Mixing Insulin Glargine With Rapid-Acting Insulin: A Review of the Literature

Address correspondence to Dana G. Carroll, PharmD, BCPS, CDE, 850 5th Avenue East, Tuscaloosa, AL 35401. Mixing Insulin Glargine With Rapid-Acting Insulin: A Review of the Literature Dana G. Carroll, PharmD, BCPS, CDE, and Lisa Meade, PharmD, CDE Purpose. To review the literature examining the mixing of insulin glargine with rapid-acting insulin (RAI). Methods. A literature search was conducted via PubMed and Medline (from 1948 to August 2012) using the search terms “diabetes,” “insulin glargine,” “short acting insulin,” “rapid acting insulin,” and “mixing.” Literature was limited to English-language articles reporting on human studies. Studies with data describing mixing glargine with any short-acting insulin or RAI were included. Four studies met inclusion criteria. Results. Of the four studies assessing mixing glargine, one was a pharmacokinetic study. The other three assessed clinical outcomes in “real-world” settings. All of these studies were conducted in pediatric patients with type 1 diabetes. Two of the clinical outcomes studies did not report significant differences in A1C levels or preprandial, postprandial, or nocturnal blood glucose levels from mixing glargine and RAI. One of the clinical outcome studies reported improved blood glucose control (A1C and fasting blood glucose) with RAI mixed with glargine compared to RAI mixed with NPH insulin. There were no significant differences in hypoglycemia in any of the clinical outcome trials at any time measured. Conclusion. Initial small clinical trials indicate that there are no significant changes in clinical outcomes (blood glucose levels, A1C levels, and hypoglycemia) when mixing glargine with RAI. Additional studies with larger patient populations and longer trial durations are needed before mixing glargine with RAI can be recommended on a routine basis in clinical practice. Type 1 diabetes accounts for about 5–10% of patients with diabetes; however, 75% of patients diagnosed with type 1 diabetes are < 18 years of age.1 The benefits of intense insulin therapy to lower A1C and prevent diabetes-related complications are well documented. Insulin glargine, the first oncedaily basal insulin approved by the U.S. Food and Drug Administration (FDA), is used in regimens to treat patients with type 1 or type 2 diabetes.2 The clear, colorless solution of glargine is buffered to a pH of 4 and is completely soluble at this level. After injection, a microprecipitate forms at the injection site that delays and prolongs glargine’s action. The FDA warns against mixing glargine with other insulins because of its pH and solubility.2 Therefore, basal-bolus therapy with glargine increases the number of daily injections compared to regimens using intermediate-acting NPH insulin. However, glargine offers less hypoglycemia than NPH because it is relatively peakless.3 Glargine is, however, more expensive than NPH. The treatment of diabetes in children presents a number of challenges, including pain at injection sites, frequent injections, injection-related anxiety (pain or needle phobia), fear of hypoglycemia, and concerns about weight gain. The insulin regimen must be acceptable to patients 113 Diabetes Spectrum Volume 26, Number 2, 2013 Feature Article / Carroll and Meade and their family, while achieving glycemic control and minimizing hypoglycemia. In patients 8–21 years of age, compliance decreases with frequency of injections.4 Some clinicians try to minimize the number of injections by mixing glargine with a rapid-acting insulin (RAI) despite FDA warnings against this practice. This review examines the data on mixing glargine with an RAI. Methodology A literature search was conducted via PubMed and Medline (articles published from 1948 to January 2012) using the search terms “diabetes,” “insulin glargine,” “short-acting insulin,” “rapid-acting insulin,” and “mixing.” The search was limited to articles published in English describing human studies. Studies with data describing mixing glargine with any short-acting insulin or RAI were included. Four studies met these inclusion criteria. Literature Review Four trials have been published regarding the mixing of insulin glargine and an RAI.5–8 Cengiz et al.5 conducted a glucose clamp study in 11 adolescents (six males and five females, mean age 15.1 ± 3 years) with type 1 diabetes. This trial compared the pharmacodynamic and pharmacokinetic effects of administering glargine mixed with insulin lispro to administering glargine separately. Patients had diabetes for at least 1 year and were on continuous subcutaneous insulin infusion for at least 3 months. The participants were admitted to the hospital the night before the study and randomized to receive 0.2 units/ kg of lispro and 0.4 units/kg of glargine, either mixed or not mixed. The insulins were mixed at room temperature immediately before the injection. The insulin pump was suspended before the dose was given. Two clamp studies were performed, with patients receiving the opposite treatment regimen during the second study, which was within 4 weeks of the first clamp study. Both the pharmacodynamic and pharmacokinetic profiles were altered with the mixing of glargine and lispro. The peak effect of lispro was significantly reduced in the mixing group (separate 7.1 ± 1 vs. mixed 3.9 ± 1 mg/kg/minute, P = 0.04). With regard to pharmacokinetics, the peak concentration of lispro was significantly less and the time to peak action was significantly delayed in the mixing group (Table 1). Mixing the two insulins flattens and delays the lispro peak. These results might lead to poorer control of postmeal glucose levels. One limitation of this study is the use of a fixed 1:2 ratio of lispro to glargine. The insulin lispro dose could be increased to overcome the delay and diminished action peak. The delay of action with the lispro can be > 5 hours. Clinically, there could be an increased risk of nocturnal hypoglycemia if lispro and glargine were dosed at supper. The results in this study are consistent with the results observed in previous animal studies when mixing regular insulin with glargine (delayed onset of action and a delayed time to maximum effect).5 Kaplan et al.6 conducted a 30-day crossover study in 14 pediatric patients (6 male; mean age 13.5 ± 0.5 years) with type 1 diabetes. This trial compared the efficacy of mixing glargine with either lispro or aspart insulin and administering the doses twice daily compared to once daily. Continuous glucose monitoring (CGM) was used to assess each regimen. Patients used glargine at baseline once daily with three to four injections of an RAI. Patients were randomized to one of two groups with a crossover design: 1) separate injections (glargine before breakfast and before supper and RAI with each meal, and 2) mixed (pre-breakfast and pre-supper glargine mixed with an RAI and an RAI dose at lunch). Each patient underwent three studies over a 4to 6-week period. Patients continued each regimen for 10 days, and CGM was performed during the final 3 days of each regimen. There was no significant difference in hypoglycemia, preprandial glucose, or postprandial glucose levels between baseline, separate, and mixed groups (Table 1). However, the mixed group experienced lower nocturnal blood glucose levels, and the authors cautioned that titration of the evening dose of glargine may be required to prevent hypoglycemia. This study was conducted under real-life conditions, and there was no difference in pain or reported reactions with the mixed regimen. The study did document cloudiness when glargine was mixed with lispro or aspart, which is consistent with data on file with the manufacturer regarding glargine mixing.2 Limitations of this study include a lack of discussion about the actual insulin doses and the short study duration (10 days for each study group). Fiallo-Scharer et al.7 conducted a 24-week prospective, case-control study in 110 pediatric patients (70 male; mean age 13.4 ± 3.8 years in the mixed group and 12.9 ± 4.0 years in the nonmixed group) with type 1 diabetes. This trial compared the efficacy and safety of administering glargine mixed with either lispro or aspart to that of glargine administered separately from an RAI. The patients mixing insulin (n = 55) were matched with controls (n = 55) based on age, sex, duration of diabetes, and use of identical types of insulin but who were not mixing before administration. Patients were allowed to continue the doses and frequency of insulin administration they had been using at the time of enrollment for both glargine and their RAI. Data were collected for 6 months before and 6 months after enrollment. The primary outcome was change in A1C. There was no significant difference between the two groups in A1C at 6 months (mixing 8.54 ± 1.14 vs. nonmixing 8.61 ± 1.14%, P = 1.0). There also were no significant differences in the incidence of nonsevere hypoglycemia, severe hypoglycemia, or diabetic ketoacidosis at 3 or 6 months (Table 1). However, it should be noted that four patients in the mixing group chose to discontinue mixing because of an increased frequency of hypoand hyperglycemic episodes. The strengths of this trial included a well-matched controlled group and a 6-month follow-up period. Limitations included the study design, lack of blinding, lack of standardized insulin dosing and frequency, and the fact that 15% of 114 Diabetes Spectrum Volume 26, Number 2, 2013 Feature Article / Mixing Glargine and Rapid-Acting Insulin Feature Article / Mixing Glargine and Rapid-Acting Insulin Ta b le 1 . T ria ls A ss es si ng G la rg in e M ix in g T ri al c ha ra cte ri st ic s C en gi z et a l., 2 01 0 5 K ap la n et a l., 2 00 4 6 Fi al lo -S ch ar er e t a l., 2 00 6 7 H as sa n et a l., 2 00 8 8 D es ig n R an do m iz ed , o pe nla be l, 2da y du ra ti on R an do m iz ed , c ro ss ov er , 3 0 -d ay du ra ti on Pr os pe ct iv e, c as eco nt ro l, 12 -m on th d ur at io n R an do m iz ed , c on tr ol le d, 3m on th d ur at io n R eg im en (s ) L is pr o ve rs us li sp ro m ix ed w it h gl ar gi ne N on m ix ed g la rg in e + lis pr o or as pa rt v er su s gl ar gi ne m ix ed w it h lis pr o or a sp ar t M ix ed g la rg in e w it h lis pr o or a sp ar t v er su s no nm ix ed gl ar gi ne p lu s lis pr o or a sp ar t tw ic e da ily M ix ed g la rg in e w it h lis pr o or as pa rt v er su s m ix ed N PH w it h lis pr o or a sp ar t t w ic e da ily n 11 14 11 0 (5 5 in e ac h gr ou p) 42 (2 1 in e ac h gr ou p) Pa rt ic ip an ts • Ty pe 1 d ia be te s • E th ni ci ty n ot r ep or te d • M ea n ag e 15 .1 ± 3 y ea rs • Se x no t r ep or te d • M ea n du ra ti on o f d ia be te s no t r ep or te d • B as el in e A 1C 7 .6 ± 0 .6 % • Ty pe 1 d ia be te s • E th ni ci ty n ot r ep or te d • M ea n ag e 13 .5 ± 0 .5 y ea rs • 6 m al e • M ea n du ra ti on o f d ia be te s 44 ± 8 m on th s • B as el in e A 1C 7 .7 ± 0 .2 % • Ty pe 1 d ia be te s • E th ni ci ty n ot r ep or te d