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Ageing and fasting glucose values – the role of cardiovascular events
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EURGER-641; No. of Pages 5 European Geriatric Medicine xxx (2015) xxx–xxx
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Research paper
Ageing and fasting glucose values – the role of cardiovascular events§ A. Dzien a, H. Winner b, E. Theurl c, C. Dzien-Bischinger a, M. Lechleitner d,* a
Medical Center Hentschelhof, Buergerstrasse, A-6020 Innsbruck, Austria Department of Economics and Social Sciences, Kapitelgasse 5-7, A-5010 Salzburg, Austria Department of Public Economics, University of Innsbruck, Universita¨tsstrasse 15/4, A-6020 Innsbruck, Austria d Department of Internal Medicine, Hospital Hochzirl, Anna Dengel-Haus, A-6170 Zirl, Austria b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 January 2015 Accepted 2 May 2015 Available online xxx
Fasting glucose values are closely related to insulin resistance and thus to the cardiovascular risk. The aim of our study was to analyze the behaviour of fasting glucose levels in a large cohort of middle-aged and elderly patients over a period of 15 years including the possible influence of cardiovascular events (CVEs). For this purpose 4061 patients (age 46.8 19.0 years) regularly attending a medical outdoor center between 1995 and 2013 were assigned to a group of patients with a CVE at least once within this time period, and one without this diagnosis throughout. The groups were properly selected with respect to age, sex, physical activity, smoking and socioeconomic characteristics. Fasting glucose levels in patients without CVEs remained stable over 15 years and thus during ageing of the population. Patients with a CVE revealed significantly higher entries on fasting glucose values with a continuous increase throughout the whole observation period and a pronounced increase after the CVE. Our data seem to suggest, that fasting glucose levels are stable laboratory results in a patient-population without CVEs. For patients with an ageing related increase in fasting glucose values consequent primary and secondary risk factor intervention is recommended. ß 2015 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Fasting glucose Ageing Cardiovascular event
1. Introduction Increased fasting glucose levels are related to insulin resistance and thus to the metabolic syndrome with a cascade of cardiovascular risk factors (CRF) [1–4]. The impact of abnormal glucose metabolism, hypertension and dyslipidemia on cardiovascular morbidity and mortality was demonstrated by numerous epidemiological and clinical studies [5–8]. Secondary prevention after a cardiovascular event (CVE) is well-accepted, but the value of statin therapy in low risk patients and the possibly increased risk of diabetes manifestation with potent statins remain a matter of debate [9,10]. The benefits and possible harms of strict glycemic control in diabetic patients [11] and the so-called obesity paradoxon with a more favourable prognosis for certain diseases in the case of overweight or mild obesity are especially discussed in elderly [12]. Data about an influence of ageing on fasting glucose values and insulin resistance remain controversial because impaired but also § Ethical statement: data evaluation was performed by the physicians, who treated the patients, in order to improve therapeutic strategies. Patients were informed about this analysis. Abbreviations: BMI, body mass index; CVE, cardiovascular event; CRF, cardiovascular risk factor; HDL, high density lipoprotein; LDL, low density lipoprotein. * Corresponding author. E-mail address: [email protected] (M. Lechleitner).
unchanged levels of insulin sensitivity are reported [13–15] in addition to a worsening of pancreatic beta-cell function [16]. Furthermore, cardiovascular events and medication, such as statins, beta-blockers and diuretics, can be related to impaired glucose metabolism [10,17]. The activated inflammatory response accompanying myocardial infarction was found to result in an increased insulin resistance and glucose impairment [18,19]. Overall, only few data are available about the long-term behaviour of fasting glucose values in an ageing population [20,21], including the role of CVE [22–24]. The main purpose of our evaluation was therefore to determine possible changes of fasting glucose levels in a large cohort of patients over a long observation period of 15 years. We distinguished further between people who never had a diagnosis of a CVE and patients who experienced a CVE at least once within this time period. 2. Methods 2.1. Assessment of cardiovascular events The term ‘‘event’’ summarized a history of angina with typical clinical symptoms and findings in electrocardiography and/or coronary angiography (ICD 20, ICD 25), status post-myocardial infarction (ICD 25) as well as stroke or cerebral ischemia (ICD 64).
http://dx.doi.org/10.1016/j.eurger.2015.05.006 1878-7649/ß 2015 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006
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EURGER-641; No. of Pages 5 A. Dzien et al. / European Geriatric Medicine xxx (2015) xxx–xxx
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Diagnosis of stroke or cerebral ischemia comprise only a small percentage of our population with CVE (5%). Diagnosis of CVE originated in all patients from hospital medical reports. Patients without a CVE were those admitted for health check-up tests. 2.2. Assessment of cardiovascular risk factors For all patients, we collected information on fasting blood glucose, body mass index (BMI), blood pressure, serum triglycerides, total cholesterol and HDL- and LDL-cholesterol. Measurements were performed at the regular clinical visits based on laboratory tests of blood samples. Blood pressure was taken as the mean of three or more readings at two separate visits. 2.3. Study population Between 1995 and 2013, a total of 19,730 Caucasian persons (55.2% female) with mean age of 43 years attended a medical outdoor center for diagnostic and/or therapeutic interventions. First, we refrained from persons with severe hepatic disorders and renal failure. From the remaining patients, we have complete information from clinical routine controls including a large set of laboratory measurements from 9331 patients. For patients with more than one doctor visit per year, we took the annual mean of each CRF to obtain person-year combinations as observational unit. On average, we observed entries from three years for each patient. A total of 4943 patients with an entry of only one year within the observation period were not included in the further evaluation. Patients with a premature CVE before the age of 30 years and those with a CVE after an age of 80 years were excluded (total of 68 patients), as well as persons who had a CVE before 1995 (259 patients). We ended up with a sample of 4061 patients (16,033 observations; Table 1). In total, 191 of them experienced a CVE within the observational period, with a mean standard deviation (SD) of 8.2 4.8 years of visits (resulting in 1560 observations). In order to compare the fasting glucose values and CRF in people without a CVE (3870 persons with a mean (SD) of 4.7 3.5 years of visits and 14,473 observations) to those of patients with a CVE, we performed a paired analysis matched with respect to age, sex, smoking, sports and educational background. None of the patients assigned to the group without CVE for paired analysis was on continuous statin therapy.
2.4. Statistical analysis To obtain reliable groups for comparison, we used the group of persons who never had a CVE and assigned each patient to one in the group with a CVE, strictly matched for the following criteria: age (in years), sex (indicator variable with entry 1 for males, 0 for females), smoking (1 for people who ever smoked, 0 else), sports (1 for patients who experienced physical activity at least once in a week, 0 otherwise), educational background (1 for people with tertiary education, 0 else) and a proxy for socioeconomic status (1 for patients with an additional ‘‘private’’ health insurance coverage, 0 else). An assignment was only completed if all of these criteria were exactly matched by at least one of the persons of the reference group, i.e., if, according to these criteria, we found at least one perfect ‘‘neighbor’’. In case where the matching algorithm allocated more than one person, we took the respective mean of each CRF. After all, we ended up with reference values for each patient’s CRF at each point in time (i.e., between t = –7 and t = 7). Out of the 947 observations where full information on CRF was available for all patients with CVE, in only 31 cases we were unable to find suitable reference values. For each patient with a CVE, we defined the year where the CVE took place as the base year (i.e., t = 0, t denotes a time index), allowing to observe CRF 7 years behind and 7 years ahead. To determine differences between patients with and without a CVE, we performed Student’s t-tests based on the mean values of CRF (Table 2). To analyze the long-term pattern of CRF before and after the CVE, we applied panel data techniques and regressed each of the CRF on the time index (t = –7, . . ., 7) and a fixed patient effect (the latter captures individual specific and time-invariant characteristics such as gender and other dimensions of the socioeconomic background). We estimated these models separately for the time periods before and after the CVE. The corresponding parameters (slopes) of the time variable inform on whether CRF increase or decrease linearly over the course of the years.
3. Results 3.1. Fasting glucose values In people without a CVE, fasting glucose values remained almost stable during the whole observation period of 15 years
Table 1 Baseline characteristics of study population. All patients (n = 4061)
Males (%) Age Physical activity (%) Smoking (%) Private insurance (%) Tertiary education (%) Fasting blood glucose (mg/dL) Body mass index Tryglicerides (mg/dL) Systolic blood pressure (mm/Hg) Diastolic blood pressure (mm/Hg) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Patients with statine therapy (%) of which Before cardiovascular event (%) After cardiovascular event (%)
Obs.
Mean
16,033 16,033 10,264 10,264 16,033 16,033 13,228 14,979 13,303 14,636 14,776 13,412 10,848 10,802 16,033
36.73 46.75 65.68 28.55 30.70 16.24 96.75 24.19 113.17 126.19 79.16 206.27 57.26 127.95 6.72
SD 18.98
25.18 3.95 58.69 18.86 9.69 39.10 14.58 34.46
Patients without cardiovascular event (n = 3870)
Patients with cardiovascular event (n = 191)
Obs.
Mean
Obs.
Mean
14,473 14,473 9146 9146 14,473 14,473 11,919 13,482 11,947 13,193 13,310 12,078 9578 9571
34.64 44.38 67.05 29.72 28.09 17.00 94.75 23.97 109.59 124.50 78.69 205.18 57.60 127.33
1560 1560 1118 1118 1560 1560 1309 1497 1356 1443 1466 1334 1270 1231 1560 834 726
56.15 68.75 54.47 18.96 54.87 9.17 114.97 26.14 144.68 141.65 83.40 216.21 54.72 132.78 69.10 62.59 76.58
SD 18.13
23.29 3.93 56.10 18.05 9.59 38.38 14.53 33.67
SD 10.81
33.13 3.56 70.45 19.09 9.61 43.88 14.72 39.76
SD: standard deviation.
Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006
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EURGER-641; No. of Pages 5 A. Dzien et al. / European Geriatric Medicine xxx (2015) xxx–xxx Table 2 Cardiovascular risk factors before/after a cardiovascular event.
Fasting blood glucose (mg/dL) Body Mass Index (mass/(height squared)) Triglycerides (mg/dL) Systolic blood pressure (mm/Hg) Diastolic blood pressure (mm/Hg) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL)
3.2. Body mass index
Difference to control group
Difference a/b event
Before event
After event
3.980 (1007)
6.653 (531)
10.291 (462)
0.028 0.171 (1149)
0.000 0.284 (631)
0.000 0.771 (515)
0.215 –3.694 (1,039) 0.200 –5.078 (1,104)
0.035 19.528 (557) 0.000 4.181 (598)
0.000 19.067 (466) 0.003 –1.156 (499)
0.000 –3.332 (1,127)
0.000 1.282 (608)
0.115 –1.568 (513)
0.000 –22.713 (1,021)
0.002 7.911 (545)
0.000 –13.712 (468)
0.000 –0.742 (976)
0.000 –0.389 (502)
0.000 –0.977 (461)
0.218 –22.781 (949)
0.295 7.717 (483)
0.089 –14.996 (452)
0.000
0.000
0.000
BMI values of patients without a CVE revealed a continuous slight decrease paralleling ageing of the study population. BMI values in patients with a CVE were constantly higher, but this difference was only significant after the CVE (Table 2; Fig. 2). 3.3. Blood pressure and lipid values During the whole observation period systolic blood pressure increased slightly in people without a CVE, while diastolic blood pressure remained almost stable. Patients with a CVE revealed significantly higher entries for systolic and diastolic blood pressure values than the reference group. A drop of systolic and diastolic blood pressure was found after the CVE (Table 2). Total cholesterol and LDL-cholesterol were higher in patients with a CVE compared to those without a CVE in the period before the cardiovascular complication. After the event both values were significantly lower and decreased slightly over time. In patients without a CVE, total cholesterol and LDL-cholesterol levels remained almost stable during the observation period. HDL cholesterol values were widely distributed in both study groups.
4. Discussion
P-values (in italics) correspond to one sided t-tests. Significant entries at least at the 1%-level in bold. Number of observations in parentheses.
(Fig. 1). In patients with a CVE, fasting glucose values revealed a continuous increase during 7 years before the CVE and an even steeper increase after the CVE. Both of the corresponding slope parameters are significant at least at the 2%-level (Fig. 1). Fasting glucose values were constantly higher in patients with a cardiovascular complication compared to patients without CVE. This difference was even more pronounced in the period after the CVE (Table 2). The CVE occurred at an age of 66.0 11.0 years (Table 1).
130
3
Our study results show that fasting glucose levels in a large cohort of middle-aged and elderly patients without a CVE remain almost stable during an observation period of 15 years and thus during ageing of the population. This finding was in contrast to the results obtained in patients with a CVE with higher fasting glucose values at entry and a continuous increase throughout the observation period. It should be noticed that we used various individual background variables to perform an exact matching procedure, which in turn allows to implicitly control for individual-specific influences when analyzing the relationship between fasting glucose and CVE.
Slope b/a event (p-value): 0.99 (0.019); 1.76 (0.000)
27.5
Slope b/a event (p-value): -0.03 (0.113); -0.01 (0.651)
125 27
mass/(height squared)
mg/dL
120
115
110
26.5
26
105 25.5
100 -7
-5
-3
-1
1
3
5
7
Year b/a event Fig. 1. Fasting glucose. Dark/grey entries display mean values of cardiovascular risk factors for patients with (without) cardiovascular events. The reported slopes and Pvalues belong to the group of patients with a cardiovascular event only and are obtained from a panel regression of the cardiovascular risk factors on the time index (t = –7. . ., 7) and individual specific effects. The corresponding control functions are plotted by the dark shaded lines; grey shaded lines are obtained analogously, but slopes and P-values are suppressed. For each risk factor, we fit linear control functions on the left and the right of the vertical line (indicating the cardiovascular event) weighted by the number of observations in each time period.
-7
-5
-3
-1
1
3
5
7
Year b/a event Fig. 2. Body mass index. Dark/grey entries display mean values of cardiovascular risk factors for patients with (without) cardiovascular events. The reported slopes and P-values belong to the group of patients with a cardiovascular event only and are obtained from a panel regression of the cardiovascular risk factors on the time index (t = –7. . ., 7) and individual specific effects. The corresponding control functions are plotted by the dark shaded lines; grey shaded lines are obtained analogously, but slopes and P-values are suppressed. For each risk factor, we fit linear control functions on the left and the right of the vertical line (indicating the cardiovascular event) weighted by the number of observations in each time period.
Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006
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A slight increase of fasting glucose levels with increasing age was described in previously published studies [13,14], but these finding did not support a strong correlation. The Baltimore Longitudinal Study of Aging could demonstrate a progressive decline in glucose tolerance in women from early to late adulthood [25]. In the longitudinal Medical Research Council Cognitive Function and Ageing Study, which included over 18,000 individuals aged 65 years and older, mortality from all causes, cardiovascular and ischemic heart disease increased with increasing glycated hemoglobin (HbA1c) values [26]. Especially in patients with diabetes, postprandial glucose values are strongly related to the cardiovascular risk [27]. With respect to the large number of participants, we have focused our evaluation on the glucose levels after an overnight fast. According to published data, high normal fasting glucose values in younger obese individuals correlate with insulin resistance and beta cell dysregulation [28]. In men without diabetes insulin resistance was of predictive value for early cardiovascular morbidity [29]. The BMI values of patients without a CVE revealed a tendency to decrease with increasing age. This is in accordance to published data about a continuous increase of BMI during adulthood [30] and a decrease at an advanced age [31]. Overweight and obesity correlate with insulin resistance [3] and an increased cardiovascular morbidity [32,33]. BMI of our patients in the CVE group were higher than in those without a cardiovascular complication. The aging associated decrease in muscle mass, increase in fat mass and subclinical inflammation are known as factors enhancing the risk for insulin resistance [34]. Waist circumference was not determined in our population because there is, until now, no consensus on the cutoffs for the elderly [35]. Lipid and blood pressure values of our patients with a CVE were on entry significantly higher than in patients without a CVE. The lower levels after the CVE might be the result of an intensified medical risk factor intervention [36,37] (Table 1). Our evaluation reveals some limitations, because the study participants were patients attending a medical outdoor center. A further critical aspect is the influence of cardiovascular medication with an influence on the risk of new-onset diabetes [38], especially regarding the effects of statin therapy with a possible association between statin use and incident diabetes in patients with underlying risk factors [39]. However, fasting glucose levels were already higher at entry to the evaluation – and thus years before the cardiovascular complication – in patients with a future CVE. Our definition of an event comprised cardiovascular events and to a small percentage cerebral ischemic complications. In literature, a worsening of insulin resistance and glucose metabolism is described in the postmyocardial state [18,19]. In ischemic stroke patients a high prevalence of abnormal glucose metabolism was found also in patients without a history of diabetes [40]. Thus both subtypes of events are of unfavourable influence on glucose metabolism. The stable results of fasting blood glucose in patients without a CVE over 15 years remain remarkable, especially in comparison to the values obtained in a strictly matched group with a CVE and a continuous increase in fasting glucose. For patients with an ageing related increase in fasting glucose values, consequent primary and secondary risk factor intervention is recommended. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Authors’ contributions: All authors were involved in the concept of the study and writing of the manuscript, Dzien and DzienBischinger recruited the patients, Winner and Theurl did the
statistical analysis, Lechleitner: data analysis and manuscript editing.
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Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006
EURGER-641; No. of Pages 5 European Geriatric Medicine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Research paper
Ageing and fasting glucose values – the role of cardiovascular events§ A. Dzien a, H. Winner b, E. Theurl c, C. Dzien-Bischinger a, M. Lechleitner d,* a
Medical Center Hentschelhof, Buergerstrasse, A-6020 Innsbruck, Austria Department of Economics and Social Sciences, Kapitelgasse 5-7, A-5010 Salzburg, Austria Department of Public Economics, University of Innsbruck, Universita¨tsstrasse 15/4, A-6020 Innsbruck, Austria d Department of Internal Medicine, Hospital Hochzirl, Anna Dengel-Haus, A-6170 Zirl, Austria b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 January 2015 Accepted 2 May 2015 Available online xxx
Fasting glucose values are closely related to insulin resistance and thus to the cardiovascular risk. The aim of our study was to analyze the behaviour of fasting glucose levels in a large cohort of middle-aged and elderly patients over a period of 15 years including the possible influence of cardiovascular events (CVEs). For this purpose 4061 patients (age 46.8 19.0 years) regularly attending a medical outdoor center between 1995 and 2013 were assigned to a group of patients with a CVE at least once within this time period, and one without this diagnosis throughout. The groups were properly selected with respect to age, sex, physical activity, smoking and socioeconomic characteristics. Fasting glucose levels in patients without CVEs remained stable over 15 years and thus during ageing of the population. Patients with a CVE revealed significantly higher entries on fasting glucose values with a continuous increase throughout the whole observation period and a pronounced increase after the CVE. Our data seem to suggest, that fasting glucose levels are stable laboratory results in a patient-population without CVEs. For patients with an ageing related increase in fasting glucose values consequent primary and secondary risk factor intervention is recommended. ß 2015 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Fasting glucose Ageing Cardiovascular event
1. Introduction Increased fasting glucose levels are related to insulin resistance and thus to the metabolic syndrome with a cascade of cardiovascular risk factors (CRF) [1–4]. The impact of abnormal glucose metabolism, hypertension and dyslipidemia on cardiovascular morbidity and mortality was demonstrated by numerous epidemiological and clinical studies [5–8]. Secondary prevention after a cardiovascular event (CVE) is well-accepted, but the value of statin therapy in low risk patients and the possibly increased risk of diabetes manifestation with potent statins remain a matter of debate [9,10]. The benefits and possible harms of strict glycemic control in diabetic patients [11] and the so-called obesity paradoxon with a more favourable prognosis for certain diseases in the case of overweight or mild obesity are especially discussed in elderly [12]. Data about an influence of ageing on fasting glucose values and insulin resistance remain controversial because impaired but also § Ethical statement: data evaluation was performed by the physicians, who treated the patients, in order to improve therapeutic strategies. Patients were informed about this analysis. Abbreviations: BMI, body mass index; CVE, cardiovascular event; CRF, cardiovascular risk factor; HDL, high density lipoprotein; LDL, low density lipoprotein. * Corresponding author. E-mail address: [email protected] (M. Lechleitner).
unchanged levels of insulin sensitivity are reported [13–15] in addition to a worsening of pancreatic beta-cell function [16]. Furthermore, cardiovascular events and medication, such as statins, beta-blockers and diuretics, can be related to impaired glucose metabolism [10,17]. The activated inflammatory response accompanying myocardial infarction was found to result in an increased insulin resistance and glucose impairment [18,19]. Overall, only few data are available about the long-term behaviour of fasting glucose values in an ageing population [20,21], including the role of CVE [22–24]. The main purpose of our evaluation was therefore to determine possible changes of fasting glucose levels in a large cohort of patients over a long observation period of 15 years. We distinguished further between people who never had a diagnosis of a CVE and patients who experienced a CVE at least once within this time period. 2. Methods 2.1. Assessment of cardiovascular events The term ‘‘event’’ summarized a history of angina with typical clinical symptoms and findings in electrocardiography and/or coronary angiography (ICD 20, ICD 25), status post-myocardial infarction (ICD 25) as well as stroke or cerebral ischemia (ICD 64).
http://dx.doi.org/10.1016/j.eurger.2015.05.006 1878-7649/ß 2015 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006
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Diagnosis of stroke or cerebral ischemia comprise only a small percentage of our population with CVE (5%). Diagnosis of CVE originated in all patients from hospital medical reports. Patients without a CVE were those admitted for health check-up tests. 2.2. Assessment of cardiovascular risk factors For all patients, we collected information on fasting blood glucose, body mass index (BMI), blood pressure, serum triglycerides, total cholesterol and HDL- and LDL-cholesterol. Measurements were performed at the regular clinical visits based on laboratory tests of blood samples. Blood pressure was taken as the mean of three or more readings at two separate visits. 2.3. Study population Between 1995 and 2013, a total of 19,730 Caucasian persons (55.2% female) with mean age of 43 years attended a medical outdoor center for diagnostic and/or therapeutic interventions. First, we refrained from persons with severe hepatic disorders and renal failure. From the remaining patients, we have complete information from clinical routine controls including a large set of laboratory measurements from 9331 patients. For patients with more than one doctor visit per year, we took the annual mean of each CRF to obtain person-year combinations as observational unit. On average, we observed entries from three years for each patient. A total of 4943 patients with an entry of only one year within the observation period were not included in the further evaluation. Patients with a premature CVE before the age of 30 years and those with a CVE after an age of 80 years were excluded (total of 68 patients), as well as persons who had a CVE before 1995 (259 patients). We ended up with a sample of 4061 patients (16,033 observations; Table 1). In total, 191 of them experienced a CVE within the observational period, with a mean standard deviation (SD) of 8.2 4.8 years of visits (resulting in 1560 observations). In order to compare the fasting glucose values and CRF in people without a CVE (3870 persons with a mean (SD) of 4.7 3.5 years of visits and 14,473 observations) to those of patients with a CVE, we performed a paired analysis matched with respect to age, sex, smoking, sports and educational background. None of the patients assigned to the group without CVE for paired analysis was on continuous statin therapy.
2.4. Statistical analysis To obtain reliable groups for comparison, we used the group of persons who never had a CVE and assigned each patient to one in the group with a CVE, strictly matched for the following criteria: age (in years), sex (indicator variable with entry 1 for males, 0 for females), smoking (1 for people who ever smoked, 0 else), sports (1 for patients who experienced physical activity at least once in a week, 0 otherwise), educational background (1 for people with tertiary education, 0 else) and a proxy for socioeconomic status (1 for patients with an additional ‘‘private’’ health insurance coverage, 0 else). An assignment was only completed if all of these criteria were exactly matched by at least one of the persons of the reference group, i.e., if, according to these criteria, we found at least one perfect ‘‘neighbor’’. In case where the matching algorithm allocated more than one person, we took the respective mean of each CRF. After all, we ended up with reference values for each patient’s CRF at each point in time (i.e., between t = –7 and t = 7). Out of the 947 observations where full information on CRF was available for all patients with CVE, in only 31 cases we were unable to find suitable reference values. For each patient with a CVE, we defined the year where the CVE took place as the base year (i.e., t = 0, t denotes a time index), allowing to observe CRF 7 years behind and 7 years ahead. To determine differences between patients with and without a CVE, we performed Student’s t-tests based on the mean values of CRF (Table 2). To analyze the long-term pattern of CRF before and after the CVE, we applied panel data techniques and regressed each of the CRF on the time index (t = –7, . . ., 7) and a fixed patient effect (the latter captures individual specific and time-invariant characteristics such as gender and other dimensions of the socioeconomic background). We estimated these models separately for the time periods before and after the CVE. The corresponding parameters (slopes) of the time variable inform on whether CRF increase or decrease linearly over the course of the years.
3. Results 3.1. Fasting glucose values In people without a CVE, fasting glucose values remained almost stable during the whole observation period of 15 years
Table 1 Baseline characteristics of study population. All patients (n = 4061)
Males (%) Age Physical activity (%) Smoking (%) Private insurance (%) Tertiary education (%) Fasting blood glucose (mg/dL) Body mass index Tryglicerides (mg/dL) Systolic blood pressure (mm/Hg) Diastolic blood pressure (mm/Hg) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Patients with statine therapy (%) of which Before cardiovascular event (%) After cardiovascular event (%)
Obs.
Mean
16,033 16,033 10,264 10,264 16,033 16,033 13,228 14,979 13,303 14,636 14,776 13,412 10,848 10,802 16,033
36.73 46.75 65.68 28.55 30.70 16.24 96.75 24.19 113.17 126.19 79.16 206.27 57.26 127.95 6.72
SD 18.98
25.18 3.95 58.69 18.86 9.69 39.10 14.58 34.46
Patients without cardiovascular event (n = 3870)
Patients with cardiovascular event (n = 191)
Obs.
Mean
Obs.
Mean
14,473 14,473 9146 9146 14,473 14,473 11,919 13,482 11,947 13,193 13,310 12,078 9578 9571
34.64 44.38 67.05 29.72 28.09 17.00 94.75 23.97 109.59 124.50 78.69 205.18 57.60 127.33
1560 1560 1118 1118 1560 1560 1309 1497 1356 1443 1466 1334 1270 1231 1560 834 726
56.15 68.75 54.47 18.96 54.87 9.17 114.97 26.14 144.68 141.65 83.40 216.21 54.72 132.78 69.10 62.59 76.58
SD 18.13
23.29 3.93 56.10 18.05 9.59 38.38 14.53 33.67
SD 10.81
33.13 3.56 70.45 19.09 9.61 43.88 14.72 39.76
SD: standard deviation.
Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006
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EURGER-641; No. of Pages 5 A. Dzien et al. / European Geriatric Medicine xxx (2015) xxx–xxx Table 2 Cardiovascular risk factors before/after a cardiovascular event.
Fasting blood glucose (mg/dL) Body Mass Index (mass/(height squared)) Triglycerides (mg/dL) Systolic blood pressure (mm/Hg) Diastolic blood pressure (mm/Hg) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL)
3.2. Body mass index
Difference to control group
Difference a/b event
Before event
After event
3.980 (1007)
6.653 (531)
10.291 (462)
0.028 0.171 (1149)
0.000 0.284 (631)
0.000 0.771 (515)
0.215 –3.694 (1,039) 0.200 –5.078 (1,104)
0.035 19.528 (557) 0.000 4.181 (598)
0.000 19.067 (466) 0.003 –1.156 (499)
0.000 –3.332 (1,127)
0.000 1.282 (608)
0.115 –1.568 (513)
0.000 –22.713 (1,021)
0.002 7.911 (545)
0.000 –13.712 (468)
0.000 –0.742 (976)
0.000 –0.389 (502)
0.000 –0.977 (461)
0.218 –22.781 (949)
0.295 7.717 (483)
0.089 –14.996 (452)
0.000
0.000
0.000
BMI values of patients without a CVE revealed a continuous slight decrease paralleling ageing of the study population. BMI values in patients with a CVE were constantly higher, but this difference was only significant after the CVE (Table 2; Fig. 2). 3.3. Blood pressure and lipid values During the whole observation period systolic blood pressure increased slightly in people without a CVE, while diastolic blood pressure remained almost stable. Patients with a CVE revealed significantly higher entries for systolic and diastolic blood pressure values than the reference group. A drop of systolic and diastolic blood pressure was found after the CVE (Table 2). Total cholesterol and LDL-cholesterol were higher in patients with a CVE compared to those without a CVE in the period before the cardiovascular complication. After the event both values were significantly lower and decreased slightly over time. In patients without a CVE, total cholesterol and LDL-cholesterol levels remained almost stable during the observation period. HDL cholesterol values were widely distributed in both study groups.
4. Discussion
P-values (in italics) correspond to one sided t-tests. Significant entries at least at the 1%-level in bold. Number of observations in parentheses.
(Fig. 1). In patients with a CVE, fasting glucose values revealed a continuous increase during 7 years before the CVE and an even steeper increase after the CVE. Both of the corresponding slope parameters are significant at least at the 2%-level (Fig. 1). Fasting glucose values were constantly higher in patients with a cardiovascular complication compared to patients without CVE. This difference was even more pronounced in the period after the CVE (Table 2). The CVE occurred at an age of 66.0 11.0 years (Table 1).
130
3
Our study results show that fasting glucose levels in a large cohort of middle-aged and elderly patients without a CVE remain almost stable during an observation period of 15 years and thus during ageing of the population. This finding was in contrast to the results obtained in patients with a CVE with higher fasting glucose values at entry and a continuous increase throughout the observation period. It should be noticed that we used various individual background variables to perform an exact matching procedure, which in turn allows to implicitly control for individual-specific influences when analyzing the relationship between fasting glucose and CVE.
Slope b/a event (p-value): 0.99 (0.019); 1.76 (0.000)
27.5
Slope b/a event (p-value): -0.03 (0.113); -0.01 (0.651)
125 27
mass/(height squared)
mg/dL
120
115
110
26.5
26
105 25.5
100 -7
-5
-3
-1
1
3
5
7
Year b/a event Fig. 1. Fasting glucose. Dark/grey entries display mean values of cardiovascular risk factors for patients with (without) cardiovascular events. The reported slopes and Pvalues belong to the group of patients with a cardiovascular event only and are obtained from a panel regression of the cardiovascular risk factors on the time index (t = –7. . ., 7) and individual specific effects. The corresponding control functions are plotted by the dark shaded lines; grey shaded lines are obtained analogously, but slopes and P-values are suppressed. For each risk factor, we fit linear control functions on the left and the right of the vertical line (indicating the cardiovascular event) weighted by the number of observations in each time period.
-7
-5
-3
-1
1
3
5
7
Year b/a event Fig. 2. Body mass index. Dark/grey entries display mean values of cardiovascular risk factors for patients with (without) cardiovascular events. The reported slopes and P-values belong to the group of patients with a cardiovascular event only and are obtained from a panel regression of the cardiovascular risk factors on the time index (t = –7. . ., 7) and individual specific effects. The corresponding control functions are plotted by the dark shaded lines; grey shaded lines are obtained analogously, but slopes and P-values are suppressed. For each risk factor, we fit linear control functions on the left and the right of the vertical line (indicating the cardiovascular event) weighted by the number of observations in each time period.
Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006
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A slight increase of fasting glucose levels with increasing age was described in previously published studies [13,14], but these finding did not support a strong correlation. The Baltimore Longitudinal Study of Aging could demonstrate a progressive decline in glucose tolerance in women from early to late adulthood [25]. In the longitudinal Medical Research Council Cognitive Function and Ageing Study, which included over 18,000 individuals aged 65 years and older, mortality from all causes, cardiovascular and ischemic heart disease increased with increasing glycated hemoglobin (HbA1c) values [26]. Especially in patients with diabetes, postprandial glucose values are strongly related to the cardiovascular risk [27]. With respect to the large number of participants, we have focused our evaluation on the glucose levels after an overnight fast. According to published data, high normal fasting glucose values in younger obese individuals correlate with insulin resistance and beta cell dysregulation [28]. In men without diabetes insulin resistance was of predictive value for early cardiovascular morbidity [29]. The BMI values of patients without a CVE revealed a tendency to decrease with increasing age. This is in accordance to published data about a continuous increase of BMI during adulthood [30] and a decrease at an advanced age [31]. Overweight and obesity correlate with insulin resistance [3] and an increased cardiovascular morbidity [32,33]. BMI of our patients in the CVE group were higher than in those without a cardiovascular complication. The aging associated decrease in muscle mass, increase in fat mass and subclinical inflammation are known as factors enhancing the risk for insulin resistance [34]. Waist circumference was not determined in our population because there is, until now, no consensus on the cutoffs for the elderly [35]. Lipid and blood pressure values of our patients with a CVE were on entry significantly higher than in patients without a CVE. The lower levels after the CVE might be the result of an intensified medical risk factor intervention [36,37] (Table 1). Our evaluation reveals some limitations, because the study participants were patients attending a medical outdoor center. A further critical aspect is the influence of cardiovascular medication with an influence on the risk of new-onset diabetes [38], especially regarding the effects of statin therapy with a possible association between statin use and incident diabetes in patients with underlying risk factors [39]. However, fasting glucose levels were already higher at entry to the evaluation – and thus years before the cardiovascular complication – in patients with a future CVE. Our definition of an event comprised cardiovascular events and to a small percentage cerebral ischemic complications. In literature, a worsening of insulin resistance and glucose metabolism is described in the postmyocardial state [18,19]. In ischemic stroke patients a high prevalence of abnormal glucose metabolism was found also in patients without a history of diabetes [40]. Thus both subtypes of events are of unfavourable influence on glucose metabolism. The stable results of fasting blood glucose in patients without a CVE over 15 years remain remarkable, especially in comparison to the values obtained in a strictly matched group with a CVE and a continuous increase in fasting glucose. For patients with an ageing related increase in fasting glucose values, consequent primary and secondary risk factor intervention is recommended. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Authors’ contributions: All authors were involved in the concept of the study and writing of the manuscript, Dzien and DzienBischinger recruited the patients, Winner and Theurl did the
statistical analysis, Lechleitner: data analysis and manuscript editing.
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Please cite this article in press as: Dzien A, et al. Ageing and fasting glucose values – the role of cardiovascular events. Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2015.05.006