Atherosclerosis 237 (2014) 140e145
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia John Skoumas, Catherine Liontou*, Christina Chrysohoou, Constantina Masoura, Konstantinos Aznaouridis, Christos Pitsavos, Christodoulos Stefanadis First Department of Cardiology, Athens Medical School, Hippokration Hospital, 114 Vasilissis Sofias str., 115 27, Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 April 2014 Received in revised form 15 August 2014 Accepted 21 August 2014 Available online 6 September 2014
Objective: Controversial findings exist regarding potential influence of statin therapy on diabetic incidence. Aim of this study was to investigate the role of long duration statin treatment on diabetes mellitus (DM) incidence of Heterozygous Familial Hypercholesterolemia (hFH) and Familial Combined Hyperlipidemia (FCH) patients. Methods: Study population consisted of 212 hFH and 147 FCH patients that visited Lipid Outpatient Department (mean follow up of 11 and 10 years respectively). Several clinical data such as history of DM, cardiovascular disease, thyroid function, metabolic syndrome, glucose levels, lipid profile and lifestyle data were obtained. In order to compare the effects of different doses of different types of statins, a “statin treatment intensity product” was used. Results: 14% of FCH and only 1% of hFH patients developed DM during follow up. Although univariate analysis showed a statistical trend (p ¼ 0.06) in the association between new onset DM and statin treatment intensity (STI) in the FCH subgroup of patients with normal baseline glucose levels, this was no longer significant after adjusting for several confounders. Furthermore, the type of statins used did not seem to play a role in the development of DM either in hFH or FCH patients. Conclusion: Long duration of high STI does not seem to be associated with diabetic risk in hFH patients. High STI used in the FCH population is not associated with increased risk of new onset DM compared to low STI. Further studies are required in order to clarify the potential diabetogenic effects of statins in these high risk populations. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Diabetes mellitus Statins Heterozygous familial hypercholesterolemia Familial combined hyperlipidemia
1. Introduction Diabetes mellitus (DM) is a well-established independent risk factor for coronary artery disease (CAD), stroke and other vascular diseases and a strong predictor of their outcomes [1]. Specifically, the risk for cardiovascular events is two to four times higher in diabetic populations compared to those without DM [2,3]. In addition, high fasting plasma glucose (FPG) levels (100e125 mg/dl) have also been associated with risk of cardiovascular death [4] and according to American Diabetes Association [5] the risk is continuous extending below the lower limit of the range and becoming disproportionally greater at higher ends of the range.
* Corresponding author. Tel.: þ30 2132089521, þ30 6973605121. E-mail addresses: [email protected] (J. Skoumas), [email protected] (C. Liontou), [email protected] (C. Chrysohoou), [email protected] (C. Masoura), [email protected] (K. Aznaouridis), [email protected] (C. Pitsavos). http://dx.doi.org/10.1016/j.atherosclerosis.2014.08.047 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
Although the role of statin treatment in preventing cardiovascular events is well known both in non-diabetic and diabetic populations, recently many concerns have arisen regarding their potential effect on diabetes incidence. Several trials have shown that statin treatment increases the risk of diabetes [6,7] most probably in a dose-dependent fashion [8] but not all types of statins have been accused for this effect [9]. It should be noted though, that none of the trials revealing the possible link between statins and DM has been designed to look for incidence of DM. Familial Combined Hyperlipidemia (FCH) is the most common genetic dyslipidemia with estimated prevalence approximately 1% in the general population [10]. It is associated with a number of metabolic disorders such as hypertension, obesity, insulin resistance, diabetes and metabolic syndrome and it is an important cause of premature CAD [11,12]. Heterozygous familial hypercholesterolemia (hFH), another common genetic disorder that leads to premature CAD, affects approximately 1 in 500 people in Europe [13]. If left untreated, the majority of patients with hFH will develop CAD before the age of 60 years, whereas if they receive appropriate
J. Skoumas et al. / Atherosclerosis 237 (2014) 140e145
treatment before the development of clinical CAD they can have a normal life expectancy [13]. No trials regarding the possible diabetogenic effects of statins have been conducted for these patients whilst the data for FCH patients are inadequate. Aim of this study was to investigate the effect of long duration of intense statin therapy in the incidence of diabetes in patients with hFH and FCH. 2. Methods
141
2.4. Anthropometric and lifestyle characteristics Weight and height were measured using standard procedures in all subjects. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2). Waist circumference was measured at the superior border of the iliac crest and values >102 cm for men and >88 cm for women were considered central obesity. Other data reported were age, gender and lifestyle characteristics such as smoking habits, alcohol consumption and physical activity.
2.1. Study population 2.5. Statin treatment intensity product This is a single-center historical prospective study. A total of 523 adult patients (314 hFH and 209 FCH patients) that visited our Lipid Outpatient Clinic from 1990 until 2013, were initially enrolled in the study. For the purposes of the current study, patients that received statin therapy of very low intensity had to be excluded. Therefore 359 patients (212 hFH and 147 FCH patients) were included in the study population (Table 1). Only patients who were not under lipid lower medications before their first visit were included. All participants were habitants of the province of Attica region. 2.2. Diagnosis of FH and FCH Diagnostic criteria for hFH were established according to the US MEDPED program [14] and included presence of documented LDLreceptor mutation, or plasma levels of LDL cholesterol above the 95th percentile for sex and age, no secondary cause of dyslipidemia and at least one of the following: presence of typical tendon xanthomas in the patient or in a first-degree relative, or meeting LDL cholesterol criteria among first- or second-degree relatives, or proven CAD in the patient or in a firstedegree relative under the age of 60 years [14e16]. Molecular diagnosis of hFH was performed in 36 patients. FCH was diagnosed according to the following criteria [17e20]: 1. total cholesterol and/or triglyceride >90th percentile according to gender and age in more than 2 measurements, according to the upper levels used in the Prospective Cardiovascular Munster (PROCAM) study [21]; and 2. presence of type IIa, IIb, or IV hyperlipidemia in at least 1 first-degree relative; and/or 3. familial history of early atherosclerotic disease before the age of 60 years. 2.3. Clinical characteristics The diagnosis of hypertension (HTN) and DM was retrospectively based on current guidelines [22,23]. Systolic and diastolic blood pressures (SBP and DBP) were measured with a mercury sphygmomanometer in the sitting position after a 10-min rest and the mean of 3 consecutive measurements 1 min apart was calculated. Patients who had arterial blood pressure >140/90 mmHg on >2 consecutive consultations or abnormal 24-h ambulatory measurements and those who were on anti-hypertensive medication were considered hypertensive. Patients with FPG 126 mg/dl (7.0 mmol/L) on >2 consecutive visits or 2-h plasma glucose >200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test, or who were on anti-diabetic medication were considered diabetic. Data on CAD history, cerebral and peripheral vascular disease, thyroid disease, family history of CAD and drug history were also collected. CAD was defined as (1) documented history of coronary revascularization; or (2) history of previous MI plus q waves at electrocardiogram or hypokinesia/akinesia in cardiac ultrasound; or (3) abnormal coronary angiogram (stenosis of >50% in an epicardial coronary artery); or (4) symptoms suggestive of angina plus positive imaging stress test [24].
In order to compare the different types and doses of statin that patients received we used the “statin treatment intensity product” according to findings of statins equivalency from the STELAR study and 2 meta-analyses [25e28], based on the ability of different statins to lower low-density lipoprotein (LDL) cholesterol levels. These studies suggest that: (1) 80 mg of simvastatin is equivalent to 20e40 mg of atorvastatin, (2) 20 mg of simvastatin is equivalent to approximately 80 mg of pravastatin, (3) 40 mg of pravastatin is equivalent to approximately 40 mg of fluvastatin, (4) 40/80 mg of lovastatin is equivalent approximately to 20 mg of simvastatin and (5) 5 mg of rosuvastatin is equivalent approximately to 20 mg of atorvastatin. Accordingly, for the purpose of the current analysis, the intensity of treatment with statins was defined as follows: 40 mg of simvastatin ¼ 15 mg of atorvastatin ¼ 5 mg of rosuvastatin ¼ 1 arbitrary unit of treatment intensity, and 80 mg of pravastatin ¼ 80 mg of fluvastatin ¼ 40/80 mg of lovastatin ¼ 0.5 arbitrary unit of treatment intensity. Subsequently the statin intensity units were multiplied by the duration of continuous statin therapy (in months), providing this way the statin treatment intensity product for each patient. We intentionally excluded from the present study the patients who received a statin treatment intensity product 110 units). 2.6. Biochemical characteristics Blood samples were collected during each visit from the antecubital vein between 8 a.m. and 10 a.m. in a sitting position after 12 h of fasting and abstinence from alcohol. Total cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides (TGL) and blood glucose were measured in all participants using colorimetric enzymic method in a Technicon automatic analyzer RA-1000 (Dade-Behring Marburg GmbH, Marburg, Germany). LDL cholesterol was calculated using the Friedewald formula: total cholesteroldHDL cholesterold1/ 5 (triglycerides), (valid when triglycerides 400 mg/dl, no LDL cholesterol value was introduced in analysis. All biochemical measurements were carried out in the same laboratory that followed the criteria of the World Health Organization Lipid Reference Laboratories.
142
J. Skoumas et al. / Atherosclerosis 237 (2014) 140e145
Table 1 Patients’ enrollment after excluding diabetics and patients on low statin treatment intensity.
2.7. Statistical analysis All continuous variables were tested for normality of distribution using the Kolmogorov-Smirnov criterion. Normally distributed variables are presented as mean ± standard deviation whereas skewed variables are presented as median (25th e 75th percentile). The categorical variables are presented as relative (%) frequencies. Associations between normally distributed continuous variables and group of patients were evaluated through the Student's t-test. Mann e Whitney U test was performed to assess the associations between skewed variables and group of patients and chi-square test was used to evaluate dependency between categorical variables. Associations between continuous variables and categorical variables with more than one group of patients were evaluated
Table 2 Enrollment characteristics of patients according to familial hypercholesterolemia category (FH/FCH). Baseline variables
FH (N ¼ 212)
FCH (N ¼ 147)
p-value
Gender (male) (%) Age (mean) Coronary Heart Disease (%) Diabetes Mellitus (%) Impaired FPGa (%) Hypertension (%) Smoking (%) BMI (kg/m2) Waist circumference (cm) SBP (mmHg) DBP (mmHg) Total cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) TGL (mg/dl) Follow up duration (yrs) STI product
38.7 44 ± 12 23.1 3.3 5.9 15.6 24.6 26.6 ± 22 81 ± 12 122 ± 16 78 ± 10 354 ± 69 277 ± 69 49 ± 12 107 (86e156) 11 ± 5 104 (51e235)
70.1 50 ± 9 27.2 4.1 24.8 27.2 32.7 27.3 ± 3 93 ± 9 126 ± 17 82 ± 10 293 ± 49 209 ± 18 45 ± 27 210 (158e271) 10 ± 5 80 (45e140)
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia John Skoumas, Catherine Liontou*, Christina Chrysohoou, Constantina Masoura, Konstantinos Aznaouridis, Christos Pitsavos, Christodoulos Stefanadis First Department of Cardiology, Athens Medical School, Hippokration Hospital, 114 Vasilissis Sofias str., 115 27, Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 April 2014 Received in revised form 15 August 2014 Accepted 21 August 2014 Available online 6 September 2014
Objective: Controversial findings exist regarding potential influence of statin therapy on diabetic incidence. Aim of this study was to investigate the role of long duration statin treatment on diabetes mellitus (DM) incidence of Heterozygous Familial Hypercholesterolemia (hFH) and Familial Combined Hyperlipidemia (FCH) patients. Methods: Study population consisted of 212 hFH and 147 FCH patients that visited Lipid Outpatient Department (mean follow up of 11 and 10 years respectively). Several clinical data such as history of DM, cardiovascular disease, thyroid function, metabolic syndrome, glucose levels, lipid profile and lifestyle data were obtained. In order to compare the effects of different doses of different types of statins, a “statin treatment intensity product” was used. Results: 14% of FCH and only 1% of hFH patients developed DM during follow up. Although univariate analysis showed a statistical trend (p ¼ 0.06) in the association between new onset DM and statin treatment intensity (STI) in the FCH subgroup of patients with normal baseline glucose levels, this was no longer significant after adjusting for several confounders. Furthermore, the type of statins used did not seem to play a role in the development of DM either in hFH or FCH patients. Conclusion: Long duration of high STI does not seem to be associated with diabetic risk in hFH patients. High STI used in the FCH population is not associated with increased risk of new onset DM compared to low STI. Further studies are required in order to clarify the potential diabetogenic effects of statins in these high risk populations. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Diabetes mellitus Statins Heterozygous familial hypercholesterolemia Familial combined hyperlipidemia
1. Introduction Diabetes mellitus (DM) is a well-established independent risk factor for coronary artery disease (CAD), stroke and other vascular diseases and a strong predictor of their outcomes [1]. Specifically, the risk for cardiovascular events is two to four times higher in diabetic populations compared to those without DM [2,3]. In addition, high fasting plasma glucose (FPG) levels (100e125 mg/dl) have also been associated with risk of cardiovascular death [4] and according to American Diabetes Association [5] the risk is continuous extending below the lower limit of the range and becoming disproportionally greater at higher ends of the range.
* Corresponding author. Tel.: þ30 2132089521, þ30 6973605121. E-mail addresses: [email protected] (J. Skoumas), [email protected] (C. Liontou), [email protected] (C. Chrysohoou), [email protected] (C. Masoura), [email protected] (K. Aznaouridis), [email protected] (C. Pitsavos). http://dx.doi.org/10.1016/j.atherosclerosis.2014.08.047 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
Although the role of statin treatment in preventing cardiovascular events is well known both in non-diabetic and diabetic populations, recently many concerns have arisen regarding their potential effect on diabetes incidence. Several trials have shown that statin treatment increases the risk of diabetes [6,7] most probably in a dose-dependent fashion [8] but not all types of statins have been accused for this effect [9]. It should be noted though, that none of the trials revealing the possible link between statins and DM has been designed to look for incidence of DM. Familial Combined Hyperlipidemia (FCH) is the most common genetic dyslipidemia with estimated prevalence approximately 1% in the general population [10]. It is associated with a number of metabolic disorders such as hypertension, obesity, insulin resistance, diabetes and metabolic syndrome and it is an important cause of premature CAD [11,12]. Heterozygous familial hypercholesterolemia (hFH), another common genetic disorder that leads to premature CAD, affects approximately 1 in 500 people in Europe [13]. If left untreated, the majority of patients with hFH will develop CAD before the age of 60 years, whereas if they receive appropriate
J. Skoumas et al. / Atherosclerosis 237 (2014) 140e145
treatment before the development of clinical CAD they can have a normal life expectancy [13]. No trials regarding the possible diabetogenic effects of statins have been conducted for these patients whilst the data for FCH patients are inadequate. Aim of this study was to investigate the effect of long duration of intense statin therapy in the incidence of diabetes in patients with hFH and FCH. 2. Methods
141
2.4. Anthropometric and lifestyle characteristics Weight and height were measured using standard procedures in all subjects. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2). Waist circumference was measured at the superior border of the iliac crest and values >102 cm for men and >88 cm for women were considered central obesity. Other data reported were age, gender and lifestyle characteristics such as smoking habits, alcohol consumption and physical activity.
2.1. Study population 2.5. Statin treatment intensity product This is a single-center historical prospective study. A total of 523 adult patients (314 hFH and 209 FCH patients) that visited our Lipid Outpatient Clinic from 1990 until 2013, were initially enrolled in the study. For the purposes of the current study, patients that received statin therapy of very low intensity had to be excluded. Therefore 359 patients (212 hFH and 147 FCH patients) were included in the study population (Table 1). Only patients who were not under lipid lower medications before their first visit were included. All participants were habitants of the province of Attica region. 2.2. Diagnosis of FH and FCH Diagnostic criteria for hFH were established according to the US MEDPED program [14] and included presence of documented LDLreceptor mutation, or plasma levels of LDL cholesterol above the 95th percentile for sex and age, no secondary cause of dyslipidemia and at least one of the following: presence of typical tendon xanthomas in the patient or in a first-degree relative, or meeting LDL cholesterol criteria among first- or second-degree relatives, or proven CAD in the patient or in a firstedegree relative under the age of 60 years [14e16]. Molecular diagnosis of hFH was performed in 36 patients. FCH was diagnosed according to the following criteria [17e20]: 1. total cholesterol and/or triglyceride >90th percentile according to gender and age in more than 2 measurements, according to the upper levels used in the Prospective Cardiovascular Munster (PROCAM) study [21]; and 2. presence of type IIa, IIb, or IV hyperlipidemia in at least 1 first-degree relative; and/or 3. familial history of early atherosclerotic disease before the age of 60 years. 2.3. Clinical characteristics The diagnosis of hypertension (HTN) and DM was retrospectively based on current guidelines [22,23]. Systolic and diastolic blood pressures (SBP and DBP) were measured with a mercury sphygmomanometer in the sitting position after a 10-min rest and the mean of 3 consecutive measurements 1 min apart was calculated. Patients who had arterial blood pressure >140/90 mmHg on >2 consecutive consultations or abnormal 24-h ambulatory measurements and those who were on anti-hypertensive medication were considered hypertensive. Patients with FPG 126 mg/dl (7.0 mmol/L) on >2 consecutive visits or 2-h plasma glucose >200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test, or who were on anti-diabetic medication were considered diabetic. Data on CAD history, cerebral and peripheral vascular disease, thyroid disease, family history of CAD and drug history were also collected. CAD was defined as (1) documented history of coronary revascularization; or (2) history of previous MI plus q waves at electrocardiogram or hypokinesia/akinesia in cardiac ultrasound; or (3) abnormal coronary angiogram (stenosis of >50% in an epicardial coronary artery); or (4) symptoms suggestive of angina plus positive imaging stress test [24].
In order to compare the different types and doses of statin that patients received we used the “statin treatment intensity product” according to findings of statins equivalency from the STELAR study and 2 meta-analyses [25e28], based on the ability of different statins to lower low-density lipoprotein (LDL) cholesterol levels. These studies suggest that: (1) 80 mg of simvastatin is equivalent to 20e40 mg of atorvastatin, (2) 20 mg of simvastatin is equivalent to approximately 80 mg of pravastatin, (3) 40 mg of pravastatin is equivalent to approximately 40 mg of fluvastatin, (4) 40/80 mg of lovastatin is equivalent approximately to 20 mg of simvastatin and (5) 5 mg of rosuvastatin is equivalent approximately to 20 mg of atorvastatin. Accordingly, for the purpose of the current analysis, the intensity of treatment with statins was defined as follows: 40 mg of simvastatin ¼ 15 mg of atorvastatin ¼ 5 mg of rosuvastatin ¼ 1 arbitrary unit of treatment intensity, and 80 mg of pravastatin ¼ 80 mg of fluvastatin ¼ 40/80 mg of lovastatin ¼ 0.5 arbitrary unit of treatment intensity. Subsequently the statin intensity units were multiplied by the duration of continuous statin therapy (in months), providing this way the statin treatment intensity product for each patient. We intentionally excluded from the present study the patients who received a statin treatment intensity product 110 units). 2.6. Biochemical characteristics Blood samples were collected during each visit from the antecubital vein between 8 a.m. and 10 a.m. in a sitting position after 12 h of fasting and abstinence from alcohol. Total cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides (TGL) and blood glucose were measured in all participants using colorimetric enzymic method in a Technicon automatic analyzer RA-1000 (Dade-Behring Marburg GmbH, Marburg, Germany). LDL cholesterol was calculated using the Friedewald formula: total cholesteroldHDL cholesterold1/ 5 (triglycerides), (valid when triglycerides 400 mg/dl, no LDL cholesterol value was introduced in analysis. All biochemical measurements were carried out in the same laboratory that followed the criteria of the World Health Organization Lipid Reference Laboratories.
142
J. Skoumas et al. / Atherosclerosis 237 (2014) 140e145
Table 1 Patients’ enrollment after excluding diabetics and patients on low statin treatment intensity.
2.7. Statistical analysis All continuous variables were tested for normality of distribution using the Kolmogorov-Smirnov criterion. Normally distributed variables are presented as mean ± standard deviation whereas skewed variables are presented as median (25th e 75th percentile). The categorical variables are presented as relative (%) frequencies. Associations between normally distributed continuous variables and group of patients were evaluated through the Student's t-test. Mann e Whitney U test was performed to assess the associations between skewed variables and group of patients and chi-square test was used to evaluate dependency between categorical variables. Associations between continuous variables and categorical variables with more than one group of patients were evaluated
Table 2 Enrollment characteristics of patients according to familial hypercholesterolemia category (FH/FCH). Baseline variables
FH (N ¼ 212)
FCH (N ¼ 147)
p-value
Gender (male) (%) Age (mean) Coronary Heart Disease (%) Diabetes Mellitus (%) Impaired FPGa (%) Hypertension (%) Smoking (%) BMI (kg/m2) Waist circumference (cm) SBP (mmHg) DBP (mmHg) Total cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) TGL (mg/dl) Follow up duration (yrs) STI product
38.7 44 ± 12 23.1 3.3 5.9 15.6 24.6 26.6 ± 22 81 ± 12 122 ± 16 78 ± 10 354 ± 69 277 ± 69 49 ± 12 107 (86e156) 11 ± 5 104 (51e235)
70.1 50 ± 9 27.2 4.1 24.8 27.2 32.7 27.3 ± 3 93 ± 9 126 ± 17 82 ± 10 293 ± 49 209 ± 18 45 ± 27 210 (158e271) 10 ± 5 80 (45e140)
