Uses and Administration
Insulin is a hormone that plays a key role in regulating carbohydrate, protein, and fat metabolism. The main stimulus for its secretion is glucose, although many other factors including amino acids, catecholamines, glucagon, and somatostatin, are involved in its regulation. The secretion of insulin is not constant and peaks occur in response to the intake of food.
The major effects of insulin on carbohydrate homoeostasis follow its binding to specific cell-surface receptors on insulin-sensitive tissues, notably the liver, muscles, and adipose tissue. It inhibits hepatic glucose production and enhances peripheral glucose disposal thereby reducing blood-glucose concentration. It also inhibits lipolysis thereby preventing the formation of ketone bodies.
Therapy with insulin is essential for the long-term survival of all patients with type 1 diabetes mellitus. It may also be necessary in some patients with type 2 disease. The management of diabetes mellitus and the role of insulin in type 1 and type 2 disease is discussed. Insulin is generally the treatment chosen for all types of diabetes mellitus during pregnancy.
Choice of insulin. The different types of insulin and their formulations are described under Definitions, above. In some countries including the UK the commercially available preparations have been standardised to a single strength containing 100 units/mL a strength of 40 units/mL is still available in some other countries, and in others concentrated injections (500 units/mL) are available to enable high doses to be given subcutaneously in a small volume. All formulations can be given by subcutaneous injection, most by intramuscular injection, but only soluble insulins can be given by the intravenous route. The long-term management of diabetic patients usually involves the subcutaneous route. Syringes and needles for subcutaneous injection are preferably disposable. Pen-injector devices which hold the insulin in cartridge form and meter the required dose are becoming increasingly popular. Soluble insulin is often given by the intraperi-toneal route to patients on continuous ambulatory peritoneal dialysis. More recently, products supplying short-acting insulin by inhalation have been developed.
The various formulations of insulin are classified, according to their duration of action after subcutaneous injection, as short-, intermediate-, or long-acting. The exact duration of action for any particular preparation, however, is variable and may depend upon factors such as interindividual variation, the patient’s antibody status, whether the insulin is of human or animal origin, the dose, and the site of injection. Short-acting insulins are the soluble insulins, which have an onset after about 30 minutes to 1 hour, a peak activity at about 2 to 5 hours, and a duration of about 6 to 8 hours. Some analogues, such as insulins lispro and aspart, are also short-acting, with a faster onset and shorter duration of action than soluble insulin and are sometimes known as rapid-acting insulins. Intermediate-acting insulins include biphasic insulins, isophane insulins, and amorphous insulin zinc suspensions. In general these have an onset within about 2 hours, peak activity after about 4 to 12 hours, and a duration of up to 24 hours. Commercially available mixtures of soluble insulins and isophane insulins have activities which would normally place them within the intermediate-acting category. Mixed insulin zinc suspensions may be classified as either intermediate- or long-acting as the duration of action may be up to 30 hours the onset of action is generally 2 to 3 hours and the time to peak activity 6 to 15 hours. Long-acting insulins include crystalline insulin zinc suspensions and protamine zinc insulins. These generally have an onset after about 4 hours, a peak activity at about 10 to 20 hours, and a duration of up to 36 hours. The insulin analogues insulin glargine and insulin detemir are also long-acting. After intramuscular injection, the onset of action of all insulins is generally more rapid and the duration of action shorter.
The type of formulation, its dose, and the frequency of administration are chosen to suit the needs of the individual patient. Whatever the formulation, human insulin is generally used for all newly diagnosed diabetics.
Control. The dosage of insulin must be determined for each patient and although a precise dose range cannot be given a total dose in excess of about 80 units daily would be unusual and may indicate the presence of a form of insulin resistance. The dose should be adjusted as necessary according to the results of regular monitoring of blood concentrations (or occasionally urine concentrations) of glucose by the patient.
The WHO has recommended that the glucose concentration of venous whole blood under fasting conditions should be kept within the range of 3.3 to 5.6 mmol/litre (60 to 100 mg per 100 mL) and after meals should not be allowed to exceed 10 mmol/litre (180 mg per 100 mL) blood-glucose concentrations should not be allowed to fall below 3 mmol/litre (55 mg per 100 mL). In practice it seems to be generally acceptable for patients to aim for blood-glucose concentrations between 4 and 10 mmol/litre, with the understanding that occasional variations outside this range may occur. It should be remembered that the glucose concentrations in venous plasma, venous whole blood, and capillary whole blood may be slightly different. Control may also be determined by monitoring of glycosylated haemoglobin concentrations ideally the aim is an HbA1c level of less than 7% or an HbA1 of less than 8.8%, compared with normal ranges of 4 to 6% and 5 to 7.5% respectively. Insulin requirements may be altered by various factors (see Precautions, above). The aim of any regimen should be to achieve the best possible control of blood glucose by attempting to mimic as closely as possible the pattern of optimum endogenous insulin secretion. Many regimens involve the use of a short-acting soluble insulin with an intermediate-acting insulin, such as isophane insulin or mixed insulin zinc suspension, often given twice daily. It may sometimes be necessary, though, to give 3 or 4 injections daily to achieve good control and this typically involves giving a soluble insulin before meals and an intermediate- or long-acting insulin in the evening. A once-daily injection of an intermediate- or long-acting insulin is now generally considered to be acceptable only for those patients with type 2 diabetes mellitus who still retain some endogenous insulin secretion but nevertheless require insulin therapy, or for those patients with type 1 disease unable to cope satisfactorily with more intensive regimens. If a more intensive regimen is desired, continuous subcutaneous infusion may be employed using soluble insulin in an infusion pump. This delivers a constantbasal infusion of insulin supplying about half of the total daily requirements, the remainder being provided by patient-activated bolus doses before each meal. The technique has a limited place in the management of diabetes patients using it need to be well-motivated, reliable, and able to monitor their own blood glucose, and must have access to expert advice at all times. Formulations in which the insulin is in suspension are not suitable for continuous subcutaneous infusion and some brands of soluble insulin are unsuitable for this purpose because of the risk of precipitation in the pump catheter.
Ketoacidosis. Insulin is also an essential part of the emergency management of diabetic ketoacidosis. Only short-acting soluble insulins should be used. Treatment includes adequate fluid replacement, usually by infusing sodium chloride 0.9% initially, and the use of potassium salts to prevent or correct hypokalaemia. Insulin should be given by continuous intravenous infusion if possible, although other routes have also been used — for details of regimens see Diabetic Emergencies, under Diabetes Mellitus, below. Since insulin normally corrects hyperglycaemia before ketosis it is usually necessary to continue giving insulin once normoglycaemia has been achieved but to change the rehydration fluid to glucose-saline so that the additional glucose prevents the development of hypoglycaemia.
Administration. ADMINISTRATION ROUTES. The long-term management of diabetic patients usually involves injection by the subcutaneous route. The advice to diabetics has been to inject their insulin using a full-depth perpendicular injection.In many non-obese patients, however, such a technique can result in inadvertent intramuscular injection. Since insulin is absorbed more rapidly after intramuscular than subcutaneous injection, this may lead to greater day-to-day variability in blood-glucose control. In particular, overnight control may be inadequate if intermediate-acting preparations such as isophane insulin are used. Some therefore consider that extended-action insulins should be injected at an angle into a raised skin fold. Although injection of soluble insulin into muscle may produce a more physiological action profile, until more data are available a technique that ensures subcutaneous injection may be prudent with soluble insulins as well.The anatomic site of subcutaneous insulin injection is usually rotated in an attempt to decrease local adverse effects (see Adverse Effects, above). However, the rate of absorption varies between sites and such a practice may also contribute to day-to-day variability in blood-glucose concentrations. For example, large variations in blood-glucose concentrations have been reported on subcutaneous injection into the thigh. Some have suggested rotation of injection sites within an anatomic region, or possibly use of the same anatomic region for injections given at a specific time of day.
Jet injectors deliver insulin at high pressure across the skin into the subcutaneous tissue without use of a needle. The greater dispersion obtained gives more rapid absorption of short- and intermediate-acting insulins and consequently reduces the total duration of action. Mild pain, bruising, and bleeding may be a problem. Despite having been available for some years, there is little information about their benefits and risks and they are not widely used. However, results in a small study in women with gestational diabetes have suggested that jet injection may be associated with less variation in postprandial blood-glucose concentration and a lower incidence of insulin antibodies.Insulin preparations may also be given by intramuscular injection. Absorption is more rapid than from a subcutaneous injection. However, exercise may produce considerable variations in insulin absorption after intramuscular injection. Soluble insulins may be given intravenously this route is used in diabetic ketoacidosis, and also in surgery and labour. Intermittent pulsed intravenous insulin therapy added to a conventional subcutaneous regimen has been reported to improve symptoms of orthos-tatic hypotension and hypertension.
The subcutaneous and intravenous routes, and, rarely, the intramuscular route have all been used for the continuous administration of insulin (see Intensive Administration Regimens, below). Formulations of insulin for intranasal use are under investigation. They have been tried in both type 1 and type 2 diabetes, but bioavailability is low and variable. Absorption enhancers have been used to facilitate uptake of insulin from the nasal mucosa and local adverse effects are dependent, in part, on their irritancy. Similarly, buccal formulations are under investigation,and have become available in some countries. Devices for delivering insulin to the lungs via oral inhalation have been developed. Inhaled insulin is effective in maintaining glycaemic control in both type 1 and type 2 diabetes,although there is some evidence from longer-term studies that it is slightly less effective than subcutaneous injection however, patient acceptability is higher. It is given before meals as a short-acting insulin in patients also receiving intermediate or long-acting subcutaneous insulins or oral antidiabetics in type 2 diabetes it has also been used alone. UK recommendations from NICE are that it should be reserved for patients who are unable to start or intensify subcutaneous insulin therapy because of a marked, persistent fear of injections or severe difficulties with injection sites (for example, due to lipoatrophy). Data regarding the long-term safety of inhaled insulin also need to be collected, given reports of pulmonary effects and higher levels of insulin antibodies in people with type 1 diabetes. A few cases of primary lung malignancies have occurred in clinical trials of inhaled insulin, at a higher incidence than in comparator-treated patients. However, the number of cases was too small to determine whether these events were related to inhaled insulin, and all affected patients had a history of cigarette smoking. Endogenous insulin is delivered into the portal venous system, and then passes immediately to the liver where a large fraction of the insulin is extracted. The above routes of administration all deliver insulin into the peripheral circulation, with the risk of peripheral hyperinsulinaemia which has been considered a risk factor for atherosclerotic complications. Giving insulin via the intraperitoneal or oral routes may overcome this problem to some extent. Peritoneal insulin is used routinely in diabetics undergoing chronic ambulatory peritoneal dialysis, but has also been used for continuous administration (see Intensive Administration Regimens, below). Various formulations of insulin for oral delivery are also under investigation. Rectal or transdermal insulin has also been tried.
INSULIN ANALOGUES AND PROINSULIN. Recombinant-DNA technology has enabled the production of insulin analogues with altered pharmacokinetic profiles. Most of the insulin in pharmaceutical preparations is in the form of hexamers, which require time to dissociate before absorption from a subcutaneous site. Substitution of amino-acid residues at the monomer-monomer interface has produced monomeric insulin analogues that retain the biological activity of insulin. Good results have been reported with an analogue, insulin lispro, in which the B28 and B29 residues are replaced with lysine and proline. This analogue is commercially available and has been widely reviewed. In comparative studies of insulin lispro versus soluble insulin given before meals to patients also receiving a long-acting insulin, insulin lispro was reported to result in good glycaemic control, and could be given immediately before meals (5 to 15 minutes) rather than 20 to 40 minutes before as with soluble insulin. There is a suggestion that it may result in fewer severe hypoglycaemic episodes in such regimens. However, an analysis of 10 clinical trials did not find any difference between insulin lispro and neutral insulin (Humulin R) with respect to overall adverse effects or development of long-term diabetic complications. (See also insulin aspart, below.) A few cases of response to insulin lispro in patients with severe insulin resistance have been reported. Insulin lispro has been complexed with protamine to produce an intermediate-acting form, which is available as a biphasic preparation.
Insulin aspart is another short-acting insulin analogue, with aspartic acid substituted for proline at position B28. It is also used immediately before meals and controls postprandial blood glucose concentrations at least as well as regular human insulin, and may cause fewer hypoglycaemic episodes. A meta-analysis involving 42 studies of insulin lispro or insulin aspart versus regular insulin found that there was evidence of a minor benefit of the analogues in improving HbA1c values in adult patients with type 1 diabetes no superiority could be shown in patients with type 2 diabetes.
Insulin glulisine is another insulin analogue, with asparagine at position B3 replaced by lysine, and lysine at B29 replaced by glutamic acid. It also has a rapid onset and short duration of action.
Recombinant-DNA technology has also been used to produce a long-acting basal insulin analogue, insulin glargine, suitable for once-daily use. It is available as a solution at pH 4 on subcutaneous injection and neutralisation by tissue buffering processes, microprecipitates are formed that slowly release insulin glargine over 24 hours with no pronounced peak in concentration or in metabolic activity. Controlled studies have reported insulin glargine to be more effective than human isophane insulin in producing glycaemic control as part of a basal-bolus regimen, and to be associated with fewer hypoglycaemic episodes. Insulin detemir is another long-acting insulin analogue that may have some benefit over isophane insulin. It is a neutral soluble human insulin analogue in which the terminal amino acid at B30 has been replaced by a 14-carbon fatty acid chain. This allows insulin detemir to bind reversibly to albumin, producing slow absorption and a prolonged and consistent metabolic effect for up to 24 hours. It appears to be at least as effective as isophane insulin in maintaining overall glycaemic control but with less intra-patient variability, a similar or lower risk of hypoglycaemia, and less body-weight gain.
Proinsulin (the natural precursor of insulin) appears to be more active than insulin in suppressing the hepatic production rather than the peripheral uptake of glucose. It has therefore been studied particularly in patients with type 2 diabetes mellitus. However, development by some manufacturers has been suspended because of a higher rate of adverse cardiac effects in patients treated with proinsulin than in controls.
INTENSIVE ADMINISTRATION REGIMENS. Intensive insulin regimens aim to mimic more closely the physiological insulin pattern in which a basal insulin concentration is supplemented by a preprandial boost of insulin. Such intensive regimens are used to provide tight control in an attempt to avoid long-term complications.
Intensified insulin regimens have the advantage of improving the patient’s lifestyle and allowing flexibility in timing of meals. However, careful dietary control must still be maintained and regular monitoring of blood-glucose concentrations is an important component of such regimens. Therefore patients must be well-motivated, reliable, and able to monitor their own blood glucose, and must have access to expert 24-hour help. Although there are reports of success with intensive regimens in brittle (labile) diabetics, these patients are generally unlikely to benefit from such regimens.
In multiple-injection regimens, the basal insulin is provided by an injection of intermediate- or long-acting insulin given usually at night, and soluble insulin is given before each main meal. Systems for continuous administration may be designed on an open-loop or closed-loop delivery system. Open-loop systems comprise an infusion pump with the infusion rate programmed or controlled manually according to manual blood-glucose monitoring. Closed-loop systems (the ‘artificial pancreas’) consist of an insulin pump, a glucose sensor, and a computer for analysis of blood-glucose data. Systems for continuous administration have most commonly used the subcutaneous route, but intraperitoneal, intravenous, or intramuscular infusion have also been used. The most extensively used open-loop system is continuous subcutaneous insulin infusion (CSII) using an external pump. A battery-powered pump infuses soluble insulin via a subcutaneous catheter which is resited every 2 to 3 days. A background infusion is given at a predetermined rate, and preprandial bolus doses given using an override switch or manual drive. CSII provides better glycaemic control than conventional injection therapy, but may be only slightly more effective than optimised multiple daily injection therapy. Complications include erythema, abscess, or cellulitis at the injection site and, rarely, contact dermatitis to components of the giving set, pump malfunction, or precipitation of insulin and catheter obstruction. Pump therapy increases the risk of ketoacidosis and intensive regimens are associated with decreased hypoglycaemic awareness and more severe hypoglycaemic episodes compared with conventional therapy, although there is some suggestion that CSII might reduce the risk of severe hypoglycaemia compared with multiple daily injection therapy. If the pump fails or there is an acute increase in insulin requirements, the onset of ketoacidosis may be more rapid and more likely to be associated with dangerous hyperkalaemia than with conventional regimens because there is no depot of insulin.
Further development of open-loop delivery systems has been in the design of implantable insulin pumps. The first pumps delivered insulin at a constant basal rate, but variable rate models are now available. Studies’ have shown that intravenous or intra-peritoneal delivery of insulin from an implantable pump can produce excellent glycaemic control, and fewer episodes of severe hypoglycaemia than are associated with intensive subcutaneous multiple-injection regimens. The main problems associated with such therapy are pump slow-down or catheter obstruction due to aggregation of insulin within the device these can normally be corrected by procedures to flush the pump and catheter, although alternative insulin formulations (e.g. with poloxamer) have been investigated. Other problems may include fibrinous obstruction of the catheter or local intolerance of the pump.
Closed-loop continuous infusion systems are generally confined to research and experimental work because glucose sensors suitable for implantation are still being developed. However, results in animals have suggested that an alternative to such systems may be a vascularised artificial pancreas containing islet cells.
MIXING OF INSULINS. Mixtures of insulin with differing durations of action may be used in order to produce a more normal pattern of blood glucose variation than can be achieved with a single insulin. However, physicochemical changes in the mixture may occur, either immediately on mixing or over time, and the physiological response to the mixture may therefore be different than if the components were given separately. An early review suggested that insulins from different manufacturers should not be mixed, since formulation differences might render them incompatible. It is important that a consistent routine is followed in preparing and using such mixtures, and manufacturers advise that the shorter-acting insulin should be drawn into the syringe first, to avoid contamination of the vial with the longer-acting component. Pre-prepared mixtures are available from many manufacturers and may be preferable provided that the proportions are suited to the patient’s needs.
The American Diabetes Association has issued guidelines for mixing of insulins, including:
• patients well controlled on a particular mixed regimen should maintain their standard procedure for preparing doses
• no other medication or diluent should be mixed with insulin unless approved by the prescriber
• insulin glargine should not be mixed with other forms of insulin because of the low pH of its diluent
• currently available isophane and short-acting insulin formulations when mixed may be used immediately or stored for future use
• rapid-acting insulins (insulin aspart, insulin lispro) can be mixed with isophane, lente, and ultralente insulins. Ultralente insulins do not affect the onset of action of the rapid-acting component a slight decrease in absorption rate but not bioavailability is seen if rapid-acting insulins are mixed with isophane insulin but postprandial blood-glucose response is similar to that seen with mixtures of rapid-acting and ultralente insulin
• mixtures of rapid-acting insulin with an intermediate- or long-acting insulin should be injected within 15 minutes before a meal
• mixing of short-acting (soluble) and lente or ultralente insulin is not recommended, as zinc ions present in the lente insulin may bind with the short-acting insulin and delay its effects. The degree and rate of binding vary with the insulins used, and may not reach equilibrium for 24 hours if such mixtures are used the patient should standardise the interval between mixing and injection
• phosphate-buffered insulins (e.g. isophane insulin) should not be mixed with zinc-containing (lente or ultralente) insulins, as zinc phosphate may be precipitated, and the longer acting insulin may be partially and unpredictably converted to a short-acting form
Insulin formulations may change and the manufacturers should be consulted if their recommendations differ from those in the guidelines.
Diabetes mellitus. Insulin is the mainstay of the treatment of type 1 diabetes mellitus. For a discussion of the treatment of diabetes mellitus, including the contexts in which insulin is used. The possible role of tight glycaemic control with insulin to prevent the development of microvascular and macrovascular complications in patients with type 1 diabetes is discussed, while further discussion of specific regimens and approaches to insulin therapy is given under Administration, above.
DIABETIC EMERGENCIES. As discussed, diabetic ketoacidosis and hyperosmolar hyperglycaemic state are medical emergencies and should be treated immediately with fluid replacement and insulin. Potassium, and possibly phosphate, replacement may also be required, but bicarbonate should not be given unless acidaemia is very severe. In the UK the BNF recommends that insulin be given by intravenous infusion for diabetic ketoacidosis, as a solution of soluble insulin 1 unit/mL via an infusion pump. An infusion rate of 6 units/hour in adults and 0.1 units/kg per hour in children is recommended initially, with the rate doubled or quadrupled if the blood glucose concentration fails to decrease by about 5 mmol/litre per hour. When blood glucose concentrations have fallen to 10 mmol/litre the infusion rate can be reduced to 3 units/hour in adults or about 0.05 units/kg per hour in children, and continued, with glucose 5% to prevent hypoglycaemia, until the patient is ready to take food by mouth. The insulin infusion should not be stopped before subcutaneous insulin has been started. Potassium chloride is included in the infusion as appropriate to prevent insulin-induced hypokalaemia. If facilities for intravenous infusion are not available the insulin is given by intramuscular injection: in adults an initial loading dose of 20 units intramuscularly is followed by 6 units intramuscularly every hour until the blood glucose concentration falls to 10 mmol/litre, when the dose is given every 2 hours. Late hypoglycaemia due to insulin accumulation should be watched for and managed appropriately. In the USA the intramuscular or the subcutaneous route have been used as alternatives to intravenous insulin, with other appropriate management. One successful set of protocols for insulin dosage in diabetic ketoacidosis is as follows: an initial intravenous bolus of 0.15 units/kg is followed by infusion of 0.1 units/kg per hour if blood glucose does not fall by about 2.5 to 3.5 mmol/litre in the first hour the infusion rate is doubled every hour until this rate of decline is achieved. (A similar insulin regimen has proved effective in patients with hyperosmolar hyperglycaemic state.) When given by the intramuscular or subcutaneous routes an initial bolus of 0.4 units/kg is divided and given half by the intravenous route and half either intramuscularly or subcutaneously as appropriate. This is followed by 0.1 units/kg every hour intramuscularly or subcutaneously if response is inadequate it is replaced by an intravenous bolus of 10 units until blood glucose falls by 2.5 to 3.5 mmol/litre. In children intravenous infusion of 0.1 units/kg per hour is recommended, or if intravenous infusion is impractical an initial intramuscular bolus of 0.1 units/kg followed by 0.1 units/kg per hour either intramuscularly or subcutaneously. Treatment is continued at this rate until a serum-glucose concentration of about 12.5 mmol/litre is reached (or about 15 mmol/litre for hyperosmolar hyperglycaemic state), when the rate is decreased to 0.05 to 0.1 units/kg per hour until acidosis is controlled and subcutaneous insulin replacement treatment can be started.
TYPE 2 DIABETES MELLITUS. Traditionally the use of insulin in patients with type 2 diabetes has tended to be reserved for those who cannot be controlled by diet and oral antidiabetics alone. Given the possible association between circulating insulin and atherosclerotic cardiovascular symptoms there has been some concern about the use of exogenous insulin in insulin-resistant patients who are already hyperinsulinaemic. Furthermore, patients switched to insulin tend to gain weightwhich is undesirable in a frequently obese patient group. Insulin is nonetheless being used more frequently in type 2 patients. This is largely because of a trend toward more intensive regimens designed to produce tighter glycaemic control, on the hypothesis that, as in patients with type 1 disease, this will reduce the development and progression of diabetic complications. Results from the UK Prospective Diabetes Study, show that insulin is an effective option in type 2 diabetes, and confirm both the value of intensive therapy in retarding microvascular complications, and that oral therapy should be used before insulin in patients with primary diet failure.
In order to minimise the dose of insulin required, and any risks it may entail, it has been suggested that insulin therapy in type 2 diabetes should be combined with other measures including oral hypoglycaemic drugs. There has long been debate about the value of combined therapy, but a meta-analysis indicated that glycaemic control was better, and insulin requirements lower, in type 2 diabetics who received insulin with a sulfonylurea. For evidence that the insulin analogues insulin lispro and insulin as-part have no advantage over regular insulin in type 2 patients see Insulin Analogues, above.
Diagnosis and testing. PITUITARY FUNCTION. Insulin-induced hypoglycaemia has been used to provide a stressful stimulus in order to assess hypothalamic-pituitary function. The insulin stress or insulin-tolerance test has been used as a standard test for assessment of growth hormone or corticotropin deficiency. However, it is unpleasant, expensive, and not without risk, and is contra-indicated in patients with angina, heart failure, cerebrovascular disease, or epilepsy some recommend its use only when results of alternative tests are equivocal, and it should only be performed in specialist units under strict surveillance.
Hyperkalaemia. Insulin promotes the intracellular uptake of potassium. It is therefore used in the management of moderate to severe hyperkalaemia, when it is given with glucose.
Liver disorders. There have been reports of benefit from the use of insulin and glucagon in the treatment of liver disorders, based on their reported hepatotrophic effect. However, randomised studies have found no benefit from insulin and glucagon infusions in fulminant hepatic failure and acute alcoholic hepatitis.
Myocardial infarction. Discussions on the effects of insulin with glucose and potassium in the ischaemic heart, including its effect in reducing blood free fatty acids, have emphasised its potential benefits in left ventricular failure and cardiogenic shock. A meta-analysis of randomised controlled studies performed before the widespread use of thrombolytics found a reduction in mortality in recipients of glucose-insulin-potassium solutions. However, although a pilot study that included patients undergoing reperfusion (thrombolysis or percutaneous coronary intervention) reported benefit, this was not confirmed in larger randomised studies using standard glucose-insulin-potassium infusions. A further study found that routine use of such infusions in patients undergoing reperfusion had no effect on myocardial salvage, although some improvement was reported in diabetics.
Intensive glucose control, with insulin-glucose infusion followed by multiple daily subcutaneous insulin injections has been reported to reduce mortality in diabetics who suffered a myocardial infarction. A similar study of treatment after myocardial infarction included only patients with type 2 diabetes mellitus who were treated with routine care, or insulin-glucose infusion followed by either long-term subcutaneous insulin or standard glucose control. The study was stopped early due to slow patient recruitment, but results did suggest that although glucose concentration was a strong independent predictor of long-term mortality, the use of long-term insulin treatment did not improve survival compared with conventional treatment at similar levels of glucose control. An observational study in non-diabetics with hyperglycaemia suggested that intensive glucose control also improved outcomes in this population, but another study found no benefit. However, the glucose control achieved in this study was similar in both the intensive and the conventional treatment groups and an analysis based on blood glucose concentrations suggested that strict glucose control was beneficial.For the conventional management of myocardial infarction.
Neonatal hyperglycaemia. Hyperglycaemia is common in very immature neonates because of delayed or reduced insulin production. It can be treated by glucose restriction until glucose tolerance improves. However, this may not provide enough glucose to meet basal metabolic needs, and the use of an insulin infusion can allow sufficient glucose to be given. It has been suggested that insulin is best given intravenously in a separate, easily titratable solution because of the frequent fluctuations of requirement in these infants.
Overdosage with calcium-channel blockers. High-dose insulin, with glucose and potassium as required to maintain normal plasma concentrations of these, has been reported to be of value in the treatment of overdosage with calcium-channel blockers that has not been adequately managed with conventional therapy (which is described under Treatment of Adverse Effects under Nifedipine). A review of 13 reported cases found that various dosage regimens had been tried. These included bolus doses of insulin 10 to 20 units, and continuous infusions of 0.1 to 1 unit/kg per hour. The authors of one report have proposed a regimen that includes an initial intravenous bolus dose of insulin 1 unit/kg, followed by a continuous infusion of 0.5 units/kg per hour this may be increased to 1 unit/kg per hour if necessary.
Preparations
British Pharmacopoeia 2008: Insulin Aspart Injection; Insulin Lispro Injection; Protamine Zinc Insulin Injection
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1and 6.2: Biphasic Insulin Injection; Biphasic Isophane Insulin Injection; Insulin Zinc Injectable Suspension; Insulin Zinc Injectable Suspension (Amorphous); Insulin Zinc Injectable Suspension (Crystalline); Isophane Insulin Injection; Soluble Insulin Injection
The United States Pharmacopeia 31, 2008: Extended Insulin Human Zinc Suspension; Extended Insulin Zinc Suspension; Human Insulin Isophane Suspension and Human Insulin Injection; Insulin Human Injection; Insulin Human Zinc Suspension; Insulin Injection; Insulin Lispro Injection; Insulin Zinc Suspension; Isophane Insulin Human Suspension; Isophane Insulin Suspension; Prompt Insulin Zinc Suspension
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: Actrapid HM; Actrapid MC¤; Biohulin C; Biohulin N; Humalog; Humulin 70/30; Humulin L; Humulin NPH; Humulin R; Humulin U; Insulatard HM; Insulatard MC¤; Insuman N; Insuman R; Mixtard 30 HM; Monotard HM¤; Monotard MC¤
Australia: Actraphane HM¤; Actraphane MC¤; Actrapid MC¤; Actrapid; Humalog Mix 25; Humalog; Humulin 20/80, 30/70 and 50/50; Humulin L; Humulin NPH; Humulin R; Humulin UL; Hypurin Isophane; Hypurin Neutral; Initard Human¤; Initard¤; Insulatard Human¤; Insulatard¤; Insulin 2¤; Isotard MC¤; Lantus; Lente MC¤; Mixtard 20/80, 30/70, 50/50; Mixtard¤; Monotard MC¤; Monotard; NovoMix 30; NovoRapid; Protamine Zinc Insulin MC¤; Protaphane MC¤; Protaphane; Rapitard MC¤; Semilente MC¤; Ultralente MC¤; Ultratard; Velosulin¤
Austria: Actrapid HM; Depot-Insulin¤; Humalog Mix 25 and 50; Humalog; Huminsulin Basal; Huminsulin Long; Huminsulin Normal; Huminsulin Profil II and III; Huminsulin Ultralong; Insulatard HM; Insulatard¤; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman komb Typ 15, Typ 25, and Typ 50¤; Insuman Rapid; Komb-Insulin¤; Lente MC¤; Mixtard 30/70 and 50/50¤; Mixtard HM 10/90, 20/80, 30/70, 40/60, and 50/50; Monotard HM; Rapitard MC¤; Ultratard HM; Velosulin HM¤; Velosulin¤
Belgium: Actrapid HM; Humaject 30/70; Humaject NPH; Humaject Regular; Humalog; Humuline 20/80, 30/70, 50/50; Humuline Long; Humuline NPH; Humuline Regular; Humuline Ultralong; Initard Humanum¤; Insulatard HM; Insulatard-X Humanum¤; Lantus; Lente MC¤; Mixtard HM 10/90, 20/80, 30/70, 40/60, 50/50; Mixtard-X Humanum¤; Monotard HM; NovoMix 30; NovoRapid; Ultralente MC¤; Ultratard HM; Velosuline HM
Brazil: Actrapid MC; Biohulin 70/30, 80/20, and 90/10; Biohulin Lenta; Biohulin NPH; Biohulin Regular; Biohulin Ultralenta; Humalog Mix 25; Humalog; Humulin 70/30; Humulin Lenta; Humulin NPH; Humulin Regular; Insuman Comb 85N/15R and 75N/25R; Insuman N; Insuman R; Iolin NPH¤; Iolin Regular¤; Lantus; Monolin NPH¤; Monolin Regular¤; Monotard MC; Neosulin Lenta¤; Neosulin NPH¤; Neosulin Regular¤; Novolin 90/10, 80/20, and 70/30; Novolin L; Novolin N; Novolin R; Novolin U; NovoRapid; Protaphane MC
Canada: Humalog Mix 25; Humalog; Humulin 20/80, 30/70; Humulin L; Humulin N; Humulin R; Humulin U; Iletin II Pork Lente; Iletin II Pork NPH; Iletin II Pork Regular; Iletin Lente¤; Iletin NPH¤; Iletin Regular¤; Iletin Semilente¤; Iletin Ultralente¤; Initard 50/50¤; Insulatard NPH Human¤; Insulatard NPH¤; Insulin-Toronto (Regular)¤; Lente Insulin¤; Mixtard 15/85, 30/70, 50/50¤; Mixtard 30/70¤; Novolin 10/90, 20/80, 30/70, 40/60, 50/50; Novolin Lente; Novolin NPH; Novolin Toronto; Novolin Ultralente; NovoRapid; PZI Iletin¤; Semilente Insulin¤; Ultralente¤; Velosulin (Regular)¤; Velosulin Human¤
Chile: Actrapid HM; Actrapid¤; Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insulatard HM; Insulatard¤; Insuman N; Insuman R; Lantus; Lenta¤; Mixtard HM¤; Monotard HM
Czech Republic: Actrapid HM; Humalog Mix 25 and 50; Humalog NPL; Humalog; Humulin L; Humulin M3; Humulin N; Humulin R; Humulin U; Hypurin Bovine Isophane; Hypurin Bovine Protamin Zink Sulfat; Hypurin Porcin Neutral; Insulatard HM; Insuman Basal; Insuman Komb Typ 15, Typ 25, and Typ 50; Insuman Rapid; Lantus; Mixtard HM 10, 20, 30, 40, 50; Monotard HM; NovoMix 30; NovoRapid; Ultratard HM; Velosulin HM
Denmark: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70; Humulin NPH; Humulin Regular; Humutard Ultra¤; Insulatard; Insuman Basal; Insuman Comb 25; Insuman Rapid; Mixtard 10/90, 20/80, 30/70, 40/60, and 50/50; Monotard; NovoMix 30; NovoRapid; Velosulin
Finland: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70¤; Humulin NPH; Humulin Regular; Humutard Ultra¤; Humutard; Insulin Lente MC¤; Insulin Lyhyt¤; Insulin Pitka¤; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Lantus; Mixtard 10, 20, 30, and 50; Monotard; NovoMix 30; NovoRapid; Protaphane; Ultratard; Velosulin¤
France: Actraphane HM¤; Actrapid HM; Apidra; Durasuline¤; Endopancrine 100¤; Endopancrine 40¤; Endopancrine Protamine¤; Endopancrine Zinc Protamine¤; Humalog Mix 25 and 50; Humalog; Insulatard Nordisk¤; Insulatard; Insuline NPH¤; Insuline Semi Tardum¤; Insuline Tardum MX¤; Insuline Ultra Tardum¤; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Intermediaire 100%¤; Insuman Intermediaire 25/75¤; Insuman Rapid; Lantus; Lente MC¤; Levemir; Lillypen Profil 10, 20, 30, and 40¤; Lillypen Protamine Isophane¤; Lillypen Rapide; Mixtard 10, 20, 30, 40, and 50 HM; Mixtard¤; Monotard¤; NovoMix 30; NovoRapid; Orgasuline 30/70¤; Orgasuline NPH¤; Orgasuline Rapide¤; Protaphane HM¤; Rapitard MC¤; Semilente MC¤; Ultralente MC¤; Ultratard¤; Umuline Profil 30; Umuline Protamine Isophane (NPH); Umuline Rapide; Umuline Zinc Compose¤; Umuline Zinc¤; Velosulin; Velosuline¤
Germany: Actraphane 10/90, 20/80, 30/70, 40/60, 50/50; Actrapid; B-Insulin; Basal-H-Insulin¤; Berlinsulin H 20/80, 30/70; Berlinsulin H Basal; Berlinsulin H Normal; Depot-H-Insulin¤; Depot-H15-Insulin¤; Depot-Insulin Horm¤; Depot-Insulin S¤; Depot-Insulin¤; H-Insulin¤; H-Tronin¤; Humalog Mix 25 and 50; Humalog; Huminsulin Basal; Huminsulin Long¤; Huminsulin Normal; Huminsulin Profil II and III; Huminsulin Ultralong¤; Insulatard Human; Insulatard MC¤; Insulin Basal; Insulin Comb 30/70; Insulin Monotard HM; Insulin Novo Semilente MC; Insulin Rapid; Insulin S; Insulin SNC; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Komb-H-Insulin¤; Komb-Insulin S¤; Komb-Insulin¤; L-Insulin SNC¤; L-Insulin¤; Lantus; Lente¤; Mixtard 30/70; Mixtard¤; Monotard; NovoMix 30; NovoRapid; Protaphane; Rapitard¤; Semilente; Ultralente¤; Ultratard HM; Velasulin Human¤; Velasulin MC¤; Velasulin¤; Velosulin
Greece: Actraphane HM¤; Actrapid HM; Humalog Mix 25; Humalog; Humulin Lente; Humulin M2, M3; Humulin NPH; Humulin Regular; Humulin Utralente; Lantus; Mixtard 10, 20, 30, 40, and 50; Monotard HM; NovoMix 30; NovoRapid; PenMix 10, 20, 30, 40, or 50¤; Protaphane HM; Ultratard
Hong Kong: Actrapid HM; Actrapid MC¤; Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insulatard MC¤; Lantus; Mixtard 20 and 30 HM; Monotard HM; Monotard MC¤; NovoRapid; Protaphane HM; Protaphane MC¤; Ultratard HM
Hungary: Humalog M25 and M50; Humalog; Humulin L; Humulin M1, M2, M3, M4; Humulin N; Humulin R; Humulin U; Insulin Actrapid; Insulin Insulatard; Insulin Mixtard 10, 20, 30, 40, 50; Insulin Monotard; Insulin Semilente; Insulin Ultratard; Monotard MC; NovoRapid
India: Actrapid; Human Actrapid; Human Insultard; Human Mixtard 30 and 50; Human Monotard; Lantus; Lentard; Mixulin; Rapidica; Rapimix; Wosulin Biphasic 30/70 and 50/50; Wosulin-N; Wosulin-R; Zinulin
Ireland: Actrapid; Humalog Mix 25 and 50; Humalog; Human Actraphane¤; Human Initard 50/50¤; Human Protaphane¤; Human Velosulin¤; Humulin I; Humulin Lente; Humulin M3; Humulin S; Humulin Zn; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Rapid; Lantus; Levemir; Mixtard 10, 20, 30, 40, and 50; Monotard; Neulente¤; Neuphane¤; NovoMix 30; NovoRapid; Ultratard; Velosulin¤
Israel: Humalog Mix 25; Humalog; Humulin 70/30, 80/20; Humulin N; Humulin R; Humulin U¤; Lantus; NovoMix 30; NovoRapid
Italy: Actraphane HM 10/90, 20/80, 30/70, 40/60, 50/50; Actrapid HM; Bio-Insulin 30/70 and 50/50¤; Bio-Insulin I¤; Bio-Insulin L¤; Bio-Insulin R¤; Bio-Insulin U¤; Humalog Mix 25; Humalog; Humulin 30/70 and 50/50; Humulin I; Humulin L; Humulin R; Humulin U; Lantus; Lenta MC¤; Monotard HM; NovoRapid; Protaphane HM; Rapitard MC¤; Ultratard HM
Japan: Humacart 3/7; InnoLet 10R, 20R, 30R, 40R, and 50R; InnoLet N; InnoLet R; Monotard; NovoLet 10R,20R, 30R, 40R, 50R¤; NovoLet N¤; NovoLet R¤; Novolin 10R, 20R, 30R, 40R, and 50R; Novolin N; Novolin R; Novolin U; NovoRapid; Penfill N; Penfill R; Penfill 10R, 20R, 30R, 40R, 50R; Velosulin
Malaysia: Actrapid; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Insulatard; Lantus; Mixtard 30 HM; Monotard HM¤; NovoRapid; Ultratard HM¤
Mexico: Anilusin¤; Humalog Mix 25; Humalog; Humanilusin¤; Humulin 70/30, 80/20; Humulin L; Humulin N; Humulin R; Insulex¤; Insuman 100N; Insuman 15R/85N, 25R/75N, and 50R/50N; Insuman R; Lantus; Novolin 30/70; Novolin L; Novolin N; Novolin R; Prodiabin-N
Netherlands: Actrapid; Humaject 10/90, 20/80, 30/70, 40/60, 50/50¤; Humaject NPH¤; Humaject Regular¤; Humalog Mix 25; Humalog; Humuline NPH; Humuline Zink¤; Humuline 20/80, 30/70; Humuline; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Isuhuman Basal¤; Isuhuman Comb 15, Comb 25, Comb 50¤; Isuhuman Infusat¤; Isuhuman Rapid¤; Mixtard 10, 20, 30, 40, and 50; Monotard; NovoRapid; Ultratard; Velosulin
Norway: Actrapid; Humalog Mix 25; Humalog; Humulin Mix 30/70¤; Humulin NPH; Humulin Regular¤; Insulatard; Insulin Basal¤; Insulin Infusat¤; Insulin Komb 25/75¤; Insulin Rapid¤; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Lantus; Mixtard 10/90, 20/80, 30/70, 40/60, 50/50; Monotard; NovoMix 30; NovoRapid; Ultratard; Velosulin¤
New Zealand: Actrapid; Humalog Mix 25¤; Humalog; Humulin 70/30, 80/20; Humulin L; Humulin N; Humulin R; Humulin U¤; Insulatard MC; Lantus; Mixtard 30 or 50; Monotard; NovoRapid; PenMix 10, 20, 30, 40, or 50; Protaphane; Ultratard; Velosulin HM; Velosulin MC
Portugal: Actrapid; Humalog; Humulin Lenta; Humulin M1, M2, M3, M4, M5; Humulin NPH; Humulin Regular; Humulin Ultralenta; Insulatard; Isuhuman Basal; Isuhuman Comb 25; Isuhuman Rapid; Mixtard 10, 20, 30, 40, and 50 HM; Monotard; Ultratard
Russia: Actrapid HM (Актрапид НМ); Actrapid MC (Актрапид MC); Biosulin N (Биосулин Н); Biosulin R (Биосулин Р); Humalog (Хумалог); Humulin M3 (Хумулин М3); Humulin NPH (Хумулин НПХ); Humulin Regular (Хумулин Регуляр); Insulidd L (Инсулидд Л); Insulidd N (Инсулидд Н); Insulidd R (Инсулидд Р); Insulin Lt (Инсулин Лт); Insulin Maxirapid (Инсулин Максирапид); Insuman Basal (Инсуман Базал); Insuman Comb 25 (Инсуман Комб 25); Insuman Rapid (Инсуман Рапид); Lantus (Лантус); Levulin L (Левулин Л); Levulin N (Левулин Н); Levulin R (Левулин Р); Mixtard 30 HM (Микстард 30 НМ); Monotard MC (Монотард Нм); NovoRapid (Новорапид); Protaphane HM (Протафан НМ)
South Africa: Actraphane HM; Actrapid HM; Humalog Mix 25; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Humulin U¤; Lantus; Mixtard 20/80; Monotard HM; NovoMix 30; NovoRapid; Protaphane HM; Ultratard HM
Singapore: Actrapid HM; Humalog Mix 25; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Insulatard HM; Lantus; Mixtard 20, 30, 50 HM; Monotard HM¤; NovoMix 30; NovoRapid; Ultratard HM¤
Spain: Actrafan HM¤; Actrap MC¤; Actrapid; Combitard Humana 15/85¤; Humalog Mix 25 and 50; Humalog NPL; Humalog; Humaplus 30/70; Humaplus NPH; Humaplus Regular; Humulina 10:90, 20:80, 30:70, 50:50; Humulina Lenta¤; Humulina NPH; Humulina Regular; Humulina Ultralenta¤; Insulatard NPH¤; Insulatard; Lantus; Lente MC¤; Meztardia Humana 50/50¤; Meztardia Nordi¤; Mixtard 10, 20, 30, 40, and 50; Mixtard 30/70¤; Monotard¤; Monotard; NovoMix 30; NovoRapid; Protafan HM¤; Rapitar MC¤; Semilen MC¤; Ultrale MC¤; Ultratard; Velosulin Humana¤; Velosulin¤
Sweden: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70; Humulin NPH; Humulin Regular; Humutard¤; Insulatard; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Isuhuman Basal¤; Isuhuman Comb 25/75, 50/50¤; Isuhuman Infusat¤; Isuhuman Rapid¤; Lantus; Mixtard 10/90, 20/80, 30/70, 40/60, 50/50; Monotard; NovoMix 30; NovoRapid; Ultratard; Velosulin
Switzerland: Actraphane HM¤; Actrapid HM; Actrapid MC; Humalog; Huminsulin Basal (NPH); Huminsulin Long; Huminsulin Normal; Huminsulin Profil III; Huminsulin Ultralong; Hypurin 30/70 Mix; Hypurin Isophane; Hypurin Neutral; Initard Humaine¤; Initard¤; Insulatard HM; Insulatard MC; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Lantus; Lente MC¤; Levemir; Mixtard 30 MC; Mixtard HM 10, 20, 30, 40, 50; Monotard HM; NovoMix 30; NovoRapid; Rapitard MC¤; Semilente MC; Ultralente MC¤; Ultratard HM; Velosulin HM; Velosulin MC¤
Thailand: Actrapid HM; Humalog Mix 25¤; Humalog¤; Humulin 70/30¤; Humulin N¤; Humulin R¤; Insulatard; Lantus; Mixtard 20, 30, 50 HM; Monotard HM; NovoMix 30; NovoRapid; Ultratard HM¤
United Arab Emirates: Jusline 70/30; Jusline N; Jusline R
United Kingdom: Actrapid; Apidra; Humaject I¤; Humaject M1, M2, M3, M4, M5¤; Humaject S¤; Humalog Mix 25 and 50; Humalog; Human Actraphane¤; Human Initard 50/50¤; Humulin I; Humulin Lente¤; Humulin M3; Humulin S; Humulin Zn¤; Hypurin 30/70; Hypurin Isophane; Hypurin Lente; Hypurin Neutral; Hypurin Protamine Zinc; Hypurin Soluble¤; Initard 50/50¤; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Rapid; Lantus; Lentard MC¤; Levemir; Mixtard 10, 20, 30, 40, and 50; Monotard¤; NovoMix 30; NovoRapid; PenMix 10/90, 20/80, 30/70, 40/60, 50/50¤; Pork Actrapid; Pork Insulatard; Pork Mixtard 30; Pur-in Isophane¤; Pur-in Mix 15/85, 25/75, 50/50¤; Pur-in Neutral¤; Rapitard MC¤; Semitard MC¤; Ultratard¤; Velosulin¤; Velosulin
United States: Apidra; Exubera; Humalog Mix 75/25 and 50/50; Humalog; Humulin 70/30, 50/50; Humulin BR¤; Humulin L; Humulin N; Humulin R; Humulin U Ultralente; Insulatard NPH Human¤; Insulatard NPH¤; Lantus; Lente Iletin I¤; Lente Iletin II; Lente L¤; Lente; Levemir; Mixtard Human 70/30¤; Mixtard¤; Novolin 70/30; Novolin L¤; Novolin N; Novolin R; NovoLog Mix 70/30; NovoLog; NPH Iletin I¤; NPH Iletin II; Protamine, Zinc & Iletin I¤; Regular Iletin I¤; Regular Iletin II; Semilente Iletin I¤; Semilente¤; Ultralente Iletin I¤; Ultralente U¤; Ultralente; Velosulin Human BR¤; Velosulin¤
Venezuela: Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insuman N; Insuman R; Novolin 70/30; Novolin L; Novolin N; Novolin R