Vol. 14 •Issue 11
• Page 28
CE Offering
A Work in Progress
With Insulin Therapy, Change Is Inevitable
By Shey Larson, NP, CDE
Continuing Education Offering: The goal of this article is to educate nurse practitioners about insulin therapy. Nurse practitioners may obtain 2 contact hours by reading this article and earning a passing score on the test that follows. For immediate test results, take the quiz online at www.advanceweb.com/np.
How to Obtain Contact Hours by Reading This Article
Instructions: Nurse practitioners may receive 2 contact hours by reading the article noted below and earning a passing score on the accompanying quiz.
To obtain credits:
1. Read the article "A Work in Progress. With Insulin Therapy, Change Is Inevitable," carefully noting the tables and other illustrative materials provided to enhance your knowledge and understanding of the content.
2. Read each question and record your answers on the registration form provided.
3. Fill out the evaluation portion completely. You will not receive CE credit if this section is not completed.
4. Type or print your full name and address in the space provided on the registration form.
5. Forward the completed registration form with your check or money order for $10.00 payable to Merion Publications, or provide your credit card information. Quizzes are accepted up to 24 months from publication.
Continuing Education Credit: Merion Publications Inc. is approved as a provider of continuing education in nursing (Provider #011-3-H-04) by the Pennsylvania State Nurses Association, which is accredited as an approver of continuing education in nursing by the American Nurses Credentialing Center Commission on Accreditation, the California Board of Registered Nursing (Provider #CEP 13230) and the Florida Board of Nursing (Provider #CEP 3298). California and Florida participants must retain certificates for 4 years.
Answers to the posttest will be graded, and you will be advised of your score within 30 to 60 days of receipt of the completed test. A score of 70% or above comprises a passing grade.
A certificate will be awarded to participants who successfully complete the test. Participants who score less than 70% can re-test one time for no additional charge. No refunds are provided.
Objectives: The purpose of this article is to educate nurse practitioners about insulin therapy. After reading this article, the nurse practitioner should be able to:
describe basal and bolus insulin needs in type 1 and type 2 diabetes
outline typical barriers to insulin initiation
describe typical insulin regimens for type 1 and type 2 diabetes
identify principles to be followed when designing a safe, effective insulin regimen.
Directions: On the registration form, check the box next to the best answer.
'Marie," age 66, is a retired secretary who was diagnosed with type 2 diabetes 7 years ago. She could not tolerate metformin (Glucophage) and has been using glyburide (Glucovance) and pioglitazone (Actos) at maximum doses. Over the last year, her hemoglobin A1c (HbA1c) has risen steadily. The most recent reading was 8.9%. What is the next step?
"Larry," age 31, is a sales representative who was diagnosed 4 years ago with type 1 diabetes. Since his diagnosis, he has been taking injections of neutral protamine hagedorn (NPH) and regular insulin twice a day. His HbA1c is 6.9%. He tells you he is experiencing hypoglycemia two to three times a week before lunch. Should anything in his treatment regimen be changed?
Determining the most effective insulin regimen for any patient requires careful consideration of many factors: basic pathophysiology of type 1 and type 2 diabetes, typical barriers to insulin use, the types and characteristics of available insulins, the variety of possible regimens, patient factors that affect outcomes, and the pros and cons of each regimen.
The importance of tight glycemic control in patients with either type of diabetes is well established. Tight glucose control decreases long-term microvascular complication rates.1-3 Unfortunately, surveys show that only 29% of patients with diabetes have their HbA1c tested each year.4 Of those patients who do test annually, 18% have an HbA1c of 9.5% or higher, signifying poor control. Only 43% have an HbA1c level less than 7%; the median is 7.5%.
The American Diabetes Association recommends that patients achieve HbA1c levels of less than 7%. The association further recommends preprandial plasma glucose targets of 90 mg/dL to 130 mg/dL and postprandial targets of less than 180 mg/dL. The American Association of Clinical Endocrinologists recommends even tighter goals: HbA1c of less than 6.5%, preprandial blood glucose levels less than 110 mg/dL, and postprandial glucose less than 140 mg/dL.5,6
Basal and Bolus Insulin
Every human body requires a continuous but low level of insulin in the blood stream, often called basal insulin. In response to rising glucose levels after a meal or snack, the pancreas quickly secretes additional insulin. This is known as bolus insulin. Insulin promotes entry of glucose from the blood stream into cells, as well as other metabolic tasks.
The normal pancreas secretes 25 to 50 units of insulin daily.7 About half the insulin typically acts as a basal insulin, while the other half meets bolus needs. Absolute insulin deficiency (type 1 diabetes) or relative insulin deficiency (type 2 diabetes) may lead to elevated blood glucose levels and dramatic alterations in metabolic pathways.
Insulin in Type 1 Diabetes
Type 1 diabetes is defined by absolute insulin deficiency. An autoimmune process destroys the pancreatic beta cells that produce insulin. Patients with type 1 diabetes require insulin every day to survive. The average patient with type 1 diabetes requires approximately 0.5 to 1.0 units per kilogram of body mass per day. In most cases, about half of this is bolus insulin, and half is basal insulin.8 Understanding the need for basal and bolus insulin to mimic the body's normal physiologic response to food intake is imperative to achieving tight glycemic control while minimizing possible side effects, namely hypoglycemia.
Insulin in Type 2 Diabetes
Type 2 diabetes accounts for 90% to 95% of all diagnosed cases of diabetes.9 This disease involves both insulin resistance and insulin deficiency. Type 2 diabetes typically begins with insulin resistance. Blood glucose levels often remain normal for several years as insulin secretion increases in the presence of rising insulin resistance. Beta cell function then slowly declines and eventually results in insulin deficiency.10
Beta cell function and insulin secretion continue to decline over time. According to one study, 50% of beta cell function has already been lost by the time of diagnosis.1 A steady declines follows: 53% of patients with type 2 diabetes who are initially treated with sulfonylureas require insulin within 6 years of diagnosis, and almost 90% require insulin within 9 years of diagnosis.10-12 An average patient with type 2 diabetes may need as much as 1.2 units of insulin per kilogram of body mass per day. Some patients may need even more.8 A clear understanding of this natural progression of type 2 diabetes will aid in determining appropriate therapy in a timely manner.
Barriers to Insulin Use
Despite the knowledge that insulin deficiency requires exogenous insulin administration and that it is not atherogenic, many providers and patients have concerns about the use of insulin.1 For some, these concerns and fears lead to an unnecessary and dangerous delay in appropriate therapy. It is imperative that these issues be addressed.
Professional Barriers
For providers, the process of initiating and adjusting insulin doses and concerns about the complexity of the various regimens can be barrier to insulin therapy. Insulin initiation has changed considerably with the use of premixed insulins and pen devices.
Although not appropriate for all patients, these advances can make starting insulin in an office setting much easier and more efficient. To further ease the burden of initial education, a less complex regimen can be started and changed over time, based on the patient's ability and glycemic response to the regimen.
Research into alternative methods of insulin delivery (inhaled, oral and aerosolized) appears promising.13 In fact, the first inhaled insulin, Exubera, is now on the market. Exubera (insulin human DNA origin) inhalation powder is a rapid-acting insulin indicated for the treatment of adults with diabetes. In patients with type 1 diabetes, it should be used in regimens that include a basal insulin.14 In patients with type 2 diabetes, it can be used as monotherapy or in combination with oral agents or basal insulin.14
Exubera blisters contain human insulin produced by recombinant DNA technology. The inhalation powder is administered using the inhaler packaged with the drug. Due to an increased risk of hypoglycemia, Exubera is contraindicated in patients who smoke or have discontinued smoking less than 6 months prior to therapy initiation.Exubera is also contraindicated in patients with unstable or poorly controlled lung disease secondary to variations in lung function that could affect absorption of Exubera. Long-term safety and effectiveness in children have not been established.
For providers working with patients to start insulin therapy, help is also available in the form of diabetes education. Although not easily accessible in all parts of the country, diabetes management and education programs are available at most large health care systems. If the patient's insurance plan covers their services, certified diabetes educators (CDEs) can take the burden of teaching off the provider in the primary care setting.
Patient Barriers
Table 1 outlines common concerns voiced by patients and their families when starting insulin. Assessing for these fears and addressing them immediately can help patients and their families more quickly adjust to and accept insulin treatment. This adjustment and acceptance are crucial.
One study evaluated patient views of the burden of therapy and its impact on self-management. Although insulin was viewed as burdensome at the outset of therapy, the researchers found that ongoing use can reduce a patient's perception of this therapy.15
Types of Insulin
All insulins are equally effective in lowering blood glucose levels.7 Some insulins are designed to mimic basal insulin action, and some are designed to mimic bolus insulin action. Table 2 lists insulins available in the United States and outlines their onset, peak and duration.
Figure 1 illustrates insulin action curves. Bovine and pork insulins are no longer available in the United States. In this country, insulins are now produced by recombinant DNA technology. New "designer" insulins (lispro, aspart, glulisine, glargine and detemir) are made by substituting amino acids in the insulin molecule. This alters its action and allows for a closer match with normal physiologic insulin production from the pancreas.16 Humulin U (Ultralente) and Humulin L (Lente) preparations are no longer available.
Conventional Regimens for Type 1
Twice-daily regimens (Figures 2 and 3) are a relatively simple option. Food intake is timed to match the insulin action.17 A morning injection of regular or a rapid-acting analogue mixed with some intermediate-acting insulin covers bolus insulin needs at breakfast and lunch, and a similar mixture before the evening meal covers dinner bolus needs and overnight basal needs. Patients can mix the insulins in a syringe, use premixed preparations with syringes or pens, or use two insulin pens at the same time.
Twice-daily regimens limit the number of injections required. If a premixed preparation is used, the patient purchases only one type of insulin, and the risk of insulin errors decreases.
Although basic regimens such as these have been used for many years, they do not allow for much flexibility, may lead to more hypoglycemia, and may not achieve the level of glycemic control possible with the more physiologic basal-bolus regimens.18-21 In patients with type 1 diabetes, twice-daily regimens should only be used if other options are not possible. Studies of these regimens have supported bedtime dosing of NPH insulin. This strategy may reduce nocturnal hypoglycemia and HbA1c levels for patients with type 1 diabetes.22 But because of the peak of action in the NPH insulin and the inflexibility and increased risk of hypoglycemia, most patients with type 1 diabetes now opt for a more advanced or intense regimen.
Intense Regimens for Type 1
Since the results of the Diabetes Control and Complications Trial were published in 1993, researchers have been attempting to determine the most efficient and safest regimens to administer basal and bolus insulin in type 1 diabetes. These regimens allow for the insulin to be timed to match the patient's desired mealtime schedule and lifestyle (Figure 4).
Basal choices include NPH preparations or the new long-acting insulin analogues glargine (Lantus) and detemir (Levemir). Numerous studies have documented a reduction in the frequency of hypoglycemia with long-acting analogues.23,24 Glargine and detemir may also have an added benefit of no appreciable weight gain in patients with type 1 diabetes.25,26 These drugs would be considered an optimal choice for a patient with type 1 diabetes.
Basal insulin is not designed to meet bolus insulin needs with meals or snacks. Its role is to keep blood glucose levels stable during the night or between meals during the day. Therefore, appropriate bolus insulin administration with a regular or a rapid-acting insulin analogue is necessary with virtually all meals and snacks to avoid postprandial spikes in blood glucose levels.17 For patients who enjoy snacks or eat small frequent meals, many injections per day are necessary.
Bolus choices include regular insulin or one of the rapid-acting insulin analogues. Many research studies in adults and children have examined the use of the new rapid-acting analogues lispro (Humalog), aspart (Novolog) and glulisine (Apidra) for bolus insulin needs. The analogues' physiologic action more closely approximates normal insulin secretory response. The rapid onset of action allows for dosing immediately before food intake with more specific postmeal coverage. The shorter duration of action with the analogues decreases the incidence of hypoglycemia.27-29
A reduction in HbA1c is not always achieved with the new analogues. One research team reviewed studies that used different combinations of insulins. No reduction in HbA1c was achieved by switching from NPH to glargine or switching from regular insulin to lispro or aspart. Only in a population of patients with a lower baseline HbA1c did substituting glargine for NPH with a mealtime bolus of lispro decrease episodes of hypoglycemia and HbA1c.18 A meta-analysis published in 2004 noted a slight improvement in HbA1c with rapid-acting insulin analogues.29 Nonetheless, it is clear that the use of the new analogues leads to a reduction in hypoglycemia.
Continuous subcutaneous insulin infusion (CSII) or pump therapy offers an alternative mode of basal and bolus insulin infusion through an external insulin pump. This approach to insulin therapy will not be discussed in this article.
Conventional Regimens for Type 2
For patients with type 2 diabetes, the level of insulin deficiency can help determine the appropriate insulin regimen. A popular initiation regimen is to start with long-acting insulin (NPH, glargine or detemir) once daily in conjunction with oral agents.30,31 The Treat-to-Target Trial studied the ability of bedtime NPH and bedtime glargine insulin added to previously used oral therapies to reduce HbA1c to less than or equal to 7% over 6 months.31 The researchers used a specific titration algorithm that sought a target fasting plasma glucose of 100 mg/dL. The trial verified that starting basal insulin this way can be highly effective in reaching the 7% HbA1c — and that although the analogues are usually more expensive, it was safer to use the new basal insulin analogues to prevent hypoglycemia.31
Some experts feel strongly that this should be viewed as a transitional regimen only.8 Patients should be carefully monitored, and home blood glucose records and HbA1c reductions should be closely documented. As in the Treat-to-Target Trial, aggressive adjustment may be necessary. If targets are not met, quick advancement to a new regimen would be in the patient's best interest.
As with type 1 diabetes, twice-daily insulin has long been used in type 2 diabetes treatment to meet basal and bolus insulin needs with as few injections as possible. The introduction of new premixed insulins that use rapid-acting analogues rather than regular insulin and NPH in the 70/30 mixture has also made this option more attractive. Studies have compared lispro (Humalog) and aspart (Novolog) premixed insulin with once-daily glargine (Lantus) given in conjunction with oral agents. The twice-daily analogue premixed insulins were superior to the basal insulin, producing a lower HbA1c and fewer hypoglycemic episodes.32,33 This would suggest that using the new analogue mixtures is a good first regimen for some patients with type 2 diabetes.
As in patients with type 1 diabetes, type 2 patients may benefit from moving the evening NPH to bedtime, particularly if fasting blood glucose levels remain high or the patient experiences nocturnal hypoglycemia.22 This might result in a regimen with a premixed preparation before breakfast, a rapid-acting preparation at dinner, and NPH at bedtime. Although patients are using three types of insulin in this scenario, many prefer it because they appreciate not having to inject insulin at lunchtime. The regimen requires careful planning of food choices at lunchtime.
Significant evidence supports the continuation of metformin with premixed insulins.34-36 Some research suggests that continuing rosiglitazone (Avandia)or pioglitazone (Actos) would also be helpful, but these drugs can be more problematic in terms of weight gain and cost.36
Regardless, the use of a twice-daily regimen with or without oral agents does allow for administration of bolus and basal insulin in a simple regimen. However, it does not allow much flexibility and may lead to hypoglycemia if food intake and meal timing are not designed to match insulin actions. If a patient has not met HbA1c and home blood glucose targets, education to improve consistency in planning and scheduling of meals may be all that is necessary.
Intense Regimens for Type 2
Providers are often reluctant to prescribe more intense basal bolus regimens for type 2 diabetes. Obviously, not all patients would be able or willing to give multiple injections to meet basal and bolus insulin needs throughout the day. Many researchers point out, however, that mimicking the body's physiologic response to food intake may be the most effective way to optimize glycemic control, reduce the risk of hypoglycemia and provide flexibility.8,30,31
Although it seems overwhelming to some patients and providers, starting with a basal insulin and titrating the dose to meet target fasting blood glucose levels is a logical first step to starting these physiologic regimens. Adding insulin at meal and snack times based on postprandial tests helps the patient see the direct relationship between the bolus insulin and the meal or snack consumed. Set bolus doses require consistent intake.
Basic carbohydrate counting education with a certified diabetes educator or registered dietitian can help patients determine approximate units-per-carbohydrate ratios that can be used to vary food and beverage intake. Starting with logical, set doses based on typical intake and transitioning to a more complex regimen as the patient learns more about carbohydrates and how the insulins work will allow the patient to tailor the regimen to his or her abilities and desires.
Some studies show that patients prefer a qualitative strategy to care rather than a simple but inflexible regimen.18 Physiologic regimens allow patients to see the effect of each insulin injection more clearly and therefore encourage better self-management and insulin adjustment. For the patient who is willing and able to understand these concepts and take more insulin injections, these regimens allow flexibility in scheduling and intake and can reduce the incidence of hypoglycemia. Physiologic regimens are therefore a suitable option for patients with type 2 diabetes.
Putting It Into Practice
A number of factors influence decisions about insulin regimen (Table 3). Be realistic about which regimen is best, and encourage creative problem solving to meet actual insulin needs as appropriately as possible.
The number of regimens available today is great. An effective regimen should incorporate principles such as the following:
Barriers to insulin use must be overcome, and insulin must be used in adequate total doses to control blood glucose levels.
The regimen must appropriately meet both basal and bolus needs.
The risk of hypoglycemia must be acceptable.
The patient must be involved in decision making about insulin treatment.
The regimen must be appropriate for the patient's lifestyle.
The regimen must be reasonable considering the patient's abilities.
It is often said that some insulin is better than none. Although this may be true, considering the epidemic of diabetes today and the seemingly poor control many patients achieve, we must avoid assuming that all patients want a simple regimen. We must not assume that once a regimen is begun, no changes will be needed. Providers must be willing to help the patient frequently and realistically evaluate his or her level of control.
We must continuously support, educate and encourage the patient toward the regimen that will help meet the recommended targets safely and effectively.
References
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2. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus: The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977-986.
3. Shichiri M, et al. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;(23 suppl 2):B21-B29.
4. Saaddine JB, et al. A diabetes report card for the United States: quality of care in the 1990s. Ann Intern Med. 2002;136(8):565-574.
5. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004;27(suppl 1):S15-S35.
6. American Association of Clinical Endocrinologists and the American College of Endocrinology. AACE Diabetes Guidelines. Endocrine Practice. 2002;8(Suppl 1):41-82.
7. Vivian EM, et al. Insulin strategies for type 2 diabetes mellitus. Annals of Pharmacotherapy. 2004;38(11):1916-1923.
8. Franz MJ, ed. A Core Curriculum for Diabetes Education: Diabetes Management Therapies. 5th ed. Chicago, Ill.: American Association of Diabetes Educators; 2003:108.
9. Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2003. Atlanta, Ga.: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2004.
10. Berganstal RM. Optimization of insulin therapy in patients with type 2 diabetes. Endocrine Practice. 2000;6(1):93-97.
11. Wright A, et al. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study. Diabetes Care. 2002;25(2):330-336.
12. Turner RC, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirements for multiple therapies. JAMA. 1999;281(21):2005-2012.
13. Rosenstock J, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2005;143(8):549-558.
14. Exubera package insert. Pfizer, 2006.
15. Vijan S, et al. Brief report: the burden of diabetes therapy. JGIM. 2005;20(5):479-482.
16. White JR, et al. Novel insulins and strict glycemic control. Postgrad Med. 2003;113(6):30-36.
17. Mazze RS, et al. Staged Diabetes Management. A Systematic Approach. Minneapolis, Minn.: International Diabetes Center; 2000:138.
18. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific reviews. JAMA. 2003;289(17):2254-2264.
19. Alemzadeh R, et al. Flexible insulin therapy with glargine insulin improved glycemic control and reduced severe hypoglycemia among preschool aged children with type 1 diabetes mellitus. Pediatrics. 2005;115(5):1320-1324.
20. Hershon K, Blevins T. Once-daily insulin glargine compared with twice-daily NPH insulin in patients with type 1 diabetes. Endocrine Practice. 2004:10(1):10-17.
21. Roach P, et al. Effects of multiple daily injection therapy with Humalog mixtures versus separately injected insulin lispro and NPH insulin in adults with type 1 diabetes mellitus. Clin Ther. 2004;26(4):502-510.
22. Fanelli CG, et al. Administration of neutral protamine hagedorn insulin at bedtime versus with dinner in type 1 diabetes mellitus to avoid nocturnal hypoglycemia and improve control. A randomized, controlled trial. Ann Intern Med. 2002;136(7):504-514.
23. Yki-Jarvinen HA, et al. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care. 2000;23(8):1130-1136.
24. Ratner RE, et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care. 2000;23(5):639-643.
25. Raskin P, et al. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care. 2000;23(11):1666-1671.
26. Chapman TM, Perry CM. Spotlight on insulin detemir in type 1 and type 2 diabetes mellitus. BioDrugs. 2005;19(1):67-69.
27. Garg SK, et al. Optimized basal-bolus regimens in type 1 diabetes: insulin glulisine versus regular human insulin in combination with basal insulin glargine. Endocrine Practice. 2005;11(1):11-17.
28. Pfutzner A, et al. Intensive insulin therapy with insulin lispro in patients with type 1 diabetes reduces the frequency of hypoglycemic episodes. Exp Clin Endocrinol Diabetes. 1996;104(1):25-30.
29. Kendall DM. Review: short-acting insulin analogues versus regular human insulin in patients with diabetes mellitus. ACP J Club. 2005;142(3):62-63.
30. Riddle MC. Making the transition from oral to insulin therapy. Am J Med. 2005;118(5A):14S-20S.
31. Riddle MC, Rosenstock J, Gerich J, on behalf of the Insulin Glargine 4002 Study Investigators. The Treat-to-Target Trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11):3080-3086.
32. Janka HU, et al. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy. Diabetes Care. 2005;28(2):254-259.
33. Malone JK, et al. Combined therapy with insulin lipro mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clin Ther. 2004;26(12):2034-2044.
34. Wulffele MG, et al. Discontinuation of metformin in type 2 diabetes patients treated with insulin. Neth J Med. 2002;60(6):249-252.
35. Yki-Jarvinen H. Combination therapies with insulin in type 2 diabetes. Diabetes Care. 2001;24(4):758-767.
36. Strowig SM, et al. Comparison of insulin monotherapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes Care. 2002;25:1691-1698.
Shey Larson is an adult acute care nurse practitioner and a certified diabetes educator at Park Nicollet Clinic in St. Louis Park, Minn.
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