Insulin Therapy – Types and Indications, Contraindications

Principles of Management of T1DM

Management of T1D involves a multidisciplinary framework that includes the following:

• Physiologic insulin replacement using basal-bolus therapy, either as MDI or CSII
• Blood glucose monitoring with SMBG and/or CGM with the development of individualized A1c goals
• Patient education
• A supportive team of providers including endocrinologists, nurses, CDEs, psychologists, dietitians, social workers, other specialists such as cardiologists, nephrologists, psychiatrists as well as family members, social support groups, etc.

Types of Insulin Therapy

Selecting the appropriate insulin depends largely on the desired time course of insulin action.

Insulin products are categorized according to their action profiles:

• Rapid-acting –  e.g., insulin lispro, insulin aspart, and insulin glulisine (genetically engineered insulin analogues)
• Short-acting –  regular (soluble) insulin
• Intermediate-acting – NPH (isophane)
• Long-acting – e.g., insulin glargine, insulin detemir, and insulin degludec (genetically engineered insulin analogues)
• Pre-mixed insulin
• Inhaled insulin

A general principle to bear in mind is the longer the time to peak, the broader the peak and the longer the duration of action. Additionally, the breadth of the peak and the duration of action will be extended with increasing dose. Figures 9 and 10 should therefore be considered a conceptual representation of insulin action curves.

Rapid-Acting Insulin

• The genetically engineered insulin analogs have a rapid onset in 15-30 minutes, peak in 30-90 minutes, and an effective duration of 4 to 5 hours when injected subcutaneously because they do not self-aggregate in solution as human (regular) insulin does. Insulin lispro differs from human insulin by an amino acid exchange of lysine and proline at positions B28 and B29. The substitution of aspartic acid for proline at position B28 characterizes insulin aspart.
• Insulin glulisine differs from human insulin in that the B3 asparagine is replaced by lysine, and B29 lysine is replaced by glutamic acid. These modifications in the primary structure of human insulin increase the rapidity of the breakdown of insulin hexamers in the analogs and thus result in more rapid absorption. When administered before meals, rapid-acting insulins used as part of multiple daily injections or with CSII, resemble physiologic insulin increases stimulated by food. Doses can be adjusted proportionately to food consumed; in patients with gastroparesis or poor appetite, insulin can be injected halfway through or after the meal.

Short-Acting Insulin

• Regular insulin is structurally similar to endogenous human insulin. It consists of dissolved zinc-insulin crystals which self aggregate in the subcutaneous tissue and results in a delayed onset of action of 30 to 60 minutes, a peak of 2 to 3 hours, and an effective duration of 6 to 8 hours. Proper use requires injection at least 20 to 30 minutes prior to meals to match insulin availability and carbohydrate absorption. Use of regular insulin is associated with greater hypoglycemia risk [39]. Regular insulin acts almost instantly when injected intravenously.

Intermediate-Acting Insulin

• Neutral protamine Hagedorn (NPH) insulin, developed in the 1950s, is a combination of recombinant human insulin with protamine which results in crystal formation. When injected subcutaneously, precipitated crystals of NPH insulin are released slowly resulting in a longer duration of action compared to regular insulin.
• The action of NPH varies quite widely within the same patient as well as between patients. Its onset of action occurs 2 to 4 hours from the time of injection, with a peak effect lasting 6 to 10 hours, and an effective duration of 10 to 16 hours. Due to this peak effect, NPH insulin acts as a basal and prandial insulin, necessitating that patients eat a meal at the time the insulin is peaking. NPH typically requires twice a day dosing [40].

Long-Acting or Basal Insulin

• Long-acting insulin analogs were created by modifying the amino acid sequence on the beta chain of insulin [41]. They exhibit much-improved pharmacokinetics and pharmacodynamics without a peak effect and maintain a longer duration of action. Improved absorption rates result in significantly decreased inter-individual and intra-individual variability with improvement in glycemic control and reduced hypoglycemia risk.
• Insulin glargine (U-100): Insulin glargine is modified human insulin produced by the substitution of glycine for asparagine at position A21 of the insulin molecule and by the addition of two arginine molecules at position B30. These changes result in an insulin molecule that is less soluble at the injection site forming a precipitate in the subcutaneous tissue to form a depot from which insulin is slowly released after injection and is slowly released into the circulation. It has no pronounced peak and a longer duration of action of about 20 to 24 hours in most patients, allowing for once daily dosing. In clinical practice, many patients with T1DM may benefit from twice-daily injections. Insulin glargine is solubilized in acidic pH and should not be mixed with rapid-acting insulins as the kinetics of both insulins will be altered. Insulin glargine shows a greater reduction in A1C and decreased hypoglycemia in patients with T1DM [42].

Pre-mixed insulins

• Premixed insulins are mixtures of prandial and intermediate-acting insulins (the same prandial insulin attached to protamine so that it becomes intermediate-acting). In the US, insulin lispro protamine mixtures are available in two forms: 75% insulin lispro protamine suspension and 25% insulin lispro injection (75/25) and 50% insulin lispro protamine suspension and 50% insulin lispro injection (50/50).
• Available preparations of insulin aspart protamine mixtures include 50/50 and 70/30 suspensions. A variety of other ratios are available in Europe. These insulins are typically administered before breakfast and dinner. This alleged twice-daily dosing is the primary advantage of these insulins. In general, use of premixed insulins restricts adjustment of doses and meal timing.
• Therefore, premixed insulins are not recommended for adult patients with T1D, where intensive regimens with the ability to make adjustments in the premeal short-acting insulin bolus are better suited for glycemic control. Premixed insulin in T1D could have benefits for some patients who do not adhere to an intensive insulin regimen.

U-500 insulin

• U-500 insulin is highly concentrated regular insulin, administered 2-3 times a day without basal insulin. Due to its concentration, the action is prolonged and variable. In T1D, use is primarily limited to individuals with significant insulin resistance (requiring >200 units of insulin a day). Caution should be used while prescribing this insulin as confusion may occur among clinicians, pharmacists, nurses, and patients who are unfamiliar with its use. Recently,
• U-500 insulin became available in a pen delivery system allowing patients to administer insulin by 5 units increments up to a maximum of 300 units at a time. Units to be delivered are clearly readable through the pen “dose window” which should minimize or eliminate confusion when administering this highly concentrated insulin formulation.

Inhaled insulin

• Currently, one form of inhaled insulin is available in the market. Afrezza was approved by the FDA in 2014. This is a drug-device combination that contains powdered human insulin in single-use dose cartridges delivered via a small inhaler. When inhaled, it dissolves immediately on contact with the alveolar surface of the lung and is rapidly absorbed into the systemic circulation, reaching a peak within 15 minutes.
• Thus Afrezza acts similarly to rapid-acting insulin analogs but with a much faster peak of action and shorter duration of action. Prior to the initiation of its use, patients should be screened for underlying lung disease with spirometry. Follow-up spirometry is recommended after 6 months’ use, and annually thereafter.
• The main advantages of inhaled insulin are avoidance of injections, faster onset of action, less weight gain and less hypoglycemia [50]. Dosing is not flexible as cartridges are available in fixed doses (4, 8 and 12 units). Afrezza is contraindicated in patients with chronic lung disease such as asthma or chronic obstructive pulmonary disease (COPD).