Intermittent Insulin Injections Insulin Overview

Insulin is the cornerstone of therapy in the management of type 1 diabetes. Insulin therapy also has a clear role in type 2 diabetes mellitus in patients with long-standing or poorly controlled disease. ^[1]

Since the discovery of insulin approximately 80 years ago, insulin therapy has undergone various changes in formulations with different pharmacokinetics. In the 1930s, protamine zinc insulin, the first long-acting preparation, was introduced. In the 1950s, the neutral protamine hagedorn (NPH) and insulin zinc (lente) were introduced. ^[2] Newer formulations have since been developed, allowing insulin to be provided in more physiologically appropriate ways. These provide more flexibility in dosing, mimic endogenous production of insulin, and lower the incidence of nocturnal hypoglycemia. ^{[3, 4, 5]}

When used as monotherapy, oral hypoglycemic drugs generally lower glycated hemoglobin (HgbA1C) by only 0.5%-1.5%. Most patients with type 2 diabetes eventually require multidrug therapy or insulin. Some guidelines encourage early use of insulin if HgbA1C remains poorly controlled on maximal-dose, single-drug therapy. Insulins have varying pharmacokinetics that allow for specific products from which to choose. Table 1 provides a comparison between insulins for onset of action and duration of action. Table 2 provides a list of combination insulin products.

Table 1. Insulin Pharmacokinetics (Open Table in a new window)

Table 2. Insulin Combination Products (Open Table in a new window)

Rapid-acting insulins with a short duration of action include insulin aspart (NovoLog), insulin lispro (Humalog), and insulin glulisine (Apidra). Their onset of action is approximately 5-15 minutes, peak action is between 30 and 90 minutes, and duration of action is approximately 4-6 hours. Regular insulin (Humulin R, Novolin R) is categorized as short-acting with a short duration of action and regular onset of action. Regular insulin's onset is 30-60 minutes, peak is 2-3 hours, and duration of action is approximately 8-10 hours. In general, insulin lispro, insulin aspart, and insulin glulisine are slightly more effective than regular insulin in decreasing HgbA1C, with less nocturnal hypoglycemia. ^[6]

In September 2017, Fiasp (insulin aspart injection) was approved by the US Food and Drug Administration (FDA) to improve glycemic control in adults with type 1 (T1D) and type 2 diabetes (T2D). This rapid-acting human insulin analog can be dosed at the start of a meal or within 20 minutes after starting a meal. Fiasp is formulated with niacinamide, which helps increase the speed of the initial insulin absorption. A pharmacokinetics study of adult patients with type 1 diabetes showed that Fiasp appeared in the circulation in approximately 2.5 minutes after administration. The time to maximum insulin concentrations was achieved in roughly 63 minutes after administration. ^[7]

In the manufacturing of regular insulin, zinc atoms are added, causing the formation of hexamers. ^[2] Because they are larger molecules, they diffuse slowly into the circulation. On the other hand, insulin lispro has lysine and proline inverted at the B28 and B29 position and insulin aspart has the proline at position 28 replaced by aspartic acid. ^[2] These changes in structure reduce the formation of dimers and hexamers, and they are rapidly absorbed. The short-acting insulins typically are used as bolus insulin given premeal. The rapid-acting insulins are administered immediately before a meal, whereas regular insulin is administered 30 minutes before a meal. ^[8]

Insulin NPH (Humulin N, Novolin N) is an intermediate-acting insulin that is a suspension of crystalline zinc insulin combined with the positively charged polypeptide protamine. Unlike the shorter-acting insulins, NPH has a longer duration of action, yet not as long as the newer long-acting insulins. Insulin NPH's onset of action is 2-4 hours, peak action is 4-10 hours, and duration of action is approximately 12-18 hours.

NPH insulin is also available in combination with regular insulin (insulin isophane human/insulin regular human). They are in a fixed combination of either 70% or 75% of NPH and 25% or 30% of regular insulin. These are marketed as Humulin 70/30 or Novolin 70/30. It is also available with NPH and a rapid-acting insulin combination. NPH/lispro mixtures are Humalog Mix 50/50, Humalog Mix 50/50 KwikPen, Humalog Mix 75/25, and Humalog Mix 75/25 KwikPen. NPH/aspart mixtures are marketed as NovoLog Mix 70/30 and NovoLog Mix 70/30 FlexPen. These combinations are a good option for patients who may be noncompliant, those who want to reduce theirnumber of self-injections, and those who are unable to use more sophisticated regimens. On the other hand, it is hard to manipulate the dosing because they are in a fixed combination.

The long-acting insulin analogs were made with recombinant DNA technology. Insulin glargine (Lantus) is made by replacing the asparagine by glycine in the A-chain and adding 2 arginines at the C-terminus of the B-chain. When injected into subcutaneous tissue, this forms microprecipitates, which then delays absorption from the injection site. Insulin detemir (Levemir) is manufactured by elimination of the amino acid threonine at position B30 and the addition of a 14-carbon fatty acid chain at position B29. Insulin detemir is also slowly absorbed from the injection site; in addition, it is also reversibly bound to albumin in the blood, which further prolongs its action and clearance. ^[2]

Of the two that are currently available, insulin glargine is considered long-acting, and insulin detemir is considered intermediate-to-long acting. Insulin detemir may have to be given twice a day because it may wear off before the subsequent dose. ^[9] The long-acting insulins, in addition to having a long duration of action, do not have a pronounced peak effect. Some European studies have shown an association of increased risk of cancer with insulin glargine, as opposed to other insulins. ^[10] Although this may be alarming, these studies have not been convincing.

Once-weekly injectable insulin is being studied in patients with type 2 diabetes. Phase 2 data show that it is comparable in efficacy and safety to insulin glargine. ^[11]

When insulin therapy is initiated in a patient who is already on oral medication, a basal (long- or intermediate-acting) rather than short-acting or premeal insulin should be chosen. Basal insulin helps improve nocturnal and fasting blood glucose levels, whereas premeal bolus insulin decreases postprandial glucose elevations. When choosing a basal insulin and drug cost is not a barrier, insulin glargine or detemir may be a better option than NPH insulin because they do not have a peak and therefore have a lower risk of nocturnal hypoglycemia.

In all patients with type 1 diabetes and in patients with type 2 diabetes with elevated levels of postprandial blood glucose, a bolus premeal insulin should be given. All patients with type 1 diabetes and patients on oral medications may be started on basal insulin. For basal insulin, either the intermediate-acting or the long-acting insulins are used, and, for bolus or preprandial insulin, the short-acting insulins are used.

Patient care providers should never assume patients’ knowledge about diabetes and insulin administration.

Patients should be instructed on the following:

• The reason for the use of insulin in his or her care

• The different types of insulin and why they are being prescribed

• The correct method for administration of insulin (see below)

• The correct time to administer each type of insulin

• A careful review of the dose of each type of insulin to be used

• A review of side effects such as hypoglycemia

• Instructions on how to treat hypoglycemia and what to do about the insulin following a hypoglycemic episode

• Provider contact information for advice, if needed

Technique for self-administration of insulin

The following are needed supplies for insulin self-administration:

• Insulin bottle

• Syringe

• Alcohol swabs

• Container for the used syringe

The steps of insulin self-administration are as follows:

1. Wash your hands

2. Check the insulin bottle to make sure it has not expired

3. In order to properly resuspend the insulin, vials should be carefully rolled between the palm of your hands several times (do NOT shake the vial or pen); prefilled pens should be rolled between the palms 10 times and inverted by 180° 10 times

4. Remove the lid from the insulin bottle

5. Wipe the rubber top of the bottle with an alcohol swab

6. Remove the cap from the syringe

7. Pull air into the syringe by pulling back on the plunger until its black tip is even with the line showing the dose you will need

8. Push the needle through the rubber top of the bottle and push in the air

9. Turn the insulin bottle and syringe upside down; to pull insulin into the syringe, slowly pull back on the plunger until the top of its black tip is even with the line showing your dose

10. Choose an area: Front of thigh/lateral thigh, abdomen (the preferred site when faster absorption is required, and it may be less affected by muscle activity on exercise), buttocks (upper outer quadrant; may be useful in small children), lateral aspect of arm (in small children with little subcutaneous fat, intramuscular injection is more likely to cause unsightly bruising)

11. Rotate the site daily

12. Pinch up some skin and quickly insert the needle at a 90° angle (or whatever angle your doctor or nurse tells you); keep the skin pinched to avoid having the insulin go into the muscle

13. Push the plunger down all the way; hold the syringe and needle in place for 5 seconds

14. Let go of the pinched skin and remove the needle from the skin; if you see blood or clear fluid (insulin) where the needle went in, press on the area for 5-8 seconds but do not rub

Using prefilled pens

Instructions for using prefilled pens are as follows:

1. Roll the pen between the palms 10 times and invert 180° 10 times

2. Twist on the needle; a new needle should be used for each administration

3. Pull off the needle cap; do not discard the outer needle cap

4. To avoid air and to ensure proper dose, you will need to prime the syringe each time; to do this, dial 2 units; hold the pen with the needle pointing up and tap the cartridge gently a few times to get rid of any air bubble; press the push button all the way in until the dose selector returns to zero; a drop of insulin must appear at the needle tip; if not, change the needle and repeat the procedure

5. Once the priming is done, check that the dose selector is set at zero

6. Dial the number of units you need to inject

7. Select the area; pinch the skin and inject into the skin; you should hear a confirmatory click

8. After injecting, the needle should remain in the skin for at least 6 seconds

9. Put outer cap back onto the needle, unscrew the needle, and dispose of it properly

Mixing two insulins

In order to properly resuspend the insulin, vials should be carefully rolled between the palms of your hands several times. Prefilled pens should be rolled between the palms 10 times and inverted 180° ten times. Properly resuspended insulin NPH should look uniformly cloudy or milky; do not use if any white insulin substance remains at the bottom of the container, if any clumps are present, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided.

When mixing insulin NPH with other preparations of insulin (eg, insulin aspart, insulin glulisine, insulin lispro, insulin regular), insulin NPH should be drawn into the syringe after the other insulin preparations. After mixing NPH with regular insulin, the formulation should be used immediately.

Rapid-acting insulin can be mixed with NPH. When this is done, the mixture should be injected within 15 minutes prior to a meal.