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Addition of pioglitazone improved glycaemic control and components of the lipid profile & weight gain
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"Addition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: results of a double-blind, multicentre, randomized study"
Diabetes, Obesity and Metabolism
Volume 8 Page 164 - March 2006
In this study, mean body weight increased consistently as anticipated. A dose response for weight gain was observed at all time points. At week 24, increases in mean body weight were 2.94 and 3.38 kg in the 30- and 45-mg groups. Weight gain is thought to be due to increased fat accumulation, fat redistribution or increased total body fluid volume. .... In patients with poorly controlled type 2 diabetes, addition of pioglitazone to insulin significantly improved glycaemic control, had a positive effect on important components of the lipid profile in a dose-dependent manner and was generally well tolerated..... Addition of pioglitazone 30 or 45 mg once daily to insulin resulted in favourable changes in important components of the lipid profile.... At 12 and 24 weeks, patients in the pioglitazone 45-mg group had significant reductions from baseline (p ≦ 0.05) in free fatty acids, triglycerides and VLDL cholesterol and significant increases from baseline (p ≦ 0.05) in HDL cholesterol (data shown only for week 24).
J. A. Davidson1*, A. Perez2, J. Zhang2 and The Pioglitazone 343 Study Group
1Endocrine and Diabetes Associates of Texas, Dallas, TX, USA
2Takeda Global Research & Development, Inc., Lincolnshire, IL, USA
Aim: To determine the effects of pioglitazone treatment combined with insulin on glucose and lipid metabolism in patients with type 2 diabetes.
Methods: In a multicentre, double-blind study, 690 patients [body mass index, 33.19 kg/m2 ± 5.47; haemoglobin A1c (A1C), 9.78 ± 1.51; mean duration, 12.9 years] with diabetes poorly controlled with a stable insulin dose (> 30 U/day for ≥30 days) were randomly allocated to pioglitazone 30 or 45 mg once daily for 24 weeks.
Results: In the pioglitazone 30- and 45-mg groups, respectively, 71 and 70% of patients completed the study. At 24 weeks, statistically significant, dose-dependent mean decreases from baseline were seen in the pioglitazone 30- and 45-mg groups for A1C (-1.17 and -1.46%, respectively) and fasting plasma glucose (-31.9 and -45.8 mg/dl, respectively). Insulin dosage also decreased significantly (-4.5 and -7.3 U, respectively; p ≦ 0.05) from baseline. Decreases in triglycerides [pioglitazone 45 mg: -5.9% (p ≦ 0.05)], very low-density lipoprotein cholesterol [pioglitazone 45 mg: -6.2% (p ≦ 0.05)] and free fatty acids [-0.94 (p ≦ 0.05) and -2.13 (p < 0.0001) mg/dl, respectively] and increases in high-density lipoprotein cholesterol (9.7 and 13.0%, respectively; p < 0.0001) also were observed from baseline. Small but significant increases in total and low-density lipoprotein cholesterol (p < 0.01) from baseline were observed. Mean weight gain was 2.9 and 3.4 kg in the respective groups; lower limb oedema was reported in 13 and 12% of patients, respectively. The incidences of oedema, weight gain and heart failure were not higher than anticipated in this population. No evidence of hepatotoxicity or clinically significant elevations in liver function test parameters was seen.
Conclusions: In patients with poorly controlled type 2 diabetes, addition of pioglitazone to insulin significantly improved glycaemic control, had a positive effect on important components of the lipid profile in a dose-dependent manner and was generally well tolerated.
BACKGROUND
As endogenous insulin production decreases with progressing type 2 diabetes, many patients require additional therapy, oftentimes insulin, to achieve target haemoglobin A1c (A1C) levels. Insulin monotherapy does not always adequately control insulin deficiency in type 2 diabetes, and the addition of an insulin sensitizer has been shown to improve glycaemic control in patients requiring insulin [1]. According to results of epidemiological studies, the majority of patients with type 2 diabetes ultimately require treatment with multiple agents to achieve recommended glycaemic targets [2,3].
Thiazolidinediones, a class of oral anti-hyperglycaemic agents, have emerged as an important component of diabetes treatment [4]. Activation of peroxisome proliferator-activated receptor gamma decreases insulin resistance (improves insulin sensitivity) and produces favourable modifications in blood glucose. Pioglitazone (ACTOS, Takeda Pharmaceuticals North America, Inc., Lincolnshire, IL, USA), a member of the thiazolidinedione class, also has been shown to decrease triglycerides and increase high-density lipoprotein (HDL) cholesterol. Combined, these glycaemic and lipid benefits may decrease the risk of microvascular and macrovascular complications of diabetes [5-7]. Pioglitazone has been shown to improve glycaemic control, either alone or in combination with a sulphonylurea, metformin or insulin in patients with type 2 diabetes [8-12].
In this article, we present results of a large, 6-month, randomized, double-blind, multicentre study conducted to compare the efficacy and safety of the maximum and middle dosages of pioglitazone (45 and 30 mg once daily) in addition to insulin in improving glycaemic control and lipid levels in patients with type 2 diabetes poorly controlled with pharmacotherapy including insulin.
Patient Disposition
Patient disposition is shown in table 1. A total of 745 patients entered the placebo lead-in period. Of the 690 patients who were randomly assigned and received study drug, 486 completed the assigned treatment regimen, and 204 patients (29 and 30% of patients in the pioglitazone 30- and 45-mg groups, respectively) prematurely discontinued participation during the double-blind treatment period. The distribution of reasons for early dropouts was similar between treatment groups. Approximately, 4 and 3% of patients discontinued because of insufficient therapeutic effect in the 30- and 45-mg pioglitazone groups, respectively; approximately 7 and 10% of patients discontinued because of adverse events in the respective treatment groups. Of those withdrawn due to adverse events, 1.5 and 1.7% of those patients were withdrawn as the result of confirmed hypoglycaemia or hyperglycaemia, respectively. Approximately 18 and 17% of patients in the 30- and 45-mg pioglitazone groups, respectively, were withdrawn for other reasons not related to adverse events or lack of efficacy, including non-compliance, being lost to follow-up and other reasons.
Baseline Demographic and Clinical Characteristics
Treatment groups were similar at baseline in terms of demographic characteristics, duration of diabetes, number of anti-hyperglycaemic agents in addition to insulin, pre-existing medical conditions, glycaemic parameters and lipid and lipoprotein parameters (table 2). Mean age of the intent-to-treat study population was 56.5 years (range, 20-80 years), and mean BMI was 33.2 kg/m2 (range, 19.1-54.6 kg/m2). The population was approximately equally represented by gender (55% men) and approximately twothirds (63%) was Caucasian. Patients had long-standing type 2 diabetes (mean duration, 12.9 years); reported microvascular and macrovascular complications included hypertension (64%), diabetic neuropathy (22%), coronary artery disease (11%), myocardial infarction (9%), peripheral vascular disease (7%), angina (6%) and CHF (5%). Dyslipidaemia was present in the overall population as evidenced by mean levels of triglycerides, HDL cholesterol and LDL cholesterol in 'borderline' risk categories according to the ADA [15].
All patients were self-administering insulin at baseline (median, 60.0 U/day; mean, 69.2 U/day), and 27% of study patients also took an oral anti-hyperglycaemic agent before enrolment into the study.
Compliance, Concurrent Medication Use and Insulin Dosage Reduction
On average, patients took 97% of the study medication as required by the protocol.
Concomitant use of lipid-lowering agents (40 and 38%, respectively), angiotensin receptor blockers (10 and 11%, respectively) and angiotensin-converting enzyme inhibitors (51 and 46%, respectively) was similar between the pioglitazone 30- and 45-mg groups.
All patients continued to self-administer insulin throughout the study. Insulin dosage decreased steadily during the study in both treatment groups, with LS mean change from baseline reaching the level of statistical significance at each evaluation point between weeks 8 and 24 in the pioglitazone 30-mg group and between weeks 4 and 24 in the 45-mg group (p ≦ 0.05 for 30 vs. 45 mg at all time points) (figure 2). At study week 24, mean (±SE) decreases in insulin dosage were -4.5 (±0.74) and -7.3 (±0.74) U/day, respectively (p ≦ 0.05, 30 vs. 45 mg).
Glycaemic Control
A1C and FPG observations from baseline to week 24 are shown in figure 3. Statistically significant mean decreases from baseline A1C were observed in both treatment groups at each monthly, post-baseline evaluation (p ≦ 0.05) (table 3). Pioglitazone 45 vs. 30 mg was statistically significant from week 8 to week 24 (p ≦ 0.05) (table 3). From baseline to week 24, LS mean A1C decreases were 1.2 from 9.9% and 1.5 from 9.7% in the pioglitazone 30- and 45-mg groups, respectively (p < 0.0001 for each relative to baseline; p = 0.0112, 30 vs. 45 mg). According to subgroup analyses, mean decreases from baseline in A1C were greater among patients with baseline A1C > 9.0% but were not affected by gender, age, race or baseline dose of insulin. In comparison with baseline, a significantly higher (p < 0.001) proportion of patients in each treatment group had A1C < 7% at week 24 (13.1 and 22.3% of patients in the pioglitazone 30- and 45-mg groups, respectively, compared with 0.3% at baseline for both groups; p < 0.001 for 30 vs. 45 mg at week 24).
A similar pattern of results was observed for FPG; insulin plus pioglitazone demonstrated statistically significant mean decreases from baseline (p ≦ 0.05) at all monthly evaluations, with the decrease being greater in the 45-mg group (figure 3). From baseline to week 24, LS mean FPG decreases were 32 mg/dl from a baseline of 202 mg/dl and 46 mg/dl from 199 mg/dl, respectively, relative to baseline values in the pioglitazone 30- and 45-mg groups (p < 0.0001 for each relative to baseline; p = 0.015, 30 vs. 45 mg).
Lipid Parameters
Addition of pioglitazone 30 or 45 mg once daily to insulin resulted in favourable changes in important components of the lipid profile (table 4). At 12 and 24 weeks, patients in the pioglitazone 45-mg group had significant reductions from baseline (p ≦ 0.05) in free fatty acids, triglycerides and VLDL cholesterol and significant increases from baseline (p ≦ 0.05) in HDL cholesterol (data shown only for week 24). Patients in the pioglitazone 30-mg group had significant reductions from baseline (p ≦ 0.05) in free fatty acids at 12 and 24 weeks and in triglycerides and VLDL cholesterol at 12 weeks.
From baseline to week 24, the percentage of patients with a triglyceride measurement < 150 mg/dl increased from 46.9 to 55.7% and from 51.7 to 69.7%, respectively, in the pioglitazone 30- and 45-mg groups. In the same period, the percentage of male patients with an HDL cholesterol measurement > 45 mg/dl increased from 17.6 to 24.4% and from 19.5 to 34.8% in the respective treatment groups, and the percentage of female patients with an HDL cholesterol measurement ≥55 mg/dl increased from 25.6 to 31.0% and from 25.4 to 37.3% in the respective treatment groups. Compared with the number of patients in the pioglitazone 30-mg group, significantly more patients in the pioglitazone 45-mg group did not have triglyceride exceed the cutoff value or HDL cholesterol decrease below the cutoff value at 24 weeks (p < 0.001).
Additional analyses showed improvements in HDL cholesterol among patients at all levels of baseline HDL cholesterol and among those receiving and not receiving concurrent lipid-lowering agents. Statistically significant mean increases from baseline of 5.8 and 8.5% were observed in the pioglitazone 30- and 45-mg groups, respectively, in patients with baseline HDL cholesterol ≦ 35 mg/dl. Increases of 17.2 and 21.6% were observed in the respective treatment groups for patients with baseline HDL cholesterol ≥ 35 mg/dl (p < 0.0001 for each change from baseline). In the pioglitazone 30 and 45-mg groups, mean increase in HDL cholesterol was 12.3 and 13.1%, respectively, in those who concurrently took a lipid-lowering agent and 7.7 and 13.8%, respectively, in those who did not (p < 0.0001 for each change from baseline).
In both dose groups, total and LDL cholesterol increased significantly from baseline at 24 weeks (p ≦ 0.05). Free fatty acids decreased and HDL cholesterol increased significantly more from baseline in the pioglitazone 45-mg group than in the 30-mg group at week 24 (p ≦ 0.05). From baseline to week 24, the percentage of patients with an LDL cholesterol measurement ≦ 130 mg/dl remained relatively consistent in the pioglitazone 30-mg group (from 65.1 to 64.7%) and decreased in the pioglitazone 45-mg group (from 68.0 to 59.9%).
Safety and Discontinuations from the Study
The overall incidences of drug-related adverse events with onset during the double-blind treatment period were 59% (202/345) in the 30-mg group and 68% (234/345) in the 45-mg group (p = 0.0072). Most adverse events were mild or moderate in intensity. The most commonly reported drug-related adverse events were hypoglycaemia (37 and 43% of patients, respectively), followed by lower limb oedema (13 and 12%), weight gain (7 and 13%) and aggravated oedema in patients with oedema at baseline (4 and 3%).
On average, patients who reported hypoglycaemia related to study drug reported five episodes. The majority of drug-related hypoglycaemic episodes were associated with clinical symptoms (97%) and were mild in intensity (77%), not requiring medical intervention. A total of 22 (<1.0%) clinical or laboratory hypoglycaemia events were considered severe. In the 30- and 45-mg groups, respectively, 26 and 17 laboratory hypoglycaemia events were documented, one of which was considered severe (in the 45-mg group only) and 12 of which were considered moderate. None of the reported symptoms related to hypoglycaemia were documented by either laboratory glucose determination or home glucose monitoring by the patients.
At the last measurement, a mean increase in mean body weight was observed in both treatment groups: 2.94 and 3.38 kg in the 30- and 45-mg groups, respectively (p < 0.001 for both groups). Body weight increased consistently over the course of the study. A statistically significant dose response for weight gain was observed at all time points.
Frequency of cardiovascular adverse events related to study drug was low and comparable between groups (1.2 and 0.6% for the 30- and 45-mg groups, respectively). Drug-related CHF was reported for three patients receiving pioglitazone 30 mg (one possibly related and two probably related) and one patient receiving 45 mg (possibly related). Three of these patients had a history of CHF, hypertension and myocardial infarction before enrolment in the study, and one patient had a history of confounding factors but no cardiovascular disease. Three of the four patients who developed symptoms of CHF completed their participation in the study.
During their lifetime, the majority of patients with type 2 diabetes will require multiple pharmacological agents to maintain glycaemic control [2,3]; the need to continue adding medication reflects the progressive nature of the disease. In recognition of this reality, current ADA clinical practice recommendations for patients with type 2 diabetes suggest a combination of pharmacological agents with complementary modes of action [16]. One such regimen, the combination of pioglitazone 30 mg and insulin, was previously shown in a 16-week study to be generally well tolerated and resulted in clinically relevant improvements in both glucose and lipid metabolism [11]. The study reported here includes results for 24 weeks using pioglitazone 30- and 45-mg once daily doses.
The current study included a large population of adults with long-standing type 2 diabetes (mean, 12.9 years) poorly controlled with a stable insulin dose of at least 30 U/day and who were known to be at high risk for complications. In this patient population, addition of pioglitazone improved glycaemic control and components of the lipid profile. These improvements occurred concurrently with statistically significant reductions in total daily insulin dose. The analyses included the intent-to-treat population, of which 71 and 70% of patients completed in the pioglitazone 30- and 45-mg groups, respectively. These completion rates were lower than those reported in the 16-week study, in which approximately 90% of patients in the pioglitazone 30-mg group completed, but were closer to the completion rate (77%) in a study with a similar population and duration with rosiglitazone 8 mg added to insulin [17].
At 24 weeks, mean values in the pioglitazone 30-mg group for A1C had decreased by more than 1% (from 9.9 to 8.7%), for FPG by 34 mg/dl (from 200 to 166 mg/dl) and for insulin dosage by 4.5 U/day. In the 45-mg group, mean values had decreased for A1C by more than 1.5% (from 9.7 to 8.2%), for FPG by 46 mg/dl (197 to 152 mg/dl) and for insulin dosage by 7.3 U/day. As previously documented [17], individuals with high baseline A1C levels benefited the most in A1C reduction. Our results support those of Rosenstock et al.[11], who reported statistically significant mean decreases in A1C (-1.3%) and FPG (-48.0 mg/dl) with once daily pioglitazone 30 mg in combination with stable insulin therapy.
At 24 weeks or earlier, combination therapy with pioglitazone and insulin also resulted in significant mean decreases in triglycerides, VLDL cholesterol and free fatty acids and statistically significant mean increases in HDL cholesterol, consistent with a possible anti-hyperlipidaemic treatment effect. The beneficial effect of pioglitazone on HDL cholesterol was not confined to the worst baseline levels and was independent of concomitant use of lipid-lowering agents. In both treatment groups, small increases in LDL cholesterol (approximately 7 mg/dl at 24 weeks) were observed, resulting in approximately 60% of patients in the pioglitazone 45-mg treatment group achieving LDL cholesterol levels less than 130 mg/dl compared with 68% of patients at baseline. These results are consistent with results in other studies in which LDL cholesterol levels remained relatively unchanged when monotherapy with pioglitazone or combination therapy with pioglitazone, sulphonylurea or insulin has been used [8-11]. The small increases in LDL cholesterol could be a function of increased LDL particle number. However, in another study with patients with type 2 diabetes, pioglitazone was shown to cause a change in LDL composition from small and dense to large and buoyant particles [18]. The effects of pioglitazone and rosiglitazone on the size and concentration of LDL particles and other lipid effects in patients with type 2 diabetes are being studied in a head-to-head trial.
No unexpected safety concerns were identified during the course of this study. Adverse events were generally mild or moderate in intensity and were consistent with those commonly associated with thiazolidinediones. In a 16-week study in a similar patient population with pioglitazone 15- and 30-mg doses, 3.2% of patients in the 30-mg group discontinued because of adverse events. The rates of discontinuation in this study because of adverse events (7 and 10% in the 30- and 45-mg groups, respectively) compare more closely to rates in a similar study in which 8% of subjects taking rosiglitazone 4 and 8 mg in addition to insulin withdrew due to adverse events [17]. Fewer than 1% of patients in either treatment group experienced either new or worsening study drug-related CHF during this 6-month study. Of the four patients who had CHF related to study drug, three had a history of active CHF, hypertension and myocardial infarction, and three of these four patients completed the trial.
Rates of hypoglycaemia in this 24-week combination study were higher than those observed in previously reported 16-week pioglitazone and insulin combination studies [11]. This likely is attributable not only to longer duration of treatment in this study but also to differences in study design related to the reporting and review of symptomatic hypoglycaemia and delay in insulin dose adjustments in response to hypoglycaemia events. In this study, a hypoglycaemia diagnosis could be based on symptoms only and did not require confirmation by a low blood glucose value. In the 16-week study, patients recorded the results of daily self-glucose monitoring in study diaries, and symptoms suggestive of hypoglycaemia were substantiated with low glucose levels. Addition of insulin sensitizers to exogenous insulin administration is known to occasionally exacerbate hypoglycaemia [19]. For thiazolidinediones, hypoglycaemia usually occurs in the first weeks of combination insulin therapy [19].
Weight gain and oedema have been shown in previous studies with pioglitazone [8-12]. Results from a randomized clinical trial with combination insulin, metformin and another thiazolidinedione suggest that weight gain can be minimized if insulin and metformin are administered before the addition of a thiazolidinedione compound [20]. In this study, mean body weight increased consistently as anticipated. A dose response for weight gain was observed at all time points. At week 24, increases in mean body weight were 2.94 and 3.38 kg in the 30- and 45-mg groups. Weight gain is thought to be due to increased fat accumulation, fat redistribution or increased total body fluid volume. Oedema was reported at rates consistent with rates in previous studies with pioglitazone (13 and 12% of patients, respectively).
Limitations of the Study
Several factors may have affected the study results and their interpretation, the most important of which is lack of a placebo-plus-insulin control group. A previously conducted, placebo-controlled study of pioglitazone with a similar study design permits anticipation of the probable findings but not statistical comparisons [11]. The lack of placebo group limits conclusions on efficacy and tolerability to a comparison between doses of pioglitazone. For example, possible lifestyle improvements that might have contributed to improvements in glycaemic and lipid parameters over the 6-month study cannot be ruled out. The lipid results are limited in that only 40% of patients were treated with statins, which may be due in part to the study starting in 2000. Also, further studies with and without statin use are needed to show whether these lipid effects depend on statin use. Exclusion of patients with significant cardiovascular disease limits the generalizability of study results to all patients with diabetes. The relatively short-term nature of the study precludes an assessment of whether the glycaemic and anti-hyperlipidaemic benefits of pioglitazone will decrease the risk of microvascular and macrovascular complications of diabetes.
Patients
Adults (≥ 18 years of age) with type 2 diabetes mellitus as defined by American Diabetes Association (ADA) criteria [13] and poorly controlled glycaemia (A1C ≥ 8% at screening) despite therapy with a stable insulin regimen were selected. Eligible patients must have received 30 or more units per day of the same insulin type for at least 30 days immediately prior to screening. Patients were required to have a body mass index (BMI) between 25 and 45 kg/m2 and have been willing to participate in dietary counseling, follow an ADA-recommended diet and measure blood glucose on a daily basis using a self-monitoring test.
Patients were excluded if they had a history of type 1 diabetes, diabetic ketoacidosis, chronic alcoholism or drug abuse in the prior year, persistent microscopic or unexplained macroscopic haematuria, or cardiac or cerebrovascular conditions (e.g. myocardial infarction, coronary angiography or bypass graft surgery, unstable angina, transient ischaemic attacks or cerebrovascular accident) within 6 months before screening. Pregnant or lactating women and patients with significant cardiovascular disease [defined as congestive heart failure (CHF) with New York Heart Association class III or IV cardiac status (adapted from Goldman et al. [14]) or with left ventricular ejection fraction <40%], active liver disease, hypothyroidism (thyrotropin ≥ 3.5 mIU/ml), abnormal laboratory data [e.g. alanine aminotransferase > 2.5 X upper limit of normal, creatinine phosphokinase > 1.5 X upper limit of normal, triglycerides > 500 mg/dl (5.64 mmol/l)], or unstable medical conditions were excluded.
Patients were required to discontinue taking any anti-diabetic medication other than insulin 2 weeks before entering the 1-week single-blind lead-in period and were to avoid concurrent use of a corticosteroid for more than 2 weeks, prescription-strength niacin, chromium-containing products and cyclophosphamide prior to study entry. Patients were permitted lipid-lowering agents (i.e. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor or fibrate), provided no dosage adjustment or initiation/discontinuation occurred during the study.
Study Design
The study was a randomized, parallel-group, multicentre (90 sites) trial consisting of a 2-week screening period followed by a 1-week placebo lead-in period, a 24-week double-blind active treatment period and a 2-week follow-up (figure 1). The institutional review board of each participating site approved the protocol. Written informed consent was obtained from each patient or the patient's legal representative before enrolment, according to Good Clinical Practice guidelines and the Declaration of Helsinki.
Patients who met study criteria entered the screening (washout) period, during which anti-hyperglycaemic medication other than insulin was discontinued. During the 2 weeks that followed (single-blind, lead-in period), patients received two placebo tablets each day (matching placebo tablets for pioglitazone 30- and 15-mg tablets). Patients continued administration of their prestudy insulin regimen (same type and dosage of insulin used in the most recent 30 days) throughout the screening and single-blind, lead-in periods. Thereafter, eligible patients were randomly allocated in equal numbers to receive insulin (stable regimen) and either pioglitazone 30 mg (30 mg plus placebo tablet) or 45 mg (30- and 15-mg tablets) once daily for 24 weeks. During the double-blind, active treatment period, investigators were permitted to modify (i.e. change timing of doses or relative proportions of insulin products) or decrease (but not increase) their patients' insulin dosage, as necessary, in response to hypoglycaemia [fasting plasma glucose (FPG) < 60 mg/dl on two occasions or symptoms of hypoglycaemia not explained by other conditions].
After patients completed the 24-week, double-blind treatment phase, they continued their usual regimen of insulin and may have resumed taking their pre-study anti-hyperglycaemic medication or initiated other anti-hyperglycaemic medications prescribed by their physician. Two weeks after the discontinuation of pioglitazone, patients returned for a final follow-up visit to identify any potential safety concerns.
Clinical Evaluations
Study participants attended clinic visits monthly during the double-blind, active treatment period. A1C and FPG were evaluated at baseline (before initiation of study drug) and at each clinic visit. Serum lipid profiles, including triglycerides, total cholesterol, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol and free fatty acids, were evaluated at baseline and weeks 12 and 24. Blood samples were collected after patients had fasted for at least 8 h and were analysed at a central laboratory (Quintiles Laboratories, Smyrna, GA, USA).
Non-esterified or free fatty acid was determined by colourimetric analysis (Wako Chemicals, Richmond, VA, USA). HDL cholesterol was measured by ultracentrifugation after precipitation with phosphotungstic acid and magnesium chloride of the VLDL and LDL cholesterol fractions. Total cholesterol was measured by enzymatic reaction, and LDL cholesterol was measured enzymatically with detergent solubilization using a BMD 747200 autoanalyser [14]. A1C was measured by column chromatography using a cation exchange cartridge technique (BIO-RAD, Hercules, CA, USA). Serum glucose was measured using the glucose hexokinase method on a BMD 747200 autoanalyser.
Study Drug Compliance
The number of tablets dispensed at each clinic visit was recorded, and subjects were instructed to return all bottles at the next visit. All returned medication was counted and documented to calculate the number of tablets taken by the subject.
Safety Assessment
Data obtained to evaluate the safety of study drug included physical examinations, vital signs, body weight and adverse event results. Patients were monitored for adverse events over a 27-week period, beginning at the visit conducted 7 days before the initiation of study drug (at the beginning of the placebo lead-in period) and concluding at the follow-up visit (up to 14 days after discontinuation of study drug).
Statistical Analyses
The primary efficacy variable was A1C, and secondary efficacy variables included FPG and serum lipids. The primary efficacy time point was the last measurement obtained during the double-blind treatment period.
Given the planned sample size of 331 patients in each treatment group, it was assumed that at least 88% of randomly assigned patients would contribute to the primary efficacy analysis. Using a type I error of 0.050 for a 2-sided test, the study had 90% power to detect a 0.35-unit difference between treatment groups for mean change from baseline A1C.
Efficacy analyses were performed using an intent-to-treat data set that included all patients who were randomly assigned and received at least one dose of study drug. To address missing evaluations, a last observation carried forward analysis was conducted for efficacy during the double-blind treatment period.
Baseline comparability between treatment groups was assessed by 2-way analysis of variance (anova), with treatment group and pooled study centre as factors, for continuous variables and was assessed by the Cochran MantelHaenszel general association test, stratified by pooled centre, for discrete variables.
For efficacy parameters, treatment differences for change from baseline (mean percentage change for triglyceride and cholesterol levels) to last measurement, as well as for change (or percent change) from baseline to each evaluation time point, were analysed using the t-test, with estimates of least squares (LS) means and variances obtained from 2-way analysis of covariance (ancova). The model included terms for treatment group, pooled study centre and treatment by pooled study centre interaction (when treatment effects were estimable) and the corresponding baseline value as a covariate. Changes from baseline were conducted using a paired t-test. The treatment by pooled study centre interaction effect was evaluated for A1C and FPG at the study end point at the 0.10 significance level. The proportion of patients reaching or exceeding established thresholds (i.e. A1C < 7%, triglyceride < 150 mg/dl, HDL cholesterol ≥ 45 mg/dl for men and ≥55 mg/dl for women, LDL cholesterol ≥ 130 mg/dl) at week 24 was compared to baseline (X2 test or Fisher exact test) and between treatment groups (X2 test).
Safety analyses were performed for all patients who received at least one dose of randomized study drug. The Fisher exact test was used to assess treatment group differences in treatment-emergent drug-related adverse event incidences as well as treatment differences in the percentage of patients prematurely discontinuing from the study.
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