Insulin preparations − Rakyat Biologi

Four principal types of insulins are available: (1) rapid-acting insulin analogs with more rapid onset and a shorter duration of action than regular insulin after subcutaneous injection; (2) short-acting regular insulin; (3) intermediate-acting; and (4) long-acting, with slow onset of action.

Table 27-10. Some insulin preparations available in the United States.¹

Preparation	Species Source	Concentration	Cost¹
Rapid-acting insulin analogs
Insulin lispro (Humalog, Lilly)	Human analog (recombinant)	U100	$67.58
Insulin aspart (Novolog, Novo Nordisk)	Human analog (recombinant)	U100	$74.88
Insulin glulisine (Apidra, Sanofi Aventis)	Human analog (recombinant)	U100
Short-acting regular insulins "Purified"²
Regular Novolin (Novo Nordisk)³	Human	U100	$30.50
Regular Humulin (Lilly)	Human	U100, U500 20 mL	$29.28, $210.68
Regular Iletin II (Lilly)	Pork	U100	$47.98
Intermediate-acting insulins "Purified"²
Lente Humulin (Lilly)	Human	U100	$29.28
Lente Iletin II (Lilly)	Pork	U100	$47.98
Lente Novolin (Novo Nordisk)³	Human	U100	$30.50
NPH Humulin (Lilly)	Human	U100	$29.28
NPH Iletin II (Lilly)	Pork	U100	$47.98
NPH Novolin (Novo Nordisk)³	Human	U100	$30.50
Premixed insulins

% NPH/% regular

Novolin 70/30 (Novo Nordisk)³

Human

U100

$30.50

Humulin 70/30 and 50/50 (Lilly)

Human

U100

$29.28

Other Mixes

75% insulin lispro protamine/25% insulin lispro (Humalog Mix 75/25 [Lilly])

Human analog (recombinant)

U100 (insulin pen, prefilled syringes, 5 × 3-mL cartridges)

Pen $144.63, Vial $71.88

70% insulin aspart protamine/30% insulin aspart (Novolog Mix 70/30 [Novo Nordisk])

Human analog (recombinant)

U100 (insulin pen, prefilled syringes, 5 × 3-mL cartridges)

Pen $144.62, Vial $74.88

Long-acting insulins
"Purified"²

Ultralente Humulin (Lilly)

Human

U100

$29.28

Insulin glargine (Lantus, Aventis)

Human analog (recombinant)

U100

$66.85

¹All of these agents (except insulin lispro and U500) are available without a prescription. Average wholesale price (AWP, for AB-rated generic when available) for 10-mL vial unless otherwise specified. Source: Red Book Update, Vol. 24, No. 4, April 2005. Wholesale prices for all human preparations (except insulin lispro and U500) are similar. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
²Less than 10 ppm proinsulin.
³Novo Nordisk human insulins are termed Novolin R, L, and N.

Rapid-acting insulin analogs and regular insulin are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. The long-acting insulin analog insulin glargine is also dispensed as a clear solution but at acidic pH. Other intermediate-acting and long-acting insulins are dispensed as turbid suspensions at neutral pH with either protamine in phosphate buffer (NPH insulin) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins). The rapid-acting insulin analogs, intermediate-acting, and long-acting insulins are designed for subcutaneous administration only, while regular insulin can also be given intravenously.

a. Rapid-acting insulins

Insulin lispro (Humalog) is an insulin analog produced by recombinant technology, wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29 and lysine has been moved from B29 to B28. Insulin aspart (Novolog) is a single substitution of proline by aspartic acid at position B28. Insulin glulisine (Apidra) differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid. These changes result in these three analogs having less tendency to form hexamers, in contrast to human insulin. When injected subcutaneously, the analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as soon as 1 hour-in contrast to regular human insulin, whose hexamers require considerably more time to dissociate and become absorbed. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with the circulating half-life, or with their immunogenicity, which are all identical with those of human regular insulin.

Clinical trials have demonstrated that the optimal times of preprandial subcutaneous injection of comparable doses of the rapid-acting insulin analogs and of regular human insulin are 20 minutes and 60 minutes, respectively, before the meal. While this more rapid onset of action has been welcomed as a great convenience by diabetic patients who object to waiting as long as 60 minutes after injecting regular human insulin before they can begin their meal, patients must be taught to ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia during the meal. Another desirable feature of insulin lispro is that its duration of action remains at about 4 hours irrespective of dosage. This contrasts with regular insulin, whose duration of action is prolonged when larger doses are used.

Table 27-11. Examples of intensive insulin regimens using rapid-acting insulin analogs (insulin lispro, aspart, or glulisine) and ultralente, NPH, or insulin glargine in a 70-kg man with type 1 diabetes.^1-3

	Pre-Breakfast	Pre-Lunch	Pre-Dinner	At Bedtime
Rapid-acting insulin analog	5 units	4 units	6 units	-
Ultralente insulin	8 units	-	8 units	-
		OR
Rapid-acting insulin analog	5 units	4 units	6 units	-
NPH insulin	3 units	3 units	2 units	8-9 units
		OR
Rapid-acting insulin analog	5 units	4 units	6 units	-
Insulin glargine	-	-	-	15-16 units

¹Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch, and 90 g at dinner.
²The dose of insulin lispro or insulin aspart can be raised by 1 or 2 units if extra carbohydrate (15-30 g) is ingested or if premeal blood glucose is > 170 mg/dL. Insulin lispro or insulin aspart can be mixed in the same syringe with ultralente or NPH insulin.
³Insulin glargine cannot be mixed with any of the available insulins and must be given as a separate injection.

b. Short-acting regular insulin

Regular insulin is a short-acting soluble crystalline zinc insulin whose effect appears within 30 minutes after subcutaneous injection and lasts 5-7 hours when usual quantities are administered. Intravenous infusions of regular insulin are particularly useful in the treatment of diabetic ketoacidosis and during the perioperative management of insulin-requiring diabetics. When intravenous insulin is needed for hyperglycemic emergencies, the rapid-acting insulin analogs have no advantage over regular human insulin, which is instantly converted to the monomeric form when given intravenously. Regular insulin is indicated when the subcutaneous insulin requirement is changing rapidly, such as after surgery or during acute infections-although the rapid-acting insulin analogs may be preferable in these situations.

The rapid-acting analogs are also commonly used in pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, persons using insulin lispro had lower HbA_1c values and improved postprandial glucose control with the same frequency of hypoglycemia. The concern remains that in the event of pump failure, users of the rapid-acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.

c. Intermediate-acting insulins

Lente insulin is a mixture of 30% semilente (an amorphous precipitate of insulin with zinc ions) with 70% ultralente insulin (an insoluble crystal of zinc and insulin). Its onset of action is delayed for up to 2 hours, and because its duration of action often is less than 24 hours (with a range of 18-24 hours), most patients require at least two injections daily to maintain a sustained insulin effect. Lente insulin has its peak effect in most patients between 8 and 12 hours, but individual variations in peak response time must be considered when interpreting unusual or unexpected patterns of glycemic responses in individual patients. NPH (neutral protamine Hagedorn or isophane) insulin is an intermediate-acting insulin whose onset of action is delayed by combining 2 parts soluble crystalline zinc insulin with 1 part protamine zinc insulin. This produces equivalent amounts of insulin and protamine, so that neither is present in an uncomplexed form ("isophane").

The onset and duration of action of NPH insulin are comparable to those of lente insulin; it is usually mixed with regular insulin and given at least twice daily for insulin replacement in type 1 patients. Occasional vials of NPH insulin have tended to show unusual clumping of their contents or "frosting" of the container, with considerable loss of bioactivity. This instability is rare and occurs less frequently if NPH human insulin is refrigerated when not in use and if bottles are discarded after 1 month of use.

d. Long-acting insulins

Humulin ultralente is a crystalline insulin whose duration of action is less than that of the previously available beef ultralente. It is generally recommended that the daily dose be split into two equal doses given 12 hours apart. Its peak is less than that of NPH insulin, and it is often used to provide basal coverage while the short-acting insulins are used to cover the glucose rise associated with meals.

Insulin glargine is an insulin analog in which the asparagine at position 21 of the A chain of the human insulin molecule is replaced by glycine and two arginines are added to the carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule closer to neutral, making it more soluble in an acidic environment. In contrast, human insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin which, when injected into the neutral pH environment of the subcutaneous tissue, forms microprecipitates that slowly release the insulin into the circulation. It lasts for about 24 hours without any pronounced peaks and is given once a day to provide basal coverage. This insulin cannot be mixed with the other human insulins because of its acidic pH. When this insulin was given as a single injection at bedtime to type 1 patients, fasting hyperglycemia was better controlled when compared with bedtime NPH insulin. The clinical trials also suggest that there may be less nocturnal hypoglycemia with this insulin when compared with NPH insulin.

In one clinical trial involving type 2 patients, insulin glargine was associated with a slightly higher progression of retinopathy when compared with NPH insulin. The frequency was 7.5% with the analog and 2.7% with the NPH. This finding, however, was not seen in other clinical trials with this analog. Insulin glargine does have a sixfold greater affinity for IGF-1 receptor compared with the human insulin. There has also been a report that insulin glargine had increased mitogenicity compared with human insulin in a human osteosarcoma cell line. The significance of these observations is not yet clear. Because of lack of safety data, use of insulin glargine during pregnancy is not recommended.

e. Mixtures of insulin

Since intermediate insulins require several hours to reach adequate therapeutic levels, their use in type 1 patients requires supplements of regular or lispro insulin preprandially. It is well established that insulin mixtures containing increased proportions of lente to regular insulins may retard the rapid action of admixed regular insulin. The excess zinc in lente insulin binds the soluble insulin and partially blunts its action, particularly when a relatively small proportion of regular insulin is mixed with lente (e.g., 1 part regular to 1.5 or more parts lente). NPH preparations do not contain excess protamine and so do not delay absorption of admixed regular insulin. They are therefore preferable to lente when mixtures of intermediate and regular insulins are prescribed. For convenience, regular and NPH insulin may be mixed together in the same syringe and injected subcutaneously in split dosage before breakfast and supper. It is recommended that the regular insulin be withdrawn first, then the NPH insulin. No attempt should be made to mix the insulins in the syringe, and the injection is preferably given immediately after loading the syringe. Stable premixed insulins (70% NPH and 30% regular or 50% of each) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or impairment of manual dexterity.

With increasing use of rapid-acting insulin analogs as a popular and convenient preprandial insulin, it has become evident that combination with a more sustained insulin is essential to maintain postabsorptive glycemic control. It has been demonstrated that the rapid-acting insulin analogs can be acutely mixed with NPH without affecting their rapid absorption. Insulin lispro can also be mixed with ultralente insulin. Premixed preparations of insulin lispro and NPH insulins are unstable because of exchange of insulin lispro with the human insulin in the protamine complex. Consequently, the soluble component becomes over time a mixture of regular and insulin lispro at varying ratios. In an attempt to remedy this, an intermediate insulin composed of isophane complexes of protamine with insulin lispro was developed called NPL (neutral protamine lispro). This insulin has the same duration of action as NPH insulin. Premixed combinations of NPL and insulin lispro (eg, 75:25, 50:50, and 25:75 of NPL:insulin lispro) have been tested. The 75% NPL:25% insulin lispro mixture (Humalog Mix 75/25) is available for clinical use. Similarly, a 70% insulin aspart protamine/30% insulin aspart (NovoLogMix 70/30) is now available. The main advantages of these new mixtures is that they can be given within 15 minutes of starting a meal and they are superior in controlling the postprandial glucose rise after a carbohydrate rich meal. These benefits have not translated into improvements in HbA_1c levels when compared with the usual 70% NPH/30% regular mixture.