacodynamics of insulin aspart in relation to human insulin and insulin lispro.     

Insulin aspart: a review of its use in the management of type 1 and 2 diabetes mellitus

Insulin aspart, a rapid-acting human insulin analogue, provides more rapid absorption than regular human insulin after subcutaneous administration. In most randomised, nonblind clinical trials in patients with type 1 diabetes mellitus, insulin aspart administered immediately before meals resulted in significantly lower mean glycosylated haemoglobin A(1c ) (HbA(1c)) levels than regular human insulin (usually administered 30 minutes before a meal). Insulin aspart also significantly improved postprandial glycaemic control compared with regular human insulin. The efficacy of insulin aspart was similar to that of insulin lispro when administered to patients with type 1 diabetes mellitus via continuous subcutaneous infusion in a randomised, nonblind trial. Preliminary data from randomised, nonblind trials suggest insulin aspart had a trend towards lower HbA(1c) levels compared with regular human insulin in patients with type 2 diabetes mellitus. Biphasic insulin aspart [30% soluble (rapid-acting) and 70% protamine-bound insulin aspart (BIAsp30)] generally provided significantly better postprandial glucose control than a similar mixture of biphasic regular human insulin (BHI30) in a randomised, nonblind trial in patients with type 1 or 2 diabetes mellitus. However, the long-term efficacy of BIAsp30 was similar to that of BHI30 after 2 years in a randomised, nonblind trial in patients with type 2 diabetes mellitus. Patients with type 1 or 2 diabetes mellitus reported greater treatment satisfaction with insulin aspart or BIAsp30 than with regular human insulin or BHI30. The overall incidence of hypoglycaemia with insulin aspart was lower than, or similar to, that of regular human insulin. Moreover, insulin aspart tended to be associated with a lower occurrence of nocturnal hypoglycaemia and severe hypoglycaemic events than regular human insulin. CONCLUSION: The standard preparation of insulin aspart has the potential to better mimic the physiological response to meals than regular human insulin. Insulin aspart when combined with a suitable basal insulin improved overall glycaemic control and led to a similar or lower number of hypoglycaemic episodes compared with a similar regular human insulin regimen. Insulin aspart was generally as effective and well tolerated as insulin lispro when administered by continuous subcutaneous infusion in a single comparative trial. The efficacy of biphasic insulin aspart has been documented in a small number of trials. Both insulin aspart and biphasic insulin aspart provide for flexible and convenient administration. Insulin aspart is now well established as an effective and convenient means of providing glycaemic control which offers clinical and practical advantages over regular human insulin.     

Premixed insulin analogues for the treatment of diabetes mellitus

Premixed insulin analogues, consisting of rapid-acting and intermediate-acting insulin analogues, were developed to more closely mimic physiological endogenous insulin secretion and meet the needs of patients who require both basal and prandial insulin but wish to limit the number of daily injections. There is considerable variability in onset and duration of action, as well as peak insulin levels, obtained with human insulin formulations such as premixed human insulin 70/30. To overcome these limitations, premixed insulin analogues were developed. Peak insulin levels are twice as high and reached in half the time with the rapid-acting insulin component of a premixed insulin analogue. In the US, two premixed insulin analogue formulations are currently available: insulin lispro 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro) and biphasic insulin aspart 70/30 (BIAsp 70/30; 70% insulin aspart protamine suspension and 30% insulin aspart). They are generally administered twice daily, just before breakfast and dinner. Data from various randomised trials show that both insulin lispro 75/25 and BIAsp 70/30 provide more effective postprandial control of blood glucose than premixed human insulin 70/30 or human insulin isophane suspension (NPH insulin). Longer-term glycaemic control, evaluated as changes in glycosylated haemoglobin, is comparable for premixed insulin analogues and premixed human insulin 70/30 in most studies. Three comparative, randomised trials have shown that patients with type 2 diabetes mellitus using premixed insulin analogues twice daily are more likely to reach glycaemic goals than those using only insulin glargine once daily. Some patients can also reach glycaemic goals with once-daily administration of a premixed insulin analogue. Although the incidence of hypoglycaemia is low, direct comparison across trials of premixed insulin analogues is difficult because of inconsistencies in reporting. Within trials, the incidence of both major (rare) and minor hypoglycaemic episodes during treatment with premixed insulin analogues is low and comparable with rates found with human insulin 70/30. Premixed insulin analogues can be safely used, and are effective and convenient for achieving overall glycaemic control in patients with diabetes. In addition, given the convenience of mealtime dose administration, compliance with insulin therapy may increase with premixed insulin analogues.     

Insulin aspart: a review of its use in the management of type 1 or 2 diabetes mellitus

Insulin aspart (NovoRapid, NovoLog) is a short-acting insulin analogue, which has a faster onset and shorter duration of action than regular human insulin. Insulin aspart administered immediately before meals provided significantly greater improvements in glycosylated haemoglobin and better postprandial glycaemic control than regular human insulin administered 30 minutes before meals, when used in a basal-bolus regimen with neutral protamine Hagedorn (NPH) insulin, in randomised, nonblind studies in patients with type 1 diabetes mellitus. In patients with type 2 diabetes, insulin aspart provided similar glycaemic control to regular human insulin, administered in a basal-bolus regimen with NPH insulin. Small studies suggest that the use of insulin aspart in combination with oral hypoglycaemic agents may be beneficial. Insulin aspart, administered by continuous subcutaneous insulin infusion (CSII) provided better glycaemic control than insulin aspart multiple daily injection regimens in patients with type 1 (but not type 2) diabetes, and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Limited studies show insulin aspart to be effective in children, adolescents and young adults with type 1 diabetes. Insulin aspart had a tolerability profile similar to that of regular human insulin in clinical trials. The incidence of major or nocturnal hypoglycaemic events reported in patients receiving insulin aspart was lower than that of regular human insulin in several studies.In conclusion, insulin aspart, administered immediately before meals in a basal-bolus regimen with NPH insulin, provided better long-term glycaemic control than regular human insulin administered 30 minutes before meals in patients with type 1 diabetes, and was as effective as regular human insulin in patients with type 2 diabetes. A significantly lower risk of hypoglycaemia was seen in several trials. Insulin aspart CSII provided better glycaemic control than insulin aspart multiple daily subcutaneous injection (MDI) in patients with type 1 (but not type 2) diabetes and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Insulin aspart is an effective and well tolerated alternative to regular human insulin and insulin lispro for the maintenance of glycaemic control in patients with type 1 or 2 diabetes.     

Insulin therapy in diabetes mellitus: how can the currently available injectable insulins be most prudently and efficaciously utilised?

The era of animal source insulins has passed and human recombinant DNA insulins are gradually being replaced because of the superior efficacy of insulin analogues. Analogue insulins are available in both rapid- and long-acting preparations. Currently available rapid-acting insulins are lispro, aspart and glulisine, and the currently available long-acting analogue basal insulins are detemir and glargine. The rapid-acting insulin analogues are also available in combination with protamine in fixed-dose pre-mixed insulins to provide a more sustained action. The chemical structure, subcutaneous behaviour, time of onset, maximal effect and duration of action of both analogue and human insulins, and how these actions can be best utilised in the diabetic patient are discussed in this review. In addition, strategies where efficacy of the available analogue insulins can be maximally utilised in both type 1 and type 2 diabetes mellitus are described. Maximal utilisation of analogue insulins will result not only in better glycaemic control, but will also minimise the frequency and severity of hypoglycaemic episodes. In addition, maximisation of glycaemic control will result in prevention, delay of onset or amelioration of both the microvascular and perhaps the macrovascular complications of diabetes.     

Insulin aspart : an evidence-based medicine review

This paper provides a review and evaluation of the published evidence relating to the efficacy, safety and ease of administration of the rapid-acting insulin analogue insulin aspart in comparison with human insulin (HI) in diabetes mellitus in the following categories: (a) in adults, (b) in children, and (c) in continuous subcutaneous insulin infusion (CSII). A search for publications on insulin aspart was conducted for the following databases: Cochrane, BIOSIS, EMBASE-DP and MEDLINE. Publications were examined for relevance by two independent assessors and were graded using a system developed by the Oxford Centre for Evidence-Based Medicine. Overall, the evidence comparing insulin aspart with HI was of high quality, with all three categories graded as grade A evidence. Studies showed strong evidence for better glycaemic control, without an increased risk of hypoglycaemia, together with evidence supporting improved convenience and flexibility in administration of insulin aspart compared with regular HI in adult diabetic patients. Evidence from three trials in adults with type 1 diabetes showed a lower incidence of major nocturnal hypoglycaemia with insulin aspart versus regular HI. Published evidence also confirmed the more rapid action of insulin aspart versus HI, and a comparable efficacy and safety profile for both insulin types in type 1 paediatric patients. There was also strong evidence that insulin aspart is well tolerated and efficacious for CSII/pump use. Insulin aspart better mimics the physiological response to meals than regular HI, and may offer advantages in terms of glycaemic control and reduction of hypoglycaemia combined with flexibility and convenience of administration. Overall, there is a good body of evidence to support the efficacy, tolerability and ease of administration of insulin aspart in patients with type 1 and type 2 diabetes.     

Insulin glulisine: efficacy and safety compared with other rapid-acting insulin analogues

Glulisine insulin is the latest addition to the class of rapid-acting insulin analogues. It is important that it is comparable in safety not only to human regular insulin, but also to the well established analogue insulins, aspart and lispro. In this summary the evidence comparing the safety and efficacy of glulisine with its counterpart insulins in various groups of diabetic patients is discussed.     

Insulin aspart: promising early results borne out in clinical practice

The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in preclinical studies to be more rapidly absorbed than human insulin (HI) when administered subcutaneously. IAsp reaches higher peak serum concentrations in a shorter time than HI, whilst maintaining a similar receptor binding and safety profile. The physiological pharmacokinetic profile of IAsp compared to that of HI has been demonstrated in both adult and paediatric populations and was accompanied by small but statistically significant reductions in HbA(1c), lower postprandial glucose excursions and a reduced risk of late postprandial and major nocturnal hypoglycaemia. Benefits may be maximised by dose optimisation, using bolus doses that result in effective postprandial glucose reduction, as well as higher and multiple basal insulin doses. The safety profile, including cardiovascular risk, is equivalent to HI.     

Effects of mealtime insulin aspart and bedtime NPH insulin on postprandial inflammation and endothelial cell function in patients with type 2 diabetes

Acute hyperglycaemia exerts deleterious effects on the arterial wall. We suggested that rapid-acting insulin has a beneficial postprandial effect on endothelial dysfunction and inflammation compared with intermediate-acting insulin because of its ability to lower postprandial hyperglycaemia. This was tested in a parallel, controlled study on well-controlled patients with type 2 diabetes randomly assigned to bedtime Neutral Protamine Hagedorn (NPH) insulin (n = 41) or mealtime insulin aspart (n = 37). They were served standard diabetic meals for breakfast (8.00) and lunch (12.00). Blood samples were collected at 7.40 (fasting), 9.30, 11.30, 13.30 and 15.30 and analysed for glucose, insulin, lipids, intercellular adhesion molecules (ICAM), C-reactive protein (CRP), von Willebrand factor (vWF) and fibrinogen. The postprandial glucose response differed significantly between insulin regimens with a postprandial increase on NPH insulin and a decrease on insulin aspart. There was a minor but significant postprandial decrease in ICAM, CRP and vWF on both insulin regimens and a decrease in fibrinogen on NPH insulin. No insulin group differences were observed in postprandial responses for ICAM, CRP, vWF and fibrinogen. The rapid-acting insulin analogue aspart and the intermediate-acting insulin NPH had different effects on postprandial glucose response but similar postprandial effects on markers of inflammation and endothelial dysfunction.     

Clinical pharmacokinetics and pharmacodynamics of insulin lispro mixtures

Rapid-acting insulin analogues such as insulin lispro and insulin aspart produce a more physiological profile of insulin activity than does conventional regular human insulin because of their unique pharmacokinetics. These insulin analogues are absorbed rapidly from the subcutaneous injection site, resulting in a better matching of the appearance of insulin in the circulation with nutrient absorption from the intestine. In addition, they are shorter-acting than regular human insulin, thus decreasing the risk of late postprandial hypoglycaemia due to inappropriate hyperinsulinaemia. Because self-prepared mixtures of these rapid-acting insulin analogues with longer-acting insulins such as neutral protamine Hagedorn (NPH) insulin have been shown to be clinically useful, and because manufactured fixed-ratio mixtures of regular human insulin and NPH already represent a large proportion of insulin use, manufactured fixed-ratio mixtures of insulin lispro and a sustained-release insulin known as NPL have been developed (insulin lispro mixtures). NPL is a protamine-based insulin lispro formulation with pharmacokinetics and glucodynamics comparable to those of human NPH insulin. NPL was developed for use within insulin lispro mixtures because an exchange between soluble insulin lispro and protamine-bound human insulin within human NPH precludes prolonged storage of mixtures of these insulins. An insulin lispro mixture consisting of 25% insulin lispro and 75% NPL is now commercially available. This preparation is intended primarily as an alternative to human insulin 30/70, which is commonly used within a twice-daily injection regimen. A mixture containing 50% insulin lispro and 50% NPL is also available. The rapid activity of insulin lispro is maintained within insulin lispro mixtures, allowing injection just prior to a meal, a convenience that is not available with commercial mixtures of regular human insulin and human NPH insulin, which should be injected 30 to 45 minutes prior to meals. As with insulin lispro itself, the rapid action of insulin lispro within the insulin lispro mixtures also results in a smaller increase in blood glucose levels after meals than with comparable human insulin mixtures. In addition, data from two studies have shown that when Mix25 is injected prior to the evening meal the incidence of nocturnal hypoglycaemia is decreased in comparison with the same dose of human insulin 30/70. The combined rapid and prolonged insulin activity provided by insulin lispro mixtures has been defined both in healthy subjects without diabetes and in patients with diabetes.     

Update on insulin analogues

Four recombinant human insulin analogues are currently available in the UK. In reviewingthefirst of these, insulin lispro, in 1997, we concluded that "it has a more rapid onset, time to peak and shorter duration of action than soluble human insulin" but "does not appear to alter overall control (haemoglobin A1c levels) and it is not clear whether it reduces the occurrence of hypoglycaemia compared with soluble human insulin". Recombinant analogues marketed in the UK since then include another short-acting analogue, [symbol: see text]insulin aspart (NovoRapid--Novo Nordisk), and two longer-acting analogues, [symbol: see text]insulin glargine (Lantus--Aventis Pharma) and [symbol: see text]insulin detemir (Levemir--Novo Nordisk). In addition, there are two biphasic formulations that contain both a short-acting analogue and a longer-acting protamine suspension of that analogue: biphasic insulin lispro (Humalog Mix25, Humalog Mix50--Lilly) and biphasic [symbol: see text]insulin aspart (NovoMix 30--Novo Nordisk). Here we review insulin analogues and consider what advantages, if any, they offer over conventional human insulin preparations.     

Insulin glulisine--a comprehensive preclinical evaluation

Receptor binding and signaling and the mitogenic potential of insulin glulisine (glulisine), regular human insulin (RHI), and Asp(B10) were compared in vivo and in vitro. Insulin and insulin-like growth factor 1 (IGF-1) receptor binding was studied with human insulin receptors (293HEK cells) and the human osteosarcoma-derived cell line B10. Insulin receptor-mediated signaling was assessed in rat-1 fibroblasts overexpressing insulin receptors. Activation of insulin receptor substrates 1 and 2 (IRS-1/ IRS-2) was studied in rat and human myoblasts and rat cardiomyocytes. DNA synthesis induction was assessed by [3H] thymidine incorporation in the human epithelial breast cell line MCF10. Interaction with the IGF-1 receptor, DNA synthesis, and intracellular signal transduction were assessed in cardiac K6 myoblasts. Immunohistochemical examination of Sprague-Dawley rat tissue treated with glulisine for 6 months (n = 40), and glulisine and RHI for 12 months (n = 60), was performed. Steady-state insulin receptor binding affinity was slightly lower for glulisine versus RHI (approximately 0.70). IGF-1 receptor binding affinity was lower (four- to fivefold) for glulisine, but significantly higher (four-fold) for Asp(B10) versus RHI. Glulisine, Asp(B10), and RHI showed similar insulin receptor-association kinetics; however, Asp(B10) revealed increased insulin receptor affinity. Glulisine and RHI showed similar insulin receptor-mediated phosphorylation and IRS-2 activation. Activation of IRS-1 was 6- to 10-fold lower with glulisine; glulisine was less potent and Asp(B10) slightly more potent in stimulating DNA synthesis versus RHI. Stimulation of DNA synthesis was comparable for glulisine and RHI in K6 myoblasts. At 12 months, there was no significant difference between glulisine and RHI in proliferative activity. This preclinical evaluation suggests that structural changes in glulisine versus RHI are not associated with any safety issues.     

Insulin glargine: the first clinically useful extended-action insulin analogue

Insulin glargine is a new extended-action insulin analogue, created by recombinant DNA modification of human insulin. Extension of the C-terminal of the B-chain with two arginine residues and the substitution of glycine for asparagine at position A-21 increases the isoelectric point, resulting in precipitation of the insulin at the injection site and a protracted absorption. Pharmacodynamic studies have demonstrated a prolonged metabolic profile without a pronounced peak and with a duration of action of 20 - 30 h. In clinical studies in people with Type 1 and Type 2 diabetes, insulin glargine has demonstrated improved pre-breakfast blood glucose control and a reduction in the frequency of hypoglycaemia, especially nocturnal hypoglycaemia, in comparison with neutral protamine hagedorn (NPH) insulin. In addition, 24h glycaemic control in Type 2 diabetes and treatment satisfaction may also be improved. However, whilst appearing achievable, insulin glargine has not yet demonstrated the ability to improve HbA(1c), though this may relate to inexperience in the use of the new compound. In order to fully exploit its metabolic advantages, it appears vital that the dose of insulin glargine should be titrated to achieve aggressive pre-breakfast blood glucose targets beyond those achievable with NPH in the absence of nocturnal hypoglycaemia. Insulin glargine appears to be a promising new addition to the insulin family and with increased experience in its use, especially in combination with rapid-acting insulin analogues, its full benefits may be realised. The use of insulin glargine with a rapid-acting insulin analogue brings us the closest we have ever been to providing the physiological insulin replacement that has long been awaited.     

Insulin therapy in type 2 diabetes

OBJECTIVE: To review the increasingly common use of insulin therapy in patients with type 2 diabetes and the practical aspects of initiating insulin therapy in these patients. DATA SOURCES: Recent scientific and clinical literature identified through MEDLINE searches for the years 1995-2001 using the terms oral agents, type 2 diabetes, insulin therapy, glycemic control and diabetic complications, glucose toxicity, insulin lispro, insulin aspart, and insulin glargine. STUDY SECTION: Reports of key large (1,000 patients or more) and significant smaller, randomized, controlled clinical trials were reviewed. For studies comparing insulin analogs, the authors reviewed a sampling of the identified trials for their characteristics and clinical importance. DATA SYNTHESIS: Tight blood glucose control can help reduce the risk of diabetes complications. Evidence suggests that early insulin therapy can help correct the underlying pathogenetic abnormalities in type 2 diabetes and improve long-term glycemic control. For these reasons, some diabetes experts advocate the initiation of insulin therapy earlier in the course of type 2 diabetes than has been common in the past. Insulin regimens should be designed to mimic the body's natural physiologic secretion of insulin, including the basal amounts released continuously by the pancreas and the insulin surges produced in response to glucose loads. Using new insulin analogs is a useful approach to achieving this ideal. Insulin glargine provides a nearly constant, peakless release of insulin when injected subcutaneously once daily. Two new rapid-acting insulin analogs, insulin lispro (Humalog--Lilly) and insulin aspart (NovoLog--Novo Nordisk), enhance patients' flexibility in terms of meals by permitting injection immediately before meals, rather than 30 minutes before meals, as with regular insulin. CONCLUSION: Patients should be reassured that early initiation of insulin therapy is a positive event that should improve their long-term health and does not represent a decline in the course of their disease.     

Preclinical safety pharmacology studies on the rapid-acting insulin analogue insulin aspart.

[B28 Asp]-human insulin (insulin aspart, CAS 116094-23-6, X14) is a rapidly absorbed analogue of human insulin currently undergoing development for the treatment of diabetes mellitus. Cardiovascular studies and a range of standard behavioural, neurological and organ function tests were conducted in various animal species to investigate potential secondary pharmacological effects of insulin aspart. Single intravenous injections (to ensure maximum bioavailability) of a range of doses of insulin aspart were compared with a soluble human insulin preparation. The validity of the test systems was always tested with appropriate positive and/or negative (vehicle) control compounds. Secondary effects due to hypoglycaemia were identified by simultaneous administration of a glucose solution along with the highest dose of insulin aspart and the vehicle as negative control. No safety issues were raised by these experiments; insulin aspart and soluble human insulin exhibited similar pharmacological profiles throughout.     

A critical appraisal of the role of insulin analogues in the management of diabetes mellitus

Insulin is one of the oldest and best studied treatments for diabetes mellitus. Despite many improvements in the management of diabetes, the nonphysiological time-action profiles of conventional insulins remain a significant obstacle. However, the advent of recombinant DNA technology made it possible to overcome these limitations in the time-action profiles of conventional insulins. Used as prandial (e.g. insulin lispro or insulin aspart) and basal (e.g. insulin glargine) insulin, the analogues simulate physiological insulin profiles more closely than the older conventional insulins. If rapid-acting insulin analogues are used in the hospital, healthcare providers will need a new mind-set. Any error in coordination between timing of rapid-acting insulin administration and meal ingestion may result in hypoglycaemia. However, guidelines regarding in-hospital use of insulin analogues are few. The safety profile of insulin analogues is still not completely established in long-term clinical studies. Several studies have shown conflicting results with respect to the tumourigenic potential of this new class of agents. The clinical implications of these findings are not clear. Although novel insulin analogues are promising 'designer drugs' in our armamentarium to overcome some of the limitations of conventional insulin therapy, cost may be a limiting factor for some patients.     

Pharmacokinetics and pharmacodynamics of insulin aspart in patients with Type 2 diabetes: assessment using a meal tolerance test under clinical conditions

1. Few studies have evaluated the pharmacokinetics of rapid-acting insulin analogues in patients with Type 2 diabetes, especially under clinical conditions. The aim of the present study was to assess both the pharmacokinetics and pharmacodynamics of insulin aspart in Type 2 diabetic patients who were being treated with the analogue alone. 2. Meal tolerance tests with and without self-injection of a customary dose of insulin aspart (0.05-0.22 U/kg) were conducted in 20 patients in a randomized cross-over study. 3. The dose of insulin aspart (per bodyweight) was significantly correlated with both the maximum concentration (r(2) = 0.59; P < 0.01) and area under the concentration-time curve for insulin aspart (r(2) = 0.53; P < 0.01). However, the time to maximum concentration (T(max)), which varied widely from < 60 to ≥ 120 min, was not associated with either dosage (r(2) = 0.02; P = 0.51) or body mass index (r(2) = 0.02; P = 0.57). Injection of insulin aspart exacerbated delayed hyperinsulinaemia after meal loading, mainly in patients with T(max) ≥ 120 min. With regard to pharmacodynamics, insulin aspart had favourable effects on postprandial hyperglycaemia, hyperglucagonaemia and hyperlipidaemia. 4. The T(max) for this insulin analogue differed greatly between individuals and delayed hyperinsulinaemia was particularly exacerbated in patients with higher T(max) values. Identification of the factors contributing to interindividual variation in the absorption lag time is essential for improving the efficacy and safety of insulin aspart.     

2种胰岛素用于胰岛素泵对2型糖尿病患者短期强化治疗的临床疗效研究

目的比较胰岛素类似物（诺和锐）与人胰岛素（诺和灵R）分别应用于胰岛素泵对2型糖尿病患者短期强化治疗的临床疗效差异。方法 58例住院需胰岛素治疗的2型糖尿病患者随机分为2组：诺和锐组和诺和灵R组,胰岛素泵治疗2周,比较2组患者治疗过程中每日3餐前后和睡前血糖,血糖达标所需天数及胰岛素用量。结果 3餐前和睡前血糖下降,2组间差异无显著性（P〉0.05）。诺和锐组FBG、PBG 2 h及全天血糖控制达标时间均短于诺和灵R组（P〈0.01）,餐后血糖指标好于诺和灵R组（P〈0.05）,胰岛素用量低于诺和灵R组（P〈0.05）。结论用胰岛素泵输注诺和锐及诺和灵R均能使2型糖尿病患者高血糖状态得到良好控制,但诺和锐对餐后血糖控制更理想,血糖控制达标所需时间更短,所需胰岛素量更少。     

Insulin analogues

The move to intensive insulin therapy following the Diabetes Control and Complications Trial has highlighted the major deficiencies in conventional insulin therapy. Patients are exposed to a high risk of hypoglycaemia due to the delay in absorption of conventional soluble insulin and peaked action of medium acting preparations. Two rapid acting insulin analogues, insulin lispro and aspart have been developed with a reduced tendency to self-association. These demonstrate faster absorption and reach higher concentrations after s.c. injection compared to conventional human insulin and this more physiological action reduces post-prandial glucose to a greater extent. However the benefits in clinical trials have been relatively modest with little or no improvement in HbA1c and minor reductions in hypoglycaemic risk. These rather disappointing results are partly due to the inability of regulatory trials to explore clinical benefit but also because it has taken time to learn how to use these preparations to their best advantage. In patient with tightly controlled diabetes the use of analogues leads to major reductions in severe noctumal hypoglycaemia and this is a robust and important indication. It is still uncertain whether either of the new long-acting insulin analogues, insulin glargine or detemir will have significant clinical benefit but it is possible that the combination of both quick and long-acting analogues will lead to tight glycaemic control without the risk of severe hypoglycaemia.