Insulin: A Primer
January 11, 2015
Authors
Jay H. Shubrook, DO, FACOFP, FAAFP, Associate Professor of Family Medicine, Director, Diabetes Fellowship Program, The Diabetes Institute at Ohio University
Nancy Mora Becerra, MD, Ohio State University, Columbus, OH
Sarah E. Adkins, PharmD, BCACP, Faculty, The Ohio State University College of Pharmacy; Assistant Professor of Pharmacology, Ohio University Heritage College of Medicine, Athens, OH
Aili Guo, MD, Assistant Professor of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine
Peer Reviewer
Jeff Unger, MD, ABFP, FACE, Director, Unger Primary Care Concierge Medical Group, Rancho Cucamonga, CA
Executive Summary
- Patients starting on insulin in the ED should be started on a basal insulin 0.1-0.2 U/kg.
- Patients being treated for acute hyperglycemia (not previously on insulin) should receive 2 U for every 50 mg/dL elevation of glucose over 150 mg/dL.
- Patients who present acutely ill with an active insulin pump should have the pump turned off and supplemental insulin given IV.
- Patients who present with unexplained hypoglycemia should have a c-peptide and insulin level drawn. High insulin levels without equal elevation of c-peptide suggest exogenous insulin administration.
Introduction
Prior to the discovery of insulin, type 1 diabetes was a uniformly fatal disease. The first use of exogenous insulin in a dog by Banting and Macloed resulted in the Nobel Prize in Physiology or Medicine.1 In January 1922, they injected exogenous insulin in a 14-year-old boy who was dying at the Toronto General Hospital. After receiving the insulin he desperately needed, he improved and by the end of that month his glucosuria and ketonuria normalized.1
Initially, bovine and porcine insulins were purified from animal pancreatic tissues and were used to treat people with diabetes. Since they were foreign to the human body, immune reactions were common, which resulted in an unpredictable treatment effect and duration. In 1958, Frederick Sanger won a Nobel Prize in Chemistry for the discovery of the molecular structure of insulin.1 Dorothy Hodgkin, who won a Nobel Prize in Chemistry in 1964, discovered the tertiary structure of insulin.2 These discoveries allowed for the pharmacologic development of human insulin.
The development of human insulin was a significant advancement as it decreased immunogenic reactions and provided longer duration of action. Human insulin is produced by recombinant DNA technology, introducing the proinsulin gene into Escherichia coli or yeast. These organisms replicate and produce insulin.
Human insulins include regular (R) and neutral protamine hagedorn (NPH), lente (L), and ultralente (U). Only R and NPH are still available today. R insulin is used most commonly as mealtime insulin. It should be dosed 30-45 minutes before a meal. NPH insulin has a longer duration of action, can be dosed 4-6 hours before a meal, and is used 1 meal in advance (taken before breakfast to cover lunch) or as a basal insulin 2-3 times per day. NPH has a prolonged effect due to the addition of a positively charged protamine.
Today there are three rapid-acting analog insulins (aspart, lispro, glulisine) and two long-acting analogs (glargine, fetemir).
Insulin and C-peptide Physiology
Insulin is produced and released specifically by the ß cells of the pancreatic islet cells within the pancreas. Insulin is a polypeptide hormone that consists of two chains (chain A with 21 amino acid residues and chain B with 30 amino acid residues) linked by two disulfide bridges. The first form is preproinsulin. Soon after production, it is released from the rough endoplasmic reticulum when proteolytic enzymes cleave into pro-insulin. Pro-insulin converts to insulin when other proteolytic action cleaves the C chain (c-peptide) and leaves the active insulin molecule in the vesicle for secretion. This physiologic feature is convenient in that one molecule of c-peptide is produced for each insulin molecule. This makes c-peptide a good measure of endogenous insulin production.3
While the cause of hypoglycemia in most patients is apparent, in patients with unexplained hypoglycemia, measurement of insulin and c-peptide, and in some cases sulfonylurea, can be important. The most important causes of hypoglycemia are shown in Table 1. In most cases the cause of the hypoglycemia will be apparent — sepsis, known excessive use of insulin, etc.
- Intentional or unintentional overdose of insulin
- Intentional or unintentional overdose of oral hypoglycemic
- Insulinoma, multiple endocrine neoplasias
- Liver disease
- End stage renal disease
- Hypopituitarism
- Hypothyroidism
- Inborn errors of metabolism
- Starvation
- epsis
- ETOH
- Reactive after gastric surgery
Patients who have an excess of exogenous insulin, such as overdose on insulin (intentional or unintentional) will have low c-peptide levels and high insulin levels. Patients with an insulin-producing tumor such as insulinoma will have high insulin levels (< 100 uU/mL) and high c-peptide levels. These tumors tend to be very small (< 2 cm) and are often missed on imaging. Patients who have an inadvertent or intentional overdose of sulfonylurea drugs will have very high levels of insulin and c-peptide exceeding those seen with insulinoma.4 Exogenous sulfonylurea levels can be measured.
Insulin secretion is based on the glucose level presenting to the pancreas. There is a diurnal pattern as well whereby insulin secretion is lowest in the middle of the night and greatest first thing in the early morning. In a fasting state, insulin secretion suppresses glycogenolysis and stimulates gluconeogenesis and lipogenesis.
Insulin secretion is also modulated by the intake of nutrients (bolus secretion). In response to meal ingestion, insulin secretion is biphasic. There is a large and rapid first-phase insulin secretion followed by a slower and more sustained second-phase secretion. The incretin system stimulates insulin release and suppresses glucagon release from the pancreas. The incretin effect provides a much larger increase in insulin secretion than glucose levels.
The liver removes at least 50% of insulin released. The remainder is taken up into systemic circulation where it interacts with target site receptors. At the target sites, insulin binds to receptor sites on plasma membranes. This binding begins a cascade of intracellular reactions that trigger significant cellular responses such as glucose uptake, glycogen synthesis, and lipogenesis.5
The insulins discussed are currently FDA approved in the United States for use in diabetes (see Table 2).
Table 2: Pharmacokinetic Profiles of Currently Available Insulins and Insulin Analogs
| Time of Action (hours) | |||||||
| Insulin | Brand Name | Manufacturer | Species Source | Concentration | Onset | Peak Effect | Duration |
|
|
|||||||
|
Glulisine |
Apidra |
Sanofi-Aventis |
human analog |
U100 |
0.2-0.5 |
1.6-2.8 |
3-4 |
|
Lispro |
HumaLOG |
Lilly |
human analog |
U100 |
0.25-0.5 |
0.5-2.5 |
≤ 5 |
|
Aspart |
NovoLOG |
Novo Nordisk |
human analog |
U100 |
0.2-0.3 |
1-3 |
3-5 |
|
|
|||||||
|
Regular |
HumuLIN R NovoLIN R |
Lilly Novo Nordisk |
human |
U100 |
0.5 |
2.5-5 |
4-12 |
|
|
|||||||
|
NPH |
HumuLIN N NovoLIN N |
Lilly Novo Nordisk |
human |
U100 |
1-2 |
4-12 |
14-24 |
|
|
|||||||
|
70 NPH 30 regular |
HumuLIN 70/30 NovoLIN 70/30 |
Lilly Novo Nordisk |
human |
U100 |
0.5 |
regular 0.8-2 NPH 6-10 |
18-24 |
|
|
|||||||
|
50 lispro protamine 50 lispro |
HumaLOG Mix 50/50 |
Lilly |
human analog |
U100 |
0.25-0.5 |
0.8-4.8 |
14-24 |
|
75 lispro protamine 25 lispro |
HumaLOG Mix 75/25 |
Lilly |
human analog |
U100 |
0.25-0.5 |
1-6.5 |
14-24 |
|
70 aspart protamine 30 aspart |
NovoLOG Mix 70/30 |
Novo Nordisk |
human analog |
U100 |
10-20 minutes |
1-4 |
18-24 |
|
Long |
|||||||
|
Detemir |
Levemir |
Novo Nordisk |
human analog |
U100 |
3-4 |
3-9 |
6-23 |
|
Glargine |
Lantus |
Sanofi-Aventis |
human analog |
U100 |
3-4 |
none |
average 24 |
|
|
|||||||
|
Regular |
HumuLIN R U500 (concentrated) |
Lilly |
human |
U500 |
0.5 |
2.5-5 |
up to 24 |
Rapid-Acting Insulins
There are three FDA-approved, rapid-acting insulin analogs available in the United States today: glulisine, lispro, and aspart. Timing of meals and monitoring for hypoglycemia are important with rapid-acting insulins.
Insulin lispro was approved in 1996 by Lilly with the brand name HumaLOG®. Upon injection, insulin lispro is quickly absorbed, faster than regular injected human insulin. Lispro also has a shorter duration of action compared to regular insulin. The recommended time of administration for insulin lispro is 15 minutes prior to a meal.6
Insulin aspart (NovoLOG®) by Novo Nordisk was approved in 2000. This insulin is recommended for subcutaneous administration approximately 5-10 minutes before a meal.7
Insulin glulisine (Aprida®) is a human insulin analog. This insulin can be given either prior to the meal or up to 20 minutes after the meal. Insulin glulisine was approved for use in 2004.8
Short-Acting Insulin
Regular insulin, which was FDA-approved in 1982, is a short-acting human insulin that is produced using recombinant DNA techniques. Regular insulin is normally administered 30-45 minutes prior to a meal and tends to last longer than rapid-acting insulins, anywhere from 4-12 hours. Regular insulin, which can be given subcutaneously or intravenously, is particularly useful as an intravenous infusion and is frequently used in hyperglycemic crises such as diabetic ketoacidosis and hyperglycemic hyperosmolar nonketosis syndrome.9
Intermediate-Acting Insulin11
Neutral protamine hagedorn (NPH), or isophane, is a cloudy suspension that contains insulin and protamine. The addition of protamine creates a longer duration of action. When administered, enzymes slowly break down the protamine to allow for the slow absorption of insulin. NPH absorption is often variable, having an onset from 1-5 hours, and duration of action from 4-12 hours.10 NPH insulin, which has been available since 1982, is available as HumuLIN N® (Lilly) or NovoLIN N® (Novo Nordisk). In the clinical setting, NPH is typically given one meal in advance or as 2-3 doses per day to serve as a basal insulin. The availability of long-acting insulins has led to decreased use of NPH insulin.
Premixed Insulins9,10-12
Human insulin regular and NPH can be mixed into a single syringe for administration. The two commercially available human insulin mixes are HumuLIN® 70/30 or NovoLIN N® 70/30 (70% NPH and 30% regular). The 70/30 mix is a cloudy suspension (as NPH is cloudy). The onset is around 30-45 minutes, with a peak effect in 4-12 hours. This insulin is typically dosed 2-3 times per day with pre-breakfast and pre-dinner dosing. This is convenient for patients who want to limit the number of injections. Responses to this insulin, though, can be less reliable dose to dose. Regular insulin can precipitate out in the NPH insulin.
Other mixed insulins available include rapid-acting analog insulin and protamined rapid-acting analog insulin. The protaminated rapid-acting analog will delay absorption and give a prolonged effect. The HumaLOG® 75/25 and NovoLOG® 70/30 mixes have a more rapid onset of action and a shorter peak effect. This allows them to be dosed immediately before mealtime, which may result in more reliable clinical effects and reduced post-meal hypoglycemia. These rapid-acting mixed insulins came to market in the mid-to-late 1990s.
Long-Acting Analog Insulin
Insulin glargine (Lantus®) came on the market in 2000, followed by the release of insulin detemir (Levemir®) in 2005. The introduction of a steady, long-acting insulin closely mimics the basal rate of endogenous insulin. These agents alone have a lower risk of hypoglycemia due to the lack of a peak response and the continuous release of low levels of insulin.
Insulin glargine is a long-acting analog of human insulin. The insulin structure was modified by attaching two arginine amino acids to the terminal end of the B chain and changing asparagine to glycine at the terminal end of the A chain. These modifications form a precipitate upon subcutaneous injection. This precipitate dissolves slowly, creating a continuous, steady release of insulin. Because of this mechanism, insulin glargine has no defined peak. Glargine is injected subcutaneously once daily and should not be administered intravenously or intramuscularly.13 Given that glargine has an acidic pH, it should not be mixed with other insulins.
Insulin detemir is a long-acting human analog insulin. The onset of action is generally 1-2 hours. It can be given once daily. Insulin detemir is administered subcutaneously, but should not be administered intravenously or intramuscularly.14
Concentrated Insulin
Currently there is only one concentrated insulin clinically available in the United States (HumuLIN U500) but there are more emerging.
Starting Insulin in the ED
In most cases, patients with severe hyperglycemia will be admitted, and treatment with insulin will be initiated by the primary care physician or endocrinologist. However, some patients with diabetic ketoacidosis are now kept in observation or in the ED until discharge. Increasingly, patients with new onset diabetes are discharged home directly or placed in an observation unit under the care of an emergency physician, who then starts insulin treatment. Traditional “diabetic teaching,” which includes diet, foot care, and eye care, is either completed in the ED or as an outpatient.
Patients with type 1 diabetes (those who present with diabetic ketoacidosis) will require insulin treatment. Many patients with type 2 diabetes (metabolic syndrome, obese, later onset) can be tried on an oral hypoglycemic, with insulin used in refractory cases. Some advocate insulin as the first treatment for type 2 diabetes.15,16 The underlying principle behind early intensive insulin use is that “resting” the pancreas in early diabetes may provide not only more rapid control of glucose but also a lasting or “legacy” effect on glucose control. While this is promising, this method of treatment requires further exploration.
How to Start Insulin? For most patients, starting insulin usually means starting a basal insulin, glargine, detemir, or NPH. Basal insulins allow for suppression of hepatic glucose production overnight and can help normalize morning blood glucose. Therefore, controlling fasting glucose is a logical first step. By removing glucose toxicity, the remaining functioning ß cells are better able to address prandial hyperglycemia.
The ADA/EASD recommend a starting dose of 0.1-0.2 units/kg as a single dose. This starting dose is rarely enough insulin to normalize morning glucose, so patients should be instructed to see their doctor within a few days to adjust their dose. Table 3 compares basal insulin titration recommendations from major diabetes organizations.
Table 3: Basal Insulin Algorithms
| Measure | ADA/EASD | AACE/ACE | IDF | CDA |
|
Abbreviations: ACE, American College of Endocrinology; ADA, American Diabetes Association; CDA, Canadian Diabetes Association; EASD, European Association for the Study of Diabetes; A1c, glycated hemoglobin; IDF, International Diabetes Federation. Adapted from: LaSalle JR, Berria R. Insulin therapy in type 2 diabetes: A practical approach for primary care physicians and other health professionals. J Am Osteopath Assoc 2013;113:152-162. |
||||
|
Algorithm Initial dosage
|
|
|
|
|
|
Target FBG, mg/dL |
70-130 |
< 110a |
<110 |
72-126 |
Patient-driven titrations have proven to be more effective than physician-driven titrations.17,18 Agreed upon stopping points include when the basal dose reaches 0.5 units/kg or when the patient experiences a hypoglycemic episode.19
PaSince diabetes is very common, many patients may already be familiar with insulin injections. In other patients, nursing can teach the proper injection technique.
As mentioned earlier, there are two long-acting basal insulins and one intermediate-acting insulin that can serve as a basal insulin. All three formulations work well to suppress hepatic glucose production. The analog insulins (glargine, detemir) have numerous benefits over NPH insulin,20-22 including less hypoglycemia, especially nocturnal hypoglycemia; less weight gain; and less frequent dosing. The downside is the expense. Analog insulins are 3-5 times more expensive than generic human insulin. When dosing a basal insulin analog, it is recommended to start with a weight-based dose once daily. Many physicians have stayed with the initial recommendations to dose glargine at bedtime, but dosing can, in fact, be any time of day based on the patient’s schedule and preference.
When NPH is used as a basal insulin, it is most commonly dosed 2-3 times per day. Twice-daily dosing, before breakfast and before dinner, is best. This minimizes hypoglycemia between meals and overnight. Use of three times daily dosing insulin will result in a very complex set of insulin actions and unpredictable hypoglycemia in a person who may not fully understand the dynamics of these insulins.
Premixed insulin allows a person to take fewer injections than a basal bolus regimen. However, it is more often associated with hypoglycemia and results in an inflexible daily and meal schedule to prevent hypoglycemic episodes.
Premixed insulin can be used for someone who has poor control but who is not motivated to engage in three or more shots per day.
Adjusting Insulin in the ED
Hyperglycemia is often noted in diabetic patients who come to the ED. If the elevation is mild, say under 300 mg/dL, and not related to the acute disease, the patient may require simple adjustment of their insulin. This is best done by the PCP, but in some cases that cannot be done. The ED provider should be able to start the insulin adjustment until the patient can see his or her physician. It is good to draw an A1c in the ED to help guide future adjustments.
If the patient is only on a basal regimen, increase the basal dose 1-3 U per day and have the patient check fasting glucose levels. If a patient has a good fasting glucose but the later glucose levels are elevated, consider adding a newer oral agent (DPP-4 inhibitors, SGLT-2 inhibitors), older agent such as the glinides or alpha-glucosidase inhibitors, or the shorter acting injectable GLP-1 receptor analogs.23 The use of non-insulin injectables or oral agents is beyond the scope of this paper. Rapid-acting insulin analogs, which include aspart, lisine, and glulisine, can also be used.
The Endocrine Society, in cooperation with a number of other professional organizations, developed a decision tool for mealtime dosing. This reference (Accurate insulin decisions) is freely available for clinicians.19
The goal of using mealtime insulin is to replicate physiologic insulin release. The patient takes an injection of mealtime insulin with each meal. The typical starting dose is 0.1 unit/kg per meal. If the patient is well-controlled in the morning, the physician may need to subtract 10% of the basal dose to prevent hypoglycemia that could result from treating daytime hyperglycemia more effectively by using a mealtime dose of insulin.
Table 4: Recommended Mealtime Insulin Titrations
| Measure | ADA/EASD | AACE/ACE | IDF | CDAa |
|
Adapted from: LaSalle JR, Berria R. Insulin therapy in type 2 diabetes: A practical approach for primary care physicians and other health professionals. J Am Osteopath Assoc 2013;113:152-162. |
||||
|
Algorithm Initial dosage
|
|
|
|
|
Recent studies support the principle of a basal plus 1 insulin schedule. In this scenario, the patient continues basal insulin, but only takes mealtime insulin with the largest meal of the day. For most people in the United States, this corresponds to the evening meal. When using a basal plus 1 regimen, the mealtime dose may be bigger at 0.1-0.2 units per kg.24
The term “sliding scale” has been replaced by “correction scale” to identify a different way to use insulin when current insulin needs are unknown.
Correction scale insulin may be used alone for initial treatment if the person’s insulin needs are unknown. However, it is intended that after 24 hours, the “correction insulin” needed the previous day would be converted to scheduled insulin the next day that will prevent the need for ongoing “sliding scale insulin.” Correction scale insulin is used in addition to scheduled mealtime insulin to supplement the current meal dose and correct a hyperglycemic reading in specific situations.
To make a specific correction scale, the physician can use the rule of 1800 (the constant may vary from 1500-1900 based on the source). To estimate the amount of glucose reduction for 1 unit of insulin, take the total daily dose of all insulin injections and then divide this into the constant of 1800.25 An example is listed below.
Example 1. A person presents to the hospital with community-acquired pneumonia. He has no history of diabetes but he is hyperglycemic at the time of admission with a glucose of 212 mg/dL and no history of diabetes. Because this patient is acutely ill, sliding scale insulin is started using 2 units for every 50 mg/dL above 150 mg/dL. After the first 24 hours, he needs 20 units of insulin from the scale. Using the correction scale correctly, on day 2 the physician takes the total of the previous correction scale insulin from day 1 and converts it to scheduled insulin. Typically, half the insulin would be once-daily basal insulin (10 units) and the remaining scale insulin would be used to cover the meal content, divided equally among the meals (about 3 units per meal). This is repeated daily until the correction insulin need is negligible.
Insulin Delivery
At present, all insulin products are delivered via subcutaneous insulin injections in addition to a syringe and insulin drawn from a vial. Insulin pens are available as reusable devices (pens) with replaceable insulin cartridges or disposable single-use pens.
Patients who currently use or plan to start insulin usually prefer insulin pens26 because they are more portable and allow for attachment of pen needles, thus reducing the necessary equipment the patient has to carry. Insulin pens hold 3 mL (or 300 units) of insulin, so they need to be replaced more often than vials, which hold 10 mL (1000 units). Additionally, adherence is improved for insulin pens compared to vials and syringe.27
Writing Insulin Prescriptions
Most insulin products in the United States are U100 insulin (100 units/mL), which translates as 100 units in each mL of insulin. Each “unit” is standardized for a similar clinical response — one unit of lispro, aspart, and glulisine should each have similar glucose-lowering effects — which allows for accurate prescribing and dosing, even when switching between insulins. A vial of U100 insulin holds 10 mL or 1000 units. An insulin pen holds 3 mL or 300 units.
Prescriptions for insulin pens also need to include pen needles, which come in regular (8 mm), short (5 mm), mini (4 mm), and nano (3 mm). Recent evidence has shown that all needle lengths are equally effective.28
Errors in insulin prescription and/or dosing are among the most common in inpatient and outpatient settings.29 To minimize the chance for error a few general rules should always be followed:
- Always write out the word “unit” — do not use the abbreviation U as it can be mistaken for a 0.
- The current recommended nomenclature (http://www.ismp.org/tools/tallmanletters.pdf) is to capitalize the last three letters of a brand name to limit confusion between similarly named products. For example: HumaLOG vs HumuLIN or NovoLOG vs NovoLIN.
- Specify whether the prescription is for pens or vials.
- Write NovoLIN R 6 units before each meal three times per day instead of writing Novolin R take as directed at mealtimes.
- If a patient needs to take a correction dose, it should be spelled out on the prescription: Write HumaLOG 6 units per meal plus correction 1 unit for every 50 mg/dL above 150 mg/dL.
- Always include the maximum dose per day on the prescription so the pharmacist can dispense the correct total volume.
The following is an example of what a prescription might look like: Apidra SolostarR pens, Take ApidraR 6 units per meal plus 1 unit for every 50 mg/dL above 150 mg/dL for a maximum of 40 units per day, 30-day supply, 5 refills.
Determining the Prescription Dose
Estimating the volume on the prescription is based on daily dose. Each vial of U100 insulin holds 1000 units. Dividing by a typical 30-day month corresponds to approximately 1 vial per month. If a person typically takes 40 units per day of insulin by vial, write for two vials. When prescribing vials, insulin syringes will also be needed. The current sizes for insulin syringes include 0.3 mL, 0.5 mL, and 1 mL, which allow for injections of 30 units, 50 units, and 100 units, respectively. Insulin pens hold 300 units of insulin and typically come in a box of five, for a total of 1500 units. This means that a person who uses 45 units per day of insulin will use one box of five pens per month.
Concentrated Insulins
Patients who are obese and have type 2 diabetes typically need more insulin for a therapeutic effect, which often means very large doses of daily insulin (200-300 units per day). Once a person needs more than 300 units of insulin per day, the number of injections increases and the pharmacokinetics of the insulin can be less consistent due to potential depot effects at the injection site. Concentrated insulins are a potential solution to this challenge.
Regular human insulin is available in a concentrated form, HumuLIN R U500, with the same mechanism of action as U100 regular insulin. However, increased concentrations create more aggregation of insulin molecules into dimers/hexamers, thus prolonging absorption. A single dose of concentrated U500 regular insulin may have effects up to 24 hours. HumuLIN R U500 is recommended for subcutaneous administration 30 minutes prior to a meal and is typically administered 2-3 times per day based on the dose.30
Table 5: Available Insulin Products and Delivery Methods
| Insulin Product | Regular Insulin | NPH | Glulisine | Aspart | Lispro | Detemir | Glargine | Afrezza |
|
Vial |
X |
X |
X |
X |
X |
X |
X |
|
|
Permanent refillable insulin pen |
X Echo pen Novo Jr. pen Novopen 3 |
X Luxura HD |
||||||
|
Disposable insulin pen |
X |
X Solostar pen |
X Flexpen |
X Kwikpen |
X Flexpen, Flextouch |
X Solostar pen |
||
|
Inhaler |
X |
Emerging Insulin Products
Researchers are constantly searching for innovative insulins and insulin delivery methods. Products currently in development include inhaled and oral insulin as well as insulin with different pharmacokinetics that allows it to be even more physiologic. In January 2006, an inhaled insulin product (Exubera®, Pfizer) came to market, but sales were not robust enough to continue its production.31
In June 2014, the FDA approved Afrezza® (MannKind Corporation),32,33 an rDNA human dry powder insulin indicated for both type 1 and type 2 diabetes. This inhaled insulin is combined with an inert excipient and used with the Technosphere® Inhalation System. An “ultra-rapid mealtime insulin,” Afrezza is designed to reach peak insulin levels 12-15 minutes after inhalation and it is cleared faster than rapid-acting insulin. Therefore, it is dosed with meals. Afrezza is expected to be available in the United States in 2015. The most common side effects are cough, throat pain, headaches, and higher rates of hypoglycemia.32 This medication should not be used in people who smoke or have problems with moderate-to-severe asthma or COPD symptoms. In these patients, there is a black box warning for bronchospasm.
Dance 501 (Dance Biopharm Inc.) is an inhaled insulin device in development that releases an insulin mist with an appropriate inhalation from the patient.34 Dance 501 is being studied in adult patients with type 2 diabetes.
In addition, several novel concentrated insulins, including U200 and U300 basal insulins, are in development for patients who take large volumes of insulin. These concentrated insulins will most likely have longer durations of action.
Degludec (Novo Nordisk), a basal insulin with a duration of 42 hours, has been studied in a U100 and a U200 concentration.35,36 Although it is available in Europe, the FDA is requiring the manufacturer to produce additional cardiovascular outcome data.35 PEGylated insulin lispro (Lilly)35,37 is insulin lispro attached to a polyethylene glycol, which makes this molecule have a large hydrodynamic size and prolonged duration of action. This insulin may also have preferential hepatic uptake and may more closely approximate normal endogenous insulin physiology.
In addition, emerging “ultra-fast insulins” that may provide faster insulin coverage for meals and correction are in development to help prevent formation of dimers and hexamers. One promising approach is the use of hyaluronidase to speed absorptions and time to onset. Another option is to add excipients to speed insulin absorption or insulin dispersion.38
A new area of insulin technology is biosimilar insulin.15 Since many insulin analogs will go off patent in the coming years, manufacturers have the opportunity to make close copies, called biosimilars. Although the compounds may have the same amino acid sequence, they may have slightly different clinical characteristics when produced under different conditions. Biosimilars are available in other countries, but there are not enough data from controlled clinical trials to adequately compare them.
The final products in development are “smart insulins,” which have built-in glucose sensors that allow the insulin delivery component according to the ambient glucose. These have the potential to resolve the serious issue of hypoglycemia, which is a concern with current insulin formulations. Examples of smart insulins include protein-binding ligands (lectins) that can reversibly bind to carbohydrates and nanotechnology and nanoplugs that sense glucose levels and control insulin release from microgels or bioactive membranes. In addition, bulk hydrogel matrices, microgel sponges, and phenyl boronic acid in hydrogel have been reported to work like closed-loop insulin delivery devices. These hydrogels will swell in the face of hyperglycemia and in turn release insulin from its pores until the glucose normalizes. Although these technologies are exciting, they have only been researched in animal models at this time.39
Advanced Insulin Delivery
V-Go is a disposable patch insulin delivery device specifically designed for use in adults with type 2 diabetes.40 The V-Go includes many of the advantages of an insulin pump and it comes in a non-motorized plastic device that is disposable. V-Go is not an insulin pump as others that will be described below, and is best used only in type 2 diabetes.
Unlike pumps, V-Go has a mechanical power source that delivers insulin with button presses rather than an electronic motor. Each disposable patch is used for 24 hours. The V-Go is waterproof to a depth of about 3 feet for 24 hours, so there is no need to remove the patch while swimming or bathing.
Similar to insulin pumps, V-Go uses a rapid-acting insulin. Only U100 lispro and aspart insulin are approved to use with this device. V-Go pumps are available in three different sizes based on the basal doses patients will receive in a 24-hour interval. For example, the V-Go-20 pump delivers 20 units of insulin over 24 hours (20/24 units = 0.83 units per hour). The delivery devices are also available in 30- and 40-unit systems. Each pump is capable of delivering an additional 36 units of prandial insulin throughout the day through the discrete depression of a bolus button on the side of the pump.
Some people require less insulin with this system for the same clinical effect compared with MDI because the delivery method is more effective. The NDC code for each pump size indicates that the device should be dispensed as a drug rather than as a device. As such, the V-Go is covered by most insurance companies, including Medicare and Medicaid.
Disadvantages of the V-Go include the potential for insurance coverage issues, the potential for skin irritation from the adhesive pad, and a risk for infections at the infusion site. It is also less specific than an insulin pump, providing only one non-adjustable basal rate and fixed dosed boluses in 2-unit increments. Finally, this device should be removed before any magnetic resonance imaging (MRI) testing.40
Insulin Pumps
Insulin pumps were first introduced more than 30 years ago in the United States. Approximately 400,000 people use insulin pump therapy in the United States today.41 Insulin pumps are a good option for people who are on multiple daily insulin injections.
Insulin is delivered from a reservoir in the insulin pump and provides a basal amount of a single insulin dose through a transcutaneous catheter. Further boluses of insulin can be manually provided in response to carbohydrate ingestion. Insulin pumps are battery-powered devices with software that allow patients to program in advance, temporarily adjust, or suspend insulin basal infusion rates. In addition, insulin pumps can deliver precise boluses. Insulin pumps deliver different basal insulin rates throughout the day based on changes in insulin sensitivity, which allows for greater precision for bolus insulin dose delivery relative to carbohydrate intake and absorption from the gastrointestinal tract. Rapid- or short-acting insulin should be used in the pump. Although not FDA-approved, Humulin R U500 insulin has been used successfully off label in insulin pumps to improve A1c without an increase in hypoglycemia.42,43 Insulin pumps are attached to patients by one of two means: 1) an infusion set consisting of long, thin, flexible tubing with a catheter or a stainless steel needle on the end that is inserted into the patient’s subcutaneous tissue, or 2) a tubing-free pump, also known as a patch pump, that is attached with a subcutaneous needle-inserted catheter and self-adhesive tape. The patient programs and operates the pump or the pump’s remote control device to deliver insulin doses that match individual needs.
Programmable Settings on an Insulin Pump
Basal rates are programmed by the provider. The basal insulin release is intended to replicate physiologic insulin release. For patients on subcutaneous injections, this replaces their glargine or detemir dose.
Typically, patients who switch from injections to a pump need less insulin. It is customary to set the first pump dose at 75-80% of the previous injection dose to reduce the chance of hypoglycemia.
Many patients with type 1 diabetes and some with type 2 diabetes utilize carbohydrate counting to make the mealtime insulin match what they are about to eat. Then patients can estimate what they are about to eat and count the carbohydrate grams (or exchanges) at the meal. This number can be input into the pump and the insulin pump will calculate what dose of insulin is needed for that amount of carbohydrates. .
Most people who are on subcutaneous injections have a “sliding scale” or correction scale. This is set to correct to a desired target range. For example, if target glucose is 100 and the correction factor is 50, then the patient will take correction insulin when he/she is above 100, 1 unit for every 50 mg/dL above 100. A pump can dispense a fraction of a unit, e.g., 0.5 units if the glucose is 125 mg/dL.
At a meal, a person can enter information for the carbohydrate content and current glucose into the pump. If the glucose is below the target range, the pump will automatically subtract insulin from the dose about to be given, allowing the person to bolus for a meal if below target and allowing him not to drop immediately.
Suspend Feature. Patients with an insulin pump who have a hypoglycemic episode first should suspend the pump so that no additional insulin is administered until it is safe again, and then treat the low. An ED patient who is acutely ill or injured should have their insulin pump suspended until they are stabilized. Glucose metabolism is often quite variable in acute disease and it is best to treat any significant hyperglycemia with subcutaneous or intravenous insulin.
Often after patients take a correction dose of insulin, their glucose is still high. If the second correction is given before the first correction has taken full effect, patients are at higher risk for dropping low by “stacking their insulin.” Patients taking injections cannot know how much of the insulin from their meal is still working, so they make an educated guess about much additional insulin to take. With an insulin pump, the amount of time that insulin is acting can be programmed, which limits the amount of additional insulin that can be given with subsequent boluses within that window of time. In other words, this feature prevents patients from taking repeated injections while the previous injection is still acting, thus avoiding “stacking insulin.”
The pump allows patients to increase or decrease the current basal for a set amount of time to respond to a change in their activity, physical state, or glucose. Often, the programmed basal rates will work for normal days but there will be exceptions that necessitate more or less insulin. For example, when a person gets sick with a respiratory illness or when a woman is menstruating, the glucose levels will rise significantly. Under these circumstances, patients can change their basal rate to a set level or by a percentage.
Advantages and Disadvantages of Insulin Pump Therapy
Intensive glucose control has clearly been shown to reduce microvascular complications in type 1 and type 2 diabetes as well to reduce macrovascular complications later in the disease.45-47 Intensive insulin therapy can include multiple daily insulin injections (MDI) or insulin pump therapy (CSII). Multiple studies have shown that insulin pump therapy with rapid-acting analog insulin improves glucose control and reduces hypoglycemia compared to MDI in type 1 diabetes.48-54 Insulin pump therapy is also equally effective in type 2 diabetes. The majority of patients (93%) with type 2 diabetes prefer insulin pump therapy over MDI.55,56
A 2010 Cochrane review compared insulin pump therapy to MDI and found that insulin pump therapy has better A1c reduction, improves quality of life, and appeared to reduce overall hypoglycemia rates.57
Complications associated with CSII include potential skin reactions to tape, diabetic ketoacidosis risk if the pump malfunctions, infusion-site problems (tunneling of insulin or clogged infusion set), and inactivated insulin (due to heat) that can lead to ketoacidosis in a few hours.58
Insulin pump patients must be familiar with the use of multiple daily injections in case of mechanical failure. In addition, pump patients should always carry rapid-acting insulin pens and needles in case the insulin pump malfunctions.
Problem Solving with Insulin Pumps
Patients who are pumping need to keep backup supplies, such as quick-acting insulin pens, in case of pump failure. In the case of mechanical failure, patients should contact the pump company directly. Most companies will replace the pump within 24 hours.
The Future of Insulin Pump Therapy
Currently, only one company in the United States has a commercially available integrated system that links glucose monitoring to insulin pump therapy. However, most insulin pump companies are working on this capacity. One pump in the United States has a sensor augmented system in which the pump will shut off for 2 hours if the glucose drops low.60 This technology has been shown to reduce the risk of severe hypoglycemia and nocturnal hypoglycemia with similar glucose-lowering effects.60,61
Manufacturers are constantly developing new technologies to improve insulin pumps. Researchers are designing artificial intelligence software to recognize glucose patterns and to alert patients and providers to possible need for changes in basal or bolus doses. In the future, there likely will be simplified and more rapid data downloading and improved connectivity. Transmission of CGM and control of insulin infusion rates by small devices with remote displays and alarms also are in development.61,62 Smartphones will be able to act as data integrators to allow sharing of information from multiple meters, CGM, and pumps between patients and clinicians. Modified smartphones with built-in glucose testing and pump controllers are also in development.62
A recent study tested a “bionic” pancreas with a linked sensor and dual hormone (insulin and glucagon) pump for people with type 1 diabetes.63 This system improved glucose control and reduced hypoglycemia compared to current insulin pump therapy. With these advances, the future of insulin pump therapy appears to be very bright.
Summary
Insulin is an increasingly important component of diabetes treatment. The number of people requiring insulin is likely to rise dramatically in response to the pandemic of obesity facing our nation and the increased rates of type 2 diabetes. The use of insulin, with new more physiologic insulins and advanced delivery methods, can be effective and convenient across a wide profile of patients. With the continued development of “smarter” pumps, the management of one of the most common chronic conditions is becoming safer and more effective.
Acknowledgements: The authors would like to thank Samantha Shubrook, MA, for her extensive editorial assistance in this manuscript.
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With the continued development of “smarter” pumps, the management of one of the most common chronic conditions is becoming safer and more effective.
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