Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and 2 diabetes mellitus

Insulin glargine is a recombinant human insulin analogue produced by DNA technology using a nonpathogenic strain of Escherichia coli. Two modifications of human insulin result in a stable molecule which is soluble in slightly acidic conditions (pH 4.0) and precipitates in the neutral pH of subcutaneous tissue. Because of these properties, absorption of insulin glargine is delayed and the analogue provides a fairly constant, basal insulin supply without peaks in plasma insulin levels for approximately 24 hours, similar to that achieved by a continuous subcutaneous insulin infusion. Insulin glargine is indicated as a once daily subcutaneous injection to provide basal glycaemic control in adults and children aged >6 years with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Fasting plasma glucose and fasting blood glucose levels generally improved to a greater extent in patients with type 1 diabetes mellitus receiving insulin glargine than patients who administered Neutral Protamine Hagedorn (NPH) insulin. In patients with type 1 or 2 disease, glycosylated haemoglobin levels were slightly reduced and to a similar extent with insulin glargine and NPH insulin. Most clinical trials in patients with type 1 or 2 diabetes mellitus demonstrated a lower incidence of hypoglycaemia, especially nocturnal hypoglycaemia, compared with NPH insulin. One of the most common adverse events with insulin glargine treatment was injection site pain which, in some studies, occurred more frequently than in patients receiving NPH insulin. In all cases the symptoms were mild and treatment discontinuation was not required. Otherwise, the drug is well tolerated and does not appear to be immunogenic. CONCLUSIONS: Insulin glargine once a day provides basal control of glycaemia for approximately 24 hours without inducing peaks in plasma insulin levels in patients with type 1 or 2 diabetes mellitus. In long term, well designed trials insulin glargine once daily improved glycaemic control at least as effectively as NPH insulin given once or twice daily. The drug was well tolerated and in most studies the incidence of nocturnal hypoglycaemia was significantly less in patients treated with insulin glargine compared with patients receiving NPH insulin. Therefore, insulin glargine is likely to be a useful addition to the armamentarium of insulin therapy by establishing basal glycaemic control with once daily administration and a reduced risk of nocturnal hypoglycaemia.     

Insulin glargine

Insulin glargine is an extended-action biosynthetic human insulin. It precipitates in the neutral environment of subcutaneous tissue and is thus gradually absorbed into the bloodstream. The addition of small amounts of zinc to the formulation further delays absorption. In small euglycaemic clamp studies, the onset of action of insulin glargine was shown to be later, the duration of action longer and the time-action profile flatter than that of Neutral Protamine Hagedorn (NPH) insulin in patients with type 1 diabetes mellitus and healthy volunteers. Four large clinical trials of up to 28 weeks' duration have shown that a single bedtime dose of insulin glargine, in combination with preprandial short-acting insulin, is as effective or more effective than once or twice daily NPH plus short-acting insulin in improving glycaemic control in patients with type 1 diabetes mellitus. In 3 large comparative trials, insulin glargine decreased glycosylated haemoglobin and/or fasting blood glucose levels to a similar extent to that seen with NPH insulin in patients with insulin-dependent or non-insulin-dependent type 2 diabetes mellitus, either as monotherapy or in combination with oral hypoglycaemic agents. Insulin glargine appears to be well tolerated. A lower incidence of hypoglycaemia, especially at night, was reported in most trials with insulin glargine when compared with NPH insulin.     

Insulin detemir: a long-acting insulin product.

PURPOSE: The pharmacology, pharmacokinetics, efficacy and tolerability, safety, drug interactions, dosage and administration, cost, and place in therapy of insulin detemir are reviewed. SUMMARY: Insulin detemir is a long-acting, neutral, and soluble insulin analogue with a lower within-subject variability of fasting plasma glucose levels than isophane insulin human (NPH insulin) and insulin glargine. The lower within-subject variability of insulin detemir may decrease hypoglycemic events, especially nocturnal events, and may contribute to a decreased incidence of weight gain. In vivo, insulin detemir is 98-99% bound to albumin-one of the mechanisms contributing to its long duration of action. Several open-labeled, randomized, multicenter trials have been conducted comparing the safety and efficacy of insulin detemir to NPH insulin in patients with type 1 or type 2 diabetes mellitus. In most trials, patients were randomized to receive insulin on three different dosing schedules: basal insulin twice daily before breakfast and at bedtime, basal insulin at 12-hour intervals, or basal insulin before breakfast and dinner. Mealtime insulin was given as part of the basal-bolus therapy. Glycosylated hemoglobin values were similar in patients receiving insulin detemir or NPH insulin. Insulin detemir appears to be well tolerated. The most common adverse effects reported during clinical trials were hypoglycemia, headache, dizziness, and injection-site reactions. CONCLUSION: Insulin detemir given once or twice daily as part of basal-bolus insulin therapy is at least as effective as NPH insulin in maintaining overall glycemic control in adult patients with type 1 or type 2 diabetes mellitus.     

Defining the role of insulin detemir in Basal insulin therapy

Insulin detemir is a novel long-acting insulin analogue with a unique mechanism underlying its prolonged duration of action. Unlike neutral protamine Hagedorn (NPH) insulin (insulin suspension isophane) and insulin glargine, which precipitate after administration, insulin detemir remains soluble after it is injected. The prolonged duration of action of insulin detemir is a result of the ability to self-associate into hexamers and dihexamers, and to bind reversibly to albumin. This mechanism of protraction provides a more prolonged, consistent and predictable glycaemic effect in patients with type 1 or type 2 diabetes mellitus compared with NPH insulin. Clinical studies have demonstrated that insulin detemir administered once or twice daily is at least as effective as NPH insulin and insulin glargine in achieving glycaemic control. Most trials have also shown that insulin detemir exhibits less intrapatient variability in glycaemic control compared with NPH insulin and insulin glargine. One of the benefits of insulin detemir is its favourable effect on bodyweight. Insulin detemir has shown weight neutrality in patients with type 1 diabetes and is associated with less weight gain than NPH insulin in clinical studies. Patients with type 2 diabetes using insulin detemir gain less weight than patients using NPH insulin and insulin glargine. In addition, a reduced risk of hypoglycaemia, particularly nocturnal hypoglycaemia, has been reported with insulin detemir compared with NPH insulin in patients with type 1 and type 2 diabetes. A reduced risk of major and nocturnal hypoglycaemia compared with insulin glargine in patients with type 1 diabetes has also been observed. Together, these data indicate that insulin detemir is a valuable new option for basal insulin therapy in patients with type 1 or type 2 diabetes.     

Insulin glargine: an updated review of its use in the management of diabetes mellitus

Insulin glargine is a human insulin analogue prepared by recombinant DNA technology. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant in relation to conventional human insulins, with no pronounced peak over 24 hours. This allows once-daily administration as basal therapy. Early randomised trials with insulin glargine generally showed greater reductions in fasting blood or plasma glucose levels and a reduced frequency of nocturnal hypoglycaemia relative to neutral protamine Hagedorn (NPH) insulin in patients with type 1 diabetes mellitus. In addition to this basal therapy, patients continued to use the regular mealtime insulin regimen to which they were accustomed. More recent data with insulin glargine have included evidence of improved glycaemic control, with improvements in satisfaction with treatment over NPH insulin. Furthermore, the time of day at which insulin glargine is injected has no clinically relevant effect on glycaemic control in these patients. There are also data from small, nonblind studies to suggest comparable glycaemic control with insulin glargine and continuous subcutaneous insulin infusion. Results from comparative studies and meta-analyses in individuals with type 2 diabetes show lower incidences of nocturnal hypoglycaemia with insulin glargine than with NPH insulin, with two studies showing a significantly greater improvement in glycosylated haemoglobin levels with insulin glargine than with NPH. Insulin glargine is well tolerated, and is not associated with greater immunogenicity or increases in bodyweight than NPH insulin. Long-term data show maintenance of glycaemic control with insulin glargine for up to 39 months in adults and children with type 1 and adults with type 2 diabetes. In conclusion, insulin glargine is an effective and well tolerated basal insulin therapy when given as a single daily subcutaneous injection to patients with diabetes, with benefits in terms of glycaemic control and reduced frequency of hypoglycaemia over regimens based on conventional basal insulins. Accumulating data and official recommendations show the suitability of insulin glargine for first-line use in selected patients with type 2 diabetes who require insulin treatment, as well as in patients with type 1 disease, and confirm its use in children and adolescents.     

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

Insulin detemir (Levemir) is a soluble long-acting human insulin analogue acylated with a 14-carbon fatty acid. The fatty acid modification allows insulin detemir to reversibly bind to albumin, thereby providing slow absorption and a prolonged and consistent metabolic effect of up to 24 hours in patients with type 1 or type 2 diabetes mellitus. Insulin detemir has a more predictable, protracted and consistent effect on blood glucose than neutral protamine Hagedorn (NPH) insulin, with less intrapatient variability in glycaemic control, compared with NPH insulin or insulin glargine. Insulin detemir, administered once or twice daily, is at least as effective as NPH insulin in maintaining overall glycaemic control, with a similar or lower risk of hypoglycaemia, especially nocturnal hypoglycaemia, compared with NPH insulin in patients with type 1 or type 2 diabetes. Insulin detemir also provides the added clinical benefit of no appreciable bodyweight gain in patients with type 1 diabetes and less bodyweight gain than NPH insulin in patients with type 2 diabetes. Insulin detemir is, therefore, a promising new option for basal insulin therapy in patients with type 1 or 2 diabetes.     

甘精胰岛素强化治疗新诊断2型糖尿病疗效观察

目的:观察睡前皮下注射甘精胰岛素与中效胰岛素(NPH)对新诊断2型糖尿病患者的疗效。方法:将64例新诊断2型糖尿病患者分为A、B组,分别睡前皮下注射甘精胰岛素和睡前皮下注射NPH,2组均在饮食控制及一定活动量基础上皮下注射短效胰岛素。比较2组治疗后平均空腹血糖、血糖达标时间、日内血糖漂移、低血糖发生率及胰岛素总用量。结果:甘精胰岛素组在治疗后平均空腹血糖、血糖达标时间、日内血糖漂移、低血糖发生率等方面均低于NPH组(P<0.05)。结论:甘精胰岛素联合短效胰岛素治疗新诊断2型糖尿病疗效好,安全性高。     

随机、开放、低精蛋白锌胰岛素注射液平行对照,联合控释格列吡嗪评价重组甘精胰岛素注射液治疗口服降糖药控制不佳的2型糖尿病患者的有效性和安全性

目的:评价甘精胰岛素与控释格列吡嗪(瑞易宁)联合应用治疗2型糖尿病患者的有效性和安全性。方法:采用随机、开放、低精蛋白锌胰岛素注射液(诺和灵N)平行对照和多中心临床研究方法,对471例服用口服降糖药(OHA)至少3个月而血糖控制不佳(FBG≥7.0mmol_L)的2型糖尿病患者随机进行试验药-甘精胰岛素或对照药-诺和灵N治疗,随访5次共12周。结果:治疗12周时,甘精胰岛素组与诺和灵N组的胰岛素平均每天用量分别为19.21单位和18.68单位,平均空腹血糖分别从入选时10.63mmol_L和10.88mmol_L降至6.96mmol_L和7.20mmol_L,HbA1c分别下降了0.96%和1.25%。甘精胰岛素组和诺和灵N组分别有21.25%(75_353)和28.81%(34_118)的受试者发生低血糖(P=0.0919),其中发生夜间低血糖的受试者分别占9.07%(32_353)和16.10%(19_118)(P=0.0334)。以低血糖的发生例次作为观察指标时,甘精胰岛素组和诺和灵N组分别有174例次和75例次,其中夜间低血糖分别有54例次和44例次,两组均没有严重低血糖事件。结论:12周的临床观察显示,睡前注射一次甘精胰岛素和清晨口服5mg瑞易宁联合应用的治疗方法可使单纯使用口服降糖药而代谢控制不佳的2型糖尿病患者得到良好的血糖控制;以HbA1c和空腹血糖水平作为判断指标,甘精胰岛素和诺和灵N分别与瑞易宁联合应用两种治疗方法对2型糖尿病患者治疗效果相当,但前者夜间低血糖事件发生率低;同时,甘精胰岛素(睡前1次)与瑞易宁联合应用的治疗方法具有良好的耐受性。     

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 glargine in the management of diabetes mellitus: an evidence-based assessment of its clinical efficacy and economic value

INTRODUCTION: Diabetes is a chronic disease associated with high morbidity and mortality, which represents a major public health concern. Interventions that can enhance patient care and reduce clinic visits will not only relieve some of this burden, they will also improve patient QOL and wellbeing. AIMS: This review assesses the evidence for the use of insulin glargine in type 1 and type 2 diabetes mellitus. EVIDENCE REVIEW: Once-daily insulin glargine has a prolonged, peakless activity profile, making it a candidate as a long-acting (basal) insulin. In combination with bolus insulin to cover prandial glucose surges, it facilitates a more physiologic approach to patient management. Evidence from large, randomized, controlled clinical trials in patients with type 1 diabetes has confirmed its effectiveness and tolerability relative to neutral protamine hagedorn (NPH) insulin, with a tendency toward causing less hypoglycemia. In patients with type 2 diabetes requiring insulin therapy, once-daily insulin glargine has proven to be clinically superior to NPH insulin in terms of providing at least as effective glycemic control, but with significantly fewer episodes of nocturnal hypoglycemia. A variety of economic analyses have confirmed the cost effectiveness of insulin glargine in type 1 and type 2 diabetes and in particular it was shown to be significantly superior to NPH insulin. CLINICAL VALUE: Insulin glargine has established itself as a first-line choice in patients with type 1 diabetes, including children (>6 years) and adolescents, and is a recommended treatment option. In patients with type 2 diabetes it is clearly associated with less hypoglycemia than NPH insulin, and this may help overcome one of the major barriers to starting insulin therapy in this class of patient. Thus, insulin glargine is a valuable addition to the therapeutic armamentarium available to physicians and it has the potential to significantly improve the quality of life of patients with diabetes.     

Insulin glargine versus NPH insulin in patients with type 1 diabetes

Type 1 diabetes is associated with a number of diabetes-related complications which may be minimized by maintaining good long-term metabolic control. The current guidelines recommend that glycosylated hemoglobin levels should be targeted to below 7.0% or 6.5% to reduce the incidence of diabetic complications, including micro- and macrovascular disorders. However, this intensive metabolic control is hindered by the occurrence of hypoglycemia. The episodes of hypoglycemia are problematic for patients taking intermediate-acting insulin preparations (i.e., NPH insulin), which have traditionally formed the mainstay basal insulin treatment. With NPH insulin, the pharmacokinetic profile is such that peak insulin activity occurs 4-6 hours following administration; therefore, nocturnal hypoglycemia commonly takes place after bedtime administration of the insulin. The development of the long-acting human insulin analogue insulin glargine now provides patients with an insulin that offers a longer duration of action (up to 24 hours) and a smoother time-action profile compared with those of NPH insulin. A number of clinical trials comparing the safety and efficacy of insulin glargine and NPH insulin in patients with type 1 diabetes show that, in addition to other clinical benefits over NPH insulin, insulin glargine may also improve glycemic control and satisfaction in this patient population.     

Effect of sulfobutyl ether-β-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats

Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-β-cyclodextrin (SBE4-β-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-β-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-β-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-β-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-β-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-β-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-β-CyD can be a useful excipient for sustained release of insulin glargine.     

甘精胰岛素治疗1型糖尿病16例临床体会

目的比较每日注射一次甘精胰岛素与中性低精蛋白锌人胰岛素（NPH）分别联合3餐前注射短效人胰岛素（Novolin R）治疗1型糖尿病的疗效。方法16例1型糖尿病患者（包括儿童1型糖尿病3例,成人迟发自身免疫糖尿病13例）根据用药情况分为2组,甘精胰岛素组10例,每日3餐前注射Novolin R,8例患者每天22：00注射甘精胰岛素,2例患者每天7：00注射甘精胰岛素;对照组6例每日3餐前注射Nov-olin R,22：00注射NPH。根据血糖水平调整胰岛素用量,观察血糖变化和低血糖发生的情况。结果2组患者治疗后血糖均较治疗前明显下降（P〈0．01）,2组血糖控制达标所用时间差异有统计学意义（P〈0．05）,甘精胰岛素组酮体消退时间短于对照组（P〈0．05）,日用胰岛素剂量低于对照组（P〈0．05）,血糖平稳下降,血糖波动小,低血糖发生率低于对照组（P〈0．05）。结论长效重组甘精胰岛素能模拟人体生理性基础胰岛素分泌,利于1型糖尿病患者的血糖控制,安全性较好。     

重组甘精胰岛素治疗2型糖尿病的有效性与安全性分析

目的探讨重组甘精胰岛素治疗2型糖尿病的有效性与安全性。方法选择本院治疗的2型糖尿病患者110例,随机分为治疗组和对照组各55例。所有患者均于入院内给予糖尿病相关知识的讲解,并于每日早餐前口服5mg格列吡嗪缓释片治疗。在此基础上,治疗组患者给予重组甘精胰岛素皮下注射治疗,对照组患者每日睡前皮下注射NPH1次。比较两组患者的血糖以及不良反应情况。结果两组患者治疗后餐前血糖、餐后2h血糖以及凌晨3：00血糖均较治疗前有明显的改善（P〈0.05）,而治疗后治疗组患者的餐前血糖、餐后2h血糖以及凌晨3：00血糖均明显优于对照组患者（P〈0.05）。治疗组患者的血糖达标天数明显短于对照组患者（P〈0.05）,低血糖发生次数明显少于对照组患者（P〈0.05）。两组患者治疗12周后,血、尿常规,肝肾功能检查、血脂检查以及心电图检查均无明显变化。结论重组甘精胰岛素治疗2型糖尿病具有疗效确切,不良反应少的特点,值得临床推广使用。     

Insulin glargine and its place in the treatment of Types 1 and 2 diabetes mellitus

Insulin treatment in Type 1 and Type 2 diabetes has come a long way since its discovery by Banting and Best in 1922. Early insulin therapy was life-saving, but was associated with practical problems and had side effects such as lipoatrophy. Initial modifications of insulin structure produced several classes of insulins with varying pharmacokinetics, but did not sufficiently mimic physiological insulin release. Novel long- and short-acting insulin analogues, the so-called 'designer insulins', developed through genetic engineering in the 1990s, paved the way for more physiological insulin therapy, which was theoretically less problematic in terms of hypoglycaemia and patient satisfaction. Insulin glargine (glargine) was the first DNA-recombinant long-acting insulin analogue. The replacement of asparagine with glycine and the addition of two arginine molecules in the molecular structure results in modified pharmacokinetics. Consequently, glargine has a longer, often 24-h profile, which is described as 'peakless' compared with other insulins such as neutral protamine Hagedorn insulin (NPH) and insulin ultralente. Since its launch, the use of glargine in Type 1 and Type 2 diabetes has been extensively reviewed to determine its place in the current insulin market. A potential advantage of glargine seems to be a lower risk of hypoglycaemia, particularly at night. The UK National Institute of Clinical Excellence has recommended that glargine is a treatment option for people with Type 1 diabetes. In Type 2 diabetes, it has been advised that glargine only be considered for: those who require assistance to administer insulin injections; those whose lifestyle is restricted significantly by recurrent symptomatic hypoglycaemic episodes; or those who would otherwise need twice-daily basal insulin injections in combination with oral glucose-lowering drugs.     

Insulin glargine and its place in the treatment of Types 1 and 2 diabetes mellitus

Insulin treatment in Type 1 and Type 2 diabetes has come a long way since its discovery by Banting and Best in 1922. Early insulin therapy was life-saving, but was associated with practical problems and had side effects such as lipoatrophy. Initial modifications of insulin structure produced several classes of insulins with varying pharmacokinetics, but did not sufficiently mimic physiological insulin release. Novel long- and short-acting insulin analogues, the so-called ‘designer insulins’, developed through genetic engineering in the 1990s, paved the way for more physiological insulin therapy, which was theoretically less problematic in terms of hypoglycaemia and patient satisfaction. Insulin glargine (glargine) was the first DNA-recombinant long-acting insulin analogue. The replacement of asparagine with glycine and the addition of two arginine molecules in the molecular structure results in modified pharmacokinetics. Consequently, glargine has a longer, often 24-h profile, which is described as ‘peakless’ compared with other insulins such as neutral protamine Hagedorn insulin (NPH) and insulin ultralente. Since its launch, the use of glargine in Type 1 and Type 2 diabetes has been extensively reviewed to determine its place in the current insulin market. A potential advantage of glargine seems to be a lower risk of hypoglycaemia, particularly at night. The UK National Institute of Clinical Excellence has recommended that glargine is a treatment option for people with Type 1 diabetes. In Type 2 diabetes, it has been advised that glargine only be considered for: those who require assistance to administer insulin injections; those whose lifestyle is restricted significantly by recurrent symptomatic hypoglycaemic episodes; or those who would otherwise need twice-daily basal insulin injections in combination with oral glucose-lowering drugs.     

Insulin analogues in the management of diabetes

Insulin therapy has been strongly influenced by the results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), both of which support intensive antidiabetic therapy. Conventional insulin therapy can be limited, due to the difficulty in achieving tight glycemic control in people with diabetes, which is crucial to reducing the risk of long-term complications associated with diabetes. In recent years, three short-acting (insulin lispro, insulin aspart and insulin glulisine) and two long-acting (insulin glargine and insulin detemir) recombinant analogues of regular human insulin have been developed for the management of diabetes. Short-acting insulin analogues are an alternative to regular human insulin before meals. Compared with regular human insulin, these new short-acting insulin analogues show faster subcutaneous absorption, a more rapid onset of activity and a shorter duration of action. As a result of these pharmacokinetic differences, an improved postprandial glycemic control is achieved, without increasing the risk of hypoglycemia. In addition, these insulin analogues can be administered immediately before a meal, thereby synchronizing insulin administration and food absorption. The long-acting insulin analogue insulin glargine was developed to provide basal insulin levels for 24 h when administered once daily at bedtime. Compared with previous intermediate- or long-acting conventional insulin, insulin glargine shows a flat profile of plasma insulin levels with no prominent peak. The use of this long-acting insulin analogue appears to be associated with a reduced incidence of hypoglycemia, especially at night. Insulin detemir is another basal insulin that may reduce nocturnal hypoglycemia and variability in glycemic values. The availability of these new insulin analogues has the potential to significantly improve long-term control over blood glucose in diabetic patients.     

Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits

Insulin glargine (LANTUS) is a new insulin analog that has a prolonged duration of action with no pronounced peak of activity, rendering it an ideal basal insulin for the treatment of diabetes. The aim of these studies was to assess the reproductive and embryotoxicity of insulin glargine. Reproductive toxicity was assessed in 25 male and 25 female Wistar rats per group treated with a daily subcutaneous injection of control; 1 IU/kg, 3 IU/kg, and 10 IU/kg insulin glargine; or 3 IU/kg NPH insulin in the premating and mating periods, and throughout pregnancy and lactation in the females. Embryotoxicity was assessed in 20 female rats per group injected with daily subcutaneous doses of control; 2 IU/kg, 6.3 IU/kg, and 20 IU/kg insulin glargine; or 6.3 IU/kg NPH insulin from the 7th to 18th day of pregnancy. Embryotoxicity was also assessed in 20 female rabbits per group treated with 0 IU/kg, 0.5 IU/kg, 1 IU/kg, and 2 IU/kg insulin glargine, or 1 IU/kg NPH insulin from the 6th to 18th day of pregnancy. The data demonstrated that, with the exception of toxicologic effects induced by hypoglycemia in response to high doses of insulin glargine and NPH insulin (including the premature dropout of female rats in the reproductive toxicity study, and increased incidence of abortions, early intrauterine deaths, and single anomalies in the rabbit embryotoxicity study), insulin glargine had no effects on reproduction, embryofetal development, and postnatal development in rats. Maternal and embryofetal toxicity in rabbits treated with middle and high doses of insulin glargine was related to the hypoglycemic effect of insulin.     

New insulin analogues and routes of delivery: pharmacodynamic and clinical considerations

Analogues of human insulin have been developed to more closely replicate the physiology of meal-related and basal insulin secretion. Three rapid-acting analogues and two basal analogues are available for clinical use. Insulin aspart and insulin lispro have nearly identical pharmacokinetic and pharmacodynamic profiles and provide better postprandial glucose control and less hypoglycaemia (primarily nocturnal and severe hypoglycaemia in type 1 diabetes mellitus) than regular insulin. Insulin glulisine is a new rapid-acting analogue and has characteristics nearly identical to those of its predecessors. Insulin glargine was the first basal analogue approved for clinical use and has shown better fasting glucose control and less risk of hypoglycaemia than conventional human neutral protamine Hagedorn (NPH) insulin. More recent studies have indicated that insulin glargine may not be truly 'peakless' at higher doses and that the adjustment of dose timing and frequency may have favourable effects on the risk of hypoglycaemia and the duration of the effect. Insulin detemir is a new basal insulin analogue with superiority to NPH insulin similar to that demonstrated by insulin glargine, though its duration of action appears to be shorter. The intraindividual variability in the response to a given dose is lower for insulin detemir than for both NPH insulin and insulin glargine. The clinical significance of this finding is not clear, though it may contribute to the lower rate of hypoglycaemia seen with insulin detemir. A number of 'alternative routes' of insulin administration have been studied, the most promising of which has been the pulmonary route. The time-action profile of inhaled insulins is generally characterized by a rapid onset of action similar to those of rapid-acting analogues and a slightly protracted duration of action similar to that of regular insulin. Inhaled insulin is similar to regular insulin with respect to efficacy and safety, though small reversible changes in pulmonary function have been noted. For technical and practical reasons, other alternative routes have generally not met with clinical success.     

Long-term efficacy of insulin glargine therapy with an educational programme in type 1 diabetes patients in clinical practice

ABSTRACT

Objective: To investigate the effect of initiating insulin glargine (glargine: LANTUS*), a once-daily basal insulin analogue, plus an educational programme, on glycaemic control and body weight in patients with type 1 diabetes in clinical practice.

Research design and methods: A retrospective analysis of the medical records of 65 patients (mean age: 40.7 ± 13.3 years) with type 1 diabetes was performed. Patients had previously been treated with NPH insulin (NPH; n = 54) or NPH insulin + lente insulin (NPH + lente; n = 11) and then received glargine once daily (bedtime), plus short-acting prandial insulin, for 30 months. Before initiation of glargine, patients participated in a diabetes educational programme and then received physician consultations throughout the study. Metabolic control, body weight and severe hypoglycaemia data were analysed at 9 and 30 months.

Results: Following initiation of glargine, patients showed a decrease in HbA_1c from 7.29 ± 1.1% to 7.06 ± 1.0%; p < 0.01 at 30 months. When the results were analysed by pre-treatment, both NPH-pre-treated and NPH+lente-pre-treated patients showed a significant reduction in HbA_1c of 0.14% and 0.82%, respectively, at 30 months (7.27 ± 1.2% to 7.13 ± 1.1% and 7.42 ± 1.2 to 6.60 ± 0.3%, respectively; p < 0.01). No change in body weight was observed in the overall group. No episodes of severe hypoglycaemia (blood glucose <?40?mg/dL [<?2.2?mmol/L] occurred.

Conclusions: In this retrospective study of medical records, patients with type 1 diabetes treated with insulin glargine over 30 months in combination with educational support and close clinical supervision decreased their HbA_1c levels without weight gain versus previous treatment with NPH insulin or insulin lente. Further studies in a larger cohort of patients would help to confirm these results.