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Abstract

The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study demonstrated the beneficial effect of low-dose pravastatin treatment (10-20 mg/d) on cardiovascular disease (CVD) in Japanese patients with mild-to-moderate hypercholesterolemia. However, it is not known whether mild lipid modification is effective even for patients at high risk. In this study, we evaluated low-dose pravastatin treatment in patients with metabolic syndrome in the MEGA Study. Metabolic syndrome (MetSyn) was defined according to the modified US National Cholesterol Education Program criteria. There were 72 coronary heart disease (CHD) events and 130 CVD events in 2636 patients with MetSyn, and 70 CHD events and 125 CVD events in 5196 patients without MetSyn (hazard ratios 1.85 and 1.90, respectively). No significant risk reduction in CHD was found in the diet plus pravastatin group compared with the diet group patients with MetSyn (hazard ratio .78, P = .29). On the other hand, there was a significant 36% CVD risk reduction (P = .01) in the diet plus pravastatin group compared with the diet group patients with MetSyn, with a small number needed to treat (45). These results indicate that low-dose pravastatin provides a substantial beneficial effect for the prevention of CVD in Japanese patients with MetSyn without known CVD, a population at proportionally high risk in primary prevention.

Keywords

cardiovascular diseases cholesterol metabolic syndrome prevention

Introduction

The Japanese have a relatively low risk of cardiovascular disease (CVD) compared with Europeans and Americans. The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study evaluated the effect of low-dose pravastatin (10-20 mg daily, approved dose in Japan) in Japanese patients with mild-to-moderate hypercholesterolemia, with no history of CVD.^1,2 The MEGA Study showed a significant risk reduction of 33% for coronary heart disease (CHD) and 30% for CVD, resulting from a mild 18% reduction in low-density lipoprotein cholesterol (LDL-C), as previously reported.² However, it remains unclear whether these results are applicable to high-risk patients with multiple risks of CVD. Metabolic syndrome (MetSyn) is defined as a clustering of abdominal obesity, glucose abnormality, high blood pressure, and dyslipidemia, and it has been identified as a strong risk factor for CVD and future onset of diabetes.^3

–6 The magnitude of cardiovascular risk is 2 to 3 times higher in persons with MetSyn than in those without, regardless of the reported definition of MetSyn used.^7

–10 The present subanalysis sought to evaluate the effect of low-dose pravastatin in the setting of MetSyn in Japanese patients with mild-to-moderate hypercholesterolemia, which is considered a high-risk population.¹¹

Methods and Patients

The details of the MEGA Study have been described elsewhere.^1,2 Briefly, 8214 men and postmenopausal women aged 40 to 70 with hypercholesterolemia whose total cholesterol levels ranged from 5.7 to 7.0 mmol/L (220-270 mg/dL) without a history of CHD and stroke and who provided written informed consent were enrolled. The study adhered to the principles of the Declaration of Helsinki and was approved by institutional review committees. The enrollment period was February 1994 to March 1999 and follow-up ended in March 2004. The trial is registered at ClinicalTrials.gov (number NCT00211705).

Eligible patients were randomly assigned to the US National Cholesterol Education Program step I diet¹² alone (diet-alone group) or to the step I diet plus pravastatin (diet plus pravastatin group). Major exclusion criteria included familial hypercholesterolemia, a history of CVD, a current diagnosis of malignancy, and secondary hyperlipidemia. The dose of pravastatin was 10 to 20 mg daily, the approved dose range in Japan. Patients in both groups were counseled to follow the US National Cholesterol Education Program step I diet throughout the study period. Treatment in the diet plus pravastatin group was initiated at pravastatin 10 mg/d. During follow-up, the dose of pravastatin could be adjusted by the treating physician, with up-titration to 20 mg/d if the total cholesterol level did not decrease to 5.7 mmol/L (220 mg/dL) or less, in compliance with the approved Japanese dose. Patients in each group exceeding total cholesterol 7.0 mmol/L (270 mg/dL), even after enhancement of assigned treatment, could be switched to other aggressive treatments, including statin therapy. Concomitant treatment of complications was not restricted in either group.

Patients were evaluated by attending physicians 1, 3, and 6 months after the start of follow-up and every 6 months thereafter. Health checks at each clinic visit included biochemical tests and assessment of patients’ compliance with dosing instructions. For each event, detailed information was obtained from the physicians and evaluated by the end point committee who were blinded to the study information, according to the established criteria.¹ Throughout the study period, total cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a) levels were centrally measured at the same laboratory using methods standardized by the US Centers for Disease Control and Prevention (Atlanta, Georgia). The LDL-C level was estimated by the Friedewald formula. The follow-up period was initially scheduled for 5 years; however, based on the recommendation of the Data and Safety Monitoring Committee, the study was continued to increase the number of events, and thus patients who provided written consent for 5 years to continue the study were followed until the end of March 2004.

The primary composite end point of the MEGA Study was the first occurrence of CHD, comprising fatal and nonfatal myocardial infarction, cardiac and sudden death, coronary revascularization procedure, and angina. Secondary end points included stroke, all CVD events (CHD, stroke, transient ischemic attack [TIA], and arteriosclerosis obliterans), total mortality, and others. In the main MEGA Study results, the observed risk reduction for stroke was different between the initially planned 5-year follow-up and the entire follow-up period that included the extended follow-up. This difference was attributed to the observation that consent to participate in the extended follow-up was obtained more frequently from patients who were in the diet plus pravastatin group than from those in the diet-alone group at 5 years.¹³ Therefore, the present analysis used the 5-year data to reduce any potential bias from the high drop-in rate for statin use in the patients in the diet group caused by the additional follow-up period.

In the present analysis, MetSyn was defined by the modified US National Cholesterol Education Program criteria.⁷ Because of the lack of waist circumference data in the MEGA Study, alternatively, we used body mass index as a substitute for waist circumference in this analysis. The criterion for the definition of MetSyn was the presence of more than 3 of the following factors: body mass index ≥25 kg/m², triglycerides ≥1.7 mmol/L (150 mg/dL), high-density lipoprotein cholesterol <1.03 mmol/L (40 mg/dL) for men and <1.29 mmol/L (50 mg/dL) for women, physician's diagnosis of hypertension and/or ≥130 mm Hg systolic blood pressure and/or ≥85 mm Hg diastolic blood pressure, and physician's diagnosis of diabetes and/or ≥5.6 mmol/L (100 mg/dL) fasting plasma glucose. The Western Pacific Region of the World Health Organization criterion for defining obesity was used in our population (body mass index ≥25 kg/m²), which is most appropriate for Asian populations.¹⁴

Event rates were compared between the diet-alone and diet plus pravastatin groups in patients with and without MetSyn. Time-to-event curves were estimated by the Kaplan-Meier method at 5 years. Hazard ratios and 95% confidence intervals were estimated by the Cox proportional hazards model adjusted by sex and age. Hazard ratios were also estimated for subgroup with LDL-C level >4.1 mmol/L (>156.9 mg/dL).

The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the manuscript as written.

Results

Of the 7832 patients in the intention-to-treat analysis, 2636 were defined as having MetSyn. They comprised 973 men and 1663 women (Table 1), therefore 39% of men and 31% of women had MetSyn in this population. The prevalence of all 5 risk components was 8.6% and 4 risk components was 32.1%. No difference was found in total cholesterol (P = .77) and LDL-C (P = .91) levels in patients with and without MetSyn. The incidence of CHD, stroke, CVD, and total mortality in the diet-alone group in patients with and without MetSyn is shown in Table 2. There were 72 CHD and 130 CVD events in the 2636 patients with MetSyn, and 70 CHD and 125 CVD events in the 5196 patients without MetSyn. The event rates for CHD, stroke, and CVD were 6.1, 4.1, and 11.2 per 1000 person years in patients with MetSyn, respectively, and therefore a significant 1.85, 1.80, and 1.90 times higher than in non-MetSyn patients, respectively (3.0, 2.1, and 5.4 per 1000 person years, respectively; P < .01). Total mortality was similar in both groups (3.9 vs 2.6 per 1000 person years in MetSyn and non-MetSyn patients, respectively; hazard ratio 1.39; P = .09).

Table 1.

Baseline Characteristics of Patients With Metabolic Syndrome

Parameter	Metabolic Syndrome (n = 2636)	Nonmetabolic Syndrome (n = 5196)	P Value
Age, years	58.5 ± 7.4	58.2 ± 7.1	.02
Age ≥65 years, %	24.8	22.3	.01
Women, %	63.1	71.1	<.01
Obesity (BMI ≥25 kg/m²), %	65.1	15.5	<.01
BMI, mean (SD), kg/m²	25.8 ± 3.0	22.8 ± 2.6	<.01
Current smoker, %	18.7	13.3	<.01
Diabetes, n (%)	897 (34.0)	735 (14.1)	<.01
FPG, mmol/L (mg/dL)	6.65 ± 2.02 (119.6 ± 36.3)	5.67 ± 1.44 (102.1 ± 26.0)	<.01
Hypertension, n (%)	1645 (62.4)	1632 (31.4)	<.01
SBP, mm Hg	138.4 ± 15.4	129.1 ± 16.6	<.01
DBP, mm Hg	81.8 ± 9.9	77.0 ± 10.1	<.01
TC, mmol/L (mg/dL)	6.28 ± 0.32 (242.7 ± 12.2)	6.27 ± 0.31 (242.6 ± 12.0)	.77
LDL-C, mmol/L (mg/dL)	4.05 ± 0.45 (156.6 ± 17.4)	4.05 ± 0.45 (156.6 ± 17.5)	.91
HDL-C, mmol/L (mg/dL)	1.25 ± 0.27 (48.3 ± 10.6)	1.61 ± 0.38 (62.2 ± 14.6)	<.01
TG, mmol/L [mg/dL]	2.07 (1.68, 2.63) [183.0 (149, 233)]	1.24 (0.95, 1.55) [110 (85, 138)]	<.01

Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SD, standard deviation; TC, total cholesterol; TG, triglycerides.

^aValues are mean ± SD of number (%) unless otherwise indicated. TG is median (interquartile range).

Table 2.

Incidence of Cardiovascular Events

Major End Point	Metabolic Syndrome	Nonmetabolic Syndrome	Hazard Ratio (95% CI)	P Value
	No. (per 1000 person years)
	(n = 2636)	(n = 5196)
CHD	72 (6.1)	70 (3.0)	1.85 (1.33-2.57)	<.01
Stroke	49 (4.1)	50 (2.1)	1.80 (1.21-2.67)	<.01
CVD	130 (11.2)	125 (5.4)	1.90 (1.49-2.43)	<.01
Total mortality	47 (3.9)	62 (2.6)	1.39 (0.95-2.03)	.09

Abbreviations: CHD, coronary heart disease (comprising fatal and nonfatal myocardial infarction, cardiac and sudden death, coronary revascularization procedure, and angina); CI, confidence interval; CVD, cardiovascular disease.

Regarding lipid changes during the 5-year follow-up, total cholesterol and LDL-C were reduced by approximately 2% and 3% (P < .001), respectively, in the diet-alone group, and 12% and 18% (P = .005), respectively, in the diet plus pravastatin group; this was similar for MetSyn and non-MetSyn patients. The average achieved LDL-C level in MetSyn in the diet plus pravastatin group was 127.8 mg/dL. High-density lipoprotein cholesterol was elevated more and triglycerides were reduced more in the diet-alone group with MetSyn than in non-MetSyn (+5.2% vs +1.7% high-density lipoprotein cholesterol, P < .001; −8.8% vs +0.9 triglycerides, P < .001). A similar trend was found in the diet plus pravastatin group (+7.7% vs +4.4% high-density lipoprotein cholesterol; −12.4% and −4.0% triglycerides).

The Kaplan-Meier curves for CHD, stroke, CVD, and total mortality are shown in Figure 1. For CHD, no significant difference was found in the diet plus pravastatin group compared with the diet group in MetSyn patients (hazard ratio 0.78, P = .29). On the other hand, for CVD, a significant 36% risk reduction was found in the diet plus pravastatin group compared with the diet group (P = .01). Furthermore, the incidence of stroke and total mortality was decreased by 55% and 50%, respectively, in the diet plus pravastatin group compared with the diet group in MetSyn patients. The corresponding numbers needed to treat to prevent 1 CVD event, stroke, and death were estimated as 45, 71, and 79, respectively (Figure 2). The incidence of cardiovascular events and total mortality was also compared in patients with and without MetSyn plus moderately high LDL-C level (4.1 mmol/L [156.9 mg/dL]) by treatment group (Figure 2). A significant 57% and 80% reduction in CVD and stroke was found in patients with MetSyn plus moderately high LDL-C in the diet plus pravastatin group, with small numbers needed to treat of 26 and 41.

Figure 1.

The Kaplan-Meier curves for coronary heart disease (CHD), stroke, cardiovascular disease (CVD), and total mortality. MetSyn indicates metabolic syndrome; non-MetSyn, nonmetabolic syndrome.

Figure 2.

Cox proportional hazard for major cardiovascular events according to baseline low-density lipoprotein cholesterol (LDL-C) level in metabolic syndrome (MetSyn) and nonmetabolic syndrome (non-MetSyn). Hazard ratio (HR) and 95% confidence interval (CI) were calculated by Cox proportional hazard model, adjusted by sex and age. Square size indicates number of events. The number needed to treat (NNT) was calculated when a significant difference was found between treatment groups. CHD, coronary heart disease; CVD, cardiovascular disease; pt-y, patient years.

Discussion

The present post hoc analysis of the MEGA Study showed that in a high-risk population, defined as patients with MetSyn, the incidence of CVD events was nearly 2 times higher than in patients without MetSyn. Notably, in the MetSyn patients, significant reductions of 55%, 50%, and 36% for stroke, total mortality, and CVD were observed in the diet plus pravastatin group compared with diet alone. Thus, the effect of low-dose pravastatin was mainly attributed to reduction in stroke or total mortality in MetSyn, but the lower incidence of CVD events, compromising mainly CHD and cerebral infarction but including arteriosclerosis obliterans and TIA, indicates that low-dose pravastatin is effective for total management of atherosclerotic disease in Japanese patients with hypercholesterolemia with high-risk profile, such as MetSyn in the primary prevention setting.

The beneficial effect of aggressive lipid-lowering therapy in MetSyn was previously demonstrated by the post hoc analysis of the secondary prevention Treating to New Targets Study.¹⁵ In contrast, our results indicate that in a Japanese primary prevention population, even in high-risk patients, a lower dose of a statin provides significant risk reductions, and the magnitude of these reductions are similar to that achieved with aggressive lipid lowering. The incidence of major coronary events was 10% in the patients with MetSyn in the Treating to New Targets Study during the 5.5-year follow-up. In contrast, the incidence of CVD was low at 3% of patients at 5 years, even in the patients with MetSyn in the MEGA Study.² A large difference in the events remained even after including strokes in the definition of major CVD (13% in Treating to New Targets vs 5% in MEGA), with the Japanese patients having a lower incidence of coronary events and a higher incidence of stroke events.¹⁶ Thus, although the patients with MetSyn in the MEGA Study had a proportionally higher risk for CVD, their absolute risk was not so high despite having multiple risk factors. Based on the Adult Treatment Panel III treatment guidelines, they are categorized as moderate risk (≥ 2 risk factors, 10-year risk <10%), and the recommended achieved LDL-C is 130 mg/dL in patients with moderate risk.¹⁷ The results of the present analysis in patients at moderate risk, in whom the average on-treatment LDL-C was 127.8 mg/dL, support this Adult Treatment Panel III recommendation. Furthermore, the present results support the efficacy of low-dose statin treatment in patients at moderate risk. The number needed to treat to prevent 1 CVD event was only 45 in the patients with MetSyn in the present analysis.

Of the MEGA population, 70% are women. The guidelines for CVD prevention in women¹⁸ classified women with MetSyn without a history of CVD as being at risk. Furthermore, they state that pharmacotherapy should be started for at-risk women with a 10-year absolute risk of CVD if LDL-C is >160 mg/dL. The present results suggest that low-dose statin therapy may also be beneficial for women with LDL-C <160 mg/dL and classified as at risk based on these guidelines. Moreover, in patients with MetSyn plus moderately high LDL-C, our results demonstrated that with low-dose pravastatin, the numbers needed to treat can be reduced to 27 for primary prevention, which is a similar level to that seen in secondary prevention.

A limitation of the present analysis is the use of body mass index instead of waist circumference to define obesity. The prevalence of MetSyn in Japanese men is 15% using the criterion of body mass index ≥25 kg/m² and 22% using the criterion of waist circumference ≥85 cm, and in women it is 6% and 4.5%, respectively, based on recent research comparing these criteria.¹⁹ However, because 70% of our study population is women, the use of body mass index rather than waist circumference may have little effect.

Conclusion

In conclusion, low-dose pravastatin provides effective and efficient CVD risk reduction as primary prevention in Japanese patients with MetSyn. These results also suggest that low-dose statin treatment can be applicable in the moderate-risk population (≥2 risks, 10-year CVD risk <10%).

Footnotes

Acknowledgment

We thank all the study participants, physicians, comedical staff, and coworkers.

This trial is registered at ClinicalTrials.gov, number NCT00211705. order=1.

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The following authors have received consultant fees, travel fees, lecture fees and/or research grants from the following companies: Dr Matsushima, Daiichi Sankyo, Banyu, Astra Zeneca, Tanabe Mitsubishi, Kowa; Dr Mizuno, Daiichi Sankyo, Banyu, Pfizer, Tanabe Mitsubishi, Kowa; Dr Nakaya, Daiichi Sankyo, Astra Zeneca, Kowa; Dr Ohashi, Daiichi Sankyo, Banyu, Astellas, Pfizer, Kowa; Dr Teramoto, Daiichi Sankyo, Banyu, Astellas, Pfizer, Astra Zeneca, Shionogi, Tanabe Mitsubishi, Kowa; Dr Yokoyama, Daiichi Sankyo, Banyu, Astellas, Pfizer, Astra Zeneca, Kowa; Dr Ichikawa, Daiichi Sankyo, Banyu, Astellas, Astra Zeneca; Dr Ishikura, Novartis; Dr Nakamura, Daiichi Sankyo.

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was controlled by the MEGA Study Publication Committee, and all analyses were conducted at the MEGA Study Data Center. Research funds were provided by Daiichi Sankyo Co Ltd, Tokyo, Japan.

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The Effect of Low-Dose Pravastatin in Metabolic Syndrome for Primary Prevention of Cardiovascular Disease in Japan