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Lipids, Lipoproteins, and Cardiovascular Risk Factors |
1 Eli Lilly and Company, Indianapolis, IN. 2 Takeda Pharmaceuticals of North America, Lincolnshire, IL.
aAddress correspondence to this author at: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. Fax 317-277-5458; e-mail tan_meng{at}lilly.com.
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Abstract |
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Methods: The data for the analysis of AIP in this report were obtained from four randomized, double-blind, multicenter, parallel-group, placebo-controlled clinical trials. Pioglitazone was used as monotherapy in one study and in combination therapy in three studies. Fasting glucose, insulin, HDL-C, and TGs plus glycohemoglobin (HbA1C) were measured at baseline and various points during each study.
Results: Patients in this study population with type 2 diabetes had high AIP values at baseline. Pioglitazone treatment significantly decreased AIP from baseline in each of the study groups. Pioglitazone treatment groups had a significantly lower AIP compared with their respective placebo controls. Finally, AIP was inversely and significantly correlated with measures of insulin sensitivity, such as the homeostasis model assessment and quantitative insulin sensitivity check index. In contrast, AIP was not significantly correlated with HbA1C.
Conclusions: Pioglitazone reduced AIP when used as monotherapy or in combination therapy with sulfonylurea, metformin, or insulin. AIP was inversely correlated with measures of insulin sensitivity.
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Introduction |
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Dobiasova and Frohlich (6) proposed the term Atherogenic Index of Plasma (AIP), defined as log(TG/HDL-C), on the basis that people with high AIP have a higher risk for CHD than those with low AIP, that AIP is positively correlated with the fractional esterification rate of HDL (FERHDL), and that AIP is inversely correlated with LDL particle size. Because FERHDL predicts particle size in HDL and LDL, which in turn predicts CHD risk, the simultaneous use of TGs and HDL-C (both readily available in a plasma lipoprotein profile) as AIP may be useful in predicting plasma atherogenicity. Furthermore, insulin resistance (decreased insulin sensitivity), which is often accompanied by increased CHD risk, is also often associated with increased TG and decreased HDL-C concentrations and a predominance of small, dense LDL particles. Reducing insulin resistance (enhancing insulin sensitivity) can potentially correct this dyslipidemia and, in so doing, AIP. We therefore studied the effect of pioglitazone, a thiazolidinedione that reduces insulin resistance, on the AIP of patients with type 2 diabetes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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8.0% at baseline (7.0% for study 001); (d) fasting plasma glucose (FPG) 7.8 mmol/L; (e) fasting C-peptide 0.331 nmol/L; and (f) body mass index of 25–45 kg/m2.
One study (study 001) examined the efficacy of pioglitazone as monotherapy, and three studies examined the efficacy of pioglitazone when added to sulfonylurea (study 010), metformin (study 027), or insulin (study 014) therapy, respectively. In each study, patients received a single-blind placebo for 5–10 weeks before randomization to allow washout of previous antihyperglycemia medications or to stabilize the dose of companion medication in the combination-therapy studies. Brief descriptions of the studies are presented in Table 1
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FPG, fasting serum insulin, and fasting serum lipids (total cholesterol, HDL-C, and TGs) were measured at a central laboratory (Covance) as described previously (7)(8)(9)(10). Insulin sensitivity was calculated by the homeostasis model assessment (HOMA-S) and by the quantitative insulin sensitivity check index (QUICKI) in studies 001, 010, and 027. Values for HOMA-S were derived from fasting serum insulin and FPG and calculated using a computer program (11). QUICKI was calculated as 1/(log10 fasting serum insulin + log10 fasting blood glucose) (12).
statistical analysis
Each study was analyzed separately. AIP was computed for each patient at baseline and at each subsequent visit according to the following equation:
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For missing post-baseline values, the previous post-baseline observation was used in a last-observation-carried-forward method. The statistical model used for analysis was a single slope analysis of covariance
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i is the effect of the ith treatment; 
j is the effect of the jth center; ß is the linear regression coefficient representing the dependence of yijk on xijk, the baseline value of the response variable; and 
ijk is the residual error term. Adjusted (least-squares) treatment means were obtained from the model. Within-group changes from baseline were tested with Student t-tests. Each of the pioglitazone treatments was compared with placebo. In studies with more than two treatment groups, Dunnett’s procedure was used to adjust for multiple comparisons between pioglitazone and placebo. An analysis of the TG/HDL ratio was performed, using the same statistical model. The fundamental assumption for analysis of variance (covariance) is that the underlying distribution of the residual errors is gaussian; thus, to compare the results of the AIP analysis with analysis of the TG/HDL-C ratio, an analysis of the residual errors was conducted and normal probability plots for each model were constructed. The correlation between standardized residuals and the expected residuals formed the basis of each comparison.
The correlation between AIP and glycemic control indices (HbA1C and FPG) and measures of insulin sensitivity (HOMA-S and QUICKI) were examined within pioglitazone-treated patients by use of Pearson correlation coefficients.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
aip results
A summary of the AIP results is shown in Table 1
. All pioglitazone treatments had statistically significant decreases from baseline in AIP. In addition, pioglitazone treatment groups were statistically significantly different from their respective placebo (or active controls) controls in reducing AIP.
A comparison of overall P values from analyses of AIP and TG/HDL-C is shown in Table 2
. The overall P values for drug effect were lower than those of the TG/HDL-C analyses in three of the four studies. In addition, normal probability plots showing the relationship of the residual error to the expected residuals from a gaussian distribution are shown in Fig. 1
. A straight line and high r2 value indicate adherence to the assumption of an underlying gaussian distribution. The correlations between standardized and expected residuals were higher in each study for AIP than for TG/HDL-C. The higher correlations and normal probability plots indicated that the AIP analyses better met the fundamental assumption for analysis of variance, i.e., that residual error terms have a gaussian distribution.
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The changes in glycemic control (HbA1C and FPG) for the intent-to-treat sample in each of the four studies have been reported previously (7)(8)(9)(10). In studies 001 (monotherapy), 010 (combination with sulfonylurea), and 027 (combination with metformin), pioglitazone increased insulin sensitivity as calculated by HOMA-S and QUICKI. The correlations between AIP and glycemic control indices as well as measures of insulin sensitivity at the end of the study are shown in Table 3
. AIP was inversely and significantly correlated with insulin sensitivity measures (HOMA-S and QUICKI). In contrast, AIP was not significantly correlated with HbA1C. In two of the four studies, AIP was significantly correlated with FPG.
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Discussion |
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The ratio TG/HDL-C was further characterized by Dobiasova and Frohlich (6) into log(TG/HDL-C). They called it AIP and provided three reasons to support it as a marker for plasma lipid atherogenicity: (a) AIP was directly related to a cohort’s risk for atherosclerosis; (b) there was a strong positive correlation (r = 0.803) between AIP and the FERHDL, which is increased in patients at risk for or with CHD (15), and a predominance of small HDL3b,c particles increases FERHDL, whereas increased HDL2b particles decrease it (16); and (c) there was a significant inverse correlation between LDL particle size and FERHDL (r = –0.82) and AIP (r = –0.78). Patients with small, dense LDL particles are at higher risk for CHD (17). Patients with type 2 diabetes have the highest AIP (6); they also have a higher FERHDL compared with nondiabetic individuals, and there is a direct correlation between FERHDL and waist:hip ratio in these patients (18). In addition, they are more likely to have a predominance of small, dense LDL particles compared with nondiabetic controls (19). All of these factors suggest that AIP is a suitable marker for plasma atherogenicity in patients with type 2 diabetes. We provide new information on the changes in AIP in patients with type 2 diabetes treated with pioglitazone.
We also demonstrated by use of normal probability plots and correlations between residual error and expected residual error terms that AIP is preferable to the TG/HDL-C ratio for use in statistical analyses such as analysis of covariance for comparing treatments. AIP is, of course, a transformation of TG/HDL-C that better meets the assumption of normality of the errors in the statistical model being used to describe the treatment effects than does the untransformed variable.
Cross-sectional studies have reported that patients with type 2 diabetes and cardiovascular disease have fasting hyperinsulinemia compared with those without cardiovascular disease (20). Because hyperinsulinemia is often clustered with other cardiovascular risk factors, the presence of endogenous hyperinsulinemia combined with hypertriglyceridemia, increased body mass index, and a decreased HDL-C increases the risk of CHD death in patients with type 2 diabetes (21). Despres et al.(22) also reported that people with hyperinsulinemia and high TGs have an increased risk for CHD.
AIP is inversely and significantly correlated with measures of insulin sensitivity. Previously, AIP has been reported to correlate with insulin resistance (HOMA IR) in Bermudians (23). We report here that pioglitazone therapy also reduces AIP in patients with type 2 diabetes whether it is used as monotherapy or in combination therapy with sulfonylurea, metformin, or insulin.
Patients with type 2 diabetes treated with fibrates (increases HDL and decreases TG concentrations) have decreased cardiovascular risk (24)(25). Fibrates are peroxisome proliferator-activated receptor-
agonists, which lower plasma TG and increase HDL-C concentrations. Whether therapy with a peroxisome proliferator-activated receptor-
agonist such as pioglitazone, which reduces insulin resistance in addition to lowering plasma TG and increasing HDL-C concentrations (thus reducing AIP), will lead to decreased cardiovascular morbidity and mortality remains to be established. A large study is currently underway to determine whether therapy with pioglitazone in patients with type 2 diabetes reduces cardiovascular events (26). Recently, it was reported that FERHDL, age, smoking, and diabetes are significant predictors of the presence of angiographically documented CHD (27). If only laboratory tests were used in the multivariate analysis, FERHDL was the sole predictor of CHD. When FERHDL was omitted from the multivariate analysis, AIP was an independent predictor of CHD.
In summary, pioglitazone, a thiazolidinedione that reduces insulin resistance in type 2 diabetes, decreases AIP when used as monotherapy or in combination therapy with sulfonylurea, metformin, or insulin. AIP is inversely correlated with measures of insulin sensitivity.
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Acknowledgments |
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Footnotes |
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References |
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The following articles in journals at HighWire Press have cited this article:
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  C. Battaglia, F. Mancini, A. Cianciosi, P. Busacchi, F. Facchinetti, G. R. Marchesini, R. Marzocchi, and D. de Aloysio Vascular Risk in Young Women With Polycystic Ovary and Polycystic Ovary Syndrome Obstet. Gynecol., February 1, 2008; 111(2): 385 - 395. [Abstract] [Full Text] [PDF]
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 I. Lambrinoudaki, G. Christodoulakos, D. Rizos, E. Economou, J. Argeitis, S. Vlachou, M. Creatsa, E. Kouskouni, and D. Botsis Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women. Eur. J. Endocrinol., June 1, 2006; 154(6): 907 - 916. [Abstract] [Full Text] [PDF]
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 M. Dobiasova Atherogenic Index of Plasma [Log(Triglycerides/HDL-Cholesterol)]: Theoretical and Practical Implications Clin. Chem., July 1, 2004; 50(7): 1113 - 1115. [Full Text] [PDF]
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