In this subanalysis of the COSMOS study, we found that baseline HbA1c was significantly associated with change in plaque volume. Notably, no significant regression was observed in patients with high HbA1c at baseline. In contrast, significant plaque regression was observed in subjects with low HbA1c at baseline, even in those with diabetes, although the decreases in LDL-C levels were similar in both groups. This suggests that glycaemic control, in addition to LDL-C-lowering, is an important determinant of plaque progression or regression. Prior observational studies have revealed a positive association between the presence of diabetes mellitus and the incidence of cardiovascular disease [13
]. Several recent trials using IVUS have also indicated that diabetes mellitus is a major determinant of plaque progression [11
]. For example, Hiro et al. investigated the effect of aggressive LDL-C lowering on coronary atherosclerosis in 230 patients with acute coronary syndrome and found that statin-induced regression of coronary plaque volume was weaker in diabetic patients than in non-diabetic patients [11
]. Interestingly, they also found that percent change in plaque volume was significantly correlated with LDL-C in patients with diabetes, but not in non-diabetic patients. Nicholls et al. performed a pooled analysis of five IVUS trials involving 2,237 subjects and compared arterial remodelling, extent of coronary atherosclerosis and disease progression between patients with diabetes and those without [20
]. They found that diabetic patients exhibited greater percent and total atheroma volumes, with more rapid progression of plaque volume and inadequate compensatory remodelling. They also found that percent atheroma volume was more strongly associated with HbA1c than with fasting glucose, although this difference became non-significant after adjustment for patient background. Similarly, Berry et al. observed significant associations between fasting glucose, HbA1c and the presence of diabetes mellitus, and the severity or progression of coronary atherosclerosis in 426 patients who underwent IVUS [21
]. Similar to these earlier studies, we observed a significant association between baseline HbA1c and change in plaque volume.
The reduced plaque regression in patients with high HbA1c suggests that hyperglycaemia or diabetes mellitus may be involved in a unique pathogenic mechanism underlying plaque formation in these patients. Indeed, hyperglycaemia could accelerate the development of atherosclerosis through enhanced production of advanced glycation end products, oxidative stress and vascular inflammation, which may contribute to diabetes-specific atherosclerosis [22
]. This is supported by the results of histological studies and imaging studies, which have revealed that several features are more pronounced in diabetic patients, including more extensive macrophage infiltration, significantly larger lipid cores, and more abundant dense-calcium or fibrocalcific tissue [24
]. More recently, Parathath et al. demonstrated that diabetes modified plaque macrophage characteristics and thus hindered plaque regression [26
As the relationship between the change in plaque volume and HbA1c was mainly observed in diabetic patients, and not in non-diabetic patients, HbA1c seems to be an important determinant of plaque regression in diabetic patients. Thus, targeting glycaemic control may aid plaque regression. Indeed several clinical trials have demonstrated significant plaque regression using oral antidiabetic drugs. For example, the Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE) trial compared the effects of treatment with pioglitazone or glimepiride for 18
months on plaque volume in 543 patients with coronary disease and type 2 diabetes [8
]. The investigators found that the least squares mean percent atheroma volume decreased from baseline in patients treated with pioglitazone but increased in patients treated with glimepiride (−0.16 vs +0.73%, respectively, p
0.002). HbA1c levels were 7.4
1.0% in both groups at baseline, with greater decreases in patients treated with pioglitazone compared with those treated with glimepiride (−0.55 vs −0.36%, p
0.03). Pioglitazone, but not glimepiride, was also associated with improvements in lipid levels, including HDL-C and triglycerides, which likely contributed to plaque regression in this group. These data suggest that interventions that improve glycaemic control alone may be insufficient to prevent increases in atheroma volume. Instead, improvements in multiple factors may be necessary to achieve clinically meaningful plaque regression. Clearly, further data from this and other studies are needed to examine the relative contributions of improved control of glucose and lipid levels to plaque regression.
HbA1c, which is an established diagnostic marker for diabetes mellitus [19
], has been reported to be a significant predictor of cardiovascular events in diabetic patients [14
]. In fact, a recent meta-analysis demonstrated that intensive glucose control could reduce the occurrence of cardiovascular events, although longer observation periods than originally expected may be required to examine this association [27
Quevedo et al. reported a high prevalence of vessel shrinkage in diabetic patients, which was associated with insulin requirement, HbA1c, apolipoprotein B and hypertension in their study using serial IVUS [28
]. Nicholls et al. reported inadequate compensatory remodelling in diabetic patients [20
]. However, unlike these earlier observations, in the present study, the percent change in vessel volume during the follow-up period indicated positive remodelling in patients with high HbA1c and negative remodelling in patients with low HbA1c. Reddy et al. also observed greater positive remodelling in diabetic patients than in non-diabetic patients [29
]. Meanwhile, Chhatriwalla et al. [30
] found that lower levels of LDL-C and systolic blood pressure were associated with negative remodelling of the elastic membrane in patients with established coronary artery disease. Differences in patient characteristics and IVUS methodologies may partly explain these differences in vascular remodelling between these studies. Multifactorial treatment strategies targeting not just LDL-C, but also other risk factors, including glycaemic control and blood pressure, may be important to achieve negative remodelling, and slow the progression of coronary atherosclerosis.
We observed a slight increase in HbA1c from 5.92 to 6.25% during the study, although this change was not significant. Some studies have reported that rosuvastatin and other statins increase markers of insulin resistance, such as homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin levels [31
]. It is possible that rosuvastatin reduces insulin sensitivity, resulting in a slight deterioration in glycaemic control. However, this effect of rosuvastatin is not consistent among studies [34
]. Therefore, we think a more likely explanation is that the change in HbA1c reflects the natural progression of insulin resistance or worsening glycaemic control in a cohort of patients, in which 37.3% had diabetes at baseline. It must also be noted that the earlier studies were much shorter (total study length of 1–3
months) than our study, possibly too short to reliably attribute the changes in HbA1c to rosuvastatin itself. Unfortunately, as we did not measure fasting glucose or fasting insulin, we were unable to determine HOMA-IR as a direct marker for insulin resistance. We should also consider that, although HbA1c is strongly associated with fasting and post-prandial plasma glucose, the use of HbA1c rather than specific glucose parameters may mask possible associations between plasma glucose and both fasting/post-prandial glucose excursions and plaque progression.
It is also important to consider that other factors not assessed here may partly explain some of the observed associations. For example, in a cohort of Korean individuals with normal glucose tolerance or type 2 diabetes, serum levels of the adipokine omentin-1 were independently associated with arterial stiffness and carotid plaque, even after adjusting for other cardiovascular risk factors [37
In the present study, there were some marked differences in the changes in lipid levels between the two groups. For example, VLDL-C decreased by 4.1% in the low HbA1c group, but increased by 18.1% in the high HbA1c group. The reason for this difference and its clinical relevance are unclear, because VLDL-C was not associated with plaque progression in univariate analyses, and was not included in the multivariate model. Further studies may be required to understand these results and their possible implications.
This subanalysis of the COSMOS study was a post-marketing study designed to investigate the effects of intensive LDL-C lowering with rosuvastatin on coronary atherosclerosis measured using IVUS and its safety; as such, the lack of glucose measurements and the small sample size limit further interpretations of the current results. It is also possible that other factors not assessed here, including insulin and adipokine concentrations, insulin resistance, and other markers of glycaemic control may partly explain the associations observed. Nevertheless, the association between HbA1c and change in plaque volume demonstrates the importance of good glucose control and the unique atherogenic processes in diabetes. The results also support a prospective interventional trial to better understand the impact of optimal glycaemic control on plaque regression.