A randomized, double-blind, placebo-controlled study of the effect of ezetimibe on glucose metabolism in subjects with type 2 diabetes mellitus and hypercholesterolemia

While diabetes, hypertension and hypercholesterolemia are each independent risk factors for coronary artery disease (CAD), concomitant occurrence of these factors may lead to a cumulative increase in CAD risk [1]. Management of these risk factors is important for reducing the risk of atherosclerosis and the risk of ischemic heart disease and CAD. In addition to lipid management and blood pressure control, glycemic control is a basic component in the management of diabetes and is achieved in part via diabetes self-management, education, exercise and improved diet, the latter elements being the cornerstones of treatment for diabetes and lipids. As such, it is important that glucose metabolism not be adversely affected when patients take lipid-lowering treatment.

Post-hoc analyses of large clinical trials and meta-analyses have demonstrated a dose- and potency-dependent effect for increased incidence of new-onset diabetes and mild elevation of hemoglobin A1c (HbA1c) and fasting plasma glucose with statin use [2]-[7]. However, it was determined that the benefits of reducing the risk of cardiovascular events with statin use significantly outweigh the potential risks of worsening glycemic control or developing new-onset diabetes [8]. Ezetimibe is an inhibitor of a small intestine cholesterol transporter. It lowers low-density lipoprotein cholesterol (LDL-C) by 15-20% through inhibition of exogenous and biliary cholesterol absorption in the digestive tract by inhibiting the Niemann-Pick C1-Like 1 in the brush border of enterocytes [9],[10]. A significant reduction in insulin resistance and/or fatty liver have been reported in small clinical trials using the combination of pravastatin with ezetimibe [11] or ezetimibe monotherapy [12],[13]. However, other small studies have observed no changes in parameters of glucose metabolism and insulin sensitivity with ezetimibe monotherapy [14]-[16]. Limited data suggest that ezetimibe, whether added to a statin or used as a monotherapy, does not have an adverse effect on glucose metabolism [17],[18]. However, in light of recent findings regarding the increased incidence of new-onset diabetes and the impact on glucose parameters with the use of statins [2]-[7], it is important to assess any potential for these same issues with ezetimibe use. This study was conducted to prospectively examine the effects of ezetimibe on glucose metabolism in patients with type 2 diabetes and hypercholesterolemia.

The primary objective of this study was to examine the safety of ezetimibe compared with placebo with regard to change in HbA1c from baseline to week 24 in subjects with type 2 diabetes and hypercholesterolemia. Secondary objectives included comparing ezetimibe to placebo in subjects with type 2 diabetes and hypercholesterolemia for change in glycoalbumin and fasting plasma glucose from baseline to week 24; the proportion of patients having onset of “exacerbation of diabetes mellitus” (assessed by index of blood glucose control, changes in diabetes medications, and compliance to diet and exercise therapy); the proportion of patients with changes to diabetes medications due to worsening of diabetes.

A total of 342 subjects were screened, resulting in 152 randomized to treatment (75 to ezetimibe 10 mg and 77 to placebo; Figure 1). In each treatment group, only 1 subject discontinued due to an AE. No patients were excluded from the safety and efficacy analyses. Baseline demographics and clinical characteristics were similar between treatment groups (Table 1). Approximately 2/3 of subjects were male, the mean (± standard deviation [SD]) age was 60 (±10) years, with a mean (± SD) body mass index of 26 (±5) kg/m². The vast majority (95%) of subjects had coexisting diseases. There was no notable difference observed between the two groups in coexisting diseases or the use of concomitant medications (Table 1). At baseline mean HbA1c was 7.0%, glycoalbumin was 17.3%, and fasting plasma glucose was 126.3 mg/dL.

The mean baseline values and change from baseline in blood glucose control indices in the ezetimibe 10 mg and placebo groups are shown in Table 2. Over the course of the 24 weeks of treatment, HbA1c significantly increased from baseline in both the ezetimibe 10 mg and placebo groups (Figure 2). At 24 weeks, the least-squares (LS) mean (95% CIs) changes from baseline in HbA1c were 0.22 (0.11 to 0.34) and 0.14 (0.03 to 0.25) for the ezetimibe 10 mg and placebo groups, respectively (Table 2). The between-treatment difference in the change from baseline was 0.08 (−0.07 to 0.23). The ezetimibe 10 mg group was statistically non-inferior to the placebo group, compared with the pre-defined non-inferiority margin of 0.5 (Table 2). The sensitivity analysis was consistent with the primary results, demonstrating non-inferiority of ezetimibe. Results were generally consistent across subgroups defined by baseline HbA1c level (<7.4%, vs. ≥7.4% to <8.4%) and by insulin administration at baseline (yes vs. no; data not shown).

		Baseline	Week 24	Change
	Treatment (n)	Mean (SE)	Mean (SE)	Mean (SE)	LS Mean (95% CI)	P-value
HbA1c (%)	Ezetimibe (n = 69)	6.94 (0.07)	7.14 (0.10)	0.20 (0.06)	0.22 (0.11, 0.34)	<0.001
	Placebo (n = 75)	6.96 (0.06)	7.09 (0.07)	0.13 (0.05	0.14 (0.03, 0.25)	0.015
	Ezetimibe vs Placebo			Difference in LS mean (95% CI)	0.08 (−0.07, 0.23)	0.281
Glyocalbumin (%)	Ezetimibe (n = 69)	17.16 (0.26)	17.14 (0.30)	−0.02 (0.17)	−0.02 (−0.37, 0.34)	0.919
	Placebo (n = 75)	17.21 (0.27)	17.20 (0.29)	−0.01 (0.17)	−0.02 (−0.37, 0.33)	0.918
	Ezetimibe vs Placebo			Difference in LS mean (95% CI)	0.00 (−0.47, 0.47)	1.000
Fasting plasma glucose (mg/dL)	Ezetimibe (n = 69)	124.7 (2.6)	128.0 (2.8)	3.3 (3.0)	6.6 (1.1, 12.1)	0.019
	Placebo (n = 75)	126.7 (2.0)	135.4 (2.9)	8.7 (2.5)	11.4 (6.1, 16.7)	<0.001
	Ezetimibe vs Placebo			Difference in LS mean (95% CI)	−4.8 (−12.1, 2.5)	0.194

At 24 weeks, the LS mean changes (95% CIs) from baseline in glycoalbumin were −0.02 (−0.37, 0.34) and −0.02 (−0.37, 0.33) for the ezetimibe 10 mg and placebo groups, respectively (Table 2). Over the course of the 24 weeks of treatment, changes from baseline in glycoalbumin levels in both treatment groups were similar (Figure 3). The between-treatment difference in the change from baseline at 24 weeks was (0.00; 95% CI: −0.47, 0.47; Table 2).

At 24 weeks, the LS mean changes (95% CIs) from baseline in fasting plasma glucose were 6.6 (1.1, 12.1) and 11.4 (6.1, 16.7) for the ezetimibe 10 mg and placebo groups, respectively (Table 2). Over the course of the 24 weeks of treatment, fasting plasma glucose significantly increased from baseline in both treatment groups (Figure 4). The between-treatment difference in the change from baseline at 24 weeks was (−4.8; 95% CI: −12.1, 2.1; Table 2).

There was no significant difference in exacerbation of diabetes between treatment groups (p = 0.78). Seven subjects (9%) in the ezetimibe group and 6 subjects (8%) in the placebo group experienced exacerbation of diabetes. Similarly, there was no significant difference between groups in the proportion of subjects with changes to diabetes medications due to worsening of diabetes (p = 0.37). Seven subjects (9%) in the ezetimibe group and 4 subjects (5%) in the placebo group made changes to their diabetes medications due to worsening of their diabetes during the study period.

The percent changes from baseline to 24 weeks in LDL-C, total cholesterol, triglycerides, HDL-C and non-HDL-C are shown in Figure 4. After 24 weeks of treatment, the change from baseline was statistically significant for all 5 lipid parameters in subjects treated with ezetimibe 10 mg (P < 0.05) but was not statistically significant in subjects who received placebo. The percent differences (95% CI) between treatment groups (ezetimibe vs. placebo) at 24 weeks were statistically significant except for HDL-C: LDL-C: −21.05% (−25.06, −17.03) P < 0.001; total cholesterol: −13.54% (−16.66, −10.42) P < 0.001; HDL-C: 2.45% (−1.71, 6.61) P = 0.25; triglycerides: −11.36% (−21.27, −1.44) P = 0.03; and non-HDL-C: −19.07% (−22.71, −15.43) P < 0.001.

The results of this study showed that the ezetimibe 10 mg group was statistically non-inferior to the placebo group with respect to change in HbA1c. Over the course of the 24 weeks of treatment, changes from baseline in glycoalbumin and fasting plasma glucose levels in both treatment groups were similar. In addition, differences in exacerbation of diabetes or changes to patients’ diabetes medications due to worsening of their diabetes during the study period did not change significantly. However, differences in change from baseline lipid parameters between ezetimibe and placebo were statistically significant at 24 weeks, except for HDL-C. Ezetimibe was generally safe and well-tolerated.

Results of 2 meta-analyses suggested that treatment with statins may be associated with a small (9%) increased risk for developing diabetes [4],[19]. This was based on measures of glucose regulation such as HbA1c, and fasting plasma glucose. However, published information regarding the incident relationship of ezetimibe treatment to glucose regulations and new onset diabetes is limited. Trials that did report on glucose changes with ezetimibe treatment included subjects with diabetes or metabolic syndrome, both populations that may have impaired glucose function at study start [20],[21]. Therefore, it is difficult to fully assess the individual impact of ezetimibe on glucose metabolism based on the published data.

Several studies in animals have suggested that ezetimibe may have positive effects on glycemic control, including reduced weight gain, diet-induced hyperglycemia and insulin resistance [22], improvement in insulin and plasma glucose response in obese fatty rats [23], and improvement in glucose tolerance, increased insulin sensitivity, and protecting the function of beta-cells in diabetic mice [24]. In addition, one clinical trial showed that after 12 weeks of treatment with ezetimibe 10 mg monotherapy, reductions in HbA1c and fasting plasma glucose were seen in Japanese patients with insulin resistance [25]. These results are consistent with those of the current trial, suggesting that ezetimibe does not confer an increased risk of glucose dysregulation. However, in the previous studies that observed neutral changes in parameters of glucose metabolism and insulin sensitivity with ezetimibe monotherapy, the study populations were small, limiting the generalizability of the results to larger populations [14]-[16]. More recent preliminary data from two post-hoc, pooled analyses in subjects without diabetes suggest that ezetimibe monotherapy or ezetimibe added to statin does not have a negative effect on glucose metabolism [17],[18].

The magnitude of change from baseline in lipids, including LDL-C, total cholesterol, triglycerides and HDL-C, was consistent with those demonstrated in previous 12-week trials of ezetimibe monotherapy vs. placebo [26]-[33]. A meta-analysis of these same trials demonstrated that ezetimibe monotherapy conferred significant reductions in LDL-C, triglyceride, and total cholesterol levels as well as a significant increase in HDL-C level compared with placebo [34]. Except for the significant HDL-C increases, the results of the meta-analysis are consistent with those of the current trial in Japanese patients.

Ezetimibe 10 mg was generally well tolerated. Most AEs were mild in intensity with few related to treatment. There were no unexpected AEs reported based on what has been observed in other clinical trials with ezetimibe monotherapy [34].

This study had some limitations and the results must be interpreted with caution. The population was limited to Japanese patients and may not be generalizable to other populations. The short-term safety profile of ezetimibe monotherapy appears to be similar to placebo. This short-term study limits the ability to extrapolate the results to long-term profiles. However, the recently completed IMPROVE-IT trial assessed the incremental cardiovascular benefit of LDL-C lowering over 7 years with ezetimibe 10 mg added to simvastatin (mainly 40 mg) compared with simvastatin monotherapy in patients presenting with acute coronary syndromes [35]-[37]. The study investigators reported that the trial met its primary and secondary composite efficacy endpoints.

In conclusion, these data suggest that treatment with ezetimibe 10 mg does not result in dysregulation of glucose metabolism over 24 weeks in Japanese patients with type 2 diabetes and hypercholesterolemia. Ezetimibe was generally well-tolerated with reduction of atherogenic lipid parameters.