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Abstract

Background:

While triglycerides (TGs) and diabetes increase the risk of cardiovascular disease (CVD), their combined effects have not been quantified. We explored the combined effect of elevated TGs and glucose on CVD in a post hoc analysis of the large-scale Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study. Material and Methods: In the MEGA Study, 8214 patients with mild to moderate hypercholesterolemia were randomly allocated to the diet alone group or diet plus pravastatin group and followed for 5 years. Of those, 7832 patients included in the intention-to-treat analysis were stratified into 4 groups: abnormal fasting glucose (AFG) plus high TGs, high TGs alone, AFG alone, and normal fasting glucose plus normal TGs (reference). Cox proportional hazard models were used to compare the incidence of and mortality from CVD in the 4 groups.

Results:

Incidence of CVD and coronary heart disease was significantly higher in the groups with AFG alone (hazard ratio [HR], 2.02 and 3.38; P < .01, respectively) and AFG plus high TGs (HR, 2.87 and 3.87; P < .01, respectively) than the reference group. A similar relation was found in models adjusting for high-density lipoprotein cholesterol (HDL-C). Although the incidence of cerebral infarction was significantly higher only in the group with AFG plus high TGs (HR, 2.16; P = .01), it was marginally significantly higher than the reference group after adjustment for HDL-C (HR, 1.86; P = .06). Diet plus pravastatin treatment reduced the risk of cerebral infarction by 66% in the group with AFG plus high TGs (P = .03).

Conclusions:

Our findings contribute to the formulation of the hypothesis that patients with hypercholesterolemia having AFG plus high TGs have an increased risk of cerebral infarction. These are compatible with the result from the main study that patients with hypercholesterolemia randomized to diet plus pravastatin had a reduced risk of cerebral infarction.

Keywords

hypercholesterolemia triglycerides glucose cerebral infarction clinical trial statin

Introduction

High levels of triglycerides (TGs) are common in patients with type 2 diabetes who are known to have a higher prevalence of high TGs or higher levels of TGs than patients without type 2 diabetes.^1
-3 Abundant evidence supports the strong association between TGs, type 2 diabetes, and cardiovascular disease (CVD).^4
-6 However, most of the data have reported the independent impact of TGs or type 2 diabetes on CVD. Hence, understanding the concomitant impact of high TGs and type 2 diabetes on CVD is paramount for thorough cardiovascular risk management in clinical practice.

The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study was a large-scale clinical trial conducted in Japan to evaluate the efficacy of pravastatin for primary prevention of CVD. A total of 7832 patients (3966 in diet alone group vs 3866 in diet plus pravastatin group) with hypercholesterolemia (total cholesterol 5.7-7.0 mmol/L) were followed for an average of 5 years. The main results of the MEGA Study showed that an 18% reduction in low-density lipoprotein cholesterol (LDL-C) was associated with a 26% risk reduction in CVD.⁷ A post hoc analysis of the MEGA Study reported insufficient risk reduction in patients with a high TGs phenotype (type IIb and type III) of hypercholesterolemia with diet plus pravastatin and that these patients had a high incidence of CVD compared to those with a high LDL-C phenotype (type IIa) hypercholesterolemia.⁸ In contrast, diet plus pravastatin produced a greater reduction in CVD risk in patients with abnormal fasting glucose (AFG: documented diabetes or fasting plasma glucose [FPG] ≥6.1 mmol/L), of whom a high proportion (43%) had high TGs (TGs ≥1.7 mmol/L), versus 34% of patients without AFG, in a subanalysis of the MEGA Study.⁹ Therefore, we conducted this analysis to assess the combined effect of elevated TGs and AFG on various CVD and all-cause mortality. Furthermore, the effect of pravastatin on all-cause mortality, CVD, coronary heart disease (CHD), stroke, and cerebral infarction was evaluated in relation to the presence of both high levels of TGs and FPG.

Material and Methods

The study design and results of the MEGA Study have been published elsewhere.⁷ Briefly, 7832 men and postmenopausal women aged 40 to 70 years old with hypercholesterolemia (total cholesterol 5.7-7.0 mmol/L) who did not have a history of CHD and stroke were randomly assigned to National Cholesterol Education Program step 1 treatment or diet plus pravastatin treatment (10-20 mg/d, approved dose in Japan) and followed for an average of 5 years.

The primary composite end point was the first occurrence of CHD including fatal and nonfatal myocardial infarction, angina, cardiac and sudden death, and a coronary revascularization procedure. Secondary end points included stroke, cerebral infarction, hemorrhagic stroke, CHD, all CVD events, and mortality from all causes.

Data were collected at 1, 3, and 6 months, and every 6 months thereafter, and recorded on the case report form by the patient’s physician. All blood sera were stored centrally, and lipid values were measured in a center validated by the US Centers for Disease Control and Prevention (CDC; Atlanta, GA). Low-density lipoprotein cholesterol level was estimated by the Friedewald formula.¹⁰ Other laboratory test values including FPG were performed at each institution.

In the current analysis, all 7832 patients in the MEGA Study were divided into 4 groups according to the presence or absence of AFG and high TGs: AFG plus high TGs, high TGs alone, AFG alone, and normal fasting glucose (NFG: FPG <6.1 mmol/L) plus normal TGs (TGs <1.7 mmol/L).

Kruskal-Wallis test for continuous values and chi-square test for categorical values were used to examine the differences in clinical characteristics across the groups. Cox proportional hazard model adjusted for treatment arm, age, sex, hypertension, smoking, and high-density lipoprotein cholesterol (HDL-C) was fitted to calculate and compare the hazard ratios (HRs) and their 95% confidential intervals for the incidence of CHD, stroke, cerebral infarction, CVD, mortality, and the effect of diet plus pravastatin on these end points across the 4 groups. Hypertension and smoking were defined according to physician diagnosis. The group of patients with NFG plus normal TGs served as the reference group.

The study was conducted in accordance with the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. All statistical analysis was performed using SAS 9.1.3 (Cary, North Carolina). All reported P values are 2 tailed, and P < .05 was regarded as statistically significant.

Results

The clinical characteristics of the patients across the 4 groups and the statistically significant differences are detailed in Table 1. The proportion of men was higher in the group with high TGs with or without AFG compared with the group with NFG plus normal TGs. The median LDL-C and HDL-C levels were higher in the group with NFG plus normal TGs and the group with AFG alone in comparison to the group with high TGs alone and the group with AFG plus high TGs.

Table 1.

Characteristics of Patients.^a

	Normal Fasting Glucose		Abnormal Fasting Glucose		^b P Value
	Normal TGs	High TGs	Normal TGs	High TGs	^b P Value
Number	3711	1911	1253	957
Age, year	58.6 ± 6.9	57.3 ± 7.9	59.5 ± 6.7	57.6 ± 7.3	<.001
Men, %	20.7	41.5	34.2	50.8	<.001
BMI, kg/m²	23.2 ± 2.9	24.6 ± 2.8	23.7 ± 3.3	25.0 ± 3.1	<.001
Known diabetes, %	0	0	76.1	70.8	<.001
Hypertension, %	36.9	47.8	41.0	50.2	<.001
Current smoking, %	9.3	21.6	14.4	25.5	<.001
TC, mol/L	6.3 ± 0.3	6.3 ± 0.3	6.3 ± 0.3	6.3 ± 0.3	<.001
LDL-C, mol/L	4.1 ± 0.4	3.9 ± 0.4	4.2 ± 0.4	3.9 ± 0.5	<.001
HDL-C, mmol/L	1.6 ± 0.4	1.3 ± 0.3	1.6 ± 0.4	1.2 ± 0.3	<.001
TGs, median, mmol/L	1.2	2.2	1.2	2.3	<.001
FPG, mmol/L	5.2 ± 0.5	5.3 ± 0.5	7.4 ± 2.0	7.8 ± 2.3	<.001
Oral hypoglycemic agents, %	0	0	33.8	33.6	<.001
Insulin, %	0	0	7.7	6.1	<.001

Abbreviations: BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride; FPG, fasting plasma glucose.

^aAbnormal fasting glucose was defined as documented diabetes or fasting plasma glucose (FPG) ≥6.1 mmol/L, while normal fasting glucose was defined as FPG <6.1 mmol/L. High TGs were defined as triglycerides (TGs) ≥1.7 mmol/L, while normal TGs were defined as TGs <1.7 mmol/L.

^bKruskal-Wallis test for continuous values and chi-square test for categorical values were used to examine the differences in clinical characteristics across the groups.

A total of 255 CVD, 142 CHD, 70 cerebral infarction, and 109 deaths from all causes occurred in 7832 patients during the 5-year follow-up of the MEGA Study (Table 2). The incidence of CHD was significantly higher by 3.38 and 3.87 times in the group with AFG alone and AFG plus high TGs, respectively, compared with the group with NFG plus normal TGs (reference group). The HR for the incidence of cerebral infarction was significantly higher only in the group with AFG plus high TGs (P = .01) without adjusting for HDL-C. A significant relation for CHD and increased risk and a nearly significant relation for cerebral infarction remained after adjusting for HDL-C. The incidence of CVD was significantly higher in the group with AFG alone and AFG plus high TGs, regardless of adjusting for HDL-C, compared with the group with NFG plus normal TGs. The incidence of CHD was similar in the groups with AFG alone and AFG plus high TGs. Diet therapy or lifestyle modification plus pravastatin reduced the risk of cerebral infarction by 66% (P = .03) in the group with AFG plus high TGs (Table 3).

Table 2.

Incidence of Cardiovascular End Points and Mortality in 4 Groups According to the Levels of Fasting Plasma Glucose and Triglycerides.^a

Categories	Events/Patients	(/10³ py)	HDL-C Unadjusted		HDL-C Adjusted
Categories	Events/Patients	(/10³ py)	Hazard Ratio (95% CI)	P Value	Hazard Ratio (95% CI)	P Value
Coronary heart disease
NFG + normal TGs	30/3711	(1.80)	1.00		1.00
High TGs alone	27/1911	(3.15)	1.35 (0.79-2.28)	.27	1.06 (0.62-1.82)	.83
AFG alone	42/1253	(7.46)	3.38 (2.11-5.43)	<.01	3.22 (2.00-5.16)	<.01
AFG + high TGs	43/957	(10.2)	3.87 (2.39-6.27)	<.01	2.99 (1.81-4.94)	<.01
Stroke
NFG + normal TGs	38/3711	(2.28)	1.00		1.00
High TGs alone	22/1911	(2.57)	0.89 (0.52-1.53)	.68	0.80 (0.46-1.41)	.44
AFG alone	14/1253	(2.46)	0.89 (0.48-1.66)	.72	0.88 (0.47-1.63)	.68
AFG + high TGs	25/957	(5.85)	1.83 (1.08-3.09)	.03	1.62 (0.93-2.83)	.09
Cerebral infarction
NFG + normal TGs	26/3711	(1.56)	1.00		1.00
High TGs alone	13/1911	(1.52)	0.76 (0.38-1.49)	.42	0.66 (0.33-1.33)	.25
AFG alone	10/1253	(1.75)	0.89 (0.43-1.86)	.76	0.87 (0.41-1.81)	.70
AFG + high TGs	21/957	(4.90)	2.16 (1.18-3.94)	.01	1.86 (0.98-3.52)	.06
Cardiovascular disease
NFG + normal TGs	72/3711	(4.34)	1.00		1.00
High TGs alone	51/1911	(6.00)	1.09 (0.76-1.57)	.63	0.91 (0.63-1.33)	.64
AFG alone	59/1253	(10.6)	2.02 (1.42-2.85)	<.01	1.94 (1.37-2.75)	<.01
AFG + high TGs	73/957	(17.6)	2.87 (2.04-4.02)	<.01	2.35 (1.65-3.36)	<.01
All-cause mortality
NFG + normal TGs	43/3711	(2.54)	1.00		1.00
High TGs alone	17/1911	(1.93)	0.67 (0.38-1.18)	.16	0.53 (0.3-0.97)	.04
AFG alone	23/1253	(3.94)	1.30 (0.78-2.17)	.32	1.26 (0.75-2.10)	.38
AFG + high TGs	26/957	(5.93)	1.89 (1.14-3.14)	.01	1.49 (0.87-2.53)	.15

Abbreviations: AFG, abnormal fasting glucose; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; NFG, normal fasting glucose; py, person-year; TG, triglyceride.

^aCox proportional hazard model adjusted for treatment arm, age, sex, hypertension, smoking, and high-density lipoprotein cholesterol was fitted to calculate and compare the hazard ratios and their 95% confidential intervals. Abnormal fasting glucose was defined as documented diabetes or fasting plasma glucose (FPG) ≥6.1 mmol/L, while normal fasting glucose was defined as FPG <6.1 mmol/L. High TGs were defined as triglycerides (TGs) ≥1.7 mmol/L, while normal TGs were defined as TGs <1.7 mmol/L.

Table 3.

Effect of Pravastatin in 4 Groups According to Levels of Fasting Plasma Glucose and Triglycerides.^a,b

Category	Diet		Diet + Pravastatin		Hazard Ratio (95% CI)	P Value
Category	Events/Patients	(/10³ py)	Events/Patients	(/10³ py)	Hazard Ratio (95% CI)	P Value
Coronary heart disease
NFG + normal TGs	21/1879	(2.45)	9/1832	(1.11)	0.42 (0.19-0.92)	.03
High TGs alone	14/970	(3.19)	13/841	(3.12)	0.94 (0.44-2.01)	.88
AFG alone	26/612	(9.55)	16/641	(5.50)	0.59 (0.32-1.10)	.10
AFG + high TGs	24/505	(10.9)	19/452	(9.41)	0.90 (0.49-1.64)	.73
Stroke
NFG + normal TGs	22/1879	(2.57)	16/1832	(1.97)	0.74 (0.39-1.41)	.36
High TGs alone	14/970	(3.19)	8/941	(1.92)	0.60 (0.25-1.43)	.25
AFG alone	7/612	(2.53)	7/641	(2.39)	0.94 (0.33-2.69)	.91
AFG + high TGs	18/505	(8.10)	7/452	(3.42)	0.43 (0.18-1.02)	.06
Cerebral infarction
NFG + normal TGs	15/1879	(1.75)	11/1832	(1.35)	0.74 (0.34-1.61)	.45
High TGs alone	8/970	(1.82)	5/941	(1.20)	0.65 (0.21-1.99)	.45
AFG alone	6/612	(2.17)	4/641	(1.36)	0.62 (0.17-2.21)	.46
AFG + high TGs	16/505	(7.19)	5/452	(2.43)	0.34 (0.12-0.92)	.03
Cardiovascular disease
NFG + normal TGs	43/1879	(5.05)	29/1832	(3.59)	0.68 (0.43-1.10)	.11
High TGs alone	30/970	(6.90)	21/941	(5.07)	0.71 (0.41-1.25)	.24
AFG alone	36/612	(13.4)	23/641	(7.96)	0.61 (0.36-1.03)	.06
AFG + high TGs	44/505	(20.3)	29/452	(14.6)	0.74 (0.46-1.18)	.20
All-cause mortality
NFG + normal TGs	25/1879	(2.86)	18/1832	(2.19)	0.74 (0.41-1.37)	.34
High TGs alone	12/970	(2.67)	5/941	(1.17)	0.45 (0.16-1.29)	.14
AFG alone	12/612	(4.23)	11/641	(3.67)	0.86 (0.38-1.96)	.72
AFG + high TGs	17/505	(7.40)	9/452	(4.32)	0.59 (0.26-1.32)	.20

Abbreviations: AFG, abnormal fasting glucose; py, person-year; TG, triglyceride; NFG, normal fasting glucose; CI, confidence interval.

^bAbnormal fasting glucose was defined as documented diabetes or fasting plasma glucose (FPG) ≥6.1 mmol/L, while normal fasting glucose was defined as FPG <6.1 mmol/L. High TGs were defined as triglycerides (TGs) ≥1.7 mmol/L, while normal TGs were defined as TGs <1.7 mmol/L.

Discussion

The relation between TGs and CVD is sometimes obscured by the relation between HDL-C and CVD. This is due to the strong relation between TGs and HDL-C,¹¹ and HDL-C is a stronger predictor of CVD than TGs. A previous post hoc analysis of the MEGA Study reported a very weak relation between TGs and CVD.¹² In the current analysis, there was a somewhat higher incidence of CVD in the group with AFG plus high TGs compared with the group with AFG alone among the patients with mild to moderate hypercholesterolemia. However, the study population was too small to reach statistical significance. Nevertheless, in the group with AFG plus high TGs and AFG alone, the HR for CVD was statistically significant after adjusting for HDL-C. In contrast, the risk of CVD was not increased in the group with high TGs alone. Moreover, the significant relation between TGs and CVD was driven by the high incidence of cerebral infarction; the incidence of CHD was similar in the group with AFG alone and the group with AFG plus high TGs. High TGs have been reported as a significant risk factor for CVD in Japanese patients with type 2 diabetes.¹³ Furthermore, a large meta-analysis has shown that TGs had a stronger impact on ischemic stroke than CHD.¹⁴ Thus, TGs may play an important role, in part, in the development of cerebral infarction in patients with AFG.

The large risk reduction in cerebral infarction in patients with AFG reported in a subanalysis of the MEGA Study⁵ was primarily attributable to the presence of AFG plus high TGs, as shown by the current analysis in which the higher incidence of CVD and larger reduction in cerebral infarction were observed in the group with AFG plus high TGs, compared to the groups with AFG alone or TGs alone and the group with NFG plus normal TGs. The Bezafibrate Infarction Prevention (BIP) Study, a large-scale clinical trial that evaluated the effect of reducing TGs by bezafibrate on cardiovascular outcomes, showed that reduction in TGs did not reduce cardiovascular risk.¹⁵ Further, no cardiovascular risk reduction was found by reducing TGs by a fenofibrate, even among patients with diabetes, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study.¹⁶ The effect of pravastatin on TGs is somewhat smaller than that on LDL-C, and only an average 2.3% reduction in TGs was observed in the patients with AFG treated by diet plus pravastatin in a previous MEGA post hoc analysis.⁹ These findings suggest there is a weak correlation between the reductions in TGs and risk of cerebral infarction observed in the group with AFG plus high TGs in the present analysis.

Several studies, including a post hoc analysis of the MEGA Study,¹⁷ demonstrated a very weak relation between LDL-C and the incidence of stroke including cerebral infarction. This suggests other pathways beyond lipid modification contributed to the greater risk reduction observed in the patients with AFG plus high TGs in the present analysis. A cerebral infarction may be caused by cerebral artery occlusion or plaque rupture induced by endothelial damage, which could be induced by abnormal lipids, hyperglycemic status, or other factors. Statins provide a protective benefit, including antioxidative and anti-inflammatory effects and stabilization of vulnerable plaques.^18,19

The present analysis has some limitations. First, enrollment in the MEGA Study was limited to patients with mild to moderate hypercholesterolemia (total cholesterol 5.7-7.0 mmol/L). Our present findings can be applied only to patients with total cholesterol levels in this range. Second, the presence of risk factors was defined solely by baseline data, not by the status during follow-up. Third, about 40% of patients with AFG took more than 1 glucose-lowering agent at baseline, but this was not tracked or evaluated in the MEGA Study. When MEGA Study was conducted, the drugs primarily used for glycemic control in Japan were sulfonylurea, α-glucosidase inhibitors, basal insulin, and limited use of pioglitazone. Finally, the number of patients in each group was not sufficient to demonstrate statistical significance in the present analysis. Furthermore, multiple statistical testing may cause type I errors. The objective of this analysis was to generate, not confirm, hypotheses. Thus, regardless of the P value, it cannot indicate a direct link with effectiveness and ineffectiveness. Further studies are needed to validate the findings and hypothesis from the present study.

Conclusion

The combination of elevated TGs and AFG increases the risk of a cerebral infarction in patients with mild to moderate hypercholesterolemia. Treatment with diet plus pravastatin was effective in reducing the risk of cerebral infarction in this population. Additional approaches are needed to further reduce CHD risk in these patients.

Footnotes

Acknowledgments

We thank the MEGA Study Group for the support of this analysis.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Tomoko Nakagami, Rimei Nishimura, Hirohito Sone and Naoko Tajima received lecture fees, and Hirohito Sone received research grants from Daiichi Sankyo.

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The Combination of Elevated Triglycerides and Abnormal Fasting Glucose Increases Risk of Cerebral Infarction in Patients With Mild to Moderate Hypercholesterolemia

Abstract

Background:

Results:

Conclusions:

Keywords

Introduction

Material and Methods

Results

Discussion

Conclusion

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Funding

References