Antidiabetic Drugs

Archive for the ‘Insulin’ Category

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 HbA_1c 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 HbA_1c 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

Drug Nomenclature

Pharmacopoeias. Most pharmacopoeias have monographs for insulin and a variety of insulin preparations.

European Pharmacopoeia, 6th ed. (Insulin, Bovine). The natural antidiabetic principle obtained from beef pancreas and purified. A white or almost white powder. Practically insoluble in water and in dehydrated alcohol. It dissolves in dilute mineral acids and, with decomposition, in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at -20° until released by the manufacturer. When thawed, insulin may be stored at 2° to 8° and used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, the insulin must be at room temperature.

European Pharmacopoeia, 6th ed. (Insulin, Porcine). The natural antidiabetic principle obtained from pork pancreas and purified. A white or almost white powder. Practically insoluble in water and in dehydrated alcohol. It dissolves in dilute mineral acids and, with decomposition, in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at-20° until released by the manufacturer. When thawed, insulin may be stored at 2° to 8° and used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, the insulin must be at room temperature.

European Pharmacopoeia, 6th ed. (Insulin, Human). A protein having the structure of the antidiabetic hormone produced by the human pancreas. It is produced either by enzymatic modification and suitable purification of insulin obtained from the pancreas of the pig or by a method based on recombinant DNA (rDNA) technology. A white or almost white powder. Practically insoluble in water and in alcohol. It dissolves in dilute mineral acids and, with decomposition, in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at or below -18° or below until released by the manufacturer. When thawed, insulin is stored at 2° to 8° and used for manufacturing preparations within a short period of time. To avoid absorption of humidity from the air during weighing, the insulin must be at room temperature.

European Pharmacopoeia, 6th ed. (Insulin Aspart, Insulinum Aspartum). It is a2-chain peptide containing 51 amino acids. The A-chain is composed of 21 amino acids and the B-chain is composed of 30 amino acids. It is identical in primary structure to human insulin, except that it has aspartic acid instead of proline at position 28 of the B-chain. As in human insulin, insulin aspart contains 2 interchain di-sulfide bonds and 1 intrachain disulfide bond. It is produced by a method based on recombinant DNA (rDNA) technology. A white or almost white powder. Practically insoluble in aqueous solutions with a pH around 5.1. In aqueous solutions below pH 3.5 or above pH 6.5, the solubility is greater than or equal to 25 mg/mL. Store in airtight containers. Protect from light. It should be stored at or below -18° until released by the manufacturer. When thawed, insulin aspart may be stored at 2° to 8° and used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, insulin aspart must be at room temperature before opening the container.

European Pharmacopoeia, 6th ed. (Insulin Lispro, Insulinum Lisprum). It is a 2-chain peptide containing 51 amino acids. The A-chain is composed of 21 amino acids and the B-chain is composed of 30 amino acids. It is identical in primary structure to human insulin, only differing in amino acid sequence at positions 28 and 29 of the B-chain. Human insulin is Pro(B28), Lys(B29), whereas insulin lispro is Lys(B28), Pro(B29). As in human insulin, insulin lispro contains 2 interchain disulfide bonds and 1 intrachain disulfide bond. It is produced by a method based on recombinant DNA (rDNA) technology. A white or almost white powder. Practically insoluble in water and in alcohol. It dissolves in dilute mineral acids and with decomposition in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at or below-18°. When thawed, insulin lispro is used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, insulin aspart must be at room temperature before opening the container.

The United States Pharmacopeia 31, 2008 (Insulin). A protein that affects the metabolism of glucose obtained from the pancreas of healthy bovine or porcine animals, or both, used for food by humans. White or practically white crystals. Soluble in solutions of dilute acids and alkalis. Store in airtight containers. Protect from light. It should be stored at -10°to -25°.

The United States Pharmacopeia 31, 2008 (Insulin Human). A protein corresponding to the active principle elaborated in the human pancreas that affects the metabolism of carbohydrate (particularly glucose), fat, and protein. It is derived by enzymatic modification of insulin from pork pancreas in order to change its amino acid sequence appropriately, or produced by microbial synthesis via a recombinant DNA process. Store in airtight containers. Protect from light. It should be stored at-10° to-25°.

The United States Pharmacopeia 31, 2008 (Insulin Lispro). Insulin Lispro is identical in structure to Insulin Human, except that it has lysine and proline at positions 28 and 29, respectively, of chain B, whereas this sequence is reversed in Insulin Human. It is produced by microbial synthesis via a recombinantDNA process. White or practically white crystals. Soluble in solutions of dilute acids and alkalis. Store in airtight containers. Protect from light. It should be stored at -10° to -25°.

Definitions and Terminology

Insulin is a hormone produced by the beta cells of the islets of Langerhans of the pancreas and consists of 2 chains of amino acids, the A and B chains, connected by 2 disulfide bridges. Insulin produced by different species conforms to the same basic structure but has different sequences of amino acids in the chains. Porcine insulin (C₂₅₆H₃₈₁N₆₅0₇₆S₆ = 5777.5) differs from human insulin (C₂₅₇H3₈₃N₆₅0₇₇S₆ = 5807.6) in only one amino acid in the B chain, whereas bovine insulin (C₂₅₄H₃₇₇N₆₅0₇₅S₆ = 5733.5) differs from human insulin not only in this same amino acid in the B chain but also in 2 amino acids in the A chain.

The precursor of insulin in the pancreas is proinsulin which is a single polypeptide chain incorporating both the A and B chains of insulin connected by a peptide termed the C-peptide (or connecting-peptide). Although the insulins of various species may be similar in composition the proinsulins are not, in that the sequence and number of amino acids in the C-peptide may vary considerably.

Early commercial insulins were obtained by extraction from bovine or porcine or mixed bovine and porcine pancreases and were purified by recrystallisation only.

Insulins obtained by such methods were often termed ‘conventional insulins’ to distinguish them from insulins which have undergone further purification processes. An extract which has been recrystallised only once can be separated into 3 components or fractions termed the ‘a’, ‘b’, and ‘c’ components. The ‘a’ component consists of high molecular weight substances and is only usually found in very impure preparations since repeated recrystallisation will remove most of it. The ‘b’ component consists largely of proinsulin and insulin dimers, and the ‘c’ component consists of insulin, insulin esters, arginine insulin, and desamidoinsulin. Other pancreatic peptides such as glucagon, pancreatic polypeptide, somatostatin, and vasoactive intestinal peptide are also usually found in products which have not undergone further purification. Gel filtration will substantially reduce the content of proinsulin but will not significantly reduce the content of insulin derivatives or pancreatic peptides products purified by gel filtration are often termed ’single-peak insulins’. Addition of ion-exchange chromatography to the purification methods will further reduce the proinsulin content and also reduce the contamination by insulin derivatives and pancreatic peptides. In the UK ‘highly purified insulins’ and ‘monocompo-nent insulins’ are terms sometimes applied to insulins which have undergone both gel filtration and ion-exchange chromatography. In the USA the FDA has designated the term ‘purified insulins’ for preparations similarly prepared and containing less than 10 ppm of proinsulin.

Much of the insulin now produced has an amino-acid sequence identical to that of human insulin. Human insulin (emp) is produced by the enzymatic modification of insulin obtained from the porcine pancreas it is also sometimes called semisynthetic human insulin. The term human insulin (crb) is used for insulin produced by the chemical combination of A and B chains which have been obtained from bacteria genetically modified by recombinant DNA technology. Human insulin (prb) is produced from proinsulin obtained from bacteria genetically modified by recombinant DNA technology. Human insulin (pyr) is insulin produced from a precursor obtained from a yeast genetically modified by recombinant DNA technology. Human insulin obtained by recombinant DNA technology is sometimes termed biosynthetic human insulin. Insulin or human insulin is supplied in a variety of forms in solution or suspension for injection. Crystalline insulin may be prepared for therapeutic use merely by making a solution, either of acidic or neutral pH. Soluble insulin or ‘neutral insulin’ is a short-acting preparation that can be given intravenously if necessary to cover emergencies. Soluble formulations are sometimes referred to as ‘regular insulin’ or ‘unmodified insulin’ these names reflect the fact that the preparation has not been formulated in order to prolong the duration of action of the insulin. In order to prolong the duration of action of insulin, preparations may be formulated as suspensions in 2 general ways. The first involves complexing insulin with a protein from which it is slowly released examples are protamine zinc insulin, which contains an excess of protamine, and isophane insulin (NPH insulin), which contains equimolecular amounts of insulin and protamine. The second method of prolonging the action of insulin is to modify the particle size and the various insulin zinc suspensions are in this category. Biphasic insulins are mixtures providing for both immediate and prolonged action. Chemical modification of the insulin molecule has resulted in insulins such as dalanated insulin (prepared by the removal of the C-terminal alanine from the B chain of insulin), insulin defalan (prepared by the removal of the terminal phenylalanine), and sulfated insulin, but these insulins have not been widely used. More recently, recombinant DNA technology has enabled production of insulin analogues with altered pharmacokinetic profiles. Insulin lispro is one such analogue, in which the B28 and B29 amino acid residues of human insulin are replaced with lysine and proline. It is available as a rapidly acting alternative to soluble insulin and as an intermediate-acting complex with protamine. Insulin aspart and insulin glulisine are other rapidly acting analogues. Insulin glargine is a long-acting form for once-daily use, and insulin de-temir is used once or twice daily. Further information on these can be found under the heading Insulin Analogues and Proinsulin, in Uses, below.

Stability and Storage

Both the European Pharmacopoeia, 6th ed. and the The United States Pharmacopeia 31, 2008 recommend that insulin preparations be stored in a refrigerator at 2° to 8° and not be allowed to freeze. The European Pharmacopoeia, 6th ed. directs that insulin preparations should be protected from light, and the The United States Pharmacopeia 31, 2008 that they should be protected from sunlight. It is recognised that patients may not follow such stringent storage guidelines and most manufacturers of commercial insulin preparations consider that storage by the patient at a temperature of up to 25° would be acceptable for up to one month. Patients should still be advised not to expose their vials or cartridges to excessive heat or sunlight. It is advisable to shake suspensions gently before a dose is withdrawn.

Insulin in powder form should be stored in airtight containers and protected from light. Storage at a low temperature is also recommended. The European Pharmacopoeia, 6th ed. advises storage at a temperature of -20° for bovine and porcine insulin and at-18° or below for Human Insulin, and for Insulin Aspart and Insulin Lispro the The United States Pharmacopeia 31, 2008 requires storage at -10° to -25° for all types of insulin. It is stressed that this temperature is for the powder and not for the preparations preparations should not be subjected to storage conditions that lead to freezing.

Adsorption. The adsorption of insulin onto glass and plastics used in giving sets has been decreased by the addition of albumin or polygeline to insulin solutions but it has been stated that in practice this was unnecessary since insulin adsorption was not a major problem. However, in studies of insulin infusions used in neonatal hyperglycaemia, various methods have been investigated and found to reduce the amount of insulin lost by adsorption to the giving set. These included flushing or priming the system with the insulin infusion, or using a concentrated insulin solution to prime the tubing. A study that compared different methods found wide variation in insulin delivery depending on solution concentration, flow rate, addition of albumin, catheter type, and priming or flushing of the system.

Aggregation. For discussion of the problems of insulin aggregation, see Intensive Administration Regimens under Uses, below.

Units

One unit of bovine insulin is contained in 0.03891 mg of the first International Standard (1986). One unit of porcine insulin is contained in 0.03846 mg of the first International Standard (1986). One unit of human insulin is contained in 0.03846 mg of the first International Standard (1986).

Adverse Effects

The most frequent complication of insulin therapy is hypoglycaemia, the speed of onset and duration of which may vary according to the type of preparation and the route used. It is usually associated with an excessive dosage of insulin, the omission of a meal by the patient, or increased physical activity. Patients, especially the elderly or those with tightly controlled diabetes or diabetes of long standing, may not experience the typical early warning symptoms of a hypoglycaemic attack. There have been reports of hypoglycaemia, sometimes with decreased warning symptoms, in patients changing from animal (especially bovine) to human insulin (see under Hypoglycaemia, below). Symptoms of hypoglycaemia resulting from increased sympathetic activity include hunger, pallor, sweating, palpitations, anxiety, and tremulousness. Other symptoms include headache, visual disturbances such as blurred or double vision, slurred speech, paraesthesia of the mouth and fingers, alterations in behaviour, and impaired mental or intellectual ability. If untreated, hypoglycaemia may lead to convulsions and coma which should not be confused with hyperglycaemic coma.

Insulin, given subcutaneously, may cause either lipoatrophy or lipohypertrophy. Lipoatrophy appears to occur less frequently with purified insulins than with conventional insulins if it has occurred, it may be reversed by the injection of a purer animal insulin or human insulin into and around the atrophied site. Lipohypertrophy is usually associated with repeated injections at the same site and may usually be overcome by rotating the site of injection, although absorption of insulin may vary from different anatomical areas. Prolonged insulin therapy may result in weight gain.

Insulin occasionally causes local or systemic hypersensitivity reactions. Local reactions, characterised by erythema and pruritus at the injection site, usually disappear with continued use. Generalised hypersensitivity may produce urticaria, angioedema, and very rarely anaphylactic reactions if continued therapy with insulin is essential hyposensitisation may be needed. Again, hypersensitivity reactions occur less frequently with purified than with conventional insulins and porcine insulin is less immunogenic than bovine insulin. Although hypersensitivity reactions have been reported in patients transferred from animal to human insulins, there are only isolated reports of such reactions in patients treated exclusively with human insulin. Many patients treated with insulin, either animal or human insulin, develop antibodies but the clinical significance of this is not entirely clear.

Of patients who received intensive insulin therapy for type 1 diabetes as part of the Diabetes Control and Complications Trial, those who experienced the greatest weight gain also had increased blood concentrations of triglycerides and low-density-lipoprotein cholesterol, and lowered high-density-lipoprotein cholesterol.^l These lipid changes, with higher blood pressure, increased waist-to-hip ratio, and greater insulin requirements, were held to be similar to the symptoms of insulin resistance and to indicate a possible increased risk of macrovascular disease. Results from the UK Prospective Diabetes Study indicated that type 2 diabetic patients treated with insulin had greater weight gain than those managed with other therapies, but demonstrated no evidence of harmful cardiovascular effects. For discussion of some of the specific problems associated with continuous infusion of insulin, see Intensive Administration Regimens under Uses, below.

Carcinogenicity. Primary lung malignancies have been found in a few patients receiving inhaled insulin for further details, see Administration Routes.

Effects on the liver. For a report of hepatomegaly occurring after insulin overdosage, see under Abuse, in Precautions, below.

Effects on the skin. Delayed pressure urticaria, in the form of large wheals occurring 4 to 6 hours after prolonged pressure, and lasting for up to 24 hours, was seen in a patient with type 1 diabetes within 6 months of changing from animal to human insulin. The condition improved after a switch back to insulin of animal origin, and grew worse again after a second attempt to switch to human insulin. Intermittent urticaria simultaneously affecting previous injection sites was reported in a child receiving human insulin, who had never received animal insulin.

Hypersensitivity. Hypersensitivity reactions to insulin preparations may be caused not only by the insulin itself, but also by other components of the formulation such as zinc or protamine. Hypersensitivity reactions and lipoatrophy (which is also thought to have an immune basis) have become rare since the introduction of highly purified and human insulins. Although insulin analogues have been used successfully in patients with a history of hypersensitivity to human insulin, there are also reports of both local and generalised reactions to insulin analogues.See also Adverse Effects, above and under Precautions, below.

HYPOSENSITISATION. After failure of standard hyposensitisation measures in a patient with cutaneous hypersensitivity to insulin, hyposensitisation was attempted by giving insulin by mouth. Aspirin 1.3 g three times daily by mouth was also given to antagonise vascular mediators of the reaction. After one week subsequent hyposensitisation using insulin by injection was successful. When the patient stopped taking aspirin after 6 months the original hypersensitivity reactions recurred aspirin was then given permanently in a dose of 1.3 g twice daily.

Hypoglycaemia. Hypoglycaemia is the major adverse effect of insulin treatment, with severe hypoglycaemic episodes occurring in up to a third of all insulin-treated patients at some point in their lives. Moves towards more intensive insulin therapy, in order to reduce the development of diabetic complications, increase the risk of hypoglycaemic episodes. Patients maintaining strict glycaemic control are prone to ‘hypoglycaemia unawareness’ in which the normal adrenergic counter-response to hypoglycaemia (characterised by symptoms such as pallor, sweating, and tremor) is reduced or lost, so that hypoglycaemia can develop without warning. Such a loss of awareness of impending hypoglycaemia also seems to develop as duration of diabetes increases One of the main reasons for reduced awareness of hypoglycaemia is that repeated hypoglycaemic episodes seem to trigger an adaptive conservation of glucose concentrations in the brain, resulting in higher central than peripheral blood glucose values avoidance of hypoglycaemia helps restore awareness. When recombinant human insulin became generally available in the late 1980s a number of patients complained of a loss of awareness of impending hypoglycaemia after transfer to human insulin, and there were reports of severe or even fatal hypoglycaemia occurring in patients who had been well stabilised on animal insulins.

This was, and remains, a somewhat controversial area. Despite some small studies suggesting a problem, others failed to find evidence of a difference between animal and human insulins, and a systematic review concluded that the available evidence did not support the suggestion that human insulin increased the frequency or severity of hypoglycaemia, or affected the symptoms of hypoglycaemia, compared with animal insulins. However, most commentators appear to consider that patients should continue to have access to animal insulins if desired, and that those well maintained on animal insulin should not be transferred to human insulin without appropriate clinical grounds, and then only with careful monitoring.

There has also been concern about possible long-term sequelae of hypoglycaemic episodes on the CNS. However, a report on patients participating in the Diabetes Control and Complications Trial (DCCT) suggested that the increased risk of hypoglycaemia seen with intensive therapy was not associated with neuropsychological impairment.For the treatment of insulin-induced hypoglycaemia, see below.

Oedema. Severe, acute oedema is a rare adverse effect of insulin treatment, occurring most often when starting therapy. It should be distinguished from chronic and subacute forms of oedema which may be complications of the diabetic disease process. Possible mechanisms of acute oedema are sodium retention resulting from a direct action of insulin on the renal tubule or an effect of insulin on vascular permeability. The oedema is usually self-limiting, but does respond to a decrease in insulin dosage, or diuretic therapy.

Treatment of Insulin-induced Hypoglycaemia

In the conscious and cooperative patient hypoglycaemia is treated by eating a readily absorbable form of carbohydrate, such as sugar lumps or a glucose-based drink all diabetics should always carry a suitable sugar source by way of precaution.

If the patient is drowsy or unconscious, then glucose must be given parenterally Doses of 50 mL of a 20% solution of glucose or 25 to 50 mL of glucose 50% can be given intravenously the higher concentration is more viscous and irritant to the veins. Lower concentrations are equally effective, and carry less risk of irritant effects, but larger volumes are required, e.g. up to 500 mL of glucose 5%, or 250 mL of 10%, titrated to patient response. Smaller quantities (e.g. 5 to 10 mL/kg of a 10% solution) are required in children. Bolus doses may need to be repeated, or a maintenance infusion started, to prevent persistent hypoglycaemia. If the patient has not regained consciousness within a few minutes after a bolus dose of glucose, the possibility of cerebral oedema should be considered. In situations where giving intravenous glucose is impractical or not feasible, glucagon 1 mg for adults and children above 25 kg or 0.5 mg for children below 25 kg by subcutaneous, intramuscular, or intravenous injection may arouse the patient sufficiently to allow oral glucose to be given. If the patient fails to respond to glucagon within about 10 to 15 minutes, then glucose has to be given intravenously despite any imprac-ticalities.

After a return to consciousness, oral carbohydrates may need to be given until the action of insulin has ceased, which for preparations with a relatively long duration of action such as isophane insulin, some insulin zinc suspensions, and protamine zinc insulin, may be several hours.

Carbohydrate. A comparative study of 7 different preparations of oral carbohydrate for the treatment of hypoglycaemia in the conscious patient found no significant difference in effectiveness between glucose or sucrose in solution or tablet form a hydrolysed polysaccharide solution containing glucose, maltose, and various more complex saccharides (Glucidex 19) was also roughly comparable. However, a glucose gel and orange juice were each less effective than the other formulations in treating hypoglycaemia.

Glucagon. A discussion of the relative merits of parenteral glucose and glucagon in unconscious hypoglycaemic patients suggested that glucagon should be encouraged as first-line treatment, although in practice (see above) parenteral glucose is usually preferred. The effect of glucagon relies upon the patient having adequate liver glycogen stores, which may not always be the case.

Overdose. The requirements for glucose are greater and more prolonged when hypoglycaemia is caused by insulin overdosage rather than therapeutic doses. Correction of insulin-induced hypokalaemia may also be required. Surgical excision of tissue at the site of injection has been used for massive overdose of a long-acting insulin.

Precautions

Dosage requirements of insulin may be altered by many factors. Increased doses are usually necessary during infection, emotional stress, accidental or surgical trauma, puberty, and the latter two trimesters of pregnancy. Decreased doses are usually necessary in patients with impaired renal or hepatic function or during the first trimester of pregnancy. On first stabilising therapy in newly diagnosed diabetic patients, a temporary decrease in requirements may also occur (the socalled honeymoon period).

Because of the possibility of differing responses to insulins from different species, inadvertent change from insulin of one species to another should be avoided. Reduction in insulin dosage may be required on transfer from animal (especially bovine) to human insulin. Hypoglycaemic problems associated with a change to human insulin are discussed under Adverse Effects, above. Care is also necessary during excessive exercise hypoglycaemia caused by metabolic effects and increased insulin absorption is the usual response, but hyperglycaemia may sometimes occur.

The use of insulin requires monitoring of therapy, such as testing blood or urine for glucose concentrations and the urine for ketones, by the patient.

Drugs which have an effect on blood-glucose concentrations may alter glycaemic control with consequent need for a change in insulin dose (see Interactions, below).

CAUTION. Biphasic insulin, insulin zinc suspensions, isophane insulin, protamine zinc insulin, insulin detemir, and insulin glargine should never be given intravenously and they are not suitable for the emergency treatment of diabetic ketoacidosis.

Abuse. Transient recurrent hepatomegaly associated with hypoglycaemia was associated with the surreptitious injection of additional insulin doses in an insulin-dependent diabetic. Increased storage of glycogen in the liver resulting from insulin excess was considered responsible for the hepatomegaly.

Decreased plasma C-peptide concentrations or the presence of anti-insulin antibodies may be used to confirm insulin abuse as a cause of hypoglycaemia in patients who have never been treated with insulin medically. Insulin has been abused by bodybuilders and other sportspersons severe brain damage after prolonged neuroglycopenia has resulted. There are rare reports of the misuse of insulin to induce mind-altering effects of hypoglycaemia.

Accelerated absorption. Factors such as a hot bath, sauna, or use of a sunbed have been reported to accelerate the absorption of subcutaneous injection, presumably by an increase in skin blood flow. There may, therefore, be a risk of hypoglycaemia

Adrenocortical insufficiency. Recurrent severe hypoglycaemia, which occurred in 2 patients with type 1 diabetes, persisted despite a reduction in insulin doses and proved to be due to Ad-dison’s disease. Insulin requirements rose again in both patients after replacement therapy with fludrocortisone and hydrocortisone.

Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemic s are required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard driving licences those treated with insulin receive restricted licences which must be renewed (with appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic attacks while driving, and should be counselled in appropriate management of the situation (stopping driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and removing the ignition key from the car) should such an event occur. Patients who have lost hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition, eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy goods vehicles or passenger carrying vehicles those treated with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses. Regulations in other countries differ widely.

Exercise. Discussions of the metabolic effects of exercise and the precautions to be taken by the exercising type 1 diabetic.

Fasting. Reduction in food intake or alteration in the pattern of meal times may affect insulin requirements and predispose to the development of hypoglycaemia (above). Muslim patients who are receiving antidiabetic therapy and who fast during Ramadan have been shown to be at increased risk of severe hypoglycaemic episodes during this month. A study in 17 fasting patients with type 1 diabetes recommended reduction of the total insulin dose to 85% of that before the fasting period, and supplying 70% as long-acting ultralente insulin and 30% as a rapidly acting soluble insulin the daily dose was divided into 2 equal portions given before sunrise and after sunset. Others have made similar recommendations: 2 daily injections of an intermediate- or long-acting insulin, given before the predawn and sunset meals, together with a short-acting insulin at the meal itself or possibly a single daily injection of insulin glargine, or twice-daily insulin detemir, plus a rapidly acting analogue just before the meal.Patients with type 2 diabetes maintained on insulin may be managed similarly, by judicious use of intermediate or long-acting insulin plus a short-acting insulin given before meals. A single injection of a long-acting analogue such as insulin glargine, or two injections of isophane or lente insulin or insulin detemir before the sunset and predawn meals, may provide adequate coverage provided the dosage is appropriately individualised. However, most patients will still require a short-acting insulin to be added at the sunset meal to cover the large caloric load. Many will also require an additional dose of short-acting insulin at predawn. Studies have suggested that insulin lispro may produce good blood sugar control in fasting patients with type 2 diabetes during Ramadan.

Care is also required in patients with type 2 diabetes being treated with oral antidiabetic drugs. Patients being treated with metformin or insulin sensitisers such as the glitazones have a low risk of hypoglycaemia, although it has been suggested that the timing of metformin doses be altered so that two-thirds of the daily dose is taken just before the sunset meal and the other third before the predawn meal. Short-acting secretagogues such as repaglinide or nateglinide can also be taken twice daily before the sunset and predawn meals. However, sulfonylureas should be used with caution, and the use of chlorpropamide may be contra-indicated because of the high risk of prolonged and unpredictable hypoglycaemia.

Hypersensitivity to protamine. Retrospective surveys have indicated that patients receiving isophane insulin, which contains protamine, have an increased risk of severe anaphylactoid reactions when protamine is used to reverse systemic heparinisation after cardiac catheterisation or cardiac surgery. The degree of increase in risk is unclear, however, as it has been reported as both large and small. A review of the literature suggested that surgical patients may be at greater risk because of a higher rate of prior sensitisation to protamine and the larger doses used. A mechanism involving IgE and IgG antibodies to protamine has been proposed. See also Hypersensitivity under Adverse Effects, above.

Infections. Decreased requirements of insulin, added to the dialysate, occurred in 6 diabetic patients undergoing continuous ambulatory peritoneal dialysis for chronic renal failure during episodes of severe bacterial peritonitis. This was contrary to the increased insulin requirements of most diabetic patients during severe infections and probably resulted from increased absorption of insulin due to mesothelial damage.

Menstruation. Changes in glycaemic control associated with the menstrual cycle have been recorded in women with type 1 diabetes mellitus. In a retrospective review of 124 women, 61% reported perimenstrual changes in glucose concentrations and 36% made adjustments to their insulin dose, usually a small increase in the premenstrual insulin dose followed by a small decrease at the onset of menstruation. Based on mean glycosylated haemoglobin measurements, there was no evidence of improved glycaemic control in women adjusting their insulin dose compared with those leaving it unchanged despite changes in capillary glucose measurements. Changes in appetite and food consumption associated with the menstrual cycle may affect variations in glucose concentrations and insulin requirements.

Morning hyperglycaemia. Morning hyperglycaemia may be the result of mere waning of subcutaneously injected insulin. It may also be rebound hyperglycaemia (posthypoglycaemic hyperglycaemia or the Somogyi phenomenon) occurring after an episode of nocturnal hypoglycaemia. Morning hyperglycaemia has also been observed without antecedent hypoglycaemia even during constant intravenous infusion of insulin, when the waning of previously injected insulin would not be a factor and this is commonly referred to as the dawn phenomenon. Clinically, it is important to distinguish between the dawn phenomenon, simple waning of previously injected insulin, and rebound hyperglycaemia as a cause of early-morning hyperglycaemia because their treatment differs. Management of the dawn phenomenon and insulin waning generally consists of adjusting the evening dose of insulin to provide additional coverage between 4 a.m. and 7 a.m. Management of rebound hyperglycaemia consists of reducing insulin doses or providing additional late-evening carbohydrate, or both, to avoid nocturnal hypoglycaemia. Mistaking rebound hyperglycaemia for the dawn phenomenon or mere waning of injected insulin could result in more serious nocturnal hypoglycaemia, if evening doses of insulin were increased.

Pregnancy. For discussion of the precautions necessary in the management of diabetes mellitus during pregnancy, see p.431. There has been a report of 2 cases of fetal malformation in the offspring of well-controlled diabetic women who received insulin lispro However, the incidence of fetal malformation is increased in infants of women with diabetes. At that time the manufacturers were aware of 19 live births among women treated with insulin lispro, 1 of which exhibited a congenital abnormality. Since then, a number of retrospective studies” have looked at the rates of fetal malformations in the offspring of women treated with insulin lispro, for either pre-existing diabetes mellitus or gestational diabetes. These have included groups ranging in size from 62 to 496 women, and none have found any evidence of an increase in the incidence of abnormalities with insulin lispro compared with rates published for women treated with other insulins.

There is less information available about the use of other insulin analogues, but a few cases and studies of insulin glargine use during pregnancy have been described. It was started in one woman during the fourteenth week of gestation, and continued until delivery with no apparent adverse effect on the baby. In another report, insulin glargine was inadvertently continued by 5 women during the first 6 to 12 weeks of unplanned pregnancies. In these cases, therapy was changed from insulin glargine to isophane insulin, and no fetal malformations were detected. The use of insulin glargine during the entire pregnancy, without adverse effect, has also been described, and successful pregnancies were reported in 4 women given insulin glargine for gestational diabetes. Furthermore, a small case-control study found no significant difference in neonatal outcomes for insulin glargine and human insulin in women with type 1 or gestational diabetes, and another study found no unexpected adverse effects in the babies of 115 women given insulin glargine. A single-dose study has reported that insulin aspart was effective in reducing postprandial glucose concentration in gestational diabetes. Randomised studies in women with type 1 diabetes or gestational diabetes have also found no indication of an increase in congenital malformations with insulin aspart compared with human insulin.

Prion disease transmission. Studies of cattle with proven bovine spongiform encephalopathy (BSE) have not detected infec-tivity in the pancreas, from which bovine insulin is derived.

Renal impairment. See under Infections, above.

Smoking. Smoking has been reported to decrease the absorption of insulin and dosage adjustment may be necessary, although glycaemic control does not seem to be significantly affected.

Surgery. For a discussion of the management of diabetes mellitus during surgery.

Travelling. Advice for the diabetic patient when travelling, including adjustment of insulin dosage when crossing time zones. Since insulin solution or suspension must not be frozen, it should not be carried in the luggage hold of an aircraft.

Interactions

Many drugs have an effect on blood-glucose concentrations and may alter insulin requirements. Drugs with hypoglycaemic activity or which may decrease insulin requirements include ACE inhibitors, alcohol, anabolic steroids, aspirin, beta blockers (which may also mask the warning signs of hypoglycaemia), disopyramide, fenfluramine, guanethidine, some MAOIs, mebendazole, octreotide, some tetracyclines, and the tricyclic antidepressant amitriptyline. On the other hand, increased requirements of insulin may possibly be seen with chlordiazepoxide, chlorpromazine, some calcium-channel blockers such as diltiazem or nifedipine, corticosteroids, diazoxide, lithium, thiazide diuretics, and thyroid hormones. Both increased and decreased requirements may occur with cyclophosphamide, isoniazid, and oral contraceptives.

ACE inhibitors. Although ACE inhibitors are favoured for use in diabetic patients with hypertension or evidence of incipient nephropathy or both, they may increase insulin sensitivity and thus decrease insulin requirements. A study of hospital admissions found that ACE inhibitors increased the risk of severe hypoglycaemia in patients receiving insulin. However, an analysis of pharmacovigilance data and a case-control study have both found no such increase in risk.

Alcohol. Severe hypoglycaemic episodes have been reported in type 1 diabetics after heavy drinking episodes. Alcohol inhibits gluconeogenesis, and its effects are therefore likely to be greatest if taken without food however, it seems to be generally agreed that diabetics need not abstain from a moderate alcohol intake with meals.

Aspirin. Aspirin produces a modest decrease in blood-glucose concentrations but a significant interaction at conventional analgesic doses appears to be unlikely. One study in children with type 1 diabetes found an average 15% decrease in blood glucose values following treatment with aspirin 1.2 to 2.4 g daily for 3 days, but there were no significant changes in insulin requirements. However, high doses of aspirin can reduce or even replace the insulin dose required. Other salicylates might be expected to have similar properties.

Beta blockers. There are a few reports of severe hypoglycaemia in patients, including insulin-treated diabetics, who were given propranolol or plndolol, there is also a report of an interaction with timolol given as eye drops. Some evidence exists of an interaction with metoprolol, but little evidence for some of the more selective beta blockers. Because of the effects of beta blockers on the sympathetic nervous system the usual premonitory signs of hypoglycaemia may not occur, allowing a severe episode to develop before the patient is aware and able to counter it.

Calcium-channel blockers. Diabetes worsened in an insulin-treated diabetic when given diltiazem. The resultant intractable hyperglycaemia improved when the drug was withdrawn, and recurred, although at a more manageable level, when diltiazem was restarted at a lower dose. There are also reports of a diabetogenic effect of nifedipine. However, reports of significant disturbances of metabolic control appear to be uncommon.

Interferons. Markedly increased insulin requirements developed in a previously well controlled diabetic after treatment with Interferon alfa 2a. Insulin requirements rapidly fell once interferon therapy was stopped.

Oral contraceptives. Both increases and decreases (mainly the former) in insulin requirements have been reported in insulin-dependent diabetics given various oral contraceptives. However, it appears that in most cases the effects of a hormonal contraceptive on diabetic control are modest or insignificant: limited data suggest that progestogenonly and combined oral contraceptives in general have little effect.

Pharmacokinetics

Insulin has no hypoglycaemic effect when given by mouth since it is inactivated in the gastrointestinal tract.

It is fairly rapidly absorbed from subcutaneous tissue on injection and although the half-life of unmodified insulin in blood is very short (being only a matter of minutes), the duration of action of most preparations is considerably longer because of their formulation (for further details see Uses and Administration, below). The rate of absorption from different anatomical sites depends on local blood flow, with absorption from the abdomen being faster than that from the arm, and that from the arm faster than from buttock or thigh. Absorption may also be increased by exercise. The absorption of insulin after intramuscular injection is more rapid than that after subcutaneous doses. Human insulin may be absorbed slightly faster from subcutaneous tissue than porcine or bovine insulin.

Insulin is rapidly metabolised, mainly in the liver but also in the kidneys and muscle tissue. In the kidneys it is reabsorbed in the proximal tubule and either returned to venous blood or metabolised, with only a small amount excreted unchanged in the urine.

For discussion of factors which may affect the absorption of insulin, see under Precautions, Accelerated Absorption, above, and Uses, Administration Routes, below.

Resistance to Insulin

The term insulin resistance has traditionally been used to describe a state in which diabetic patients exhibit considerably increased insulin requirements. It is now used in a much wider sense, and is for instance also applied to patients in whom a subnormal biological response to insulin can be demonstrated, although many of these patients do not apparently present difficulties in their clinical management. Insulin resistance is found particularly in obese patients resistance to endogenous insulin is thought to be linked to the development of type 2 diabetes in such patients. Insulin resistance is frequently associated with lipid disorders, hypertension, and ischaemic heart disease, a complex sometimes described as the metabolic syndrome. In women, it may also be linked to polycystic ovary syndrome.

Insulin resistance of the type manifested by greatly increased insulin requirements may be due to factors including antibody formation and inadequate absorption of insulin from subcutaneous sites. A few patients with severe insulin resistance have responded to insulin lis-pro (see Insulin Analogues and Proinsulin under Uses, below).

Mecasermin (insulin-like growth factor I) has been observed to improve insulin sensitivity in insulin resistance.

Non-insulin-dependent diabetes mellitus (NIDDM) is a common disease, with a prevalence approaching 6% in people aged 45- 64 and 11% in people aged 65-74. Since approximately half of the patients with NIDDM are not diagnosed, the actual number of Americans with the disease is an estimated 15-16 million. There has been an eight-fold increase in the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) in the US over the past 50 years, due in part to increased emphasis on screening and more sensitive tests, and in part to the aging of the population and to increases in sedentary lifestyle and obesity. Obesity is a major risk factor for non-insulin-dependent diabetes mellitus (NIDDM), which is three times more common in persons who are 40% or more overweight; yet obesity may also be the result insulin resistance, which is the initial underlying metabolic defect in non-insulin-dependent diabetes mellitus (NIDDM).

Given the statistics, it is not surprising that the United States uses more insulin than any other country – perhaps more than is necessary. A study of 55 patients with non-insulin-dependent diabetes mellitus (NIDDM) has shown that insulin can be successfully withdrawn and patients reintroduced to oral hypoglycemics if they are given a combination of metformin plus a sulfonylurea. The combination is synergistic because sulfonylureas stimulate insulin production while metformin improves insulin utilization. The study, conducted by researchers at the University of Alabama at Birmingham, involved patients who had been diagnosed less than 30 years ago with non-insulin-dependent diabetes mellitus (NIDDM) and had been on insulin therapy for less than 10 years (twice daily injections of mixed insulins).

The switch from insulin to combination oral therapy was successful in 76% of patients. Response was better in patients with lower body weight, lower insulin requirements, and non-insulin-dependent diabetes mellitus (NIDDM) of shorter duration. Diabetic control was actually better with the combination oral therapy than with insulin; patients who were successfully switched showed significant reductions in glycosylated hemoglobin levels on combination therapy compared with insulin therapy. The investigators said that that many non-insulin-dependent diabetes mellitus (NIDDM) patients currently receiving insulin therapy were placed on insulin several years ago when metformin was not available and sulfonylurea therapy had failed. They concluded, “There’s no question that the findings mean that a large number of NIDDM patients can treat their diabetes without the pain of injections.”

The polycystic ovary syndrome (POS) is a fairly common condition, affecting about 6% of women of reproductive age. It is characterized by anovulation, oligomenorrhea or amenorrhea, and hirsuitism. About half of the women with this syndrome are obese and some have diabetes mellitus. There are three hormones involved in POS: testosterone, luteinizing hormone (LH), and insulin. For years, medical scientists were aware that the local and systemic symptoms of POS were due to increased ovarian production of androgens, particularly testosterone, but only recently has the role of insulin in POS been carefully examined.

In the ovaries of normal women, progesterone is converted within the theca cells to 17alpha-hydroxyprogesterone, then to androstenedione, and finally to testosterone. Testosterone, in turn, is converted to estradiol in the granulosa cells. In women with polycystic ovaries, there is an increase in the enzyme cytochrome P450c17alpha that converts progesterone to androstenedione. Since androstenedione is rapidly converted into testosterone, the result is increased testosterone production. Some of the excess testosterone causes premature follicular atresia and anovulation, some of the excess reaches the circulation.

What causes the increase in ovarian enzyme activity? It appears that the culprit is insulin, or more to the point, insulin resistance with compensatory hyperinsulinemia. Insulin increases testosterone production by stimulating ovarian function, specifically, by stimulating the activity of cytochrome P450c17alpha. Insulin also decreases serum sex hormone-binding globulin by decreasing the hepatic production of the binding protein; with less binding capacity, there is more free testosterone in the serum. Finally, it appears that insulin increases LH production. Дuteinizing hormone (LH) contributes to POS by stimulating theca-cell growth and thus enhancing testosterone production.

Recently Nestler and Jakubowicz published a report in the New England Journal of Medicine describing the results of their study of an oral hypoglycemic agent – metformin (Glucophage/Bristol Myers Squibb) – on glucose tolerance and serum steroid concentrations in 24 obese women with polycystic ovary syndrome (POS). Metformin is a biguanide that reduces insulin resistance and secondarily inhibits insulin secretion. The subjects were given either placebo or metformin (500 mg three times daily) for 4-8 weeks. Compared with placebo, metformin reduced insulin secretion by about 50% and caused a reduction of approximately 50% in levels of basal and peak serum 17alpha- hydroxyprogesterone and serum free testosterone. Metformin also reduced serum LH about 75% and increased serum sex- binding globulin concentration about 75%. These values remained basically the same in the placebo group.

In some of the study participants, metformin actually induced ovulation. The fact that the reduction in insulin secretion caused a prompt drop in serum basal and stimulated-peak 17alpha-hydroxyprogesterone levels indicates that insulin has a direct effect on cytochrome P450c17alpha, enhancing the production of the hydroxyprogesterone. The effects of insulin on this enzyme are probably heritable, since not all women with insulin resistance and hyperinsulinemia have POS.

In an accompanying editorial in the New England Journal of Medicine, Robert Utiger said that POS is currently treated with weight loss and oral contraceptives and/or an antiandrogen such as spironolactone of cyproterone. The infertility is treated with clomiphene or assisted- reproduction procedures. However, if metformin can reduce androgen production, restore cyclic pituitary-gonadal function, and improve fertility, “it could represent a substantial advance in treatment for women with polycystic ovary syndrome.”

The above data indicate that despite the heterogeneous and progressive nature of type 2 diabetes, the insulin sensitizers are appropriate treatments at virtually all stages of type 2 diabetes. Possible treatment options with these agents include monotherapy, combination therapy with sulfonylureas and metformin, or as adjunctive agents to insulin therapy (only pioglitazone is FDA-approved for this indication). Unique properties of these compounds include their lack of hypoglycemic potential in monotherapy, safety in the setting of renal insufficiency, beneficial effects on lipid parameters (more so for pioglitazone), potential for reduced cardiovascular morbidity, and potential preservation of beta cell function.

Patient Counseling Pointsfor the Pharmacist:

- Patients should continue to adhere to a proper diet and exercise regularly while taking pioglitazone or rosiglitazone. Weight gain is the most common adverse effect of these agents.

- Common side effects that may occur with their use include weight gain and edema. These effects are generally mild to moderate and decrease over time. Patients with pre-existing edema should be counseled to assess this finding daily, should be initially treated with low doses of glitazones, and should be counseled to seek medical attention if signs or symptoms (leg swelling, shortness of breath) of fluid retention develop.

- Patients should report any symptoms of hepatic toxicity, including unexplained nausea or vomiting, abdominal pain, or dark urine. Patients should also be told that blood tests will be performed prior to initiation of therapy and every two months thereafter for the first year to monitor their liver for any abnormalities.

- Both pioglitazone and rosiglitazone may be taken without regard to meals.

- If used in combination with insulin or with oral hypoglycemic medications, patients may be predisposed to episodes of hypoglycemia, especially in the first few weeks of therapy. Counsel patients about the signs and symptoms of hypoglycemia, which include weakness, confusion, sweating, trembling, fast heartbeat, and blurred vision. Emphasize the importance of keeping a quick source of sugar (e.g., fruit juice or glucose tablets) readily available to correct their low blood sugar should this happen.

- Female patients should be advised that these agents could result in resumption of ovulation if they are currently anovulatory; thus, they should take appropriate contraceptive precautions if pregnancy is not desired.

Both pioglitazone and rosiglitazone have been shown to increase HDL levels, and pioglitazone has also been shown to decrease triglyceride levels. Data indicate that pioglitazone raises HDL levels by up to 19% and decreases triglyceride levels by up to 15% relative to baseline. Data on rosiglitazone from a 52-week study indicate mean significant increases in HDL of 19% from baseline, with variable, insignificant changes in triglycerides. Increases in LDL levels are associated with both agents as well. Pioglitazone has shown small, insignificant increases in LDL cholesterol (identical to placebo), while each of the rosiglitazone studies referenced in this article has demonstrated statistically significant increases of 10%-25% in mean LDL cholesterol from baseline.

Recently, a small observational study compared the lipid-lowering efficacy of both pioglitazone and rosiglitazone. This study reported that both pioglitazone and rosiglitazone increased HDL levels, but pioglitazone demonstrated a greater increase overall. Pioglitazone decreased triglycerides, and increased LDL to a lesser extent than rosiglitazone. These results are consistent with previously published data. To date, this represents the only reported comparative study between the two agents, although a randomized long-term study evaluating this issue is currently in progress.

Adverse Effects: The two available thiazolidinediones are generally well-tolerated and show similar safety profiles. They can produce several mild class effects which occur at similar rates with the different agents. The incidence of edema with pioglitazone or rosiglitazone was greater than that for placebo in clinical trials. The incidence of edema is particularly high in combination therapy with insulin in both clinical trial sets. The mechanism underlying this effect is unclear, but has been postulated to be a result of the loss of the osmotic diuresis associated with hyperglycemia as well as enhanced insulin sensitivity in the kidney tubule, resulting in greater renal tubular absorption of sodium and in peripheral vasculature.

Mild anemia occurs with both drugs, resulting in clinically insignificant hemoglobin reductions of approximately 2%-4%. This generally occurs during the first 4-12 weeks of therapy and remains constant thereafter. The mechanism has been attributed to hemodilution (increased plasma volume).

Weight gain of a moderate extent has been reported with both agents (1.2-3.5 kg with rosiglitazone monotherapy over 26 weeks, 0.5-2.8 kg with pioglitazone monotherapy). Weight gain is somewhat greater when pioglitazone is used in combination with sulfonylurea and when pioglitazone is combined with insulin. The mechanisms contributing to the weight gain have included improved glycemic control and diminished urinary caloric losses, fluid retention, and potentially through stimulation of adipocyte differentation via effects on PPAR.

Relevant to this issue are data reported with troglitazone, in which underwater weighing was used to measure total body fat content, and MRI assessed body fat distribution in 21 subjects before and after 12 weeks of troglitazone monotherapy. Intriguingly, in that study, while the body weight did not change significantly, there was a redistribution to a more favorable pattern, with a significant reduction of intra-abdominal fat content.

Blood Pressure: Troglitazone has been shown to decrease systolic and diastolic blood pressure to a modest but significant extent in several clinical trials. This property is attributed to its effects on insulin resistance, since an association between hypertension and insulin resistance has been previously demonstrated. Rosiglitazone and pioglitazone have been shown to improve hypertension in animal models.

Vascular Reactivity: In addition to having tendencies for essential hypertension, insulin-resistant patients are also prone to having altered vascular reactivity, which may be due to defective production or activation of nitric oxide by vascular endothelial cells. In a few small clinical studies with troglitazone, impaired brachial artery vasoactivity was normalized with troglitazone, and response to acetylcholine in the coronary arteries was improved in troglitazone-treated patients but not in those treated with diet or a sulfonylurea.

Atherosclerosis: Substantial in vitro data show various thiazolidinediones affect vascular smooth muscle proliferation. Pioglitazone has been shown to inhibit the effects of insulin, epidermal growth factor, and serum-induced growth of cultured arterial vascular smooth muscle cells, and troglitazone has also been shown to inhibit DNA synthesis induced by various growth factors implicated in atherosclerosis. Recent in vivo data now corroborate these experimental findings. Troglitazone was shown to reduce carotid intimal and medial thickness, a marker of early atherosclerosis, in a placebo-controlled, 6-month study involving 135 Japanese subjects with type 2 diabetes.Similarly, subjects with type 2 diabetes who had undergone coronary stenting for atherosclerosis were studied at baseline and after a 6-month trial period during which they received troglitazone 400 mg/day. Luminal area increased and intimal area decreased significantly in troglitazone-treated vs. control subjects, implying that troglitazone reduces neointimal proliferation after stent implantation and could potentially reduce the risk of restenosis following this procedure.

To date there are no direct comparative studies of these agents within the same cohort. Accordingly, caution must be exercised when comparing results of the available data, as they are subject to bias effects of different study populations.

Monotherapy: In two placebo-controlled studies of rosiglitazone monotherapy, HbA1c was 1.5% lower in the treatment vs. the placebo group after 26 weeks on maximal dose rosiglitazone monotherapy (4 mg BID), and was 1.6% lower than placebo in a series of three placebo-controlled studies of pioglitazone monotherapy of 26 weeks duration. As monotherapy for type 2 diabetes, rosiglitazone and pioglitazone thus appear to be roughly equivalent in glucose-lowering potential.

The primary failure rate of the thiazolidinediones is approximately 25%-30%, and has been correlated with low levels of endogenous insulin secretion and C-peptide levels <1.5 ng/mL in nonresponders.The efficacy of thiazolidinediones as monotherapy may be compared to that of the sulfonylurea-metformin combination, although the blood glucose-lowering effects of the thiazolidinediones are more gradual (requiring about 2 weeks for initial effects and up to 3 months for complete effects). An additional important feature of monotherapy with thiazolidinediones is a virtual lack of hypoglycemic potential. As they do not raise (and in fact they often lower) endogenous insulin levels, hypoglycemia with monotherapy is exceedingly rare.

Combination Therapy: There are data indicating the efficacy of combination therapy with sulfonylurea, metformin and as add-on to insulin therapy.

Sulfonylureas: In a multicenter, placebo-controlled study of subjects failing sulfonylurea monotherapy, addition of pioglitazone 30 mg for 16 weeks reduced HbA1c 1.2% (p < 0.05) relative to baseline. In a similar multicenter placebo-controlled study involving addition of rosiglitazone 4 mg/day for 24 weeks to sulfonylurea monotherapy, HbA1c was reduced by 0.9% (p < 0.001) relative to baseline.

Metformin: The effects of thiazolidinediones in combination with metformin are similar. The addition of pioglitazone 30 mg/day to metformin therapy resulted in reduction in HbA1c of 0.6% relative to baseline (p < 0.05 significant only relative to placebo). Similarly, when rosiglitazone 4 mg/day or 8 mg/day was added to metformin therapy (2,500 mg/day) for 26 weeks, HbA1c decreased by 0.56% and 0.78% relative to baseline (p < 0.001). While the magnitude of HbA1c reduction with this combination is generally less than with sulfonylurea combination, the lack of hypoglycemic potential, and the potential for cardiovascular risk reduction and beta cell function preservation make this combination particularly attractive.

Insulin: When 15-mg or 30-mg pioglitazone was added for 16 weeks to patients with type 2 diabetes uncontrolled on insulin monotherapy (median insulin dose 60.5 units daily), HbA1c decreased 1.0% and 1.26%, respectively, relative to baseline (p < 0.05 significant only relative to placebo). Additionally, 16% of subjects on the 30-mg dose had a >25% reduction in their average daily insulin dose at the end of the study. When rosiglitazone 4 mg BID was added to insulin monotherapy for 26 weeks, HbA1c was similarly reduced by 1.2% relative to baseline (p < 0.006 significant only relative to placebo), and average daily insulin dose was reduced by 9 units; however, as of the February 2001 rosiglitazone package insert, insulin combination therapy is not indicated due to an increased incidence of congestive heart failure.

The two thiazolidinediones approved for use in type 2 diabetes are rosiglitazone and pioglitazone. These agents became available in 1999 and are approved as monotherapy and in combination with sulfonylurea or metformin for the treatment of type 2 diabetes. Pioglitazone is also approved in combination with insulin. Troglitazone (Rezulin),which was the first member of this class to be commercially available, was approved in 1997 but withdrawn in early 2000 due to reports of severe liver injury. In the premarketing trials of rosiglitazone and pioglitazone, the incidence of abnormal liver function was similar to that for placebo (0.2%), and significantly lower than had been observed with troglitazone (1.9%). Accordingly, the newer agents appear to have less potential for hepatotoxicity than troglitazone. There have, however, been two reports of hepatic injury in patients receiving rosiglitazone, although it has not been possible to confirm a definitive causal relationship of the drug in these cases. In light of these issues, monitoring liver function is recommended before and during the first year of therapy with both rosiglitazone and pioglitazone (see below).

Dosing: Rosiglitazone is available in 2-mg, 4-mg and 8-mg tablets. The usual dose is 4-8 mg/day. Peak concentrations occur ~1 hour after dosing and the half-life is 3-4 hours. The medication is somewhat more efficacious when dosed twice daily; this may be a result of its relatively short pharmacologic half-life. Bioavailability is not affected by meals. Rosiglitazone is extensively metabolized by the hepatic CYP450 2C8 system, with the 2C9 system contributing as a minor pathway. All metabolites are notably less potent than the parent compound. No dose adjustment is necessary in subjects with renal impairment or in those on hemodialysis.

Pioglitazone is available in 15-mg, 30-mg and 45-mg tablets. The usual dose is 15-30 mg administered once daily. Peak concentrations occur 1-2 hours after dosing. The compound is hepatically metabolized to three weakly active metabolites via the CYP450 2C8 and 3A4 systems. The mean half life is 3-7 hours for the parent compound and 16-24 hours for total pioglitazone including active metabolites. No dose adjustment is necessary in subjects with renal impairment.

Both compounds are contraindicated in the presence of active liver disease and if serum ALT levels are >2.5 times the upper limit of normal. Due to idiosyncratic liver disease with troglitazone, the FDA recommends that for the first year of therapy with either available compound, liver function be monitored every 2 months, and then periodically after the first year of treatment. Because of their potential to exacerbate fluid retention, the drugs are also not indicated in class III or IV congestive heart failure unless the benefit is judged to outweigh the risk in individual patients.

The thiazolidinediones were initially developed in efforts to identify structural analogues of clofibrate, a lipid-lowering agent also known to possess a weak glucose-lowering effect in humans. Ciglitazone, the first thiazolidinedione to be extensively studied, was shown to reduce plasma glucose, insulin, free fatty acid and triglyceride levels in several rodent models of type 2 diabetes, but was ineffective in animals with absolute insulin deficiency. Additional agents were subsequently synthesized with enhanced potency and have included troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). These compounds share a common thiazolidine 2,4-dione moiety, but differ considerably in their side chain substituents. Troglitazone, for example, has a side chain that is structurally similar to vitamin E and hence has antioxidant properties.

Mechanism of Action: The mechanism of action of the thiazolidinediones is still being investigated, but many of their actions seem to be mediated through binding and activation of PPARg (peroxisome proliferator-activated receptor g). PPARg is a nuclear receptor that has a regulatory role in cell differentiation, particularly fat cell differentiation. Although concentrations of PPARg tend to be highest in fat cells, the receptor is present in many other tissues, including skeletal muscle and pancreatic beta cells. The potencies of the thiazolidinediones as antihyperglycemic agents are also correlated with their binding affinities and functional agonist potencies at PPARg. Intriguingly, while some agents are virtually complete PPARg agonists, other agents, particularly pioglitazone, are partial agonists with mixed a- and g-activation. This property has been suggested as a mechanism underlying the differential effects of these agents on lipid parameters.

Available data indicate that the major effects of these agents in vivo are to increase peripheral glucose disposal, primarily by enhancing skeletal muscle uptake of glucose. Some studies have also shown an effect of the agents on endogenous glucose production. It also remains unclear whether the glucose-lowering effects of these agents are produced directly, via activation of PPARg in skeletal muscle, or indirectly, via their effects on PPARg in adipocytes and potentially mediated by reductions in free fatty acids (FFA). Reductions in FFA concentrations have been documented to improve insulin sensitivity, and all of the clinically available thiazolidinediones produce significant reductions in FFA, despite having apparently disparate effects on overall lipid profiles.

There are extensive data from long-term, prospective, randomized clinical trials showing that improved glycemic control in type 2 diabetes reduces the incidence and progression of diabetic complications. The largest and most recent trial to address this is the United Kingdom Prospective Diabetes Study (UKPDS), which reported its findings in 1998. In this trial, approximately 4,000 newly diagnosed diabetic patients were followed for an average of 10 years, and improvements in microvascular outcomes were demonstrated with intensive diabetes control (HbA1c ~7.0%) compared with conventional control (HbA1c ~7.9%).

Treatment arms in the study included insulin, sulfonylurea, or metformin monotherapy, or combination therapy with metformin and sulfonylurea. Improved cardiovascular outcomes reached statistical significance only in the metformin monotherapy subgroup, implying that an agent that has some effects on insulin sensitivity may offer unique benefit in improving cardiovascular outcomes. The thiazolidinediones, which affect insulin sensitivity to an even greater extent than metformin, were not available at the inception of the UKPDS, and were thus not treatment options in the study.

Another important outcome of the UKPDS was the observation that all treatment groups, independent of treatment option, showed gradual and similar deterioration of glycemic control over time. This decrease in glycemic control was interpreted to result from progression of diabetes; when analyzed with the Homeostasis Model Assessment (HOMA), a computer-generated model of insulin-glucose interactions, it was found to specifically result from a decline in beta-cell insulin secretion. This is particularly relevant with regard to the thiazolidinediones, since they are the only diabetes agents that have been shown to preserve beta cell function. Thus, they may have unique potential to delay the progression of type 2 diabetes.

Based on the above and additional data, the American Diabetes Association (ADA) annually reviews its recommendations regarding standards of care for glycemic and lipid goals in patients with diabetes. In brief, the recommendations are to aim for glycemic control as near to the normal range as possible, without producing unacceptably frequent hypoglycemia, and to achieve intensive lipid control with the same targets as for patients with established coronary heart disease.The most recent recommendations are summarized in Tables 1 and 2.

*Adapted from the Position Statement on Standards of Medical Care for Patients with Diabetes Mellitus

**The values shown in this table are generalized to the entire population of individuals with diabetes. Patients with comorbid diseases, the very young and older adults, and others with unusual conditions or circumstances may warrant different treatment goals. These values are for nonpregnant adults. “Additional action suggested” depends on individual patient circumstances and may include enhanced diabetes self-management education, comanagement with a diabetes team, referral to an endocrinologist, change in pharmacological therapy, initiation of or increase in self-monitoring of blood glucose, or more frequent contact with the patient. HbA1c is referenced to a nondiabetic range of 4.0-6.0% (mean 5.0%, SD 0.5%).

†Measurement of capillary blood glucose; ‡Values calibrated to plasma glucose.

Data are given in milligrams per deciliter.

*Adapted from the Position Statement on Standards of Medical Care for Patients with Diabetes Mellitus