Unlike its beneficial effects on CIMT progression,6, 11
pioglitazone did not alter the progression of CAC over 72 weeks compared to glimepiride in patients with T2DM (). Our analysis identified only age, race/ethnicity, and ApoB as predictors of CAC score over 72 weeks in a cohort of 299 subjects with T2DM. In addition, we found no relationship between CIMT and CAC baseline measures or progression rates in this cohort.
Recent statin trials have demonstrated that ApoB is the single best lipid predictor of clinical events on statin therapy.12
Of interest is that LDL-C or LDL-particle number were not identified as significant predictor of CAC progression in our study. This result suggests that triglyceride-rich ApoB lipoproteins prior to conversion to LDL may be the primary drivers of CAC progression in T2DM. Our data expands on that of the Penn Diabetes Heart Study13
that reported, in a cross-sectional analysis, that ApoB but not LDL-C predicted prevalent CAC in white subjects with Type 2 diabetes. Our study suggests that ApoB, but not LDL-C or LDL-particle number, significantly predicts CAC progression in a multiracial cohort with T2DM.
The Multi-Ethnic Study of Atherosclerosis (MESA) has reported that age, male gender, Caucasian race, and BMI were associated with increases in CAC.14
Therefore, both the CHICAGO and MESA data support racial difference for predicting both in baseline and progression of CAC in patients with diabetes.15, 16
The causes of these racial differences are uncertain and deserve further study.17, 18
In our analyses, differences in lipoprotein, inflammatory or anthropometric measures did not appear to explain racial differences in CAC score progression (not shown).
Similar to what has been shown for statins, pioglitazone treatment reduces progression of both CIMT6
and coronary atheroma19
volume as determined by intravascular ultrasound but does not influence the change in CAC after 72 weeks of treatment. Pioglitazone has also been shown to significantly reduce by 16% the risk of the main secondary endpoint (a composite of all cause mortality, myocardial infarction (MI), or stroke) in the PROactive trial.20
This outcome benefit was sustained with a 28% relative risk reduction in a subgroup of patients with a previous MI.21
Therefore, pioglitazone, while demonstrating a clinical benefit utilizing two surrogate endpoints (CIMT and IVUS) and in reducing major hard cardiac events, did not affect progression of the surrogate endpoint of CAC. In addition, we could find no correlation between baseline CIMT or change in CIMT with baseline or progression of CAC in this patient population with T2DM. Further, in our previous analysis of factors that predicted slowing of CIMT progression, an increase in HDL cholesterol with pioglitazone was the strongest predictor of slowed progression,11
but changes in HDL cholesterol did not predict change in CAC.
In the MESA trial, CAC was associated more strongly than CIMT with risk of incident CVD (2.5 vs. 1.2-fold).22
However, in a recent metanalysis of five CAC trials that evaluated therapeutic effects including statins and anti-hypertensive therapy, the authors concluded that there were no consistent or reproducible treatment effects of any therapy on progression of CAC measured at one year.23
The CHICAGO data, along with this metanalysis, call into question the clinical value of serial CAC scanning to evaluate the efficacy of therapeutic interventions for preventing clinical CVD. The process of coronary calcification is complex, involving both an increase in plaque burden and the healing of lipid-rich atheromata.1
A change in CAC may reflect these potentially competing processes, thereby making this surrogate invalid for assessing a therapeutic response.
There are several limitations that should be considered when interpreting our study. The CHICAGO trial was designed using CIMT as its primary endpoint, and there was not complete overlap in subjects completing the CIMT and CAC measurements. However, comparison of the two CAC treatment groups showed no significant baseline differences ( and page 7) in important CVD risk factors, and no difference in baseline CAC score. The trial was also powered using change in CIMT as its primary endpoint. However, assuming a progression rate of 50 Agatston units over the trial, and a measurement standard deviation of 30 Agatston units, we estimate a 90% power to detect a 25 Agatston unit difference between the GLM and PIO treatment groups. Further, the data in demonstrates complete overlap of CAC progression in the PIO and GLM treatment groups. It seems unlikely that inclusion of additional subjects or observation for a longer period of time would have changed this result. Finally, the data in identify age, race/ethnicity, and ApoB as the only important predictors of CAC progression in this multiracial cohort with T2DM. The size of our cohort or the duration of our trial may have precluded detection of other important predictors of CAC progression in T2DM. However, our identification of ApoB as an important predictor of progression is consistent with cross-sectional analyses from this and another cohort, 7, 13
indicating that ApoB level is an important predictor of prevalent CAC in T2DM.
Baseline Factors Predicting CAC Score Progression in Forward and Backward Selection Models
The major points of our analysis can be summarized as follows. In a racially diverse cohort of patients with T2DM treatment with PIO, already demonstrated to produce a beneficial effect on CIMT and coronary atheroma progression compared to treatment with GLM, did not beneficially affect progression of CAC compared to treatment with GLM. In addition, there was no relationship between baseline or progression measurements of CAC and CIMT. Exploratory models to identify predictors of CAC progression identified ApoB as the only modifiable risk factor that was related to CAC progression over 72 weeks in subjects with T2DM. This latter finding supports the Joint Consensus Statement from the American Diabetes Association and the American College of Cardiology that recommends incorporating ApoB into managing patients with cardiometabolic risk once LDL and non-HDL cholesterol goals have been achieved.24