Insulin Therapy

*Available in prefilled, disposable pens or cartridges for reusable pens.

†Note difference between Novolin 70/30 (70% NPH/30% regular) and NovoLog Mix 70/30 (70% aspart protamine/30% rapid-acting aspart).

Insulin delivery devices

There are a variety of options available for insulin delivery. The most basic option is the traditional syringe. Currently available syringe needles are finer than their predecessors, and they also have special coatings designed to ease the pain of injection.[6] Syringes must accommodate the dosage of insulin required. Specifically, the 3/10 cc syringe can only be used to deliver 30 units of insulin or less. For patients requiring 50 units of insulin or less, a 1/2 cc syringe can be used. Patients who require up to 100 units of insulin will need a 1 cc syringe. Syringe needles also come in a range of gauges and lengths.[7] There are also a number of devices available to assist patients in giving injections. Such devices include spring-loaded syringe holders that insert the needle by pressing a button and attachments designed to conceal the needle when administering an injection.

One alternative to the traditional syringe is the insulin pen. An insulin pen is a multidose device that delivers insulin by dialing the appropriate dosage.

Pens are a convenient way to provide accurate dosing. However, insulin types cannot be mixed in pens, and not all insulin types are available in pen form. Further, there may be challenges associated with reimbursement of insulin pens due to the higher cost of pens relative to traditional syringes.

The jet injector is a needle-free alternative for insulin injection that may be helpful for patients with needle phobia. Jet injectors work by using a powerful stream of insulin that penetrates the skin. Although jet injectors do not require a needle to inject insulin, they may cause bruising.[7]

The insulin pump is yet another option for insulin delivery. Also known as continuous subcutaneous insulin infusion (CSII), insulin pumps can provide insulin delivery that more closely mimics normal physiology. Insulin pumps are small devices that are worn externally and hold insulin in a reservoir. The insulin reservoir is connected to plastictubing attached to a flexible cannula. The cannula is inserted using a guide needle that is removed after insertion. Only rapid-acting or short-acting insulin is used in pumps, and it is delivered as both basal and bolus insulin.[8] Although pump therapy has been shown to improve metabolic outcomes, it requires a high level of patient education and involvement.[9] It is also a costly method of insulin delivery.

Inhaled insulin is the newest delivery option.[10] The first FDA-approved inhaled insulin is Exubera, a rapid-acting insulin in dry powder form. Other powdered insulins currently in late-stage clinical trials include Technosphere (which uses lattice arrays of spherical particles and 18% insulin), and AIR (which has a porous, low-density particle permitting a duration of action that extends for days).[11] The AERx Insulin Diabetes Management System, also in late-stage clinical trials, uses liquid insulin with a proprietary inhaler designed to facilitate the proper breathing technique needed for optimal administration.[11] The safety and efficacy of Exubera for patients with type 1 and type 2 diabetes has been evaluated in short-term, randomized, controlled trials.[11,12,13,14] Pulmonary function should be assessed prior to initiating inhaled insulin therapy, after the first 6 months of therapy, and annually thereafter.[4 ]Patients treated with Exubera for up to 2 years had a decline in pulmonary function.[4]

Insulin therapy

Type 1 diabetes

In type 1 diabetes, insulin threapy is initiated at the time of diagnosis. The first objective is to correct any existing metabolic abnormalities, such as moderate hyperglycemia or diabetic ketoacidosis (DKA).[15] If DKA is not present, then newly diagnosed type 1 patients may be managed on an outpatient basis, as this approach has been determined to be both safe and efficacious.[16]

After the acute hyperglycemic crisis has been resolved, an insulin regimen must begin. Choice of insulin regimen should take into account patient metabolic needs, schedule and lifestyle, willingness to monitor and take injections, and ability to understand the complexities of an insulin regimen.[16] Attaining contemporary standards of glycemic control will usually require intensive therapy using multiple daily injections (MDI) of insulin,[17] which has been shown to be effective for reducing the risk of microvascular complications.[18] All intensive therapy regimens requires self-monitoring of blood glucose (SMBG) at least 4 times a day. Among current MDI regimens, a basal-bolus regimen permits the greatest flexibility accommodating irregular meals, activity patterns, or sleep schedule. [18] The basal-bolus regimen uses short- or rapid-acting insulin before each of 3 daily meals in addition to a basal insulin. For patients unable or unwilling to perform frequent SMBG and/or insulin injections, an alternative is to maintain a consistent pattern of meal times, food intake, physical activity, and sleep schedule together with 2 daily injections of a mixture of short- or rapid- and intermediate-acting insulins.[18] Alternative insulin regimens using between 3-6 MDI may be constructed to accommodate individual needs.[18] Patients experiencing excessive hypoglycemic events on MDI may be candidates for insulin pump therapy.[19]

A variety of factors affect insulin requirements. Food consumption, glucose level, and activity level should be considered when making decisions about insulin dose. There are also numerous factors that affect the rate at which insulin is absorbed, including factors related to insulin preparation, injection site, and other external factors[11,16,20,21] A summary of factors affecting insulin absorption and insulin action appears in Table 3.

Table 3. Factors affecting injected insulin absorption and action

Table 4. Factors affecting inhaled insulin absorption and action

Because there are numerous factors that affect insulin absorption and insulin action, insulin regimens require frequent adjustment in order to maintain optimal metabolic control. When metabolic goals are not being met, it is important to consider a variety of potential reasons for this outcome, including recent change in insulin type (eg, from short-acting to rapid-acting), changes in β-cell function (eg, beginning or end of honeymoon phase), suboptimal injection technique, changes in lifestyle, life stressors, change of season (and concomitant changes in activity), menstrual periods, other hormonal changes such as onset of puberty or menopause, illness or injury, and gastroparesis.[16]

Type 2 diabetes

The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the efficacy of tight glycemic control for the prevention of complications among people with type 2 diabetes.[22] Because type 2 diabetes is progressive, monotherapy with any one agent is generally only effective for a period of five years. Traditionally, initial treatment is done with lifestyle modification, then progresses to a single oral agent, multiple oral agents, and then finally to insulin therapy. This approach is problematic because of the repeated metabolic failures, which increase the likelihood of complications and decrease motivation to adhere to treatment. Accordingly, the earlier addition of insulin to the treatment regimen may be a useful way to prevent complications and achieve tight glycemic control.[23]

The issue of when to initiate insulin therapy in a patient with type 2 diabetes is one of considerable debate.[25] There is some evidence to suggest that newly-diagnosed patients wtih type 2 diabetes should take a brief course of insulin to correct hyperglycemia and improve insulin sensitivity and insulin secretion[25] although this approach is not commonly used. Earlier insulin use raises concerns about side effects such as weight gain and hypoglycemia. More traditionally, insulin initiation has been done when oral medications failed. However, critical issues to consider are 1) what defines failure, and 2) how much time should elapse before insulin is initiated. Ideally, failure should be defined as any patient not meeting glycemic targets on oral medications, and insulin should be initiated as soon as that failure is identified. However, a recent study demonstrated that both primary care physicians and specialists were failing to advance a majority of patients to insulin therapy, in spite of inadequate glycemic control with oral medications.[26] One major barrier to the timely initiation of insulin therapy is the number of resources required to do so.[27]

When advancing a patient with type 2 diabetes to insulin therapy, there are 3 main approaches that have been used: 1) addition of a basal insulin along with 1 or more oral medications, 2) addition of a prandial insulin along with 1 or more oral medications, and 3) cessation of oral medications and initiation of twice-daily NPH insulin combined with rapid-acting insulin (usually in a premixed formulation). All of these approaches have been shown to assist patients in meeting glycemic targets.[29,20,31]

Insulin self-administration

Patients must go through a series of steps when administering an insulin injection.[8] The first step is to inspect the insulin vial to check for crystallization, clumping, or discoloration. If any of these situations occur, the vial should be discarded. After hands have been washed, the insulin vial should be gently rolled, and the top should be wiped with alcohol. Next, the plunger should be pushed to the correct number of units required, inserted into the vial, and pushed to empty the air into the vial. Following that, the insulin should be drawn into the syringe, taking a few extra units to make up for air bubbles that will need to be pushed out. The syringe should then be gently tapped to remove air bubbles, checking to ensure that the dose is still correct. Finally, the skin should be lightly pinched, and the needle should be inserted. The plunger should be pushed slowly, and the patient should wait 5 seconds before removing the syringe. Then the syringe can be disposed of in a sharps container. Patients starting on insulin therapy need to be properly educated on this technique.

Conclusion

Insulin therapy is an essential component of treatment for type 1 diabetes and is taking on an increasing role in the treatment of type 2 diabetes. With proper patient education and timely initiation of insulin therapy, patients can be assisted in their pursuit of glycemic targets.

References

1. Insulin. Diabetes Forecast. January 2005. RG10-RG15.
2. Apidra: Insulin Glulisine [rDNA origin] injection. Available at: http://www.aventis-us.com/RIs/apidra_TXT.html.Accessed July 28, 2005.
3. Levemir: Insulin Detemir. Available at: http://www.novonordisk.com/diabetes/hcp/pharmaceuticals/Levemir/prescribinginformation.asp.Accessed July 28, 2005.
4. Exubera (insulin human [rDNA origin]) inhalation powder. Available at: http://www.pfizer.com/pfizer/download/uspi_exubera.pdf. Accessed June 6, 2006.
5. Lantus: Insulin Glargine [rDNA origin] injection. Available at: http://www.aventis-us.com/PIs/lantus_TXT.html. Accessed August 2, 2005.
6. Insulin Delivery. Diabetes Forecast. January 2005. R16-R35.
7. Costello M. Insulin syringes, pens, and glucose monitoring equipment. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY; 2002:21-46.
8. Beaser RS, Gallego MC. Physiologic insulin treatment programs. In: Beaser RS and the Staff of the Joslin Diabetes Center eds. Joslin’s Diabetes Deskbook: A Guide for Primary Care Providers, Revised Edition. Boston, MA;2003:273-329.
9. Weissberg-Benchell J, Antisdel-Lomagio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care. 2003;26:1079-1088.
10. Mandal TK. Inhaled insulin for diabetes mellitus. Am J Health-Syst Pharm. 2005;62:1359-1364.
11. Garg S, Rosenstock J, Silverman BL, et al. Efficacy and safety of preprandial human insulin inhalation powder versus injectable insulin in patients with type 1 diabetes. Diabetologia. 2006;49:891-899.
12. Hollander PA, Blonde L, Rowe R, et al; Exubera Phase III Study Group. Diabetes Care. 2004;27:2356-2362.
13. Skyler JS, Weinstock RS, Raskin P, et al; Inhaled Insulin Phase III Type 1 Diabetes Study Group. Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects. Diabetes Care. 2005;28:1630-1635.
14. Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes. Ann Intern Med. 2005;143:549-558.
15. Beaser RS. Designing a conventional insulin treatment program. In: Beaser RS and the staff of the Joslin Diabetes Center, eds. .Joslin’s Diabetes Deskbook: A Guide for Primary Care Providers, Revised Edition. Boston, MA: Joslin Diabetes Center; 2003:233-272.
16. Siminerio LM, Charron-Prochownik D, Banion C, Schreiner B. Comparing outpatient and inpatient diabetes education for newly diagnosed pediatric patients. Diabetes Educator. 1999;25:895-906.
17. Skyler JS. Insulin treatment. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. 4th ed. Alexandria, Virginia: American Diabetes Association; 2004:207-223.
18. Diabetes Control and Complications Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
19. Bode B. Insulin pump therapy. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. 4th ed. Alexandria, Virginia: American Diabetes Association; 2004:224-231.
20. American Diabetes Association. Insulins. Available at http://www.diabetes.org/uedocuments/Insulin-tables.pdf. Accessed April, 2004.
21. American Diabetes Association. Insulin administration. Diabetes Care. 2004;27 (suppl 1):S106-S110.
22. United Kingdom Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 1998;352:845-865.
23. LeRoith D, Levetan CS, Hirsch IB, Riddle MC. Type 2 diabetes: the role of basal insulin therapy. J Fam Pract. 2004;53:215-222.
24. Eldor R, Stern E, Milicevic Z, Raz I. Early use of insulin in type 2 diabetes. Diabetes Res Clin Pract. 2005;68(suppl 1):S30-S35.
25. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care. 2004;27:1028-1032.
26. Shah BR, Hux JE, Laupacis A, Zinman B, van Walraven C. Clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians? Diabetes Care. 2005;28:600-606.
27. Hayward RA, Manning WG, Kaplan SD, Wagner EH, Greenfield S. Starting insulin therapy in patients with type 2 diabetes: effectiveness, complications, and resource utilization. JAMA. 1997;278:1663-1669.
28. Riddle MC. Making the transition from oral to insulin therapy. Am J Med. 2005;118:14S-20S.
29. 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 NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086.
30. Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28:260-265. 
31. Feinglos MN, Thacker CH, English J, Bether MA, Lane JD. Modification of postprandial hypoglycemia with insulin lispro improves glucose control in patients with type 2 diabetes. Diabetes Care. 1997;20:1539-1542.