Matching Insulin to Patient: How to Make the Best Use of Premixed Insulin Analog Formulations
Article Outline
Abstract
When prescribing, health care professionals have to weigh multiple options in terms of efficacy, cost, safety, practical patient-centered issues, and our precious, limited time. Innovations in insulin therapy for the treatment of type 2 diabetes include not only the development of premixed insulin analogs but easy-to-use delivery systems as well. This article is intended as a guide for defining the advantages and disadvantages of premixed analogs with a focus on identifying patients who would benefit from using them.
Keywords: Premixed insulin analogs , type 2 diabetes , case-based approach
What kind of toothpaste do you buy? Is it the cavity-fighting whitening formula, the original toothpaste that you remember from childhood, or whatever is on sale? Do you lighten your coffee with 2% milk, Half and Half, light cream, soy, skim, or whole milk? The explosion of consumer choices can paralyze us. Although sometimes we stick with the tried and true or boldly take a chance with something new, the choices can be overwhelming. The same explosion of new products applies to health care as well. But in your professional life, the therapies you prescribe have far greater implications. Our either/or world has evolved to multiple options, and health care professionals have to weigh the options in terms of efficacy, cost, safety, practical patient-centered issues, and our precious, limited time.
This rings especially true in the complex world of diabetes management in which numerous treatment options are available. Innovations in insulin therapy for the treatment of type 2 diabetes include not only the development of premixed insulin analogs but easy-to-use delivery systems as well. This article is intended as a guide for defining the advantages and disadvantages of one group of insulin formulations known as premixed insulin analogs with a focus on identifying patients who would benefit from using them.
Create the Space
Because our minds are cluttered with so many treatment options, it helps to create the best space for using a specific treatment. Premixed insulin analog formulations fill the space revealed when the patient
Single injection addresses fasting and postprandial blood glucose
The ideal insulin therapy would match physiologic time-action profiles of insulin secretion that would be expected in a person without diabetes. When the pancreas produces the amount of insulin required to keep blood glucose levels within the appropriate range, the background or basal insulin secretion is at a relatively constant rate of 0.25 to 1.5 U/hour. This basal secretion provides the anabolic functions of insulin, such as storing glycogen, and counteracts ongoing hormonal glycemic influences. Food stimulates the pancreas to secrete a biphasal bolus of insulin so that the food can be metabolized. The first phase of insulin is released immediately. The second phase follows 30 to 45 minutes after a meal, and secretion of insulin returns to baseline within 2 to 4 hours.
Basal-bolus therapy, using multiple daily injections of insulin or an insulin pump, is often used to approach this profile, but both options involve a level of complexity that may not be suitable for all patients. The action of rapid-acting insulin analogs mimics that of physiologic insulin secretion in terms of both rapid onset and high peak activity. Premixed insulin analogs retain these pharmacokinetic advantages of rapid-acting analogs while providing simultaneous basal coverage through their intermediate-acting insulin analog component. As a result, premixed insulin analogs can be used as a single formulation that addresses both basal and postprandial insulin needs.
Three premixed insulin analog formulations are available for patients to use. Humalog Mix 75/25 (insulin lispro 75/25) consists of 75% insulin lispro protamine combined with 25% soluble insulin lispro, Humalog Mix 50/50 (insulin lispro 50/50) consists of 50% insulin lispro protamine combined with 50% soluble insulin lispro, whereas NovoLog Mix 70/30 (insulin aspart 70/30) consists of 70% insulin aspart protamine with 30% soluble insulin aspart.
The soluble and insoluble fraction of each formulation results in rapid onset and intermediate duration of action, respectively. The important point is that a single peak in serum insulin level follows administration of premixed insulin analogs, as opposed to the two peaks that one might expect to result from mixtures of regular human insulin and NPH.1, 2
Type 2 diabetes is a progressive disease. β-cell deterioration in type 2 diabetes occurs progressively, and eventually the pancreas cannot synthesize and secrete enough insulin to meet the demands of patients with insulin resistance.3 Although insulin secretion can be boosted with secretagogues and the action of endogenous insulin can be enhanced with sensitizers, pancreatic β-cell failure occurs over time. In addition, recent studies have shown that control of postmeal glycemia is as important as keeping fasting readings within range.4 Twice daily premixed insulin analog dosing may be sufficient for basal coverage while also addressing postprandial insulin requirements in many patients. In a randomized trial of insulin aspart 70/30 versus regular human insulin 70/30 each dosed twice daily, the premixed insulin analog had a greater effect on postprandial blood glucose, although no significant difference was observed in hemoglobin A1C after 12 months of use. In addition, after lunch blood glucose readings (between injections) were significantly improved within the insulin aspart group, providing evidence for the efficacy of twice-daily premixed insulin analogs.5 Similarly, improved glycemic control was reported for insulin lispro 75/25 over regular human insulin 70/30.6
No mixing errors
Learning to mix different insulin formulations accurately takes considerable time and effort, both for the patient and members of the health care team. Many patients new to insulin therapy may already feel overwhelmed by the self-injection process, blood glucose monitoring, and other aspects involved in managing diabetes. The additional complexity of self-mixing insulin is unlikely to provide a welcoming transition period. No one can argue that beginning with a single daily dose of a premixed insulin analog provides a more simplified and manageable approach to initiating therapy.
Simple and convenient insulin delivery
The best part of using premixed insulin analogs is that simple and convenient insulin delivery devices are available for patient use. Both disposable and reusable pens are reimbursed and part of prescription formularies. Together with short, small-gauge pen needles, insulin penlike devices remove one of the most common objections to insulin use: the cumbersome, impractical preparation of a syringe using a vial of insulin. They can be stored at room temperature, which eliminates yet another barrier to insulin administration (Table 1).
Table 1. Insulin Pens for Premixed Insulin Analog Formulations
| Insulin Formulation | Storage at Room Temperature, d | Amount Delivery, U | Delivery System |
|---|---|---|---|
| Humalog Mix 50/50 | 10 | 1-60 | Disposable pen |
| Humalog Mix 75/25 | 10 | 1-60 | Disposable pen |
| NovoLog Mix 70/30 | |||
| NovoLog Flex Pen | 14 | 1-60 | Disposable pen |
| NovoPen 3 | 14 | 2-70 | Durable pen/disposable cartridge |
| NovoPen Junior | 14 | 1-35, in half-unit increments | Durable pen/disposable cartridge |
| Innovo | 14 | 1-70 | Durable pen/disposable cartridge |
Consistent with the concept of creating the space, patients need to be prepared from diagnosis that treatment with insulin is one of many options that may be used over a lifetime with type 2 diabetes because of the potential decline of the β-cell. Insulin is never used as a threat; rather nurse practitioners need to create the space for insulin therapy as a potential treatment option. Advanced practice nurses are skilled at supporting patients through the emotional transition to insulin therapy. Insulin therapy is fraught with emotional symbolism. Many patients associate insulin with disability and death or feel that they failed by not taking care of themselves. Injection barriers are usually quickly overcome, but the emotional barriers require the support and counsel of a skilled practitioner.
Making the Match
Who are the ideal candidates for premixed insulin analogs?
Francine is a 56-year-old woman who was diagnosed with type 2 diabetes at age 44. She has participated in diabetes self-management education and describes her best efforts with making healthful food choices and exercise. She has been taking metformin, glimepiride, and rosiglitazone, yet her fasting and postprandial blood glucose readings remain elevated. Her hemoglobin A1C is creeping toward 8%. She cries when you mention insulin and begs for another chance.
Despite your best efforts of presenting insulin as just another treatment option, Francine fears insulin. When you ask her what is the one thing that bothers her most about insulin, Francine tells you the story of her friend whose life is so limited because she has to carry syringes, keep her insulin cold, and wait a half hour before she can eat. Francine stops crying when you show her an insulin pen. “I can do that,” she tells you. You prescribe a low dose of a premixed insulin analog and begin teaching.
Emilio's diabetes was diagnosed when his wife insisted that he see you after their vacation when he visited every restroom they encountered. Emilio is 45 years old and overweight. His hemoglobin A1C is 13.2%, and his fasting blood glucose reading is 415 mg/dL.
You recognize that changes in Emilio's eating habits, weight loss, and exercise will all have a positive effect on his blood glucose, but right now he is symptomatic and glucotoxic. You prescribe a premixed insulin analog twice per day delivered by a pen and explain to Emilio and his wife that you are prescribing insulin to quickly reduce his blood glucose and help him feel better. With reversal of glucotoxicity and return of some β-cell function, lifestyle changes and oral agents may be effective in achieving glycemic targets. After you have explained the plan of action and need for follow-up, Emilio and his wife agree to see a dietitian. Among all the things that Emilio has learned from you is that insulin is not a big, bad wolf.
Lillian is a thin, 80-year-old woman whom you are following during an acute admission for pneumonia. Lillian will be discharged to home, where she resides alone. As the pneumonia resolves, she will need to continue the insulin therapy used during her hospitalization.
Between Meals on Wheels and her neighbors, Lillian is confident that she will have healthful food options as her appetite improves. You choose to use a premixed formulation packaged in the Innolet, which is an insulin doser with a large kitchen timerlike dial. Although the premixed formulation is not an analog, it is the delivery device that matches this patient's needs. Independent-spirited Lillian embraces the Innolet. She can see the numbers and easily manipulate the device. Careful follow-up by you and home care nurses ensures a safe discharge.
Silvia, age 63, comes back for her follow-up visit feeling defeated. She just cannot tolerate the gastrointestinal side effects of metformin despite your efforts with adjusting the dosing and timing. Her fasting and postdinner blood glucose readings are elevated, and she is undereating from fear of raising her blood glucose.
You agree that Silvia should discontinue metformin and begin to discuss insulin therapy. Silvia is relieved and admits that she will be eager to eat a meal again. You prescribe a predinner injection of a premixed insulin analog delivered by a pen. She agreed to continue to monitor her 2-hour postdinner and fasting blood glucose and see you again in 2 weeks.
Syed is a busy, 48-year-old thin man who works 2 jobs and does not put much effort into his diabetes management because it is not a priority. He forgets to take his predinner medications because he is not home and eats on the run. His hemoglobin A1C is approaching 10%, and he complains of fatigue.
The one anchor in Syed's life is that he has breakfast at home at the same time every day. You have adjusted as many medications as you can so he can take them in the morning, but he needs insulin therapy. After considerable discussion, you and Syed decide that an injection of a premixed insulin analog before breakfast would be the first step. You know it is not ideal, and that with his lifestyle he would probably benefit from the flexibility of a basal and bolus regimen using multiple injections, but agreeing to one injection was a big step for Syed. By making an effort to treat the physiologic cause of his fatigue and respecting him as the decision maker, you have established a relationship of mutual trust that you can build on in future visits.
Advantages and Disadvantages
Clearly, the advantages of using premixed insulin analogs especially with a pen are summed up in the phrase more bang for your buck. Premixed insulin analogs provide physiologic replacement of insulin, ease of delivery, greater patient convenience, and a less time-intensive approach to easing patients into treatment with insulin. The rapid onset of action allows patients using premixed insulin analogs to inject closer to meal time, as compared with those using regular human insulin that, not which requires dosing 30 minutes before eating.
Premixed insulin analogs may be initiated as a single daily dose administered before the main evening meal and supplemented with metformin or a secretagogue to provide glycemic control during the daytime. Practitioners usually prescribe premixed insulin analogs in twice daily doses, immediately before breakfast and the main evening meal. The initial cumulative dose for insulin-naive patients is usually less than 0.40 U/kg divided according to the patient's meals and blood glucose readings. Coffee for breakfast and postbreakfast readings less than 200 mg/dL would require a lower dose than a large dinner meal with postprandial readings greater than 300 mg/dL. Overweight patients require higher doses of insulin because of greater insulin resistance. Although 0.4 to 0.8 U/kg can be used as an initial daily dose in overweight patients, many patients with type 2 diabetes need a total daily dose of 1.0 to1.2 U/kg to achieve a hemoglobin A1C of less than 7%.7
The initial dose is increased by 2- to 4-U increments every 3 to 4 days until reaching target blood glucose values.8 Targeted blood glucose monitoring allows for dose adjustment without multiple skin punctures. If you are adjusting the evening dose, ask the patient to check before dinner, 2 hours after dinner, and before breakfast for a few days.
Renal disease can affect the pharmacokinetics of insulin. Exercise, illness, stress, alcohol, and travel may necessitate dose adjustments.
When using premixed insulin formulations, keep in mind that a modification in dose changes the effect of 2 phases of insulin action, so small dosage adjustments can have a large effect. Similarly, if a patient's meal times vary widely, then consider a different insulin formulation, because timing of injections will have an effect on efficacy.
Patient education surrounding insulin therapy includes not only direction about timing, dosage, and use of the pen device but also symptoms and treatment of hypoglycemia with emphasis on prevention. Culturally relevant literature coupled with web-based resources provide reinforcement of your teaching efforts.
Premixed insulin analog formulations offer multiple benefits for patients with diabetes. By matching the insulin formulation to the patient's needs, you can easily identify the best candidates for premixed insulin analogs.
References
- . Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart . Eur J Clin Pharmacol. . 2000;56(5):399–403
- Time-action profiles of novel premixed preparations of insulin lispro and NPL insulin . Diabetes Care. . 1998;21(5):800–803
- UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients. UKPDS Group . Metabolism. . 1990;39(9):905–912
- . Optimal glycemic control in type 2 diabetes mellitus: fasting and postprandial glucose in context . Arch Intern Med. . 2004;164(5):486–491
- Premixed insulin aspart 30 vs premixed human insulin 30/70 twice daily: a randomized trial in type 1 and type 2 diabetic patients . Diabetic Med. . 2002;19(5):393–399
- Humalog Mix 25 improves 24-hour plasma glucose profiles compared with the human insulin mixture 30/70 in patients with type 2 diabetes mellitus . S Afr Med J. . 2003;93(3):219–223
- . Using new insulin strategies in the outpatient treatment of diabetes: clinical applications . JAMA . 2003;289(17):2265–2269
- . Insulin therapy in type 2 diabetes . Endocrinol Metab Clin North Am. . 2001;30(4):935–982
PII: S1555-4155(06)00678-7
doi:10.1016/j.nurpra.2006.09.005
© 2007 American College of Nurse Practitioners. Published by Elsevier Inc. All rights reserved.