Ragaglitazar Improves Glycemic Control and Lipid Profile in Type 2 Diabetic Subjects: A 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm

This was a double-blind, parallel-group, placebo-controlled study with an open-label pioglitazone arm. The study was conducted at 31 sites in the U.S. The protocol was approved by the institutional review board of each center, and all subjects provided informed consent. Subjects who passed screening underwent a 4-week washout period and were then randomized to 12 weeks of treatment with single daily doses of ragaglitazar (0.1, 1, 4, or 10 mg/day), placebo, or pioglitazone (45 mg/day, maximum indicated dose). The 4-week washout period was chosen to avoid any carryover effect from previous oral hypoglycemic agent (OHA) treatment on fasting plasma glucose (FPG). Subjects assigned to the ragaglitazar or placebo treatment groups received, on day 1, a loading dose of five times the prescribed daily dose. Subjects were advised to maintain their usual diet and physical activity routine throughout the study. Clinic visits occurred at screening, before the 4-week washout, at baseline (week 0), and at the end of treatment weeks 2, 4, 8, 11, and 12.

Subjects with type 2 diabetes (American Diabetes Association criteria) (19) were included in the study if they were 18–73 years old, had a fasting C-peptide >0.4 ng/ml, had a BMI 25–42 kg/m², and had triglycerides 151–500 mg/dl. The subjects had been previously treated for at least 2 months with diet or an OHA, such as an α-glucosidase inhibitor, β-cell secretagogue, or metformin. At randomization, subjects had an FPG 126–240 mg/dl.

Subjects were excluded if they had received treatment with lipid-lowering drugs within 3 weeks or thiazolidinediones within 3 months before screening or had clinically significant, active (or over the past 12 months) cardiovascular, hepatic, or renal disease.

Efficacy assessments included fasting plasma levels of glucose, triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, apolipoprotein B, insulin, C-peptide, A1C, and 8-point self-monitored blood glucose profiles. Lipid profiles, insulin levels, FPG, and A1C were assessed at the baseline visit and weeks 4, 8, and 12. Blood and urine samples were analyzed by Medical Research Laboratories (Highland Heights, KY). Subjects were asked to perform 8-point blood glucose profiles (before each of three meals, 90 min after the start of each meal, at bedtime, and at 2:00 a.m.) for 2 days before the baseline and week 4, 8, and 12 visits.

Safety was assessed by physical examination, measurements of vital signs, clinical laboratory tests (hematology, clinical chemistry), urinalysis, 12-lead electrocardiogram, funduscopy, slit lamp corneal examination, and reporting of adverse events during clinic visits.

Treatment comparisons were made using the ANCOVA model with treatment and previous treatment as fixed effect and corresponding baseline measurements as covariates. Change-from-baseline data were used in the analysis of all lipid and glycemic parameters. Efficacy parameters are expressed as least squares mean values ± SE.

Demographic and baseline characteristics of the 177 subjects who participated in the study are shown in Table 1. There were no significant differences among the treatment groups in demographic or baseline characteristics.

A total of 125 subjects (71%) completed the study, and 52 subjects discontinued treatment prematurely (10 in the placebo group; 6, 7, 9, and 13 in the 0.1-, 1-, 4-, and 10-mg ragaglitazar groups, respectively; and 7 in the pioglitazone group). Most of the discontinuations from the 4- and 10-mg ragaglitazar treatment groups were due to adverse events (5 and 10 subjects, respectively). Ten of the subjects in the 4- and 10-mg ragaglitazar groups withdrew because of adverse events related to edema (two in the 4-mg group and eight in the 10-mg group). Most subjects withdrawing from the placebo (seven subjects) and pioglitazone (four subjects) groups did so because of inadequate glycemic control. No subjects withdrew from the placebo or pioglitazone groups because of adverse events.

The 1-, 4-, and 10-mg ragaglitazar and the pioglitazone treatment groups showed significant improvements in glycemic control at the end of the study (Fig. 1 and Table 2). As compared with placebo, the 1-, 4-, and 10-mg ragaglitazar treatment groups had significant decreases from baseline values of FPG (least squares mean decreases of −48, −74, −77 mg/dl, respectively) and A1C (least squares mean decreases of −0.5, −1.3, −1.1%, respectively). At the end of the study, the placebo group had increases from baseline of 0.8% for A1C and 22.5 mg/dl for FPG. The pioglitazone-treated subjects had reductions from baseline in FPG (−43 mg/dl) and A1C (−0.3%) values that were similar to those of the 1-mg ragaglitazar group. Most of the improvements in FPG values for subjects in the 1- to 10-mg ragaglitazar or pioglitazone groups were observed by week 8. Fasting insulin levels decreased significantly as compared with placebo for subjects in the 1-, 4-, and 10-mg ragaglitazar treatment groups and the pioglitazone group (5.0, 6.8, 7.9, and 4.3 μU/ml, respectively) (Table 2). Subjects in the placebo group showed no significant change in fasting plasma insulin.

Treatment with ragaglitazar was associated with significant decreases from baseline in triglycerides, free fatty acids (FFAs), LDL cholesterol, total cholesterol, and apolipoprotein B levels and significant increases in HDL cholesterol levels (Fig. 2 and Table 2). Treatment with 4 mg of ragaglitazar decreased plasma triglycerides from 265 ± 102 mg/dl at baseline to 109 ± 41 mg/dl at the end of the study, whereas triglycerides in the placebo group increased from 351 ± 168 to 393 ± 277 mg/dl. In addition, ragaglitazar (4 mg) significantly increased HDL cholesterol from 41 ± 7 to 54 ± 9 mg/dl, whereas HDL cholesterol level was unchanged in the placebo group (39 ± 12 mg/dl; end of study, 41 ± 14 mg/dl). The lipid parameter results for subjects treated with the lowest dose of ragaglitazar (0.1 mg) were similar to those for placebo. For subjects treated with pioglitazone, triglycerides and FFA values decreased significantly from baseline (Table 2); however, the LDL cholesterol was slightly increased (not significant) for these subjects at the end of the study.

Overall, the ragaglitazar treatment groups demonstrated a dose-dependent increase in the incidence of reported treatment emergent adverse events (TEAEs) of edema, weight gain, decrease in white blood cell (WBC) count, and anemia. Accordingly, the most commonly reported TEAEs for the 4- and 10-mg ragaglitazar groups were edema (∼20 and 40% of subjects, respectively), weight gain (∼22% of subjects in both groups), leukopenia (9 and 13% of subjects), and anemia (12 and 23% of subjects). Edema was the most commonly cited reason for subjects in the 4- and 10-mg ragaglitazar treatment groups to withdraw from the study (two subjects in the 4-mg group and eight subjects in the 10-mg group). Mean increases in body weight were greatest for the 4- and 10-mg ragaglitazar treatment groups (5.7 ± 4.1 and 5.9 ± 5.1 kg, respectively).

Dose-dependent decreases in hemoglobin and WBC count were observed for ragaglitazar treatment. Hemoglobin decreased in the pioglitazone and 1-, 4-, and 10-mg ragaglitazar groups by −7.3, −6.7, −13.3, and −19.4%, respectively. Decreases in hemoglobin resulting in adverse events of anemia were reported by four subjects in the 4-mg ragaglitazar group and seven subjects in the 10-mg ragaglitazar group. Hemoglobin values in the 1-mg ragaglitazar group were similar to those in the pioglitazone group. The end-of-study WBC count and absolute neutrophil count (ANC) values in the 4- and 10-mg ragaglitazar groups decreased significantly from baseline compared with the placebo group (WBC, 30 and 36% and ANC, 36 and 44% for 4- and 10-mg ragaglitazar, respectively). For each parameter, most of the reductions had occurred by the week 4 visit, and values remained relatively constant throughout the remainder of the study. Decreases in WBC and ANC returned to normal upon follow-up testing after the study. WBC and ANC values in the 1-mg ragaglitazar group were similar to those in the pioglitazone and placebo groups. One subject in the 4-mg ragaglitazar group was discontinued from the study because of leukopenia, but there were no observed dose-dependent increases in the incidence of infection in the ragaglitazar groups.

The most commonly reported TEAEs (∼4–6% of subjects) for the placebo, 0.1-, and 1-mg ragaglitazar treatment groups were similar and comprised symptoms of upper respiratory tract infection (pharyngitis, sinusitis, headache, coughing). Symptoms of edema were reported for two subjects in the placebo group, and one subject each in the 0.1- and 1-mg ragaglitazar group. Gastrointestinal symptoms (e.g., diarrhea, nausea) (4–7% of subjects) and edema (∼10% of subjects) were the most commonly reported adverse events for pioglitazone-treated subjects.

Only three episodes of hypoglycemia were confirmed by a self-monitored blood glucose value of <50 mg/dl. No serious hypoglycemic events (loss of consciousness, need for third-party assistance) were reported by any subject in any treatment group. There were no clinically remarkable changes from baseline in other clinical chemistry, physical examinations, vital signs, funduscopy, or slit lamp corneal examinations.

The present 12-week study demonstrated the effect of ragaglitazar on both glycemic and lipid parameters in type 2 diabetic hypertriglyceridemic subjects. The 0.1-mg ragaglitazar was similar to placebo, whereas a maximal hypoglycemic effect was observed at 4 mg. The maximum effect was achieved by 8 weeks of treatment and was maintained to the end of the 12-week study. Although the effect of ragaglitazar on A1C values could not be fully evaluated in such a short-term trial, significant reductions were observed.

Improvement in the entire lipid profile was also noted with doses from 1 to 10 mg of ragaglitazar. The drug lowered triglycerides and raised HDL cholesterol at 4 weeks of treatment and maintained these changes to the end of the 12-week study. Although a direct comparison of ragaglitazar and pioglitazone was not performed, ragaglitazar appeared to be more effective than pioglitazone in improving the lipid profile, particularly in regard to LDL cholesterol, HDL cholesterol, and apolipoprotein B levels. Although pioglitazone lowered triglycerides, it also raised the LDL cholesterol level, a finding observed in previous studies of thiazolidinediones (20,21). Because hypertriglyceridemia and low HDL cholesterol are risk factors for CVD, ragaglitazar and similar compounds could provide an important benefit to subjects with diabetic dyslipidemia.

The lipid results were consistent with PPAR-α activation, which stimulates uptake and catabolism of FFA in hepatocytes, inhibits hepatic production and secretion of VLDL cholesterol, and increases production of HDL cholesterol. Lowering of FFA may result in an improvement of insulin resistance and insulin secretion (22). Activation of PPAR-γ by ragaglitazar lowers insulin resistance and increases glucose uptake into muscle and adipose tissue. All ragaglitazar dose groups showed a reduction of fasting insulin levels. Correction of insulin resistance may have implications in altering long-term complications.

For the ragaglitazar groups, dose-related adverse events typical of the thiazolidinediones were observed (23). The adverse event profiles of the 0.1- and 1-mg groups were similar to that of the placebo group. However, an increased frequency of anemia, body weight increase, edema, and leukopenia were found in subjects in the 4- and 10-mg groups. The decrease in WBC, more specifically in ANC, occurred within the first 4 weeks of treatment, generally stabilized thereafter, and was not associated with an increase in infection-related adverse events. These reductions in WBC were reversed upon poststudy follow-up. The mechanism behind the observed reductions in WBC, ANC, and erythrocyte counts remains to be established. However, these reductions may be due to a combination of an increase in plasma volume and a direct effect on the hematopoiesis possibly involving fatty cell infiltration of the bone marrow. In addition, suppression of the bone marrow may play a role. The clinical implications of these WBC findings are unknown.

In summary, the results of this study have demonstrated the potent effect of ragaglitazar in the improvement of glycemia and dyslipidemia in patients with type 2 diabetes. A compound with such a profile of effects could have tremendous potential to reduce the morbidity and mortality associated with long-term cardiovascular complications.

Investigators of the Ragaglitazar Dose-Ranging Study Group: Mira Baron, Patrick Carmichael, Christopher R. Edwards, Victor Elinoff, Geoffrey D. Furman, Gumaro Garza, Susan Greco, James Greenwald, Maria Greenwald, George Grundberger, Israel Hartman, Robert Henry, James R. Herron, Walter Hood, Samuel Lerman, Andrew J. Lewin, Janet McGill, Bernard A. Michlin, Daniel Nadeau, Margarita Nunez, Kwame Osei, Mukesh R. Patel, Philip Raskin, Dennis Ruff, Mohammed F. Saad, Leah Schmidt, Michael E. Schwartz, Stephen A. South, Melvin Tonkon, Richard Weinstein, and Robert J. Williams.