Patients with type 2 diabetes mellitus (DM) have a marked increase in the risk of myocardial infarction (MI), and a substantially worse prognosis after MI compared with patients without diabetes.1–3 In recent years, it has become apparent that optimal control of blood pressure and low-density lipoprotein cholesterol (LDL-C) level can substantially reduce excess cardiovascular risk in patients with diabetes.4–6 However, even with optimal control of these potent cardiovascular risk factors, incremental risk for cardiovascular events remains high compared with individuals without diabetes.2–3,6 New approaches are, therefore, needed to further reduce cardiovascular risk in patients with diabetes.
Emerging evidence suggests that thiazolidinediones could be useful for reducing cardiovascular risk. In isolated vessel-wall cells, troglitazone, pioglitazone, and rosiglitazone have been shown to modulate gene expression in a manner that would be predicted to be atheroprotective in vivo.7–8 In humans, these agents have been shown to have beneficial effects on systemic inflammatory and coagulation markers, lipoprotein profile, and endothelial cell function.9–12 Some of these beneficial effects may be independent of effects on glycemia.13–15 In animal models of atherosclerosis, thiazolidinediones have been shown to reduce atherosclerotic plaque area independent of changes in glycemia or lipid profile.16–17
When investigating the usefulness of therapies for preventing cardiovascular events, several surrogate end-points for estimating future risk of such events have been evaluated. The measurement of carotid intima-media thickness (CIMT) is among the best validated of these surrogate end-points.18 CIMT has been shown to highly correlate with risk of future cardiovascular events, and changes in CIMT over time have additional predictive value.18–19 Statins, established agents for reducing risk of cardiovascular disease events, have been shown to reduce progression of CIMT.18,20
There have been recent reports examining the effect of thiazolidinediones on CIMT in diabetes.13,21-24 Minamikawa et al.23 reported that troglitazone compared with no added treatment reduced CIMT at three and six months in 135 Japanese patients. Langenfeld et al.22 compared pioglitazone with glimepiride in 173 white German participants and reported a reduction in CIMT at 24 weeks.
The participants had a baseline systolic blood pressure of approximately 148mmHg and an LDL-C level of approximately 136mg/dl (3.5mmol/l). In spite of this elevated LDL-C level, statin use was less than 20% at the start of the study. Hodis et al.24 recently reported results from 299 patients with type 2 DM. This cohort was more than 66% female and more than 86% Hispanic-American and was randomized to receive troglitazone or placebo for two years. Overall, the change in CIMT was not different between the two treatment groups, although a beneficial effect of troglitazone was observed in the subgroup with a baseline CIMT of 0.8mm or greater. Because of important issues related to small cohort size, short duration of treatment, homogeneity of study population with respect to race/ethnicity, the presence of uncontrolled cardiovascular risk factors, and inconsistent results, there remains an important question regarding the effect of thiazolidinediones on CIMT in type 2 DM.
Below are the findings of a long-term randomized and comparator-controlled clinical trial conducted in patients with type 2 DM recruited from an ethnically/racially diverse population of a large US metropolitan area. The study compared the effect of pioglitazone with that of glimepiride on progression of CIMT. Glimepiride was chosen as a comparator because a placebo control could not be ethically justified in terms of maintaining adequate glycemic control. In addition, glimepiride represents a class of drugs that is commonly used to treat diabetes in the US, and its mechanism of action is distinct from that of pioglitazone.
Study Discussion and Comment
In this randomized trial of 462 patients with type 2 DM, we found that, compared with glimepiride, pioglitazone reduced CIMT progression, a validated surrogate end-point for coronary artery disease and cardiovascular risk.18–19 The CHICAGO trial was conducted in a single geographical region, allowing measurement of CIMT to be performed at a single location by a single sonographer. The analysis used automated digital edge-detection technology and included multiple measurements in each carotid artery segment. Our study population was recruited from a racially and ethnically diverse population of a large US city and generally reflects the diversity of the type 2 DM population in the US. Our results demonstrate reduction of CIMT progression with pioglitazone treatment in a cohort with a better level of management of cardiovascular risk factors (i.e., a higher rate of statin use, LDL-C levels near 100 mg/dl [2.6mmol/l], and near-optimal blood pressure control) compared with previously reported cohorts.22
Our study also included repeated measurements up to 72 weeks, beyond the three- to six-month treatment period in previous trials using pioglitazone.13,21–22 A pre-specified subgroup analysis based on age, sex, systolic blood pressure, duration of type 2 DM, body mass index, glycosylated hemoglocin (HbA1c) value, and statin use showed a uniform beneficial effect of pioglitazone treatment.
Systolic blood pressure was reduced by a small amount in both treatment groups. This effect was slightly larger in the pioglitazone group, but treatment differences did not reach statistical significance. Pre-specified cardiovascular end-points were adjudicated in a double-blinded fashion by an independent panel and more of these events, mostly related to coronary revascularization, occurred in the glimepiride group. There was one case of new congestive heart failure with pioglitazone therapy, while hypoglycemia was slightly more common with glimepiride. As expected, edema and weight gain were more common in the pioglitazone group. CIMT has been extensively evaluated as a surrogate marker of atherosclerosis and cardiovascular risk.18–19 It has recently been suggested that changes in maximum CIMT may be preferred for measuring treatment-related changes in carotid atherosclerosis.25 Our results demonstrate beneficial effects of pioglitazone on progression for both mean and maximal CIMT values.
In patients with type 2 DM, measurement of CIMT significantly improves prediction of cardiovascular disease risk compared with the Framingham Risk Score.26 It has also been shown that changes in CIMT over time correlate with future cardiovascular event rates.18–19 Diabetes, which confers increased risk of cardiovascular disease, also accelerates CIMT progression.27 However, CIMT progression rates vary widely in patients with diabetes, from 0.083mm over six months to 0.007mm over onw year.27,28 In a recent review of 11 CIMT intervention trials in diabetes,29 the mean CIMT progression rate in the control groups was 0.034mm per year, but varied considerably between trials based on level of control of cardiovascular risk factors. The low rate of progession in the control group of the current study likely reflects the control of systolic blood pressure and LDL-C level.
The beneficial effect of pioglitazone on CIMT in patients with type 2 DM is consistent with results of the recently reported PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study.30 This trial randomized more than 5,000 patients with type 2 DM who had evidence of macrovascular disease to receive pioglitazone or placebo in addition to existing therapy. While treatment with pioglitazone did not significantly reduce the risk of the composite primary end-point (which included death from any cause, nonfatal MI, stroke, acute coronary syndrome, leg amputation, coronary revascularization, or leg revascularization), it did significantly reduce by 16% the risk of the main secondary end-point (a composite of all-cause mortality, MI, or stroke).
Several potential mechanisms can be considered for a beneficial effect of pioglitazone on atherosclerosis. Treatment with thiazolidinediones has been shown to modify nontraditional markers of cardiac risk such as circulating inflammatory and coagulation markers and to improve endothelial-cell function.9–12,31–32 Thiazolidinedione treatment can also positively modify blood pressure, glycemia, and lipid levels.9–12 In the current study, blood pressure changes were not significantly different between the pioglitazone and glimepiride groups. HbA1c values were reduced more in the pioglitazone group compared with the glimepiride group (by 0.32% at 72 weeks). However, it is noteworthy that the treatment advantage for pioglitazone on HbA1c values in this study did not become significant until week 48. In prior studies, treatment with pioglitazone has been shown to have a substantial benefit on diabetic dyslipidemia, including increasing HDL-C levels and reducing triglycerides levels.12 Both of these effects were observed in our study and could have contributed to improvement in CIMT. Finally, it also remains possible that thiazolidinediones can have a directly beneficial effect on the vessel wall.16–17
Our study has several limitations. First, it was not powered to detect a difference in cardiovascular end-points and, therefore, does not establish that treatment with pioglitazone compared with glimepiride will reduce these end-points in patients with type 2 DM. Because we used glimepiride as an active comparator, we also cannot definitively rule out that the treatment difference was due to a proatherogenic effect of glimepiride. We believe, however, that this explanation is somewhat unlikely in view of the fact that the treatment difference was largely the result of an effect of pioglitazone to suppress or delay the progression of CIMT. Our study also had a dropout rate that approximated 30%.
However, dropout rates were balanced in the two treatment groups, and the participants who remained in the study (i.e., the CIMT population) were similar to those in the intention-to-treat population. In addition, an analysis of baseline characteristics of participants who dropped out showed no difference compared with those who remained in the study. Finally, thiazolidinediones may cause acute changes in intravascular volume and affect vascular tone. Such changes also result from antihypertensive therapy, and an issue has been discussed in the literature regarding a potential role for changes in intravascular volume, vascular tone, or both in producing rapid changes in CIMT.18 In the current study, the observation that treatment difference appeared to increase over time argues against an important role for changes in intravascular volume or vascular tone. In a recent evaluation of the effect of antihypertensive therapy on CIMT, Zanchetti et al.33 concluded that only 1% of CIMT change could be attributed to overall change in carotid artery diameter.
Notwithstanding these limitations, our results demonstrate, in a relatively large and long-term randomized trial, that pioglitazone slowed progression of CIMT compared with glimepiride. This benefit was measured in participants with excellent blood pressure control, statin use greater than 50%, and mean LDL-C levels of 113.8mg/dl (SD, 2.4) (2.95 [SD, 0.062] mmol/l). Additional data will be needed to determine the clinical significance of these findings: specifically, whether a strategy of routine use of pioglitazone instead of glimepiride substantially reduces major cardiovascular events.
Republished with permission from The Journal of the American Medical Association.