Clinical Care/Education/Nutrition O R I G I N A L
A R T I C L E
Improved Postprandial Glycemic Control During Treatment With Humalog Mix25, a Novel Protamine-Based Insulin Lispro Formulation PARIS ROACH, MD LILLY YUE, PHD
VIPIN ARORA, PHD THE HUMALOG MIX25 STUDY GROUP
OBJECTIVE — Humalog Mix25 is a manufactured premixed insulin formulation containing insulin lispro and a novel insulin lispro-protamine formulation (NPL) in a ratio of 25:75%. The objective of this study was to compare Humalog Mix25 to human insulin 30/70 (30% regular insulin/70% NPH) with respect to glycemic control. RESEARCH DESIGN AND METHODS — Humalog Mix25 was compared with human insulin 30/70 in 89 individuals with type 2 diabetes during a 6-month randomized open-label two-period crossover study. Each insulin was administered twice daily, before the morning and evening meals. Information regarding self-monitored blood glucose (BG), hypoglycemic episodes (hypoglycemic signs or symptoms or BG #3.0 mmol/l), insulin dose, and HbA1c was collected. RESULTS — Treatment with Humalog Mix25 resulted in better postprandial glycemic control after the morning and evening meals compared with treatment with human insulin 30/70. Overall glycemic control and the incidence of hypoglycemia were comparable between the treatments. CONCLUSIONS — In comparison to treatment with human insulin 30/70, twice daily administration of Humalog Mix25 resulted in improved postprandial glycemic control, similar overall glycemic control, and the convenience of dosing immediately before meals. Diabetes Care 22:1258–1261, 1999
njection of short- and intermediate-acting insulin mixtures twice daily, typically before the morning and evening meals, is an effective and convenient insulin treatment regimen (1). Twice-daily regimens provide glycemic control similar to that achieved with multiple daily injections in patients with type 2 diabetes (1). Manufactured premixed insulin formulations consisting of fixed ratios of regular and NPH human insulins are commonly used within twice-daily regimens and account for ,40%
I
of insulin use worldwide (IMS Health, unpublished observations on file at Eli Lilly). These formulations offer convenience and increased dosing accuracy in comparison to insulins mixed from separate vials (3,4). They are also particularly well suited for use in insulin injection pen devices, obviating the need for two injections from separate devices. Insulin lispro is a rapid-acting insulin that exhibits a higher and earlier peak of activity and a shorter duration of action compared to regular human insulin (5).
From Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana. Address correspondence and reprint requests to Paris Roach, MD, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 2042, Indianapolis, IN 46285. E-mail:
[email protected]. Received for publication 19 January 1999 and accepted in revised form 19 April 1999. This work was sponsored by Eli Lilly and Company. P.R., L.Y., and V.A. hold stock in Eli Lilly. Abbreviations: BG, blood glucose; NPL, neutral protamine lispro. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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These characteristics of insulin lispro result in better postprandial blood glucose (BG) control and a lower risk of hypoglycemia compared to regular human insulin (6,7). Insulin lispro also provides the convenience of immediate premeal injection, whereas regular human insulin must be injected 30–45 min before meals to provide optimal postprandial BG control (8). Because insulin lispro and NPH human insulin are often used in combination, premixed insulins consisting of insulin lispro and an intermediate-acting insulin referred to as NPL (neutral protamine lispro) have been developed. NPL is a protamine-based insulin lispro formulation in which insulin lispro has been co-crystallized with protamine to produce an intermediate-acting insulin with an activity profile similar to that of NPH (9,10). NPL is used, instead of NPH, because of an exchange between soluble insulin lispro and protamine-bound human insulin that occurs with prolonged storage (weeks to months) of insulin lispro–NPH mixtures. Because this exchange occurs over a prolonged period of time, it is not an issue within the context of mixing insulin lispro and human NPH from separate vials for immediate injection. A manufactured mixture containing 25% insulin lispro and 75% NPL (Humalog Mix25) has been formulated. This lispro:NPL ratio was chosen based on previous clinical experience with the use of self-prepared mixtures of insulin lispro and NPH (16). The objective of this study was to compare a manufactured mixture containing 25% insulin lispro and 75% NPL (Humalog Mix25) to human insulin 30/70 (30% regular human insulin, 70% NPH) within a twice-daily injection regimen with respect to standard measures of glycemic control: selfmonitored BG, HbA1c, insulin dose requirements, and the occurrence of hypoglycemia. (Note: Manufactured fixed ratio mixtures of 30% regular human insulin and 70% NPH are referred to as 70/30 in the U.S. (e.g., Humulin 70/30, which is 30% human insulin injection [recombinant DNA origin] [regular] and 70% human insulin isophane
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Table 1—Patient characteristics Treatment sequence Humalog Mix25; Human 30/70; human 30/70 Humalog Mix25 n Female Male Age (years) BMI (kg/m2) Duration of diabetes (years) Duration of insulin therapy (years)
44 21 23 56.5 28.3 12.8 5.8
45 26 19 57.4 29.4 11.5 3.7
Data are n or means.
suspension [NPH]; Eli Lilly, Indianapolis, IN and as 30/70 in other countries.) RESEARCH DESIGN AND METHODS Patient population Patient demographics are outlined in Table 1. Patients were invited to participate if they had type 2 diabetes according to World Health Organization criteria (11), were between the ages of 18 and 75 years, and had received insulin therapy using mixtures of short-acting or rapid-acting insulin (regular insulin or insulin lispro) and intermediate- or long-acting insulin twice daily (self-mixed or manufactured) for at least 30 days before their enrollment in this study. Patients were excluded if they had an HbA1c concentration .9.2%, significant renal, hepatic, or cardiac disease, cancer, drug or alcohol abuse, insulin allergy, recurrent severe hypoglycemia, anemia, hemoglobinopathy, proliferative retinopathy, or BMI .35 kg/m2; were lactating, pregnant, or intended to become pregnant; or were being treated with oral antidiabetic agents, systemic glucocorticoids, or insulin doses .2.0 U/kg. The study protocol was approved by the ethical review committee of each participating center. All patients gave informed consent according to Good Clinical Practice guidelines and the Declaration of Helsinki. Study design This study was a 6-month open-label randomized crossover clinical trial conducted in three countries (Spain, South Africa, and the U.K.) at a total of 12 sites. At the initial visit, a complete history and physical examination were performed. Patients were then treated with human insulin 30/70 before the morning and evening meals for a 2- to
4-week lead-in period. All insulin preparations were provided at a concentration of 100 U/ml in cartridge/pen injection devices (Becton Dickinson, Franklin Lakes, NJ). After the lead-in period, baseline studies were performed, and 89 patients were randomized to one of two treatment sequences: twice-daily therapy with Humalog Mix25 (Eli Lilly, Indianapolis, IN) given before the morning and evening meals for 3 months, followed by twice-daily therapy with human insulin 30/70 (Humulin 70/30, Eli Lilly) given before the morning and evening meals for an additional 3 months or the alternate treatment sequence. Patients were asked to measure capillary BG before and 2 h after the morning and evening meals on 6 days during the week before the baseline visit and the 2- and 3-month visits of each study period using a commercially available handheld BG meter with memory capacity (Accu-Chek Advantage; Boehringer Mannheim, Indianapolis, IN). On 2 of the 6 days, these four readings were supplemented by four additional readings, so that an eight-point BG profile was obtained including measurements before and 2 h after meals (morning, midday, and evening meals), at bedtime, and at 3 A.M. The values obtained were recorded in a diary, and study-site personnel validated the BG values recorded in the diary against the corresponding values stored in the memory meter. HbA1c measurements were performed by a central laboratory (Covance, Indianapolis, IN) using high-performance cation exchange chromatography (reference range 4.3–6.1%) at baseline and at the end point of each study period. Between each visit, patients recorded hypoglycemic episodes in their study diary. A hypoglycemic episode was defined as: 1) any time a patient experienced a symptom or another person observed a sign that was believed to
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be associated with hypoglycemia, or 2) a BG measurement ,3.0 mmol/l. The incidence of hypoglycemia was defined as the percentage of the total number of patients experiencing at least one hypoglycemic episode since the preceding visit. The rate of hypoglycemia was defined as the number of episodes of hypoglycemia since the last visit normalized to a 30-day period, and the rate was expressed as episodes per patient per 30 days. For each episode of hypoglycemia, patients were asked to indicate whether they were able to self-treat, and if they were aware that their BG was low. Patients recorded the insulin dose and the time the insulin dose was administered in their diary on the days the eight-point BG profiles were performed. BG values, insulin dose data, and information regarding hypoglycemia from the 3-month visit were reported and analyzed as end-point values. According to the intentto-treat approach, data from the last visit during the study period were carried forward to the end point when 3-month data were unavailable. Statistical methods A last-value-carried-forward analysis, which included all data from all patients by the treatment they received, was performed. All comparisons were performed using two-tailed tests with a nominal significance level of 0.05. All CIs were computed as two-tailed using a 95% significance level. Both parametric and nonparametric analyses were performed using methods suggested by Koch (12), Taulbee (13), and Grizzle (14). The statistical model used to analyze the BG and HbA1c data included a term for treatment-bycountry interaction. A statistically significant treatment-by-country interaction would indicate that the observed difference between the treatments differed among the countries participating in the study. RESULTS — A total of 80 patients completed the study. Nine patients (10.1%) discontinued from the study, six during period 1 (five during treatment with human insulin 30/70 and one during treatment with Humalog Mix25) and three during period 2 (two during treatment with human insulin 30/70 and one during treatment with Humalog Mix25). During period 1, one patient was lost to follow-up, one was found to have not met entry criteria, one discontinued due to investigator decision, and three discontinued due to 1259
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personal conflict/patient decision (including one patient receiving Humalog Mix25). During period 2, one patient was found to have not met entry criteria (the patient being treated with Humalog Mix25), one discontinued because of a protocol violation, and one discontinued because of investigator decision. Mean insulin doses were similar or identical between the treatments. The mean morning insulin doses were 0.37 and 0.36 U/kg and the mean evening insulin doses were 0.28 and 0.27 U/kg for Humalog Mix25 and human insulin 30/70, respectively. The median time intervals between insulin injections and meals were 28 min (interquartile range 19–31) for human insulin 30/70 and 3 min (0–6) for Humalog Mix25. Figure 1 shows the results of self-blood glucose monitoring. The 2-h postprandial BG after the morning meal was significantly lower during treatment with Humalog Mix25 (Humalog Mix25 8.95 ± 2.17 vs. human insulin 30/70 10.00 ± 2.28 mmol/l, P = 0.017, two-sample t test). The 2-h postprandial BG after the evening meal was also significantly lower during treatment with Humalog Mix25 (Humalog Mix25 9.28 ± 2.51 vs. human insulin 30/70 10.27 ± 2.76 mmol/l, P = .014, two-sample t test). BG concentrations at other time points were not significantly different between the two treatments. The HbA1c level was 7.8% after treatment with Humalog Mix25 and 8.1% after treatment with human insulin 30/70 (P = 0.408, two-sample t test). Glycemic profiles were similar between the countries, and no significant treatment-by-country interaction was present for any of the BG or HbA1c results presented above. Hypoglycemia was infrequent during the study in this population of patients with type 2 diabetes. The incidence of hypoglycemia (the percentage of patients reporting any hypoglycemia since the previous visit) was not different between the treatments (Humalog Mix25 = 42%, human insulin 30/70 = 35%, P = 0.398, Fisher’s exact test). In order to account for varying between-visit intervals (23–37 days), hypoglycemia was also expressed as a rate per patient normalized to a 30-day interval. Because of the skewed distribution of the hypoglycemia rate, median rates are presented. As noted above, the majority of patients did not report any hypoglycemia at the end point during treatment with either Humalog Mix25 or human insulin 30/70. Thus, the median 30-day hypoglycemia rate at the end point for both treatments was 1260
0 episodes per patient per 30 days. Only 19 patients (21%) and 13 patients (15%) reported more than two episodes per 30 days during treatment with Humalog Mix25 and human insulin 30/70, respectively (P = 0.538, Fisher’s exact test). There was no difference between treatments with respect to the incidence of nocturnal hypoglycemia, defined as hypoglycemia occurring between the mean reported bedtime and the mean reported breakfast time for each country. At the end point, only 13 patients (15%) and 8 patients (9%) reported any nocturnal hypoglycemia (P = 0.266, Fisher’s exact test), and only 3 patients (3%) and 2 patients (2%) reported more than 2 episodes of nocturnal hypoglycemia per 30 days (P value not computed because of small counts) during treatment with Humalog Mix25 and human insulin 30/70, respectively. There was no difference between treatments at the end point with respect to the percentage of patients reporting hypoglycemia who also reported hypoglycemia unawareness, defined as having at least one episode of hypoglycemia during which they were not aware that they were hypoglycemic, 15 (32%) and 13 (30%) during treatment with Humalog Mix25 and human insulin 30/70, respectively. Only two patients required the assistance of a third party for hypoglycemia, one during treatment with Humalog Mix25 and one during treatment with human 30/70.
There were no clinically significant differences between the treatments with respect to the incidence of adverse events, weight, systolic or diastolic blood pressure measurements, or clinical laboratory measurements. CONCLUSIONS — In patients with type 2 diabetes who require insulin, twicedaily insulin dosing regimens are aimed at providing acceptable BG control combined with a convenient insulin dosing schedule. Because insulin lispro and NPH are commonly administered simultaneously in clinical practice, manufactured premixedinsulin formulations that combine the convenience and accuracy of a premixed insulin with the pharmacokinetics of insulin lispro are desirable. In comparison to human insulin 30/70, Humalog Mix25 given twice daily resulted in lower postprandial BG concentrations after the morning and evening meals. These differences were observed despite the shorter reported time interval between the injection and the meal during treatment with insulin lispro mixtures (3 min for insulin lispro mixtures versus 28 min for human insulin mixtures, median values). In addition, BG concentrations were not different between the treatments at any of the other time points within the eight-point BG profile. These findings are consistent with the observed difference between insulin lispro and regular human insulin with regard to postprandial
Figure 1—Mean BG values from self-monitored eight-point BG profiles at the end point. j, human insulin 30/70; , Humalog Mix25. Error bars represent SEM. DIABETES CARE, VOLUME 22, NUMBER 8, AUGUST 1999
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glycemic control (6,7), with pharmacokinetic data demonstrating that the rapid action of insulin lispro is maintained within insulin lispro-NPL mixtures (15), and with the results of a study in which insulin lispro and regular human insulin were self-mixed in various ratios and administered before the morning and evening meals in ,700 patients with type 1 or type 2 diabetes (16). In the latter study, improvement in postprandial BG levels was observed after the meals at which the self-prepared insulin mixtures were administered, whereas BG levels at other times of the day were not different between the two treatments. Thus, despite the shorter duration of action of the soluble insulin lispro component of the mixtures, afternoon and overnight glycemic control did not differ between the insulin lispro and human insulin mixtures. In addition, it is interesting to note that the HbA1c levels achieved in the self-mixing study and in the present study using manufactured fixed-ratio preparations were very similar. In the referenced study (16), HbA1c levels were 7.8% after treatment with insulin lispro/NPH and 7.9% after treatment with regular human insulin/NPH in patients with type 1 diabetes and 8.1% for both treatment groups in patients with type 2 diabetes, suggesting that the use of manufactured fixedratio insulin preparations results in similar overall glycemic control compared with the use of self-prepared insulin mixtures. The mean ratio of rapid-/short-acting to intermediate-acting insulins used in the referenced study (16) was ,25–30%. Similar findings have been noted in studies of patients with type 2 diabetes comparing premixed human insulins containing regular human insulin and NPH with self-prepared mixtures of the same insulins (17–19). Hypoglycemia was relatively infrequent during treatment with both Humalog Mix25 and human insulin 30/70 in this population of patients with type 2 diabetes. There was no difference between the treatments with respect to the incidence of hypoglycemia or the occurrence of adverse events. We conclude that twice-daily injection of Humalog Mix25, compared with human insulin 30/70 in patients with type 2 diabetes, resulted in improved postprandial BG control after the meals at which the insulins were administered, while provid-
ing the convenience of injection closer to meals. Humalog Mix25 is a favorable alternative to human insulin 30/70 in twicedaily insulin injection regimens in patients with type 2 diabetes. Acknowledgments — The authors acknowledge the contributions of the Humalog Mix25 Study Group: Birmingham, U.K.: Professor A. Barnett, BSc, MD; Cape Town, South Africa: F. Bonnici, MD; Johannesburg, South Africa: L. Distiller, BSc, MB, BCh; Cambridge, U.K.: O. Edwards; Paisley, U.K.: B. Fisher, MB, ChB, MD; Bar-celona, Spain: R. Gomis, MD, PhD, J. Mesa Manteca, MD, PhD, J. Soler, MD, PhD; Madrid, Spain: F. Hawkins, MD, PhD, Professor J. Herrera-Pombo, MD, PhD; Pretoria, South Africa: W. Lourens, MB, ChB, MMed; Salamanca, Spain: J. Miralles, MD, PhD; Liverpool, U.K.: J. Vora, MD; Valladolid, Spain: J. Zurro, MD, PhD. The authors acknowledge the assistance of Kenneth E. Robertson, PharmD, in the preparation of this manuscript.
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