Fasting Glucose Levels Predict Cardiovascular Outcome
The CARMA study was designed to investigate cardiometabolic risk factors in healthy male and female adults of white ethnicity. The study has been conducted at the Executive Screening Survey (ESS) at the Sheba Medical Center in Israel. The ESS performs approximately 9,000 screening examinations of adult males and females annually. This population is composed mainly of senior executives referred for periodic health screening by their organizations and so represents a higher-than-average socioeconomic class. When compared with data available for the general Israeli population, our study population had lower rates of obesity (body mass index [BMI] ≥ 30 kg/m) and active smoking. A computerized database established in 2000 is the source of data for the study. At each annual visit, participants completed a detailed questionnaire assessing demographic, nutritional, lifestyle, and medical factors. Thereafter, blood samples were drawn after a 12-hour fast and were analyzed immediately. A physician at the center performed a complete physical examination. Blood pressure measurements were performed by medical professionals with the use of mercury sphygmomanometers. All medical information was recorded in a central database, thus allowing an ongoing follow-up. The Institutional Review Board of Sheba Medical Center approved this study on the basis of strict maintenance of participants' anonymity during database analyses. Data from subjects were recorded anonymously. No individual consent was obtained.
Men and women older than 34 years with FPG levels < 126 mg/dL at their first annual visit at the ESS have been included. In addition, follow-up data must have been available from at least 1 subsequent visit, > 2 years after the first visit (average no. of visits per person, 5; range, 2–9). We selected patients without confirmed type 1 or type 2 DM at the time of enrollment and without a current or past diagnosis of CVD (ischemic heart disease, acute coronary syndrome, acute myocardial infarction [MI], or ischemic stroke). Assessed for eligibility were 18,034 participants who visited the ESS between January 2000 and December 2009. Excluded were 4,101 with preexisting DM or CVD and 3,020 with only a single visit (Figure). Baseline characteristics of the 3,020 individuals who had a single visit to the ESS were not statistically different from the characteristics of the included participants (data not shown). Included for analysis were 10,913 participants, (7,940 men and 2,973 women).
(Enlarge Image)
Figure.
Flowchart of study participants. A total of 18,034 men and women were evaluated initially; among them, 4101 were excluded because of a medical history of DM or CVD, and 3020, because of having only a single visit to the ESS. Eventually, 10,913 participants, 7940 men and 2973 women, participated in the study. During follow-up, 548 developed DM, 1,119 developed CVDs, and 131 died.
Diagnosis of CVD was the primary end point of the study. Cardiovascular disease was defined as a composite of coronary heart disease (CHD), MI, cerebral vascular events, or transient ischemic attacks (TIAs). Coronary outcome was defined by clinically significant CHD (angiography-proven stenosis of > 50% in at least 1 coronary artery), MI, or a positive Bruce test. The diagnosis of MI was self-reported, and when available, medical records were reviewed. At each annual ESS visit, each participant had a treadmill exercise test (Bruce protocol) in the presence of a board-certified cardiologist. End points for the exercise test were clinically significant ST-segment depression (> 2 mm depression in 2 contiguous leads, measured 80 milliseconds after the J point), intolerable symptoms of angina and exhaustion, or achievement of the target heart rate without such findings. All cases with a pathologic stress test were referred for coronary angiography. For individuals with a positive Bruce stress test, for whom data on coronary angiography or single-photon emission computed tomography was not available, a positive Bruce test was considered as confirmation for a positive CHD. In participants with a borderline stress test, or when participants reported angina symptoms without diagnostic electrocardiographic changes, stress perfusion imaging with thallium-201 was performed. Those with a pathologic thallium-201 cardiac scan underwent coronary angiography. Cerebrovascular accident/TIA outcome included self-reported cerebral vascular events or TIAs. When available, medical records were reviewed.
The diagnosis of DM was defined as the secondary outcome of this study. Subjects with 2 fasting glucose tests ≥ 126 mg/dL (preformed on different days) were diagnosed with DM.
Biochemical analyses of blood were performed on fresh samples in a core laboratory facility. Tests were performed in the Sheba Medical Center, Tel Hashomer, using the Olympus AU2700TM Chemistry-Immuno Analyzer (Olympus; Shinjuku, Tokyo, Japan).
Included for analysis were 7,940 men and 2,973 women. For each participant, person-time of follow-up was calculated from the date of the first ESS visit until censoring, as detailed above. We used 1-way analysis of variance to compare the means and proportions of the population baseline characteristic across the FPG groups, which were arbitrarily divided to 5-mg/dL intervals for levels between 80 and 100 mg/dL. In addition, we have also included the 2 extreme groups, FPG < 80 mg/dL and IFG (100–126 mg/dL). Levels below 100 were considered as "fasting normoglycemia." Log transformation was used for triglyceride (TG) and high-density lipoprotein (HDL) cholesterol. χ test was used for categorical data. We conducted Cox proportional hazard analysis to estimate the hazard ratio (HR) and 95% CIs for developing CVD outcome. We controlled for age, gender, systolic blood pressure (continuous), TG (continuous), HDL and low-density lipoprotein (LDL) cholesterol (both continuous), smoking status (current vs past or never), BMI (continuous), pharmacologic treatment (grouped into β-blockers, cholesterol-lowering drugs ,antiarrhythmics, antithrombotics, diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers), and family history for coronary disease (yes or no). Mortality rates, according to FPG levels, were assessed by Kaplan-Meier survival analysis. The Wald score was used to rank the strength of each independent risk factor for cardiovascular diseases. All statistical analyses were performed with SPSS statistical software version 15.0 (IBM, Armonk, NY).
This study was supported by a grant from the Shlavi foundation for medical research. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Methods
The CARMA Study
The CARMA study was designed to investigate cardiometabolic risk factors in healthy male and female adults of white ethnicity. The study has been conducted at the Executive Screening Survey (ESS) at the Sheba Medical Center in Israel. The ESS performs approximately 9,000 screening examinations of adult males and females annually. This population is composed mainly of senior executives referred for periodic health screening by their organizations and so represents a higher-than-average socioeconomic class. When compared with data available for the general Israeli population, our study population had lower rates of obesity (body mass index [BMI] ≥ 30 kg/m) and active smoking. A computerized database established in 2000 is the source of data for the study. At each annual visit, participants completed a detailed questionnaire assessing demographic, nutritional, lifestyle, and medical factors. Thereafter, blood samples were drawn after a 12-hour fast and were analyzed immediately. A physician at the center performed a complete physical examination. Blood pressure measurements were performed by medical professionals with the use of mercury sphygmomanometers. All medical information was recorded in a central database, thus allowing an ongoing follow-up. The Institutional Review Board of Sheba Medical Center approved this study on the basis of strict maintenance of participants' anonymity during database analyses. Data from subjects were recorded anonymously. No individual consent was obtained.
Inclusion and Exclusion Criteria
Men and women older than 34 years with FPG levels < 126 mg/dL at their first annual visit at the ESS have been included. In addition, follow-up data must have been available from at least 1 subsequent visit, > 2 years after the first visit (average no. of visits per person, 5; range, 2–9). We selected patients without confirmed type 1 or type 2 DM at the time of enrollment and without a current or past diagnosis of CVD (ischemic heart disease, acute coronary syndrome, acute myocardial infarction [MI], or ischemic stroke). Assessed for eligibility were 18,034 participants who visited the ESS between January 2000 and December 2009. Excluded were 4,101 with preexisting DM or CVD and 3,020 with only a single visit (Figure). Baseline characteristics of the 3,020 individuals who had a single visit to the ESS were not statistically different from the characteristics of the included participants (data not shown). Included for analysis were 10,913 participants, (7,940 men and 2,973 women).
(Enlarge Image)
Figure.
Flowchart of study participants. A total of 18,034 men and women were evaluated initially; among them, 4101 were excluded because of a medical history of DM or CVD, and 3020, because of having only a single visit to the ESS. Eventually, 10,913 participants, 7940 men and 2973 women, participated in the study. During follow-up, 548 developed DM, 1,119 developed CVDs, and 131 died.
Definitions of CVD Outcomes
Diagnosis of CVD was the primary end point of the study. Cardiovascular disease was defined as a composite of coronary heart disease (CHD), MI, cerebral vascular events, or transient ischemic attacks (TIAs). Coronary outcome was defined by clinically significant CHD (angiography-proven stenosis of > 50% in at least 1 coronary artery), MI, or a positive Bruce test. The diagnosis of MI was self-reported, and when available, medical records were reviewed. At each annual ESS visit, each participant had a treadmill exercise test (Bruce protocol) in the presence of a board-certified cardiologist. End points for the exercise test were clinically significant ST-segment depression (> 2 mm depression in 2 contiguous leads, measured 80 milliseconds after the J point), intolerable symptoms of angina and exhaustion, or achievement of the target heart rate without such findings. All cases with a pathologic stress test were referred for coronary angiography. For individuals with a positive Bruce stress test, for whom data on coronary angiography or single-photon emission computed tomography was not available, a positive Bruce test was considered as confirmation for a positive CHD. In participants with a borderline stress test, or when participants reported angina symptoms without diagnostic electrocardiographic changes, stress perfusion imaging with thallium-201 was performed. Those with a pathologic thallium-201 cardiac scan underwent coronary angiography. Cerebrovascular accident/TIA outcome included self-reported cerebral vascular events or TIAs. When available, medical records were reviewed.
Diagnosis of DM
The diagnosis of DM was defined as the secondary outcome of this study. Subjects with 2 fasting glucose tests ≥ 126 mg/dL (preformed on different days) were diagnosed with DM.
Laboratory Methods
Biochemical analyses of blood were performed on fresh samples in a core laboratory facility. Tests were performed in the Sheba Medical Center, Tel Hashomer, using the Olympus AU2700TM Chemistry-Immuno Analyzer (Olympus; Shinjuku, Tokyo, Japan).
Statistical Analysis
Included for analysis were 7,940 men and 2,973 women. For each participant, person-time of follow-up was calculated from the date of the first ESS visit until censoring, as detailed above. We used 1-way analysis of variance to compare the means and proportions of the population baseline characteristic across the FPG groups, which were arbitrarily divided to 5-mg/dL intervals for levels between 80 and 100 mg/dL. In addition, we have also included the 2 extreme groups, FPG < 80 mg/dL and IFG (100–126 mg/dL). Levels below 100 were considered as "fasting normoglycemia." Log transformation was used for triglyceride (TG) and high-density lipoprotein (HDL) cholesterol. χ test was used for categorical data. We conducted Cox proportional hazard analysis to estimate the hazard ratio (HR) and 95% CIs for developing CVD outcome. We controlled for age, gender, systolic blood pressure (continuous), TG (continuous), HDL and low-density lipoprotein (LDL) cholesterol (both continuous), smoking status (current vs past or never), BMI (continuous), pharmacologic treatment (grouped into β-blockers, cholesterol-lowering drugs ,antiarrhythmics, antithrombotics, diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers), and family history for coronary disease (yes or no). Mortality rates, according to FPG levels, were assessed by Kaplan-Meier survival analysis. The Wald score was used to rank the strength of each independent risk factor for cardiovascular diseases. All statistical analyses were performed with SPSS statistical software version 15.0 (IBM, Armonk, NY).
This study was supported by a grant from the Shlavi foundation for medical research. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
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