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Query: UMLS:C0011849 (diabetes)
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The DCCT and UKPDS studies have definitely established that in type 1 as well as in type 2 diabetes mellitus, long-term near-normoglycaemia strongly protects against onset and/or progression of microangiopathic complications. Therefore, implementation of insulin strategies to maintain long-term near-normoglycaemia is of key importance in the management of diabetes mellitus. To successfully reach the goal of near-normoglycaemia, insulin therapy has to be physiological, i.e. it has to mimic nature by providing a bolus of insulin at meal ingestion, and by replacing the need for basal insulin between meals and during the night. The meal-time insulin needs can be best met by s.c. injection of a short-acting insulin analogue (lispro, aspart). Short-acting insulin analogues should be preferred to human regular insulin for three main reasons. First, convenience (meal-time injection, better adaptation of insulin dose to carbohydrate content of the meal); second, lower blood glucose 2-hour after meals; third, less risk for late post-prandial hypoglycaemia. However, the benefits of meal-time treatment with short-acting insulin analogues become apparent only by the extent to which replacement of basal insulin is optimised as well. The interprandial (especially nocturnal) need for basal insulin can be best met by the continuous s.c. insulin infusion by an external minipump, the gold standard of basal insulin replacement. Continuous s.c. insulin infusion in the basal state is so good because it uses a short-acting insulin analogue (low variability in s.c. absorption, flat and peak-less action profile), not insulin preparations with retarded action (high variability of s.c. absorption, peak of action) likewise the model of multiple daily insulin injections. A second choice option is s.c. injection of an insulin preparation with retarded action. At present, the long-acting insulin analogue glargine is the retarded insulin preparation of choice because its action profile is flat, peakless and long-lasting (approximately 24 hours). This is in contrast with the peak action profile of NPH insulin which exhibits a short duration of action (10-15 h). Thus, the modern insulin strategies for intensive therapy always include use of a short-acting insulin analogue at meal-time, and use of either continuous s.c. insulin infusion, or a s.c. injection of insulin glargine to replace basal insulin. Insulin glargine reproduces closely the pharmacokinetics and pharmacodynamics of continuous s.c. insulin infusion, and should always be preferred to NPH in all insulin-requiring diabetic patients, both type 1 and type 2.
Exp Clin Endocrinol Diabetes 2001
PMID:Physiological insulin replacement in type 1 diabetes mellitus. 1146 May 80

Modern diabetes therapy is positively introduced insulin administration including intensive insulin therapy to type 1 and type 2 diabetes to prevent or delay the development of long-term complications. However, conventional insulin derivatives could not mimic more closely physiological insulin secretion profiles, resulting in frequent hypoglycemia attacks and brittle diabetes. Recent advanced technologies have allowed to modify insulin molecules to obtain several insulin analogues. Lys.Pro insulin and insulin aspart, rapid-acting insulin analogues, have demonstrated improved post-prandial glucose control in comparison with regular insulin, even although they are usually administered immediately prior to the meal. Insulin glargine and SoLongln, long-acting insulin analogues, could preserve the stable basic insulin profiles during a day as compared with NPH insulin. These insulin analogues are very useful to supply the post-prandial and basic insulin secretions in type 1 and type 2 diabetics.
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PMID:[Recent trends of development of rapid-acting and long-acting human insulin analogues--its biological characteristics and clinical availability]. 1171 96

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.
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PMID:Insulin glargine: the first clinically useful extended-action insulin analogue. 1182 24

To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time-action profile most studies have not been able to show any improvement in overall glycaemic control with the fast-acting analogues. A reduced post-prandial increase in blood glucose has been found in all studies, whereas between 3 and 5 h after the meal and during the night an increased blood glucose level is the normal course. This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin administered several times daily at mealtimes can improve glycaemic control without increasing the risk of hypoglycaemia. The fast-acting analogues are now also available as insulin mixed with NPH. Insulin glargine is a new long-acting insulin which is soluble and precipitates after injection, resulting in a long half-life with a residual activity of about 50% 24 h after injection. Insulin glargine is a peakless insulin and studies in both type 1 and type 2 diabetic patients indicate that glargine improves fasting blood glucose control and reduces the incidence of nocturnal hypoglycaemia. Surprisingly, the new fast-acting analogues have not achieved the expected commercial success, which emphasises the need for new strategies for basal insulin supplementation, exercise, diet and blood glucose monitoring.
Diabetes Metab Res Rev
PMID:Insulin analogues: have they changed insulin treatment and improved glycaemic control? 1192 26

The pharmacodynamics, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of insulin glargine are reviewed. Current treatment regimens for patients with type 1 diabetes mellitus and some with type 2 are designed to provide a basal insulin level with intermittent preprandial insulin coverage. Insulin glargine precipitates after subcutaneous injection, slowing absorption. Insulin glargine is used as a basal insulin and exhibits a flat pharmacokinetic profile, with a duration of action of at least 24 hours. Hypoglycemia is the most commonly reported adverse effect, especially within the first four weeks after a switch to insulin glargine. Insulin glargine should not be mixed with any other insulin product and should be administered with a syringe that has not been used for other insulin products or other medications. Insulin glargine is administered once daily at bedtime. Patients previously receiving twice-daily isophane insulin (NPH) should receive an insulin glargine dosage 20% less than the total daily dose of NPH insulin. Clinical trials did not consistently show improvements in hemoglobin A1c levels when patients with type 1 diabetes mellitus were switched from NPH insulin once or twice daily to insulin glargine. Insulin glargine should be considered for patients who continue to have elevated morning blood glucose levels and problems with nocturnal hypoglycemia despite receiving NPH insulin at bedtime. In patients with type 2 diabetes mellitus, insulin glargine significantly improved glycemic control compared with once-daily NPH insulin, but not when it was compared with combined treatment with once- or twice-daily NPH insulin. Clinical trials assessing progression of retinopathy and nephropathy and comparing insulin glargine therapy with continuous subcutaneous insulin infusion therapy are needed to more clearly determine insulin glargine's role. Insulin glargine is a new long-acting formulation that can provide prolonged basal glucose control in patients with diabetes mellitus.
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PMID:Insulin glargine: a new long-acting insulin product. 1194 2

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.
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PMID:Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits. 1205 19

The DCCT and UKPDS have established that in type 1 and in type 2 diabetes respectively, long-term near-normoglycaemia protects against the onset and/or progression of microangiopathic complications. Therefore, insulin strategies to maintain long-term near-normoglycaemia are of key importance in the management of diabetes. To successfully achieve near-normoglycaemia, insulin therapy must mimic nature by providing a bolus of insulin at meal ingestion and by replacing basal insulin between meals and overnight Mealtime insulin needs can be best met by subcutaneous (s.c.) injection of a rapid-acting insulin analogue such as insulin lispro or insulin aspart. Rapid-acting insulin analogues are preferred to human regular insulin for three reasons: convenience (meal-time injection, better adaptation of insulin dose to carbohydrate content of the meal); lower blood glucose 2 hours after meals; and less risk for late postprandial hypoglycaemia. However, in type 1 diabetes the benefits of mealtime treatment with rapid-acting insulin analogues become apparent only to the extent that replacement of basal insulin is optimised. The interprandial need for basal insulin can be best met by continuous s.c. insulin infusion (CSII). CSII is very good for basal insulin replacement because it uses a rapid-acting insulin analogue with low variability in s.c. absorption, resulting in a flat and peakless action profile. A second option for basal insulin replacement is s.c. injection of an insulin preparation with retarded action. The two most commonly used are NPH and insulin glargine. NPH exhibits an action profile with a peak 4 to 5 hours after injection and duration of action of 10 to 15 hours. Insulin glargine has a peakless action profile and lasts approximately 24 hours. To optimise replacement of basal insulin with NPH, a few units of NPH must be combined with rapid-acting analogues at meals and also given at bedtime (0.2 U/kg). With insulin glargine, 0.2 to 0.4 U/kg should be injected once or, in some patients, twice daily. Modern insulin strategies for intensive therapy should include use of a rapid-acting insulin analogue at meal-time, and use of CSII to replace basal insulin. Insulin glargine reproduces closely the pharmacokinetics and pharmacodynamics of CSII and should be considered for substitution of basal insulin, especially in type 1 diabetes.
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PMID:Clinical strategies for controlling peaks and valleys: type 1 diabetes. 1216 10

Insulin glargine is an innovative, long-acting human insulin analogue, whose prolonged mean activity profile has no pronounced peak. Accordingly, it mimics more closely the natural physiological profile of basal endogenous insulin secretion than do traditional extended-acting insulins such as NPH insulin. As would be expected for a more satisfactory basal insulin, clinical trials comparing insulin glargine with NPH insulin show less nocturnal hypoglycaemia, improved pre-breakfast blood glucose levels, or both. Furthermore, no substantive safety concerns have emerged for insulin glargine. Thus, insulin glargine represents the first major advance in the provision of basal insulin injection therapy for people with type 1 and type 2 diabetes for over 50 years.
Diabetes Metab Res Rev
PMID:An overview of insulin glargine. 1232 87

The United Kingdom Prospective Diabetes Study (UKPDS) showed that tight glycemic control with any of several therapeutic regimens has the potential to significantly reduce the risk for long-term microvascular complications of type 2 diabetes. An important question that remains to be answered is what is the best approach to optimizing glycemic control in patients with this disease. This article reviews results of studies in which insulin was used alone or in combination with oral antidiabetic agents for treatment of patients with type 2 diabetes. Analysis of comparative studies (13 in insulin-naive and 26 in previously insulin-treated patients) showed that combination therapy involving one to two insulin injections per day plus oral therapy is usually more effective than insulin monotherapy for achieving and maintaining glycemic control. Combination treatment for type 2 diabetes can be significantly improved by newly developed preparations that lack the major limitations of older products. Once-daily administration of isophane insulin (NPH insulin) is limited by a 15-18-h duration of action and a peak effect that occurs about 6 h after injection. Insulin glargine, a new insulin analogue developed using recombinant DNA technology, has a flat pharmacodynamic profile and a 24-h duration of action. Results from a recent comparative study indicate that insulin glargine plus oral therapy may provide better post-dinner glucose control as well as less symptomatic and nocturnal hypoglycemia than oral therapy combined with NPH insulin. The studies reviewed in the present article support the conclusion that combination therapy with insulin glargine combined with one or more oral antidiabetic agents may be the treatment of choice for achieving glycemic control in patients with type 2 diabetes.
Diabetes Metab Res Rev
PMID:Combination therapy with insulin and oral agents: optimizing glycemic control in patients with type 2 diabetes mellitus. 1232 90

Optimal glucose control is the primary goal for treating diabetes mellitus and preventing long-term complications of diabetes, such as coronary heart disease, nephropathy, neuropathy and retinopathy. Insulin glargine is a novel, long-acting human insulin analog that is indicated in type 1 diabetic patients aged >or=6, or in type 2 diabetic patients who require basal insulin for glycemic control. Insulin glargine is a recombinant insulin with a modified structure that allows it to dissolve in an acidic solution, but to precipitate in the physiological subcutaneous tissue forming a depot effect. In contrast to Neutral Protamine Hagedorn (NPH) insulin, insulin glargine has a slower onset, a longer duration of action, and no peak in metabolic activity. Once-daily subcutaneous administration of insulin glargine at bedtime has comparable efficacy to that of NPH insulin once or twice daily when used in combination with bolus insulin in type 1 diabetic patients, or in conjunction with oral antidiabetic drugs in type 2 diabetic patients. Overall, insulin glargine has similar adverse effects when compared with NPH insulin. Insulin glargine has been associated with less nocturnal hypoglycemia and improved treatment satisfaction in several clinical trials with durations of < 52 weeks. Pharmacoeconomic analysis comparing insulin glargine with other intermediate- or long-acting insulin preparations used as basal insulin therapy has not been performed. In summary, insulin glargine offers a promising alternative as a once-daily basal insulin therapy in patients with type 1 and type 2 diabetes.
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PMID:Insulin glargine: a new once-daily basal insulin for the management of type 1 and type 2 diabetes mellitus. 1278 37


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