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Addition of biphasic insulin aspart 30 to rosiglitazone in type 2 diabetes mellitus that is poorly controlled with glibenclamide monotherapy
CLINICAL THERAPEUTICS® / VOL. 25, NO. 12, 2003
Addition of Biphasic Insulin Aspart 30 to Rosiglitazone in Type 2 Diabetes Mellitus That Is Poorly Controlled with Glibenclamide Monotherapy Itamar Raz, MD,1 Ulrik Mouritzen, MD,2 Julius Vaz, MD,2 Tommy Hershkovitz, MD,3 Julio Wainstein, MD,4 and Ilana Harman-Boehm, MD5 1Hadassah
Ein Karem Medical Center, Jerusalem, Israel, 2Novo Nordisk A/S, Bagsvaerd, Denmark, Galilee Hospital, Nahariya, Israel, 4Wolfson Medical Center, Holon, Israel, 5 and The Diabetes Unit, Soroka University Medical Centre, Beer Sheva, Israel 3Western
ABSTRACT
Background: The incidence of type 2 diabetes mellitus (DM) is rapidly increasing worldwide. Results from large-scale studies show that tight blood glucose (BG) control improves the outcome of patients with type 2 DM. Objective: This trial assessed the short-term efficacy and tolerability of adding a thiazolidinedione (rosiglitazone [ROS]) to existing sulfonylurea (SU) therapy (glibenclamide) compared with switching to combination treatment with a premixed insulin (biphasic insulin aspart 30 [BIAsp 30], a rapid-acting insulin analog) and the thiazolidinedione in a select group of patients with type 2 DM whose metabolic control was inadequate with SU monotherapy. Methods: In this 6-week, multicenter, open-label, parallel-group trial, patients with type 2 DM whose BG level was not adequately controlled with glibenclamide monotherapy (glycosylated hemoglobin [HbA1c] 8%–13%) were randomized either to replace glibenclamide with BIAsp 30 (individually titrated dosages starting with 6–8 U BID) plus rosiglitazone (4 mg once daily) (BIAsp 30 + ROS group) or to add rosiglitazone (4 mg once daily) to their pretrial doses of glibenclamide (GLIB + ROS group). Patients measured their BG levels immediately before each of the 3 main meals, 90 minutes after the start of each meal, and at bedtime, and mean BG levels were calculated at weeks 0 (baseline), 1, 2, 4, 6, and at 2-week follow-up (week 8). The primary end point was change in mean daily BG level during treatment. Secondary end points included preprandial, postprandial, and Accepted for publication October 22, 2003. Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2003 Excerpta Medica, Inc.
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bedtime BG levels; serum fructosamine level; HbA1c; and fasting BG level, which were measured at each study visit. Tolerability was assessed using hematologic and biochemical parameters, vital signs, and physical examination. Results: Forty-nine patients (32 men, 17 women; mean [SD] age, 59.1 [8.9] years; mean [SD] body mass index, 27.7 [3.7] kg/m2) participated in the study. A significant difference was found between treatments in the change in mean daily BG level from baseline to week 6 (P = 0.01). After the 6-week treatment period, change in mean serum fructosamine level was significantly greater for BIAsp 30 + ROS compared with GLIB + ROS (P = 0.02). HbA1c decreased in both treatment groups from baseline to study end, but the difference between groups was nonsignificant. The changes in fasting BG from baseline to study end also were nonsignificant between groups. Both combinations were well tolerated. Conclusions: This short-term study in patients with type 2 DM whose BG level was poorly controlled with glibenclamide monotherapy suggests that switching to a combination of BIAsp 30 + ROS was efficacious and well tolerated and provided an alternative to adding rosiglitazone to existing glibenclamide treatment. The study also suggests that BIAsp 30 may be associated with greater improvements in short-term metabolic control. (Clin Ther. 2003;25:3109–3123) Copyright © 2003 Excerpta Medica, Inc. Key words: BIAsp 30, glycemic control, type 2 diabetes, HbA1c.
INTRODUCTION
Type 2 diabetes mellitus (DM) is a progressive disorder in which a deficiency in beta-cell insulin secretion coupled with peripheral insulin resistance results in chronic hyperglycemia, thus increasing the risk for morbidity and mortality. The incidence of type 2 DM is rapidly increasing worldwide; the worldwide prevalence of DM is 5.1% and is predicted to increase to 6.3% by 2025, with type 2 DM constituting ~85% to 95% of all cases of DM.1 The management of the disease and its complications, such as cardiovascular disease, nephropathy, and neuropathy, pose significant challenges for both patients and health care workers. Results from large-scale studies2,3 show that tight blood glucose (BG) control improves the outcome of patients with type 2 DM, particularly by decreasing the risk for microvascular complications, but not the risk for macrovascular disease.2 Importantly, research indicates that patients with type 2 DM have a delayed and diminished early postprandial insulin response4; a large body of research5–9 shows that elevated postprandial BG level plays an important role in determining risk for cardiovascular disease and death. The United Kingdom Prospective Diabetes Study Group2 addressed tight control of fasting BG (FBG) level and glycosylated hemoglobin (HbA1c), not post3110
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prandial BG level, perhaps explaining the less marked impact on cardiovascular outcomes in this study. Thus, treatments aimed at controlling postprandial BG levels among patients with type 2 DM are particularly warranted. Monotherapy with oral antidiabetic drugs (OADs) is often used as first-line therapy for reducing BG levels, although many patients do not achieve optimal control with maximal doses of 1 OAD alone, and combination therapy with OADs from different classes may be prescribed. However, although various OAD combinations may achieve adequate control of FBG level, oral treatments do not always optimally control postprandial BG level, thus limiting their overall effectiveness. Furthermore, the progressive decline in beta-cell function, which defines the natural history of type 2 DM, eventually necessitates the use of exogenous insulin in most patients.10 Neutral protamine hagedorn (NPH) insulin commonly is the first insulin to be given to patients who require intensified treatment, but its absorption rate varies and its long duration and peak of action11 may be associated with an increased risk for fasting and nighttime hypoglycemia. Furthermore, NPH insulin primarily addresses FBG levels. Thus, many patients experience difficulty achieving sufficient overall metabolic control while avoiding hypoglycemic episodes. Insulin aspart is a rapid-acting insulin analog that is homologous to human insulin, with the exception of the substitution of proline with aspartic acid at position B28. This modification results in reduced tendency of the molecules to selfassociate, leading to faster absorption and improved postprandial and long-term BG control compared with human insulin.12–15 Biphasic insulin aspart 30 (BIAsp 30) is a premixed formulation of 30% soluble aspart and 70% protamine-crystallized insulin aspart, the latter of which has a delayed pattern of absorption similar to that of NPH insulin. Phase III trials have shown BIAsp 30 to be efficacious and well tolerated and to yield favorable BG profiles compared with biphasic human insulin.16–19 BIAsp 30 provides a rapid-acting component with proven efficacy in reducing postprandial glycemia12,14,15,20 and a long-acting component to provide consistent basal control17,19 with reduced hypoglycemic risk.17,19 Although biphasic human insulin must be administered 30 minutes prior to meals, BIAsp 30 requires no waiting period before eating. Also, because BIAsp 30 is a premixed analog, fewer daily injections are necessary compared with more intensive basal-bolus therapy, appealing to patients for whom more intensified regimens may be too challenging. These features imply that regimens that include BIAsp 30 are likely to provide convenience and improved overall control while reducing the risk for hypoglycemia. This trial assessed the short-term efficacy and tolerability of adding a thiazolidinedione (rosiglitazone [ROS]) to existing sulfonylurea (SU) therapy (glibenclamide) compared with switching to combination treatment with a premixed in3111
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sulin (BIAsp 30), a rapid-acting insulin analog) and the thiazolidinedione in a select group of patients with type 2 DM whose metabolic control was inadequate with SU monotherapy. PATIENTS AND METHODS Patients
Patients with type 2 DM, based on etiology, aged ≥30 years, with a body mass index (BMI) of ≤35 kg/m2, and who were not responding to glibenclamide monotherapy were eligible for the trial. All patients had been treated with glibenclamide (7.5–15.0 mg/d) as the only antidiabetic therapy for at least 4 weeks prior to an initial screening visit and had an HbA1c of 8.0% to 13.0%. These patients may not be considered to have “failed glibenclamide therapy” because they had not yet reached the maximum recommended dose of glibenclamide when they were included in the study. Patients with any significant disease or condition (including history of drug or alcohol dependence, impaired hepatic function, or cardiac disease) or other condition deemed by the investigator as likely to affect the trial or health outcomes were excluded. Written informed consent was obtained, and the trial was conducted in accordance with the Declaration of Helsinki.21 The protocol, consent form, and patient information sheet were reviewed and/or approved by the independent ethics committees at each recruitment center. Pregnant, possibly pregnant, or breastfeeding women were excluded from the study. Women who were not using an effective method of contraception also were excluded. Study Design
This 6-week, multicenter, open-label, parallel-group trial was conducted at 5 outpatient clinics in Israel. After the initial screening visit (visit 1), patients were randomized (using random number scratch-labels) to either switch from their existing glibenclamide treatment to insulin plus rosiglitazone therapy (BIAsp 30* + ROS†) or to add rosiglitazone to their existing glibenclamide therapy (GLIB + ROS). Patients were randomized at visit 2 (≤2 weeks after the screening visit), at which time treatment was started immediately. Patients randomized to BIAsp 30 + ROS discontinued glibenclamide treatment and instead received individually titrated doses of BIAsp 30 (starting with 6–8 U BID) given immediately before breakfast and dinner plus a daily 4-mg oral (tablet) dose of rosiglitazone before breakfast. The BIAsp 30 dose was assessed periodically throughout the trial and increased as needed to achieve BG target levels of 90 to 144 mg/dL for fasting/preprandial/nighttime BG levels and <180 mg/dL for *Trademark: †Trademark:
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NovoMix® (Novo Nordisk A/S, Bagsvaerd, Denmark). Avandia® (GlaxoSmithKline, Research Triangle Park, North Carolina).
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postprandial BG level (1–3 hours after a meal). Insulin BIAsp 30 was administered by SC injection at the same location (thigh or abdomen) using a NovoPen 3 injection device (Novo Nordisk A/S). Patients randomized to GLIB + ROS treatment continued to receive their usual oral dosage of glibenclamide (7.5–15.0 mg/d) before dinner plus a daily 4-mg oral dose of rosiglitazone before breakfast. Efficacy Assessments Primary End Point
The primary efficacy end point, change in mean daily BG level during treatment, was derived from 7-point BG measurements performed by patients using OneTouch Profile meters (LifeScan, Inc., Milpitas, California) that were calibrated regularly according to the manufacturer’s instructions. Measurements were taken immediately before each of the 3 main meals, 90 minutes after the start of each meal, and at bedtime. These measurements were performed at baseline (week 0) and at weeks 1, 2, 4, and 6 of treatment, and also at the 2-week posttreatment follow-up visit (week 8). The mean BG value was calculated by the investigators from these 7 measurements, each taken on 1 day. Secondary End Points
Changes in the following secondary end points were studied in the trial: preprandial, postprandial, and bedtime BG levels, which were determined from the 7-point profiles performed by the patient; and serum fructosamine, HbA1c, and FBG levels, determined from samples drawn by the investigator at randomization and study end. Tolerability Assessment
Tolerability was assessed at each study visit by the investigator using hematologic and biochemistry parameters (screening and follow-up visits), vital signs (each study visit), physical examination (screening visits), and body weight (assessed without coat and shoes at the screening visit and at the follow-up visit [week 8]). An adverse event (AE) was defined as an undesirable medical event, regardless of whether the event was related to the study drugs. AEs were considered serious if they endangered life, required hospitalization or prolonged existing hospitalization, or caused persistent, significant disability or incapacity. All AEs were observed by the investigator or reported spontaneously by the patients and recorded and assessed by the investigator. In addition, at each contact to the center (visit or telephone), the patients were asked whether they had experienced any AEs since the last assessment. A major hypoglycemic episode was defined per protocol as one in which the patient was unable to self-treat and either BG level decreased to <50 mg/dL or severe central nervous system symptoms remitted af3113
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ter administration of IV glucose or IM glucagon or ingestion of food. A minor hypoglycemic episode was defined per protocol as a BG level <50 mg/dL that the patient handled without assistance from others. Symptomatic episodes were defined per protocol as those in which symptoms of hypoglycemia, including dizziness, sweating, pallor, and/or irritability, were present but not confirmed with a BG measurement and no outside assistance was required. Hypoglycemic episodes were recorded as AEs if they met the criteria for a serious AE. Statistical Analysis
Power calculations were based on the primary end point, change in mean BG level taken from the 7-point BG profiles. An SD of 40 mg/dL (based on a previous Phase III trial16) was used to determine that a sample size of ≥40 patients would be sufficient to detect a true difference of >40 mg/dL between treatment groups with a power of ≥80%. CIs were calculated at 95%. Change in mean BG level was analyzed using an analysis of covariance (ANCOVA) model22 that included baseline BG level as the covariate and treatment as the only other effect. If data departed sharply from the assumptions of ANCOVA, the data were log-transformed. A similar ANCOVA model was used to analyze changes that occurred during treatment for the following secondary end points: individual BG levels for 7-point profiles, serum fructosamine level, HbA1c, and FBG level. A Wilcoxon rank-sum test23 was used to compare the rates of hypoglycemic events (defined as the number of events divided by exposure time in years) between treatments. SAS version 6.12 (SAS Institute Inc., Cary, North Carolina) was used for all analyses. P ≤ 0.05 was considered statistically significant. RESULTS
Forty-nine patients (32 men, 17 women; mean [SD] age, 59.1 [8.9] years; mean [SD] BMI, 27.7 [3.7] kg/m2) were randomized to receive BIAsp 30 + ROS (n = 26) or GLIB + ROS (n = 23) (Table). Most of the patients (83.7%) were white. All patients received at least 1 dose of trial medication and were included in the analysis. Five patients (10.2%) withdrew before trial completion, 1 because of ineffective treatment (in the GLIB + ROS group) and the others because of noncompliance with the protocol or for personal reasons. None of the patients withdrew due to an AE. Patient demographic characteristics and metabolic control parameters were similar at baseline in the 2 groups. Mean Daily Blood Glucose Level
Analysis of changes from baseline to the end of the trial in mean daily BG level showed that the reduction was significantly greater in the BIAsp 30 + ROS group than in the GLIB + ROS group (–67.7 vs –37.8 mg/dL). Because the data were abnormally distributed, the values were log-transformed. The adjusted mean dif3114
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Table. Baseline demographic and clinical characteristics of the intent-to-treat population. (Values are expressed as mean [SD] unless otherwise indicated.) Characteristic Age, y Mean (SD) Range Sex, no. (%) Men Women Race, no. (%) White Asian Other BMI, kg/m2 HbA1c, % Serum fructosamine, µmol/L Fasting plasma glucose, mg/dL Duration of diabetes, y GLIB dosage, mg/d
Normal Value24
GLIB + ROS (n = 23)
BIAsp 30 + ROS (n = 26)
All Patients (N = 49)
57.8 (7.9) 43–71
60.3 (9.7) 43–77
59.1 (8.9) 43–77
–
– 13 (56.5) 10 (43.5)
19 (73.1) 7 (26.9)
32 (65.3) 17 (34.7)
–
≤25 4–7 205–285 70–110 – –
19 2 2 27.6 10.3 409.2 265.2 10.3 13.6
(82.6) (8.7) (8.7) (4.0) (1.3) (60.7) (64.9) (6.5) (2.5)
22 1 3 27.7 9.9 398.0 259.8 10.9 13.1
(84.6) (3.8) (11.5) (3.6) (1.3) (70.5) (74.3) (5.2) (3.8)
41 3 5 27.7 10.1 403.2 262.4 10.6 13.3
(83.7) (6.1) (10.2) (3.7) (1.3) (65.6) (69.3) (5.8) (3.2)
GLIB = glibenclamide; ROS = rosiglitazone; BIAsp 30 = biphasic insulin aspart 30; BMI = body mass index; HbA1c = glycosylated hemoglobin.
ference between treatment groups for reduction in mean BG from baseline to study end was found to be statistically significant (adjusted mean difference, 0.3 log mg/dL; 95% CI, 0.07–0.48; P = 0.01). Diurnal Blood Glucose Level Variation
BIAsp 30 + ROS treatment was associated with the following reductions in BG level compared with GLIB + ROS at 6 of the 7 daily time points: before breakfast (58.0 vs 34.2 mg/dL), 90 minutes after the start of breakfast (88.6 vs 56.0 mg/dL), before lunch (73.9 vs 35.6 mg/dL), 90 minutes after the start of lunch (71.1 vs 61.5 mg/dL), 90 minutes after dinner (72.8 vs 47.0 mg/dL), and at bedtime (80.7 vs 7.7 mg/dL). Reductions in mean BG before dinner were numerically higher for GLIB + ROS compared with BIAsp 30 + ROS (43.3 vs 36.2 mg/dL). When the data were adjusted (log transformed), differences reached statistical significance immediately before lunch; log-transformed mean changes in BG level were –70.4 and –39.7 mg/dL for BIAsp 30 + ROS and GLIB + ROS, respectively (mean difference, 30.7 mg/dL; 95% CI, 0.33–61.01; P = 0.05), and at bedtime, 72.7 and 17.3 mg/dL, respectively (mean difference, 55.4 mg/dL; 95% CI, 14.43–96.34; P = 0.01) 3115
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(Figure 1). The log-transformed, adjusted mean change in BG levels 90 minutes after lunch was similar in both treatment groups (5.3 mg/dL). Changes in mean preprandial and postprandial BG levels are shown in Figure 2. Although both treatments reduced preprandial and postprandial BG levels, differences in the extent of reduction were found between the 2 treatments. At the end of the 6-week treatment period, preprandial and postprandial BG levels decreased 56.3 and 80.6 mg/dL, respectively, in the BIAsp 30 + ROS group and 30.1 and 52.9 mg/dL, respectively, in the GLIB + ROS group. Serum Fructosamine Level, HbA1c , and FBG
Baseline and end-of-trial (week 6) mean serum fructosamine levels were 398 and 353 µmol/L for BIAsp 30 + ROS and 409 and 398 µmol/L for GLIB + ROS, Time of Measurement 90 min 90 min Immediately Immediately Immediately after the start before before before after the start of dinner lunch dinner breakfast of breakfast
At bedtime
0
Adjusted Mean Change in BG Level (mg/dL)
–10 –20 –30 –40 –50 –60 –70 *
†
–80 –90
GLIB + ROS BIAsp 30 + ROS
Figure 1. Adjusted mean (SEM) change in blood glucose (BG) level during 7-point BG monitoring for the intent-to-treat population (N = 49). Mean values were adjusted for baseline and unbalanced experimental factors. Values for 90 minutes after lunch were log-transformed because the distribution of the data departed sharply from the assumptions of the analysis of covariance. These data points could not be included in this figure because all other data points were not log-transformed. *P = 0.05 between groups. †P = 0.01 between groups. BIAsp 30 + ROS = biphasic insulin aspart 30 + rosiglitazone; GLIB + ROS = glibenclamide + rosiglitazone. 3116
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Change in Mean Preprandial BG Level (mg/dL)
A
GLIB + ROS BIAsp 30 + ROS
20
0
–20
–40
–60
–80 0
1
2
4
6
8
4
6
8
Study Week
Change in Mean Postprandial BG Level (mg/dL)
B
0 –20 –40 –60 –80 –100 –120 0
1
2
Study Week
Figure 2. Changes in mean (SEM) preprandial (A) and postprandial (B) blood glucose (BG) levels. The arrows indicate the end of the treatment period. BIAsp 30 + ROS = biphasic insulin aspart 30 + rosiglitazone; GLIB + ROS = glibenclamide + rosiglitazone. 3117
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respectively. The adjusted mean change in serum fructosamine levels was significantly greater in the BIAsp 30 + ROS group compared with the GLIB + ROS group (–52.8 vs –10.8 µmol/L, respectively; mean difference, 42.8 µmol/L; and 95% CI, 6.93–76.96; P = 0.02). The adjusted mean changes in HbA1c were similar in both treatment groups (0.7% and 0.2% in the BIAsp 30 + ROS and the GLIB + ROS groups, respectively). Baseline and end-of-trial HbA1c levels were 9.9% and 9.4% for BIAsp 30 + ROS and 10.3% and 10.1% for GLIB + ROS. At the end of the trial, HbA1c levels remained high in both study groups. The adjusted mean change in FBG level during the treatment period was similar in the 2 treatment groups (–59.3 and –54.9 mg/dL in the BIAsp 30 + ROS and the GLIB + ROS groups, respectively). Tolerability
No major hypoglycemic events occurred during the trial. As expected, significantly fewer hypoglycemic episodes occurred in the GLIB + ROS group than the BIAsp 30 + ROS group; mean rates of minor hypoglycemic events were 0.0 versus 1.8 events/y, respectively (P = 0.03), and mean rates of all hypoglycemic episodes (including major, minor, and symptom-only events) were 0.0 versus 5.3 events/y, respectively (P < 0.01). Although the BIAsp 30 + ROS group had a higher frequency of minor and symptomatic hypoglycemic events, the majority of these (n = 17; 68.0%) consisted of hypoglycemic symptoms only without BG confirmation, whereas the remainder were minor hypoglycemic episodes. AEs were generally mild and infrequent. A similar number of patients reported AEs in both groups (13 [50.0%] and 10 [43.5%] patients in the BIAsp 30 + ROS and GLIB + ROS groups, respectively). Only 1 patient (3.8%), in the BIAsp 30 + ROS group, experienced a serious AE (myocardial infarction), and this was judged unlikely to be related to the study drugs. The most frequently reported AEs were respiratory tract infection (3 [13.0%] and 1 [3.8%] patient in the GLIB + ROS and BIAsp 30 + ROS groups, respectively), general cardiovascular disorders (2 [8.7%] and 2 [7.7%] patients in the GLIB + ROS and BIAsp 30 + ROS groups, respectively), and headache (1 [4.3%] and 3 [11.5%] patients in the GLIB + ROS and BIAsp 30 + ROS groups, respectively). The mean increase in body weight during the trial was minimal (0.23 and 0.03 kg in the BIAsp 30 + ROS and GLIB + ROS groups, respectively). No clinically significant differences in hematologic and biochemistry parameters, vital signs, or physical examination assessments between treatment groups were reported. DISCUSSION
Several studies have documented that, at least in the short term, intensive insulin therapy for up to 4 weeks in patients with type 2 DM improves insulin sensitiv3118
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ity and beta-cell function.25–27 The underlying mechanism of this improvement presumably is a reduction in BG level and glucose toxicity, as well as attenuated lipotoxicity.28 Thus, although the addition of a second OAD often is effective, there may be greater benefits with early initiation of insulin in preserving existing beta-cell function.29 In this trial, results showed that BIAsp 30 + ROS may be more effective in reducing overall BG level, evidenced by statistically significant differences between the 2 treatments in the reduction of mean daily BG level derived from 7-point profiles and serum fructosamine levels. Treatment differences were particularly apparent before lunch and at bedtime, with BIAsp 30 + ROS treatment yielding significantly greater reductions in BG than GLIB + ROS treatment. BIAsp 30 + ROS treatment provided numeric, but not statistically significant, advantages over GLIB + ROS treatment at 5 of the 7 time points studied, the only exceptions being the 2 measurements taken between lunch and dinner, corresponding to times when no BIAsp 30 had been administered. These differences reflect, in part, the properties of the rapid-acting insulin aspart component of BIAsp 30 and its efficacy in achieving postprandial BG control. The longitudinal data from the current study suggest tighter postprandial glucose control in the BIAsp 30 + ROS group after 2 weeks of treatment, when the BIAsp 30 combination group showed a mean reduction in postprandial BG concentration approximately double that achieved with GLIB + ROS. Furthermore, preprandial glucose control in the BIAsp 30 + ROS group was numerically, but not statistically significantly, lower than that in the GLIB + ROS group, contributing to an overall improvement in metabolic control. The reductions in BG seen throughout the treatment period suggest that, given a longer trial duration in a similar patient population, improved postprandial BG control would be manifested in significant reductions in HbA1c among patients treated with BIAsp 30 + ROS. Hypoglycemic episodes can occur with greater frequency when insulin is a component of diabetes therapy compared with OADs alone30; thus it is encouraging to note that, although more minor and symptomatic hypoglycemic episodes occurred in the BIAsp 30 + ROS group than the GLIB + ROS group, no major hypoglycemic episodes occurred in either group. And although the majority of hypoglycemic events consisted of symptoms only (no BG measurement recorded), it might be suggested that a patient’s state of hypoglycemia was a limiting factor to their carrying out the BG-measuring procedure. It also is encouraging to note that body weight gain was minimal in both treatment groups, despite the fact that treatment with either insulin2 or rosiglitazone31 is generally associated with moderate weight gain. Longer studies, however, are required to show treatment-related changes in body weight. Although this study focused specifically on combination BIAsp 30 plus rosiglitazone treatment, evidence from other clinical trials32,33 suggests that BIAsp 30 3119
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also may combine well with other OADs, such as metformin and SUs, namely glibenclamide. Indeed, because BIAsp 30 provides good BG control during the postprandial period when SUs and thiazolidinediones may not, BIAsp 30 has the potential to offer unique postprandial control in a variety of therapeutic combinations for the treatment of type 2 DM. In addition to postprandial control, because BIAsp 30 is a premixed formula, few injections are required to provide tight metabolic control, making this an acceptable and useful therapeutic option for introducing insulin to patients with type 2 DM who are transitioning into a more intensified treatment regimen. Furthermore, because BIAsp 30 need not be injected 30 minutes prior to meals, it provides the advantage of increased flexibility in timing of meals and injections, as well as the opportunity to adjust the insulin dose according to meal size and composition. These advantages suggest that in patients poorly controlled on glibenclamide monotherapy, combined BIAsp 30 + ROS treatment may enhance short-term metabolic control. However, further studies are required to confirm these implications. Insulin therapy is often added to OAD therapy for patients with type 2 DM, yet the advantages of adding premixed insulin analogs have not been studied thoroughly. The present study is important not only because it provides evidence of the efficacy and tolerability of a specific treatment combination (BIAsp 30 + ROS), but also because it adds to existing data pertaining to combination insulinthiazolidinedione treatment for type 2 DM and offers baseline data for future studies. The results of the present study may be useful in establishing treatment guidelines for initiating combination therapy in patients with type 2 DM whose BG level is poorly controlled on glibenclamide monotherapy. It should be pointed out, however, that in some countries the combination of thiazolidinediones and insulin, including BIAsp 30, is contraindicated due to an associated increased risk for peripheral edema,34 and may exacerbate heart failure.35 CONCLUSIONS
This short-term study in patients with type 2 DM whose BG level was poorly controlled with glibenclamide monotherapy suggests that switching to a combination of BIAsp 30 + ROS was efficacious and well tolerated and provided an alternative to adding rosiglitazone to existing glibenclamide treatment. The study also suggests that BIAsp 30 may be associated with greater improvements in short-term metabolic control. The potential advantages of BIAsp 30 + ROS suggest that in patients poorly controlled on glibenclamide monotherapy, combined BIAsp 30 + ROS treatment may enhance metabolic control, an essential feature in any diabetes management plan that can truly deliver improved long-term outcomes for patients. ACKNOWLEDGMENT
Novo Nordisk A/S (Kfar Saba, Israel) supplied the study drugs. 3120
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REFERENCES 1. International Diabetes Federation (IDF). Diabetes Atlas. 2nd ed. Brussels, Belgium: IDF; 2003:11. 2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999;354:602]. Lancet. 1998;352:837–853. 3. Stratton IM, Adler AI, Neil HA, et al, for the United Kingdom Prospective Diabetes Study (UKPDS) Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ. 2000;321:405–412. 4. Owens DR, Luzio SD, Coates PA. Insulin secretion and sensitivity in newly diagnosed NIDDM Caucasians in the UK. Diabetic Med. 1996;13(Suppl 6):S19–S24. 5. Donahue RP, Abbott RD, Reed DM, Yano K, for the Honolulu Heart Program. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Diabetes. 1987;36:689–692. 6. Glucose tolerance and mortality: Comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. Diabetes Epidemiology: Collaborative analysis of diagnostic criteria in Europe. European Diabetes Epidemiology Group. Lancet. 1999;354:617–621. 7. Fuller JH, Shipley M, Rose G, et al. Coronary-heart-disease risk and impaired glucose tolerance. The Whitehall study. Lancet. 1980;1:1373–1376. 8. Hanefeld M, Fischer S, Julius U, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: The Diabetes Intervention Study, 11-year follow-up. Diabetologia. 1996;39:1577–1583. 9. Balkau B, Shipley M, Jarrett RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-Year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care. 1998;21:360–367. 10. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303. 11. Heinemann L, Richter B. Clinical pharmacology of human insulin. Diabetes Care. 1993;16(Suppl 3):90–100. 12. Rosenfalck AM, Thorsby P, Kjems L, et al. Improved postprandial glycaemic control with insulin Aspart in type 2 diabetic patients treated with insulin. Acta Diabetol. 2000;37:41–46. 13. Home PD, Lindholm A, Hylleberg B, Round P, for the UK Insulin Aspart Study Group. Improved glycemic control with insulin aspart: A multicenter randomized doubleblind crossover trial in type 1 diabetic patients. Diabetes Care. 1998;21:1904–1909. 14. Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care. 1999;22:801–805. 3121
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15. Home PD, Lindholm A, Riis A, for the European Insulin Aspart Study Group. Insulin aspart vs. human insulin in the management of long-term blood glucose control in Type 1 diabetes mellitus: A randomized controlled trial. Diabetic Med. 2000;17:762– 770. 16. Boehm BO, Home PD, Behrend C, et al. Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: A randomized trial in Type 1 and Type 2 diabetic patients [published correction appears in Diabetic Med. 2002;19:797]. Diabetic Med. 2002;19:393–399. 17. Jacobsen LV, Søgaard B, Riis A. Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart. Eur J Clin Pharmacol. 2000;56:399–403. 18. Weyer C, Heise T, Heinemann L. Insulin aspart in a 30/70 premixed formulation. Pharmacodynamic properties of a rapid-acting insulin analog in stable mixture. Diabetes Care. 1997;20:1612–1614. 19. McSorley PT, Bell PM, Jacobsen LV, et al. Twice-daily biphasic insulin aspart 30 versus biphasic human insulin 30: A double-blind crossover study in adults with type 2 diabetes mellitus. Clin Ther. 2002;24:530–539. 20. Raskin P, Guthrie RA, Leiter L, et al. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care. 2000;23:583–588. 21. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 2000;284:3043–3045. 22. Montgomery DC, ed. Design and Analysis of Experiments. 3rd ed. New York: Wiley; 1991:569–587. 23. Hollander M, ed. Nonparametric Statistical Methods. New York: Wiley; 1973:68–75. 24. Reinauer H, Home PD, Kanagasabapathy AS, Heuck CC. Laboratory Diagnosis and Monitoring of Diabetes Mellitus. Geneva, Switzerland: World Health Organization; 2002. Available at: http://www.who.int/bct/Main_areas_of_work/DIL/Lab_Tech/PDF_ Documents/diabetes.pdf. Accessed November 24, 2003. 25. Andrews WJ, Vasquez B, Nagulesparan M, et al. Insulin therapy in obese, non-insulindependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes. 1984;33:634–642. 26. Garvey WT, Olefsky JM, Griffin J, et al. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34:222–234. 27. Scarlett JA, Gray RS, Griffin J, et al. Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care. 1982;5:353–363. 28. Rossetti L. Glucose toxicity: The implications of hyperglycemia in the pathophysiology of diabetes mellitus. Clin Invest Med. 1995;18:255–260. 29. Laedtke T, Kjems L, Porksen N, et al. Overnight inhibition of insulin secretion restores pulsatility and proinsulin/insulin ratio in type 2 diabetes. Am J Physiol Endocrinol Metab. 2000;279:E520–E528. 3122
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30. United Kingdom Prospective Diabetes Study Group. United Kingdom Prospective Diabetes Study 24: A 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med. 1998;128:165–175. 31. Kaplan F, Al-Majali K, Betteridge DJ. PPARS, insulin resistance and type 2 diabetes. J Cardiovasc Risk. 2001;8:211–217. 32. Kilo C, Mezitis N, Nadeau D, et al. Dinnertime NovoLog Mix 70/30 in combination with metformin—A combination to use? Diabetes. 2002;51(Suppl 2):A130. 33. Kvapil M, Mikolajczyk-Swatko A, Ostergaard AH, Shestakova M. In patients with poorly controlled Type 2 diabetes, biphasic insulin aspart 30 combined with metformin provides better glycaemic control than sulphonylurea/metformin combination. Diabetologia. 2002;45(Suppl 2):A18. 34. Buch HN, Baskar V, Barton DM, et al. Combination of insulin and thiazolidinedione therapy in massively obese patients with Type 2 diabetes. Diabetic Med. 2002;19:572– 574. 35. Kermani A, Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc. 2003;78:1088–1091.
Address correspondence to: Itamar Raz, MD, Hadassah Ein Karem Medical Center, Jerusalem, Israel. E-mail: [email protected] 3123
Addition of Biphasic Insulin Aspart 30 to Rosiglitazone in Type 2 Diabetes Mellitus That Is Poorly Controlled with Glibenclamide Monotherapy Itamar Raz, MD,1 Ulrik Mouritzen, MD,2 Julius Vaz, MD,2 Tommy Hershkovitz, MD,3 Julio Wainstein, MD,4 and Ilana Harman-Boehm, MD5 1Hadassah
Ein Karem Medical Center, Jerusalem, Israel, 2Novo Nordisk A/S, Bagsvaerd, Denmark, Galilee Hospital, Nahariya, Israel, 4Wolfson Medical Center, Holon, Israel, 5 and The Diabetes Unit, Soroka University Medical Centre, Beer Sheva, Israel 3Western
ABSTRACT
Background: The incidence of type 2 diabetes mellitus (DM) is rapidly increasing worldwide. Results from large-scale studies show that tight blood glucose (BG) control improves the outcome of patients with type 2 DM. Objective: This trial assessed the short-term efficacy and tolerability of adding a thiazolidinedione (rosiglitazone [ROS]) to existing sulfonylurea (SU) therapy (glibenclamide) compared with switching to combination treatment with a premixed insulin (biphasic insulin aspart 30 [BIAsp 30], a rapid-acting insulin analog) and the thiazolidinedione in a select group of patients with type 2 DM whose metabolic control was inadequate with SU monotherapy. Methods: In this 6-week, multicenter, open-label, parallel-group trial, patients with type 2 DM whose BG level was not adequately controlled with glibenclamide monotherapy (glycosylated hemoglobin [HbA1c] 8%–13%) were randomized either to replace glibenclamide with BIAsp 30 (individually titrated dosages starting with 6–8 U BID) plus rosiglitazone (4 mg once daily) (BIAsp 30 + ROS group) or to add rosiglitazone (4 mg once daily) to their pretrial doses of glibenclamide (GLIB + ROS group). Patients measured their BG levels immediately before each of the 3 main meals, 90 minutes after the start of each meal, and at bedtime, and mean BG levels were calculated at weeks 0 (baseline), 1, 2, 4, 6, and at 2-week follow-up (week 8). The primary end point was change in mean daily BG level during treatment. Secondary end points included preprandial, postprandial, and Accepted for publication October 22, 2003. Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2003 Excerpta Medica, Inc.
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bedtime BG levels; serum fructosamine level; HbA1c; and fasting BG level, which were measured at each study visit. Tolerability was assessed using hematologic and biochemical parameters, vital signs, and physical examination. Results: Forty-nine patients (32 men, 17 women; mean [SD] age, 59.1 [8.9] years; mean [SD] body mass index, 27.7 [3.7] kg/m2) participated in the study. A significant difference was found between treatments in the change in mean daily BG level from baseline to week 6 (P = 0.01). After the 6-week treatment period, change in mean serum fructosamine level was significantly greater for BIAsp 30 + ROS compared with GLIB + ROS (P = 0.02). HbA1c decreased in both treatment groups from baseline to study end, but the difference between groups was nonsignificant. The changes in fasting BG from baseline to study end also were nonsignificant between groups. Both combinations were well tolerated. Conclusions: This short-term study in patients with type 2 DM whose BG level was poorly controlled with glibenclamide monotherapy suggests that switching to a combination of BIAsp 30 + ROS was efficacious and well tolerated and provided an alternative to adding rosiglitazone to existing glibenclamide treatment. The study also suggests that BIAsp 30 may be associated with greater improvements in short-term metabolic control. (Clin Ther. 2003;25:3109–3123) Copyright © 2003 Excerpta Medica, Inc. Key words: BIAsp 30, glycemic control, type 2 diabetes, HbA1c.
INTRODUCTION
Type 2 diabetes mellitus (DM) is a progressive disorder in which a deficiency in beta-cell insulin secretion coupled with peripheral insulin resistance results in chronic hyperglycemia, thus increasing the risk for morbidity and mortality. The incidence of type 2 DM is rapidly increasing worldwide; the worldwide prevalence of DM is 5.1% and is predicted to increase to 6.3% by 2025, with type 2 DM constituting ~85% to 95% of all cases of DM.1 The management of the disease and its complications, such as cardiovascular disease, nephropathy, and neuropathy, pose significant challenges for both patients and health care workers. Results from large-scale studies2,3 show that tight blood glucose (BG) control improves the outcome of patients with type 2 DM, particularly by decreasing the risk for microvascular complications, but not the risk for macrovascular disease.2 Importantly, research indicates that patients with type 2 DM have a delayed and diminished early postprandial insulin response4; a large body of research5–9 shows that elevated postprandial BG level plays an important role in determining risk for cardiovascular disease and death. The United Kingdom Prospective Diabetes Study Group2 addressed tight control of fasting BG (FBG) level and glycosylated hemoglobin (HbA1c), not post3110
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prandial BG level, perhaps explaining the less marked impact on cardiovascular outcomes in this study. Thus, treatments aimed at controlling postprandial BG levels among patients with type 2 DM are particularly warranted. Monotherapy with oral antidiabetic drugs (OADs) is often used as first-line therapy for reducing BG levels, although many patients do not achieve optimal control with maximal doses of 1 OAD alone, and combination therapy with OADs from different classes may be prescribed. However, although various OAD combinations may achieve adequate control of FBG level, oral treatments do not always optimally control postprandial BG level, thus limiting their overall effectiveness. Furthermore, the progressive decline in beta-cell function, which defines the natural history of type 2 DM, eventually necessitates the use of exogenous insulin in most patients.10 Neutral protamine hagedorn (NPH) insulin commonly is the first insulin to be given to patients who require intensified treatment, but its absorption rate varies and its long duration and peak of action11 may be associated with an increased risk for fasting and nighttime hypoglycemia. Furthermore, NPH insulin primarily addresses FBG levels. Thus, many patients experience difficulty achieving sufficient overall metabolic control while avoiding hypoglycemic episodes. Insulin aspart is a rapid-acting insulin analog that is homologous to human insulin, with the exception of the substitution of proline with aspartic acid at position B28. This modification results in reduced tendency of the molecules to selfassociate, leading to faster absorption and improved postprandial and long-term BG control compared with human insulin.12–15 Biphasic insulin aspart 30 (BIAsp 30) is a premixed formulation of 30% soluble aspart and 70% protamine-crystallized insulin aspart, the latter of which has a delayed pattern of absorption similar to that of NPH insulin. Phase III trials have shown BIAsp 30 to be efficacious and well tolerated and to yield favorable BG profiles compared with biphasic human insulin.16–19 BIAsp 30 provides a rapid-acting component with proven efficacy in reducing postprandial glycemia12,14,15,20 and a long-acting component to provide consistent basal control17,19 with reduced hypoglycemic risk.17,19 Although biphasic human insulin must be administered 30 minutes prior to meals, BIAsp 30 requires no waiting period before eating. Also, because BIAsp 30 is a premixed analog, fewer daily injections are necessary compared with more intensive basal-bolus therapy, appealing to patients for whom more intensified regimens may be too challenging. These features imply that regimens that include BIAsp 30 are likely to provide convenience and improved overall control while reducing the risk for hypoglycemia. This trial assessed the short-term efficacy and tolerability of adding a thiazolidinedione (rosiglitazone [ROS]) to existing sulfonylurea (SU) therapy (glibenclamide) compared with switching to combination treatment with a premixed in3111
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sulin (BIAsp 30), a rapid-acting insulin analog) and the thiazolidinedione in a select group of patients with type 2 DM whose metabolic control was inadequate with SU monotherapy. PATIENTS AND METHODS Patients
Patients with type 2 DM, based on etiology, aged ≥30 years, with a body mass index (BMI) of ≤35 kg/m2, and who were not responding to glibenclamide monotherapy were eligible for the trial. All patients had been treated with glibenclamide (7.5–15.0 mg/d) as the only antidiabetic therapy for at least 4 weeks prior to an initial screening visit and had an HbA1c of 8.0% to 13.0%. These patients may not be considered to have “failed glibenclamide therapy” because they had not yet reached the maximum recommended dose of glibenclamide when they were included in the study. Patients with any significant disease or condition (including history of drug or alcohol dependence, impaired hepatic function, or cardiac disease) or other condition deemed by the investigator as likely to affect the trial or health outcomes were excluded. Written informed consent was obtained, and the trial was conducted in accordance with the Declaration of Helsinki.21 The protocol, consent form, and patient information sheet were reviewed and/or approved by the independent ethics committees at each recruitment center. Pregnant, possibly pregnant, or breastfeeding women were excluded from the study. Women who were not using an effective method of contraception also were excluded. Study Design
This 6-week, multicenter, open-label, parallel-group trial was conducted at 5 outpatient clinics in Israel. After the initial screening visit (visit 1), patients were randomized (using random number scratch-labels) to either switch from their existing glibenclamide treatment to insulin plus rosiglitazone therapy (BIAsp 30* + ROS†) or to add rosiglitazone to their existing glibenclamide therapy (GLIB + ROS). Patients were randomized at visit 2 (≤2 weeks after the screening visit), at which time treatment was started immediately. Patients randomized to BIAsp 30 + ROS discontinued glibenclamide treatment and instead received individually titrated doses of BIAsp 30 (starting with 6–8 U BID) given immediately before breakfast and dinner plus a daily 4-mg oral (tablet) dose of rosiglitazone before breakfast. The BIAsp 30 dose was assessed periodically throughout the trial and increased as needed to achieve BG target levels of 90 to 144 mg/dL for fasting/preprandial/nighttime BG levels and <180 mg/dL for *Trademark: †Trademark:
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NovoMix® (Novo Nordisk A/S, Bagsvaerd, Denmark). Avandia® (GlaxoSmithKline, Research Triangle Park, North Carolina).
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postprandial BG level (1–3 hours after a meal). Insulin BIAsp 30 was administered by SC injection at the same location (thigh or abdomen) using a NovoPen 3 injection device (Novo Nordisk A/S). Patients randomized to GLIB + ROS treatment continued to receive their usual oral dosage of glibenclamide (7.5–15.0 mg/d) before dinner plus a daily 4-mg oral dose of rosiglitazone before breakfast. Efficacy Assessments Primary End Point
The primary efficacy end point, change in mean daily BG level during treatment, was derived from 7-point BG measurements performed by patients using OneTouch Profile meters (LifeScan, Inc., Milpitas, California) that were calibrated regularly according to the manufacturer’s instructions. Measurements were taken immediately before each of the 3 main meals, 90 minutes after the start of each meal, and at bedtime. These measurements were performed at baseline (week 0) and at weeks 1, 2, 4, and 6 of treatment, and also at the 2-week posttreatment follow-up visit (week 8). The mean BG value was calculated by the investigators from these 7 measurements, each taken on 1 day. Secondary End Points
Changes in the following secondary end points were studied in the trial: preprandial, postprandial, and bedtime BG levels, which were determined from the 7-point profiles performed by the patient; and serum fructosamine, HbA1c, and FBG levels, determined from samples drawn by the investigator at randomization and study end. Tolerability Assessment
Tolerability was assessed at each study visit by the investigator using hematologic and biochemistry parameters (screening and follow-up visits), vital signs (each study visit), physical examination (screening visits), and body weight (assessed without coat and shoes at the screening visit and at the follow-up visit [week 8]). An adverse event (AE) was defined as an undesirable medical event, regardless of whether the event was related to the study drugs. AEs were considered serious if they endangered life, required hospitalization or prolonged existing hospitalization, or caused persistent, significant disability or incapacity. All AEs were observed by the investigator or reported spontaneously by the patients and recorded and assessed by the investigator. In addition, at each contact to the center (visit or telephone), the patients were asked whether they had experienced any AEs since the last assessment. A major hypoglycemic episode was defined per protocol as one in which the patient was unable to self-treat and either BG level decreased to <50 mg/dL or severe central nervous system symptoms remitted af3113
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ter administration of IV glucose or IM glucagon or ingestion of food. A minor hypoglycemic episode was defined per protocol as a BG level <50 mg/dL that the patient handled without assistance from others. Symptomatic episodes were defined per protocol as those in which symptoms of hypoglycemia, including dizziness, sweating, pallor, and/or irritability, were present but not confirmed with a BG measurement and no outside assistance was required. Hypoglycemic episodes were recorded as AEs if they met the criteria for a serious AE. Statistical Analysis
Power calculations were based on the primary end point, change in mean BG level taken from the 7-point BG profiles. An SD of 40 mg/dL (based on a previous Phase III trial16) was used to determine that a sample size of ≥40 patients would be sufficient to detect a true difference of >40 mg/dL between treatment groups with a power of ≥80%. CIs were calculated at 95%. Change in mean BG level was analyzed using an analysis of covariance (ANCOVA) model22 that included baseline BG level as the covariate and treatment as the only other effect. If data departed sharply from the assumptions of ANCOVA, the data were log-transformed. A similar ANCOVA model was used to analyze changes that occurred during treatment for the following secondary end points: individual BG levels for 7-point profiles, serum fructosamine level, HbA1c, and FBG level. A Wilcoxon rank-sum test23 was used to compare the rates of hypoglycemic events (defined as the number of events divided by exposure time in years) between treatments. SAS version 6.12 (SAS Institute Inc., Cary, North Carolina) was used for all analyses. P ≤ 0.05 was considered statistically significant. RESULTS
Forty-nine patients (32 men, 17 women; mean [SD] age, 59.1 [8.9] years; mean [SD] BMI, 27.7 [3.7] kg/m2) were randomized to receive BIAsp 30 + ROS (n = 26) or GLIB + ROS (n = 23) (Table). Most of the patients (83.7%) were white. All patients received at least 1 dose of trial medication and were included in the analysis. Five patients (10.2%) withdrew before trial completion, 1 because of ineffective treatment (in the GLIB + ROS group) and the others because of noncompliance with the protocol or for personal reasons. None of the patients withdrew due to an AE. Patient demographic characteristics and metabolic control parameters were similar at baseline in the 2 groups. Mean Daily Blood Glucose Level
Analysis of changes from baseline to the end of the trial in mean daily BG level showed that the reduction was significantly greater in the BIAsp 30 + ROS group than in the GLIB + ROS group (–67.7 vs –37.8 mg/dL). Because the data were abnormally distributed, the values were log-transformed. The adjusted mean dif3114
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Table. Baseline demographic and clinical characteristics of the intent-to-treat population. (Values are expressed as mean [SD] unless otherwise indicated.) Characteristic Age, y Mean (SD) Range Sex, no. (%) Men Women Race, no. (%) White Asian Other BMI, kg/m2 HbA1c, % Serum fructosamine, µmol/L Fasting plasma glucose, mg/dL Duration of diabetes, y GLIB dosage, mg/d
Normal Value24
GLIB + ROS (n = 23)
BIAsp 30 + ROS (n = 26)
All Patients (N = 49)
57.8 (7.9) 43–71
60.3 (9.7) 43–77
59.1 (8.9) 43–77
–
– 13 (56.5) 10 (43.5)
19 (73.1) 7 (26.9)
32 (65.3) 17 (34.7)
–
≤25 4–7 205–285 70–110 – –
19 2 2 27.6 10.3 409.2 265.2 10.3 13.6
(82.6) (8.7) (8.7) (4.0) (1.3) (60.7) (64.9) (6.5) (2.5)
22 1 3 27.7 9.9 398.0 259.8 10.9 13.1
(84.6) (3.8) (11.5) (3.6) (1.3) (70.5) (74.3) (5.2) (3.8)
41 3 5 27.7 10.1 403.2 262.4 10.6 13.3
(83.7) (6.1) (10.2) (3.7) (1.3) (65.6) (69.3) (5.8) (3.2)
GLIB = glibenclamide; ROS = rosiglitazone; BIAsp 30 = biphasic insulin aspart 30; BMI = body mass index; HbA1c = glycosylated hemoglobin.
ference between treatment groups for reduction in mean BG from baseline to study end was found to be statistically significant (adjusted mean difference, 0.3 log mg/dL; 95% CI, 0.07–0.48; P = 0.01). Diurnal Blood Glucose Level Variation
BIAsp 30 + ROS treatment was associated with the following reductions in BG level compared with GLIB + ROS at 6 of the 7 daily time points: before breakfast (58.0 vs 34.2 mg/dL), 90 minutes after the start of breakfast (88.6 vs 56.0 mg/dL), before lunch (73.9 vs 35.6 mg/dL), 90 minutes after the start of lunch (71.1 vs 61.5 mg/dL), 90 minutes after dinner (72.8 vs 47.0 mg/dL), and at bedtime (80.7 vs 7.7 mg/dL). Reductions in mean BG before dinner were numerically higher for GLIB + ROS compared with BIAsp 30 + ROS (43.3 vs 36.2 mg/dL). When the data were adjusted (log transformed), differences reached statistical significance immediately before lunch; log-transformed mean changes in BG level were –70.4 and –39.7 mg/dL for BIAsp 30 + ROS and GLIB + ROS, respectively (mean difference, 30.7 mg/dL; 95% CI, 0.33–61.01; P = 0.05), and at bedtime, 72.7 and 17.3 mg/dL, respectively (mean difference, 55.4 mg/dL; 95% CI, 14.43–96.34; P = 0.01) 3115
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(Figure 1). The log-transformed, adjusted mean change in BG levels 90 minutes after lunch was similar in both treatment groups (5.3 mg/dL). Changes in mean preprandial and postprandial BG levels are shown in Figure 2. Although both treatments reduced preprandial and postprandial BG levels, differences in the extent of reduction were found between the 2 treatments. At the end of the 6-week treatment period, preprandial and postprandial BG levels decreased 56.3 and 80.6 mg/dL, respectively, in the BIAsp 30 + ROS group and 30.1 and 52.9 mg/dL, respectively, in the GLIB + ROS group. Serum Fructosamine Level, HbA1c , and FBG
Baseline and end-of-trial (week 6) mean serum fructosamine levels were 398 and 353 µmol/L for BIAsp 30 + ROS and 409 and 398 µmol/L for GLIB + ROS, Time of Measurement 90 min 90 min Immediately Immediately Immediately after the start before before before after the start of dinner lunch dinner breakfast of breakfast
At bedtime
0
Adjusted Mean Change in BG Level (mg/dL)
–10 –20 –30 –40 –50 –60 –70 *
†
–80 –90
GLIB + ROS BIAsp 30 + ROS
Figure 1. Adjusted mean (SEM) change in blood glucose (BG) level during 7-point BG monitoring for the intent-to-treat population (N = 49). Mean values were adjusted for baseline and unbalanced experimental factors. Values for 90 minutes after lunch were log-transformed because the distribution of the data departed sharply from the assumptions of the analysis of covariance. These data points could not be included in this figure because all other data points were not log-transformed. *P = 0.05 between groups. †P = 0.01 between groups. BIAsp 30 + ROS = biphasic insulin aspart 30 + rosiglitazone; GLIB + ROS = glibenclamide + rosiglitazone. 3116
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Change in Mean Preprandial BG Level (mg/dL)
A
GLIB + ROS BIAsp 30 + ROS
20
0
–20
–40
–60
–80 0
1
2
4
6
8
4
6
8
Study Week
Change in Mean Postprandial BG Level (mg/dL)
B
0 –20 –40 –60 –80 –100 –120 0
1
2
Study Week
Figure 2. Changes in mean (SEM) preprandial (A) and postprandial (B) blood glucose (BG) levels. The arrows indicate the end of the treatment period. BIAsp 30 + ROS = biphasic insulin aspart 30 + rosiglitazone; GLIB + ROS = glibenclamide + rosiglitazone. 3117
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respectively. The adjusted mean change in serum fructosamine levels was significantly greater in the BIAsp 30 + ROS group compared with the GLIB + ROS group (–52.8 vs –10.8 µmol/L, respectively; mean difference, 42.8 µmol/L; and 95% CI, 6.93–76.96; P = 0.02). The adjusted mean changes in HbA1c were similar in both treatment groups (0.7% and 0.2% in the BIAsp 30 + ROS and the GLIB + ROS groups, respectively). Baseline and end-of-trial HbA1c levels were 9.9% and 9.4% for BIAsp 30 + ROS and 10.3% and 10.1% for GLIB + ROS. At the end of the trial, HbA1c levels remained high in both study groups. The adjusted mean change in FBG level during the treatment period was similar in the 2 treatment groups (–59.3 and –54.9 mg/dL in the BIAsp 30 + ROS and the GLIB + ROS groups, respectively). Tolerability
No major hypoglycemic events occurred during the trial. As expected, significantly fewer hypoglycemic episodes occurred in the GLIB + ROS group than the BIAsp 30 + ROS group; mean rates of minor hypoglycemic events were 0.0 versus 1.8 events/y, respectively (P = 0.03), and mean rates of all hypoglycemic episodes (including major, minor, and symptom-only events) were 0.0 versus 5.3 events/y, respectively (P < 0.01). Although the BIAsp 30 + ROS group had a higher frequency of minor and symptomatic hypoglycemic events, the majority of these (n = 17; 68.0%) consisted of hypoglycemic symptoms only without BG confirmation, whereas the remainder were minor hypoglycemic episodes. AEs were generally mild and infrequent. A similar number of patients reported AEs in both groups (13 [50.0%] and 10 [43.5%] patients in the BIAsp 30 + ROS and GLIB + ROS groups, respectively). Only 1 patient (3.8%), in the BIAsp 30 + ROS group, experienced a serious AE (myocardial infarction), and this was judged unlikely to be related to the study drugs. The most frequently reported AEs were respiratory tract infection (3 [13.0%] and 1 [3.8%] patient in the GLIB + ROS and BIAsp 30 + ROS groups, respectively), general cardiovascular disorders (2 [8.7%] and 2 [7.7%] patients in the GLIB + ROS and BIAsp 30 + ROS groups, respectively), and headache (1 [4.3%] and 3 [11.5%] patients in the GLIB + ROS and BIAsp 30 + ROS groups, respectively). The mean increase in body weight during the trial was minimal (0.23 and 0.03 kg in the BIAsp 30 + ROS and GLIB + ROS groups, respectively). No clinically significant differences in hematologic and biochemistry parameters, vital signs, or physical examination assessments between treatment groups were reported. DISCUSSION
Several studies have documented that, at least in the short term, intensive insulin therapy for up to 4 weeks in patients with type 2 DM improves insulin sensitiv3118
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ity and beta-cell function.25–27 The underlying mechanism of this improvement presumably is a reduction in BG level and glucose toxicity, as well as attenuated lipotoxicity.28 Thus, although the addition of a second OAD often is effective, there may be greater benefits with early initiation of insulin in preserving existing beta-cell function.29 In this trial, results showed that BIAsp 30 + ROS may be more effective in reducing overall BG level, evidenced by statistically significant differences between the 2 treatments in the reduction of mean daily BG level derived from 7-point profiles and serum fructosamine levels. Treatment differences were particularly apparent before lunch and at bedtime, with BIAsp 30 + ROS treatment yielding significantly greater reductions in BG than GLIB + ROS treatment. BIAsp 30 + ROS treatment provided numeric, but not statistically significant, advantages over GLIB + ROS treatment at 5 of the 7 time points studied, the only exceptions being the 2 measurements taken between lunch and dinner, corresponding to times when no BIAsp 30 had been administered. These differences reflect, in part, the properties of the rapid-acting insulin aspart component of BIAsp 30 and its efficacy in achieving postprandial BG control. The longitudinal data from the current study suggest tighter postprandial glucose control in the BIAsp 30 + ROS group after 2 weeks of treatment, when the BIAsp 30 combination group showed a mean reduction in postprandial BG concentration approximately double that achieved with GLIB + ROS. Furthermore, preprandial glucose control in the BIAsp 30 + ROS group was numerically, but not statistically significantly, lower than that in the GLIB + ROS group, contributing to an overall improvement in metabolic control. The reductions in BG seen throughout the treatment period suggest that, given a longer trial duration in a similar patient population, improved postprandial BG control would be manifested in significant reductions in HbA1c among patients treated with BIAsp 30 + ROS. Hypoglycemic episodes can occur with greater frequency when insulin is a component of diabetes therapy compared with OADs alone30; thus it is encouraging to note that, although more minor and symptomatic hypoglycemic episodes occurred in the BIAsp 30 + ROS group than the GLIB + ROS group, no major hypoglycemic episodes occurred in either group. And although the majority of hypoglycemic events consisted of symptoms only (no BG measurement recorded), it might be suggested that a patient’s state of hypoglycemia was a limiting factor to their carrying out the BG-measuring procedure. It also is encouraging to note that body weight gain was minimal in both treatment groups, despite the fact that treatment with either insulin2 or rosiglitazone31 is generally associated with moderate weight gain. Longer studies, however, are required to show treatment-related changes in body weight. Although this study focused specifically on combination BIAsp 30 plus rosiglitazone treatment, evidence from other clinical trials32,33 suggests that BIAsp 30 3119
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also may combine well with other OADs, such as metformin and SUs, namely glibenclamide. Indeed, because BIAsp 30 provides good BG control during the postprandial period when SUs and thiazolidinediones may not, BIAsp 30 has the potential to offer unique postprandial control in a variety of therapeutic combinations for the treatment of type 2 DM. In addition to postprandial control, because BIAsp 30 is a premixed formula, few injections are required to provide tight metabolic control, making this an acceptable and useful therapeutic option for introducing insulin to patients with type 2 DM who are transitioning into a more intensified treatment regimen. Furthermore, because BIAsp 30 need not be injected 30 minutes prior to meals, it provides the advantage of increased flexibility in timing of meals and injections, as well as the opportunity to adjust the insulin dose according to meal size and composition. These advantages suggest that in patients poorly controlled on glibenclamide monotherapy, combined BIAsp 30 + ROS treatment may enhance short-term metabolic control. However, further studies are required to confirm these implications. Insulin therapy is often added to OAD therapy for patients with type 2 DM, yet the advantages of adding premixed insulin analogs have not been studied thoroughly. The present study is important not only because it provides evidence of the efficacy and tolerability of a specific treatment combination (BIAsp 30 + ROS), but also because it adds to existing data pertaining to combination insulinthiazolidinedione treatment for type 2 DM and offers baseline data for future studies. The results of the present study may be useful in establishing treatment guidelines for initiating combination therapy in patients with type 2 DM whose BG level is poorly controlled on glibenclamide monotherapy. It should be pointed out, however, that in some countries the combination of thiazolidinediones and insulin, including BIAsp 30, is contraindicated due to an associated increased risk for peripheral edema,34 and may exacerbate heart failure.35 CONCLUSIONS
This short-term study in patients with type 2 DM whose BG level was poorly controlled with glibenclamide monotherapy suggests that switching to a combination of BIAsp 30 + ROS was efficacious and well tolerated and provided an alternative to adding rosiglitazone to existing glibenclamide treatment. The study also suggests that BIAsp 30 may be associated with greater improvements in short-term metabolic control. The potential advantages of BIAsp 30 + ROS suggest that in patients poorly controlled on glibenclamide monotherapy, combined BIAsp 30 + ROS treatment may enhance metabolic control, an essential feature in any diabetes management plan that can truly deliver improved long-term outcomes for patients. ACKNOWLEDGMENT
Novo Nordisk A/S (Kfar Saba, Israel) supplied the study drugs. 3120
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Address correspondence to: Itamar Raz, MD, Hadassah Ein Karem Medical Center, Jerusalem, Israel. E-mail: [email protected] 3123