Comparison of health-related quality of Life (HRQOL) among patients with pre-diabetes, diabetes and normal glucose tolerance, using the 15D-HRQOL questionnaire in Greece: the DEPLAN study

Comparison of health-related quality of Life (HRQOL) among patients with pre-diabetes, diabetes... Background: Diabetes mellitus is usually preceded by a pre-diabetic stage before the clinical presentation of the disease, the influence of which on persons’ quality of life is not adequately elucidated. The purpose of this study was to compare the Health-Related Quality of Life (HRQOL) of persons with pre-diabetes with that of diabetes or normal glucose tolerance (NGT), using the validated HRQOL-15D questionnaire. Methods: The HRQOL-15D scores of 172 people with pre-diabetes (108 with Impaired Fasting Glucose [IFG], 64 with Impaired Glucose Tolerance [IGT], aged 58.3 ± 10.3 years) and 198 with NGT (aged 54.4 ± 10.1 years) from the Greek part of the DEPLAN study (Diabetes in Europe - Prevention using Lifestyle, Physical Activity and Nutritional Intervention), were compared to 100 diabetes patients’ scores (aged 60.9 ± 12.5 years, diabetes duration 17.0 ± 10.0 years, HbA1c 7.2 ± 1.2%), derived from the outpatient Diabetes Clinic of a University Hospital. Results: The diabetes patients’ HRQOL-15D score (0.8605) was significantly lower than the pre-diabetes’ (0.9008) and the controls’ (0.9092) (p < 0.001). There were no differences in the total score between the controls and the group with pre-diabetes. However, examination of individual parameters of the score showed that people with IGT had lower scores compared to the control group, as related to the parameters of “mobility” and “psychological distress”. No differences were found in any component of the HRQOL-15D score between the control group and the IFG group, nor between the two groups with pre-diabetes (IFG vs. IGT). Conclusions: Persons with pre-diabetes had a similar HRQOL score with healthy individuals, and a higher score than persons with diabetes. Specific components of the score, however, were lower in the IGT group compared to the controls. These findings help clarify the issue of HRQOL of persons with pre-diabetes and its possible impact on prevention. Keywords: Diabetes mellitus, Pre-diabetes, Quality of life, HRQOL-15D questionnaire * Correspondence: kmakrila@med.uoa.gr First Department of Propaedeutic Medicine, National and Kapodistrian University of Athens Medical School, Laiko General Hospital, 17 Ag. Thoma St, 11527 Athens, Greece Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 2 of 10 Background Fasting Glucose [IFG], Impaired Glucose Tolerance Diabetes mellitus (DM) is a chronic disease with serious [IGT] or both) and people with NGT (that had provided complications, imposing a significant burden on the health data on their HRQOL in the Greek part of the DEPLAN status of affected individuals, both on physical and mental study), as well as persons with known DM from the out- aspects [1, 2]. Its commonest form, Type 2 DM (T2D), usu- patient Diabetes Center of “Laiko” University hospital, in ally follows distinct stages in its development: from normal Athens, Greece. This study has been previously glucose tolerance (NGT), to impaired glucose metabolism described in detail [14, 17]. In brief, the FINDRISC ques- (pre-diabetes), and overt onset of the disease [3]. It is well tionnaire [19] was distributed to around 7900 persons established that the quality of life (QOL) of people with dia- without known diabetes, aged 35–75 years, residing in betes (total physical, mental, and social well-being) is the metropolitan area around Athens, in order to find adversely affected by the disease and its complications [4]. people at high risk for developing T2D (a score ≥ 15 Concerning the QOL of persons with pre-diabetes, signifying high probability). Out of the 3240 completed however, there is sparse and controversial data in the litera- questionnaires, 869 persons accepted to undergo an oral ture [5–8], possibly related to different methods of glucose tolerance test (OGTT), so as to identify people health-related QOL (HRQOL) measurement, small sample with unknown (screen-detected) diabetes and exclude sizes or focus on selected populations (for example, elderly, them from further intervention. On the day of the instead of the general population) [9]. Especially in the OGTT, weight, height, waist circumference and blood Greek population, to our knowledge, no data exist at all on pressure of the participants were measured and their this matter. medical histories recorded. Presence of co-morbidities Although people with pre-diabetes experience no symp- (defined as hypertension and/or dyslipidemia) and vas- toms and usually have no knowledge of their condition cular complications (any combination of coronary heart [10], thereisevidencethataround10–20% of them already disease, stroke, peripheral arterial disease, nephropathy, have some mild micro- or macro- vascular complications retinopathy or neuropathy) were also recorded. Plasma [11], which might confer some adverse impact on their glucose, total- and high density lipoprotein (HDL)-cho- HRQOL, or at least in some aspects of it [12]. The preva- lesterol and triglyceride levels were measured from fast- lence of DM in Greece remains high, and according to ing blood samples at a central accredited university recent data [13] it accounts for 7.0% of the population research laboratory, using enzymatic assays. Low density (with 8.2% prevalence of T2D for people ≥15 years of age). lipoprotein (LDL)-cholesterol was calculated using the On the other hand, pre-diabetes prevalence is not well Friedewald formula [20]. studied, with some estimates from regional studies raising According to the OGTT results, subjects were catego- it to around 22% of the adult population [14]. rized as having normal glucose tolerance (NGT), The DEPLAN study (Diabetes in Europe - Prevention impaired fasting glucose (IFG), impaired glucose toler- using Lifestyle, Physical Activity and Nutritional ance (IGT) or diabetes. IFG was defined based on a fast- Intervention) [15] is a European Commission-funded ing plasma glucose of 100–125 mg/dl, IGT as a 2-h multinational project, aiming to establish a model for plasma glucose between 140 and 199 mg/dl and the efficient identification of individuals at high risk for (screen-detected) DM as a fasting plasma glucose T2D in the community, in the primary care structure, in ≥126 mg/dl and/or 2-h plasma glucose ≥200 mg/dl [3]. the EU member countries and to test the feasibility and People with both IFG and IGT were considered as IGT. cost-effectiveness of the translation of the intervention Persons with screen-detected DM from the DEPLAN concepts learned from the prevention trials into existing cohort were not included in the present analysis. These health-care systems [16]. Data on the quality of life of people did not know they had DM before performing subjects with pre-diabetes and NGT from the Greek part the OGTT and were thus thought they represented a of this study [14, 17], based on the validated special category of patients with diabetes (newly diag- health-related quality of life [HRQOL]-15D question- nosed), resembling more to the pre-diabetes group as naire [18], were compared to respective data of patients regards to complications and QOL issues. The HRQOL with diabetes, derived from the outpatient Diabetes data of the persons with pre-diabetes and the controls Clinic of the “Laiko” University Hospital, in Athens, from the DEPLAN cohort were compared to respective Greece, in an effort to elucidate if any differences exist data of people with known diabetes, derived from the in the HRQOL among these groups. outpatient Diabetes Center of “Laiko” University hospital. Methods The participants’ HRQOL was recorded using the 15D Participants questionnaire [18], a preference-based HRQOL instru- The sample population of the present cross-sectional ment that has also been validated in the Greek popula- study consisted of persons with pre-diabetes (Impaired tion [21]. The reason that this measure was used in the Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 3 of 10 present study is that this is the HRQOL instrument that Results had already been used in the DEPLAN study where the Out of the total 869 persons screened with an OGTT in participants with pre-diabetes and NGT were derived the DEPLAN cohort, 383 (44.1%) had complete HRQOL from. License to use this HRQOL questionnaire had data. The present analysis included 370 participants been centrally obtained from the Steering Committee of (mean age [±SD] 57.2 ± 11.0 years, 46% males), out of the original European DE-PLAN study and was used by whom 172 had pre-diabetes (108 with IFG, 64 with IGT, all participating centers [15]. No other QOL measure- aged 58.3 ± 10.3 years) and 198 had NGT (aged 54.4 ± ments were available for the DEPLAN participants. The 10.1 years). Thirteen individuals (age 64.2 ± 4.1 years, 15D-questionnaire contains 15 dimensions (questions): BMI 30.4 ± 6.4 kg/m ) had screen-detected diabetes and, mobility, vision, hearing, breathing, sleeping, eating, as explained above, due to their recent diagnosis and speech, excretion, usual activities, mental function, small number, precluding any meaningful statistical ana- discomfort and symptoms, depression, distress, vitality lysis as a separate group, were excluded from further and sexual activity, each having five different levels of analysis. The diabetes group in the present analysis was functional status. These dimensions can be presented as comprised of 100 persons (mean age 60.9 ± 12.5 years, a 15-dimensional profile or as a one-index score. The DM duration 17.0 ± 10.0 years, HbA1c: 7.2 ± 1.2%) from 15D index score is obtained by weighing the dimensions the outpatient Diabetes Center of “Laiko” University with population-based preference weights based on an hospital. application of the multi-attribute utility theory. Obtained The demographic, clinical and laboratory characteris- index scores vary between 0 and 1, where 0 represents a tics of the study participants are presented in Table 1. state of being dead and 1 represents perfect HRQOL As shown, people with diabetes were older, mostly males [22]. Questionnaires were distributed to the participants (59%), smoked less and had more frequently and were self-filled, blindly to the investigators. co-morbidities and vascular complications than the The study was approved by the cooperating hospital’s other two groups. Of note, individuals with pre-diabetes ethics committee (Laiko General Hospital Ethics Review were more obese than the other two groups and had Board), and the Hellenic National Drug Organization. more co-morbidities than the NGT group (48.8% vs. All participants signed an informed consent according 35.2%, respectively, p = 0.008), but the frequency of to the general recommendations of the Declaration of vascular complications did not differ between them Helsinki [23]. (11.9% vs. 8.2%, respectively, p > 0.05). Simple correlation analyses showed that the Statistical analysis HRQOL-15D score was negatively correlated with age Continuous variables are presented as mean ± one-stan- (Spearman’s rho = − 0.13, p = 0.010), HDL-cholesterol (rho dard deviation, while qualitative variables as absolute = − 0.11, p = 0.030), and BMI (rho = − 0.14, p = 0.004), and and relative frequencies (%). Normal distribution of vari- positively with LDL-cholesterol (rho = 0.10, p = 0.050). Spe- ables was tested with the Shapiro-Wilk test. Compari- cifically, within the group of patients with diabetes, there sons between 2 normally distributed continuous was a negative correlation of the HRQOL-15D score with variables were performed with the calculation of the DM duration (rho = − 0.34, p = 0.001) and a trend for a Student’s t-test, whereas the Wilcoxon Mann-Whitney negative correlation with glycemic control (as measured by U-test was used for non-parametric variables. Associa- HbA1c) (rho = − 0.20, p = 0.058). tions between categorical variables were tested with the Table 2 shows the results of the comparison of the use of contingency tables and the calculation of the HRQOL-15D score (and its components) among the Chi-squared test. Pearson’s correlation coefficient (r) or groups of NGT, pre-diabetes (IFG – IGT) and DM par- Spearman’s rho (for non-normal distributions) were used ticipants. Patients with diabetes had a lower total for the evaluation of statistical correlations between vari- HRQOL-15D sore (0.8605) compared to the other two ables. For comparisons of ≥3 variables, one-way analysis groups (0.9092 and 0.9008, for the NGT and pre-DM of variance (ANOVA) (for normally distributed vari- group, respectively, p < 0.001 by Kruskal-Wallis analysis), ables), or the Kruskal-Wallis test (for non-normally while IFG and IGT participants had similar scores distributed variables) was used. For controlling of con- (0.9043 and 0.8946, respectively). In post-hoc analyses, it founding variables (such as age, gender, smoking, body was shown that there was a significant difference be- mass index [BMI], hypertension, complications, tween the group of patients with diabetes and the NGT co-morbidities) analysis of covariance (ANCOVA) was group (p < 0.001) as well as between the diabetes and the used. All reported p-values are derived from two-sided IFG group (p = 0.007). On the contrary, there were no tests and compared to a significance level of 5%. Data statistically significant differences in the HRQOL score were analyzed using the Statistical Package SPSS, version between any two of these three groups (NGT, IFG and 23.0 (SPSS Inc., Chicago, IL). IGT) (Fig. 1). Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 4 of 10 Table 1 Demographic, clinical and laboratory characteristics of participants (mean ± SD) Variable NGT Pre-Diabetes DM P* IFG IGT All Pre-DM Number 198 108 64 172 100 – Gender (male) [n (%)] 74 (37.4) 59 (54.6) 25 (39.1) 84 (48.8) 59 (59.0) 0.001 Age (years) 54.4 (10.1) 57.2 (10.1) 60.3 (10.5) 58.3 (10.3) 60.9 (12.5) < 0.001 Weight (kg) 81.1 (15.6) 88.6 (13.6) 87.2 (14.7) 88.1 (14.0) 85.2 (20.4) 0.001 BMI (kg/m ) 29.4 (5.3) 31.5 (4.3) 32.2 (5.4) 31.7 (4.8) 29.6 (6.5) < 0.001 Smoking (%) 56.6 58.3 53.1 56.4 37.1 0.007 Co-morbidities [n (%)] 69 (35.2) 48 (44.4) 36 (56.3) 84 (48.8) 74 (87.1) < 0.001 Complications [n (%)] 5 (8.2) 7 (9.1) 8 (16.3) 15 (11.9) 26 (30.6) < 0.001 SBP (mmHg) 119.3 (18.5) 129.5 (16.2) 128.0 (16.1) 128.9 (16.1) 134.9 (18.9) < 0.001 DBP (mmHg) 75.9 (12.0) 78.9 (11.5) 77.4 (11.5) 78.3 (11.5) 74.9 (10.4) NS Cholesterol (mmol/L) 5.47 (0.97) 5.70 (0.97) 5.82 (1.01) 5.75 (0.99) 4.24 (1.08) < 0.001 Triglycerides (mmol/L) 1.18 (0.57) 1.49 (0.88) 1.57 (0.71) 1.52 (0.36) 1.43 (0.74) < 0.001 HDL-C (mmol/L) 1.20 (0.21) 1.22 (0.23) 1.25 (0.19) 1.23 (0.22) 1.22 (0.28) NS LDL-C (mmol/L) 3.72 (0.88) 3.82 (0.84) 3.86 (0.94) 3.84 (0.88) 2.35 (0.91) < 0.001 DM duration (years) –– –– 17.0 (10.0) – HbA1c (%) –– –– 7.2 (1.2) – NGT Normal Glucose Tolerance, DM Diabetes mellitus, SBP Systolic blood pressure, DBP Diastolic blood pressure, BMI Body mass index, NS Non- significant, Co-morbidities Hypertension and/or dyslipidemia, Complications Any combination of coronary heart disease, stroke, peripheral arterial disease, nephropathy, retinopathy, neuropathy *P = Comparison among the 4 groups (NGT, IFG, IGT, DM) by Chi-squared or Kruskal-Wallis analysis Table 2 Comparison of the HRQOL-15D score and its components among the DM patients, people with pre-DM (IFG – IGT) and NGT NGT Pre-diabetes DM P* IFG IGT All pre-DM Mobility 0.9179 0.9122 0.8711 0.8969 0.8264 < 0.001 Vision 0.8688 0.8963 0.8938 0.8954 0.8333 NS Hearing 0.9487 0.9562 0.9455 0.9522 0.9152 NS Breathing 0.9150 0.8849 0.8862 0.8854 0.8473 0.044 Sleeping 0.8335 0.8385 0.8256 0.8338 0.8172 NS Eating 0.9983 1.0000 0.9945 0.9980 0.9901 NS Speech 0.9887 0.9880 0.9844 0.9867 0.9676 NS Excretion 0.9433 0.9511 0.9234 0.9410 0.9048 NS Usual activities 0.9214 0.9329 0.8956 0.9191 0.8226 < 0.001 Mental function 0.9153 0.9095 0.9068 0.9085 0.9007 NS Discomfort and symptoms 0.8841 0.8779 0.8683 0.8743 0.8694 NS Depression 0.8601 0.8627 0.8472 0.8569 0.8574 NS Distress 0.7561 0.7333 0.6971 0.7205 0.7657 0.019 Vitality 0.8474 0.8150 0.8424 0.8246 0.8112 NS Sexual activity 0.9000 0.8838 0.8895 0.8858 0.6642 < 0.001 Total score 0.9092 0.9043 0.8946 0.9008 0.8605 < 0.001 NGT Normal Glucose Tolerance, IFG Impaired Fasting Glucose, IGT Impaired Glucose Tolerance, DM Diabetes mellitus, NS Non-significant *P = Comparison among the 4 groups (NGT, IFG, IGT, DM) by Kruskal-Wallis analysis Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 5 of 10 Fig. 1 HRQOL-15D scores in NGT, pre-diabetes (IFG-IGT) and diabetes persons In a multifactorial analysis of covariance (ANCOVA), shown in Table 2, there were statistically significant after controlling for age, gender, BMI and smoking differences for the components of “mobility”, “breath- (model 1, Table 3), the HRQOL-15D score was signifi- ing”, “usual activities”, “distress” and “sexual activity” cantly associated with the glycemic status (NGT, among the groups as a whole. In post-hoc analyses, a pre-diabetes [IFG/IGT] or diabetes) (p < 0.001). Male statistically significant difference was found between gender (p < 0.001) and higher BMI (p = 0.003) were also the NGT and IGT groups as regarded to the compo- significantly associated with a lower HRQOL score, and nents of “mobility” (p = 0.042) and “distress” (p = 0.01) this model explained the variance of HRQOL score by (lower values for the IGT group), as well as between 14% (R = 0.14). When the presence, however, of the IGT and DM groups as regarded to the compo- co-morbidities and vascular complications were added nents of “distress” (p = 0.029) (lower for the IGT to the model (model 2, Table 4), the relationship of the group) and “sexual activity” (p < 0.001) (lower for the glycemic status with the HRQOL-15D score was attenu- DM group). These associations were attenuated but ated and lost significance. Male gender still had a signifi- persisted after adjustment for age, gender, BMI, pres- cant contribution to the model (p < 0.001), whereas the ence of co-morbidities and complications. There were independent effect of vascular complications (p = 0.004) no differences in any component of the HRQOL-15D negated the effects of the glycemic status and of BMI score between the two groups of the pre-diabetes par- (the model now explained the overall variance of the ticipants (IFG and IGT), or the NGT vs. the IFG HRQOL score by 21.8% [R = 0.218]). group (Fig. 2). The different components of the HRQOL-15D score were evaluated separately among the groups. As Discussion There is a lot of interest in the past few decades in stud- Table 3 Analysis of covariance (ANCOVA) for the relationship ies of health-related quality of life (HRQOL) and the im- between the HRQOL-15D score with glycemic status, controlling pact of various diseases and disease-states upon it, for age, gender, BMI and smoking (persons with pre-diabetes which has led to the development and refinement of a were considererd separately as IFG - IGT) (Model 1) number of generic and disease-specific HRQOL mea- Variable F P sures [24, 25]. It should be emphasized also that clinical Age 0.72 NS variables alone do not comprehensively capture patients’ Gender (male) 20.05 < 0.001 perceptions of their health, which is in part due to the BMI 8.53 0.003 fact that HRQOL is influenced by many other factors, Smoking (yes) 0.26 NS such as the existence of other health problems, social relationships, marital status, patient knowledge, treat- Glycemic status 3.62 < 0.001 2 ment satisfaction and perceived ability to control R 0.14, BMI Body mass index Glycemic status: 1 = NGT, 2 = IFG, 3 = IGT, 4 = Diabetes one’sdisease [26]. Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 6 of 10 Table 4 Analysis of covariance (ANCOVA) for the relationship (owing mainly to the presence of vascular complica- between the HRQOL-15D score with glycemic status, controlling tions), while there were no significant differences in the for age, gender, BMI, smoking, presence of co-morbidities and overall HRQOL score between the NGT and the vascular complications (persons with pre-diabetes were considererd pre-diabetes groups. Examination, however, of the indi- separately as IFG - IGT) (Model 2) vidual components of the HRQOL score showed signifi- Variable F P cant differences between the NGT and the pre-diabetes Age 2.08 NS group in certain aspects. In particular, the IGT group Gender (male) 19.07 < 0,001 had lower scores compared to the NGT, as regarded to the components of “mobility” and “distress”. No differ- BMI 3.48 NS ence was noted in any of the 15 dimensions of the score Smoking (yes) 1.28 NS between the NGT and IFG group, nor between the two Co-morbidities 0.37 NS groups of the pre-diabetes subjects (IFG vs. IGT). Complications 6.39 0.004 The deterioration of the HRQOL in people with DM Glycemic status 0.53 NS [4] and the contribution of vascular complications to R 0.218, Co-morbidities arterial hypertension and/or dyslipidemia, that effect found in the present study is in line with pre- Complications any combination of coronary heart disease, stroke, peripheral vious reports in the literature [27, 28]. For people with arterial disease, nephropathy, retinopathy or neuropathy pre-diabetes, however, there are only few published stud- Glycemic status: 1 = NGT, 2 = IFG, 3 = IGT, 4 = Diabetes ies examining the relationship of their quality of life as In the present study, the HRQOL of patients with dia- regards to physical [5, 12] or psychological/mental betes was compared with that of pre-diabetes (IFG/IGT) parameters [7, 8, 10], sometimes with conflicting results, and persons with normal glucose tolerance (NGT), using either because of the use of different HRQOL measure- the HRQOL-15D questionnaire. It was found, that, in ment methods (e.g. by recording only the physical health general, the HRQOL of patients with diabetes was sig- condition and not the psychological-mental), or because nificantly worse than that of the other two groups of the use of small sample sizes or because of focusing Fig. 2 Profiles of the HRQOL-15D components among the NGT, Pre-DM (IFG – IGT) and DM participants Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 7 of 10 on specific population groups (e.g. the elderly) [6, 9, 29]. physical dimensions of quality of life, especially bodily Specifically using the HRQOL-15D questionnaire, stud- pain and physical functioning, and in general health sta- ies in people with pre-diabetes are extremely sparse [22]. tus [32]. On the contrary, in a population study in Since these people (with pre-diabetes) usually have Western Finland (the Harmonica Project) in 1383 sub- no symptoms and no major complications and very jects, aged 45–70 years, no differences in HRQOL were often no knowledge of their condition [10], their detected (with the same questionnaire SF-36) in partici- HRQOL should not be expected to be affected. The pants with pre-diabetes compared with non-diabetes fact, however, that around 10–20% of them may subjects [6]. In this study, people with known cardiovas- already have some mild micro- or macro- vascular cular disease were excluded in advance, which limits the complications [11], could explain the findings of their generalization and validity of the results. In the largest affected HRQOL in some aspects of it. For example, population study to date [8], that included 55,882 people limited joint action, prayer’ssign and Dupuytren’s of the general population in Sweden (Västerbotten contracture were more common in elderly IGT per- Intervention Program), using the Health Utility Weight sons compared to controls [12]. [HUW] SF-6D questionnaire (that included the dimen- In the present study, ‘mobility’ was found to be im- sions of physical functioning, role limitations, social paired in the group of pre-diabetes subjects with IGT function, bodily pain, mental health, and vitality), there (compared to those of the control group), which is was also a gradual decrease in HUWs with a progressive broadly in line with findings in the literature [22, 30]. It deterioration of the glycemic status from normal glucose is possible that mild, even subconscious abnormalities in tolerance to pre-diabetes and overt diabetes. physical functioning could explain this finding. In a re- Another significant finding in the present study was cently published prospective study [22] using 3 different that the “psychological distress” appeared to be highly assessment tools of HRQOL (SF-36, SF-6D and 15D), affected in the group of pre-diabetes individuals with and dividing the subjects into 5 groups (normal glucose IGT (relative to normal, and surprisingly even to people tolerance, IFG, IGT, newly diagnosed diabetes and with diabetes). Of note, the recording of this fact in the known diabetes), it was found that the deterioration of HRQOL-15D questionnaires was done before the partic- the glycemic status from the stage of normal glucose ipants were informed about the results of the OGTT tolerance to the pre-diabetes and overt diabetes was as- tests that they belonged to the pre-diabetes group. Sev- sociated with a worsening of HRQOL scores, as mea- eral studies in the literature have reported worsening of sured with all three questionnaires. Specifically for the the psychological state in people with diabetes [2, 33], 15D questionnaire, decreases in the components of “mo- which may be caused by the impact of the diagnosis of bility” (similar to the present study), “breathing”, “usual diabetes itself, the psychological stress associated with activities”, “discomfort and symptoms”, “vitality” and the management of diabetes or the burden of diabetic “sexual activity” were found, but not for the psycho- complications [34], or even through physiological path- logical dimensions of the questionnaire. These reduc- ways, including inflammatory processes and reductions tions - similar to the present study – did not occur in in neurotrophic function [35], which in turn may lead to subjects with IFG but only in those with IGT or diabetes reduced plasticity of neuronal networks and subse- who exceeded the limits of minimal clinical significance quently depression [36]. For pre-diabetes, however, the [minimal (clinically) important differences (MIDs)] the correlations that have been found are less robust. In ini- study had set (i.e. the smallest change a patient or health tial studies, it was observed that depressive symptoms professional can notice - for the 15D questionnaire MID were more frequent in women with pre-diabetes [37], was proposed at ≥0.02–0.03 units of the total score). A but a recent meta-analysis concluded that the risk for similar population study from Spain (Di@bet.es Study) depression was not increased in impaired glucose me- [30], in 5047 individuals of the general population, using tabolism compared to normal glucose metabolism or the SF-12 questionnaire, showed that women had wors- even undiagnosed diabetes subjects [38]. In the present ening quality of life scores (relating both to physical and study, “depression” did not differ between the groups of psychological parameters) with the deterioration of the NGT, pre-diabetes or diabetes subjects. glycemic status towards the pre-diabetes and diabetes The relationship between mental disorder and the states, while in men only physical parameters were affected glucose metabolism is likely to be bidirectional, affected (similarly in the present study male gender was as depressive symptoms or psychological distress may independently associated with worsening HRQOL). also lead to a higher risk of developing pre-diabetes Other population studies from Australia (AusDiab (especially in men) [39] or diabetes [40]. Higher work study), using the quality of life short form-36 (SF-36) distress has also been associated with prevalent diabetes questionnaire, showed that people with IFG (especially and especially pre-diabetes in a German cohort, espe- women) [5] or IGT [31], had reduced values in mainly cially in men [41], which could also explain the findings Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 8 of 10 of increased “distress” of participants with pre-diabetes the states of pre-diabetes and diabetes strengthens the in the present study, although no etiology of distress findings of the study. (e.g. work-related, social, family, etc) was elucidated. There are several limitations of the present study. Conclusions They include the relatively small sample size examined In conclusion, the quality of life of individuals with and the fact that it is a cross-sectional study, and thus pre-diabetes was overall not significantly different from cannot demonstrate cause and effect or the time frame that of normal glucose tolerance subjects, whereas for par- in which indices of the HRQOL deteriorate. For this ticipants with diabetes it was lower (mainly due to the purpose, prospective studies are required, with a signifi- presence of vascular complications). However, certain cant population sample and sufficient monitoring time. components of the quality of life were already affected in In such a relatively small study from Germany [7], there the pre-diabetic state of IGT (compared to the control was a trend for a decline in the quality of life (only for group), specifically “mobility” and “psychological distress”. physical parameters, as measured by the SF-12 question- Providing an understanding of the stages of diabetes naire) within 7 years from the transition of NGT to where health status is diminished will allow prioritization pre-diabetes, but the association was statistically signifi- of intervention efforts, and enable more effective targeting cant only for the subjects converting from NGT to of policy and strategic interventions to improve health diabetes. outcomes. Thus, quality of life issues (in particular phys- Another limitation of this study is that the population ical and psychological-emotional issues) should be investi- examined is not necessarily representative of the general gated when people with pre-diabetes are diagnosed in population, since the participants without diabetes every-day routine clinical practice, since their identifica- selected themselves to participate in the study, while tion could potentially lead to more effective overall man- people with diabetes were derived from a large Diabetes agement of their condition. University Center (Laiko Hospital), and thus the findings are not necessarily applicable to the general population. Abbreviations DM: Diabetes mellitus; HRQOL: Health related quality of life; IFG: Impaired Also, the fact that the HRQOL-15D questionnaire is not fasting glucose; IGT: Impaired glucose tolerance specific for diabetes [25], may probably have as a result that the responses to it reflect problems associated with Acknowledgements other conditions. The fact that it was applied only once We would like to thank the following Health Centers/individuals for helping may additionally preclude its ability to find fluctuations implement the present study: the medical staff of the Health Center of Alimos (especially Dr. Ourania Zacharopoulou), the staff of the Center for the of HRQOL over time. Elderly Agioi Anargyroi, the medical and nursing staff of the Health Center of It has to be emphasized also, that there were many miss- Markopoulo (especially Mrs. R. Salonikioti), the medical and nursing staff of ing data regarding presence of vascular complications in the Hellenic Telecommunications Company (especially Drs C. Pietris and C. Alexopoulos), the medical and nursing staff of the Hellenic Radiotelevision the group of individuals with pre-diabetes (46 persons) (especially Dr. M. Katsorida), the medical and nursing staff of the Bank of and NGT (137 persons), which may have influenced the Greece (especially Drs V. Spandagos and P. Konstantopoulou), the medical aforementioned comparisons. staff of the Olympic Village complex (especially Dr. S. Tigas), the staff of the electrical equipment manufacturer “Pitsos-Bosch”, the medical and nursing On the other hand, strengths of the present study staff of the Health Center of Vari (especially Dr. M. Dandoulakis) and the include the fact that the determination of the glycemic medical and nursing staff of the Health Center of Vyronas (especially Dr. K. status was performed with a glucose tolerance test Kyriakopoulos). (OGTT) and was not self-reported, which enhances the Funding reliability of the reported correlations. Also the This project was partly funded by the Commission of the European HRQOL-15D questionnaire was completed by the par- Communities, Directorate C – Public Health, grant agreement No. 2004310. ticipants of the DEPLAN cohort before they had learned Under the rules of the agreement, it was also partly co-funded by the private sector and in this case it was supported by an unrestricted educational grant the results of the OGTT, and thus their answers were from Bristol-Myers-Squibb, Greece. not affected by the knowledge of their glycemic status. In addition, in a comparative evaluation of the Availability of data and materials HRQOL-15D questionnaire with other HRQOL assess- The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. ment questionnaires in the Greek population [42], the 15D was found to be superior as regards to the assess- Authors’ contributions ment of vascular complications in diabetes (particularly KM designed the study, obtained the data, analyzed and interpreted the for coronary heart disease and diabetic retinopathy). Fur- patient data and wrote the manuscript; SL designed the study, obtained the thermore, the exclusion of the few newly diagnosed data and reviewed the first draft of the manuscript; AT, CS, EP obtained the data; DP analyzed the data; NK, NK and DN designed the study and provided (screen-detected) people with diabetes from the analysis, critical revisions of important intellectual content to the manuscript. All whose participation could cause distortion of the associ- authors revised the manuscript and approved the final version prior to the ations found, because of their actual position in-between submission. Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 9 of 10 Ethics approval and consent to participate 16. Cos FX, Barengo NC, Costa B, Mundet-Tudurí X, Lindström J, Tuomilehto JO. The study was approved by the cooperating hospital’s ethics committee DEPLAN study group. Screening for people with abnormal glucose (Laiko General Hospital Ethics Review Board), and the Hellenic National Drug metabolism in the European DE-PLAN project. Diabetes Res Clin Pract. 2015; Organization. All participants signed an informed consent according to the 109(1):149–56. general recommendations of the Declaration of Helsinki. 17. Makrilakis K, Liatis S, Grammatikou S, Perrea D, Katsilambros N. 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Comparison of health-related quality of Life (HRQOL) among patients with pre-diabetes, diabetes and normal glucose tolerance, using the 15D-HRQOL questionnaire in Greece: the DEPLAN study

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Medicine & Public Health; Endocrinology; Metabolic Diseases; Diabetes; Andrology
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Abstract

Background: Diabetes mellitus is usually preceded by a pre-diabetic stage before the clinical presentation of the disease, the influence of which on persons’ quality of life is not adequately elucidated. The purpose of this study was to compare the Health-Related Quality of Life (HRQOL) of persons with pre-diabetes with that of diabetes or normal glucose tolerance (NGT), using the validated HRQOL-15D questionnaire. Methods: The HRQOL-15D scores of 172 people with pre-diabetes (108 with Impaired Fasting Glucose [IFG], 64 with Impaired Glucose Tolerance [IGT], aged 58.3 ± 10.3 years) and 198 with NGT (aged 54.4 ± 10.1 years) from the Greek part of the DEPLAN study (Diabetes in Europe - Prevention using Lifestyle, Physical Activity and Nutritional Intervention), were compared to 100 diabetes patients’ scores (aged 60.9 ± 12.5 years, diabetes duration 17.0 ± 10.0 years, HbA1c 7.2 ± 1.2%), derived from the outpatient Diabetes Clinic of a University Hospital. Results: The diabetes patients’ HRQOL-15D score (0.8605) was significantly lower than the pre-diabetes’ (0.9008) and the controls’ (0.9092) (p < 0.001). There were no differences in the total score between the controls and the group with pre-diabetes. However, examination of individual parameters of the score showed that people with IGT had lower scores compared to the control group, as related to the parameters of “mobility” and “psychological distress”. No differences were found in any component of the HRQOL-15D score between the control group and the IFG group, nor between the two groups with pre-diabetes (IFG vs. IGT). Conclusions: Persons with pre-diabetes had a similar HRQOL score with healthy individuals, and a higher score than persons with diabetes. Specific components of the score, however, were lower in the IGT group compared to the controls. These findings help clarify the issue of HRQOL of persons with pre-diabetes and its possible impact on prevention. Keywords: Diabetes mellitus, Pre-diabetes, Quality of life, HRQOL-15D questionnaire * Correspondence: kmakrila@med.uoa.gr First Department of Propaedeutic Medicine, National and Kapodistrian University of Athens Medical School, Laiko General Hospital, 17 Ag. Thoma St, 11527 Athens, Greece Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 2 of 10 Background Fasting Glucose [IFG], Impaired Glucose Tolerance Diabetes mellitus (DM) is a chronic disease with serious [IGT] or both) and people with NGT (that had provided complications, imposing a significant burden on the health data on their HRQOL in the Greek part of the DEPLAN status of affected individuals, both on physical and mental study), as well as persons with known DM from the out- aspects [1, 2]. Its commonest form, Type 2 DM (T2D), usu- patient Diabetes Center of “Laiko” University hospital, in ally follows distinct stages in its development: from normal Athens, Greece. This study has been previously glucose tolerance (NGT), to impaired glucose metabolism described in detail [14, 17]. In brief, the FINDRISC ques- (pre-diabetes), and overt onset of the disease [3]. It is well tionnaire [19] was distributed to around 7900 persons established that the quality of life (QOL) of people with dia- without known diabetes, aged 35–75 years, residing in betes (total physical, mental, and social well-being) is the metropolitan area around Athens, in order to find adversely affected by the disease and its complications [4]. people at high risk for developing T2D (a score ≥ 15 Concerning the QOL of persons with pre-diabetes, signifying high probability). Out of the 3240 completed however, there is sparse and controversial data in the litera- questionnaires, 869 persons accepted to undergo an oral ture [5–8], possibly related to different methods of glucose tolerance test (OGTT), so as to identify people health-related QOL (HRQOL) measurement, small sample with unknown (screen-detected) diabetes and exclude sizes or focus on selected populations (for example, elderly, them from further intervention. On the day of the instead of the general population) [9]. Especially in the OGTT, weight, height, waist circumference and blood Greek population, to our knowledge, no data exist at all on pressure of the participants were measured and their this matter. medical histories recorded. Presence of co-morbidities Although people with pre-diabetes experience no symp- (defined as hypertension and/or dyslipidemia) and vas- toms and usually have no knowledge of their condition cular complications (any combination of coronary heart [10], thereisevidencethataround10–20% of them already disease, stroke, peripheral arterial disease, nephropathy, have some mild micro- or macro- vascular complications retinopathy or neuropathy) were also recorded. Plasma [11], which might confer some adverse impact on their glucose, total- and high density lipoprotein (HDL)-cho- HRQOL, or at least in some aspects of it [12]. The preva- lesterol and triglyceride levels were measured from fast- lence of DM in Greece remains high, and according to ing blood samples at a central accredited university recent data [13] it accounts for 7.0% of the population research laboratory, using enzymatic assays. Low density (with 8.2% prevalence of T2D for people ≥15 years of age). lipoprotein (LDL)-cholesterol was calculated using the On the other hand, pre-diabetes prevalence is not well Friedewald formula [20]. studied, with some estimates from regional studies raising According to the OGTT results, subjects were catego- it to around 22% of the adult population [14]. rized as having normal glucose tolerance (NGT), The DEPLAN study (Diabetes in Europe - Prevention impaired fasting glucose (IFG), impaired glucose toler- using Lifestyle, Physical Activity and Nutritional ance (IGT) or diabetes. IFG was defined based on a fast- Intervention) [15] is a European Commission-funded ing plasma glucose of 100–125 mg/dl, IGT as a 2-h multinational project, aiming to establish a model for plasma glucose between 140 and 199 mg/dl and the efficient identification of individuals at high risk for (screen-detected) DM as a fasting plasma glucose T2D in the community, in the primary care structure, in ≥126 mg/dl and/or 2-h plasma glucose ≥200 mg/dl [3]. the EU member countries and to test the feasibility and People with both IFG and IGT were considered as IGT. cost-effectiveness of the translation of the intervention Persons with screen-detected DM from the DEPLAN concepts learned from the prevention trials into existing cohort were not included in the present analysis. These health-care systems [16]. Data on the quality of life of people did not know they had DM before performing subjects with pre-diabetes and NGT from the Greek part the OGTT and were thus thought they represented a of this study [14, 17], based on the validated special category of patients with diabetes (newly diag- health-related quality of life [HRQOL]-15D question- nosed), resembling more to the pre-diabetes group as naire [18], were compared to respective data of patients regards to complications and QOL issues. The HRQOL with diabetes, derived from the outpatient Diabetes data of the persons with pre-diabetes and the controls Clinic of the “Laiko” University Hospital, in Athens, from the DEPLAN cohort were compared to respective Greece, in an effort to elucidate if any differences exist data of people with known diabetes, derived from the in the HRQOL among these groups. outpatient Diabetes Center of “Laiko” University hospital. Methods The participants’ HRQOL was recorded using the 15D Participants questionnaire [18], a preference-based HRQOL instru- The sample population of the present cross-sectional ment that has also been validated in the Greek popula- study consisted of persons with pre-diabetes (Impaired tion [21]. The reason that this measure was used in the Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 3 of 10 present study is that this is the HRQOL instrument that Results had already been used in the DEPLAN study where the Out of the total 869 persons screened with an OGTT in participants with pre-diabetes and NGT were derived the DEPLAN cohort, 383 (44.1%) had complete HRQOL from. License to use this HRQOL questionnaire had data. The present analysis included 370 participants been centrally obtained from the Steering Committee of (mean age [±SD] 57.2 ± 11.0 years, 46% males), out of the original European DE-PLAN study and was used by whom 172 had pre-diabetes (108 with IFG, 64 with IGT, all participating centers [15]. No other QOL measure- aged 58.3 ± 10.3 years) and 198 had NGT (aged 54.4 ± ments were available for the DEPLAN participants. The 10.1 years). Thirteen individuals (age 64.2 ± 4.1 years, 15D-questionnaire contains 15 dimensions (questions): BMI 30.4 ± 6.4 kg/m ) had screen-detected diabetes and, mobility, vision, hearing, breathing, sleeping, eating, as explained above, due to their recent diagnosis and speech, excretion, usual activities, mental function, small number, precluding any meaningful statistical ana- discomfort and symptoms, depression, distress, vitality lysis as a separate group, were excluded from further and sexual activity, each having five different levels of analysis. The diabetes group in the present analysis was functional status. These dimensions can be presented as comprised of 100 persons (mean age 60.9 ± 12.5 years, a 15-dimensional profile or as a one-index score. The DM duration 17.0 ± 10.0 years, HbA1c: 7.2 ± 1.2%) from 15D index score is obtained by weighing the dimensions the outpatient Diabetes Center of “Laiko” University with population-based preference weights based on an hospital. application of the multi-attribute utility theory. Obtained The demographic, clinical and laboratory characteris- index scores vary between 0 and 1, where 0 represents a tics of the study participants are presented in Table 1. state of being dead and 1 represents perfect HRQOL As shown, people with diabetes were older, mostly males [22]. Questionnaires were distributed to the participants (59%), smoked less and had more frequently and were self-filled, blindly to the investigators. co-morbidities and vascular complications than the The study was approved by the cooperating hospital’s other two groups. Of note, individuals with pre-diabetes ethics committee (Laiko General Hospital Ethics Review were more obese than the other two groups and had Board), and the Hellenic National Drug Organization. more co-morbidities than the NGT group (48.8% vs. All participants signed an informed consent according 35.2%, respectively, p = 0.008), but the frequency of to the general recommendations of the Declaration of vascular complications did not differ between them Helsinki [23]. (11.9% vs. 8.2%, respectively, p > 0.05). Simple correlation analyses showed that the Statistical analysis HRQOL-15D score was negatively correlated with age Continuous variables are presented as mean ± one-stan- (Spearman’s rho = − 0.13, p = 0.010), HDL-cholesterol (rho dard deviation, while qualitative variables as absolute = − 0.11, p = 0.030), and BMI (rho = − 0.14, p = 0.004), and and relative frequencies (%). Normal distribution of vari- positively with LDL-cholesterol (rho = 0.10, p = 0.050). Spe- ables was tested with the Shapiro-Wilk test. Compari- cifically, within the group of patients with diabetes, there sons between 2 normally distributed continuous was a negative correlation of the HRQOL-15D score with variables were performed with the calculation of the DM duration (rho = − 0.34, p = 0.001) and a trend for a Student’s t-test, whereas the Wilcoxon Mann-Whitney negative correlation with glycemic control (as measured by U-test was used for non-parametric variables. Associa- HbA1c) (rho = − 0.20, p = 0.058). tions between categorical variables were tested with the Table 2 shows the results of the comparison of the use of contingency tables and the calculation of the HRQOL-15D score (and its components) among the Chi-squared test. Pearson’s correlation coefficient (r) or groups of NGT, pre-diabetes (IFG – IGT) and DM par- Spearman’s rho (for non-normal distributions) were used ticipants. Patients with diabetes had a lower total for the evaluation of statistical correlations between vari- HRQOL-15D sore (0.8605) compared to the other two ables. For comparisons of ≥3 variables, one-way analysis groups (0.9092 and 0.9008, for the NGT and pre-DM of variance (ANOVA) (for normally distributed vari- group, respectively, p < 0.001 by Kruskal-Wallis analysis), ables), or the Kruskal-Wallis test (for non-normally while IFG and IGT participants had similar scores distributed variables) was used. For controlling of con- (0.9043 and 0.8946, respectively). In post-hoc analyses, it founding variables (such as age, gender, smoking, body was shown that there was a significant difference be- mass index [BMI], hypertension, complications, tween the group of patients with diabetes and the NGT co-morbidities) analysis of covariance (ANCOVA) was group (p < 0.001) as well as between the diabetes and the used. All reported p-values are derived from two-sided IFG group (p = 0.007). On the contrary, there were no tests and compared to a significance level of 5%. Data statistically significant differences in the HRQOL score were analyzed using the Statistical Package SPSS, version between any two of these three groups (NGT, IFG and 23.0 (SPSS Inc., Chicago, IL). IGT) (Fig. 1). Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 4 of 10 Table 1 Demographic, clinical and laboratory characteristics of participants (mean ± SD) Variable NGT Pre-Diabetes DM P* IFG IGT All Pre-DM Number 198 108 64 172 100 – Gender (male) [n (%)] 74 (37.4) 59 (54.6) 25 (39.1) 84 (48.8) 59 (59.0) 0.001 Age (years) 54.4 (10.1) 57.2 (10.1) 60.3 (10.5) 58.3 (10.3) 60.9 (12.5) < 0.001 Weight (kg) 81.1 (15.6) 88.6 (13.6) 87.2 (14.7) 88.1 (14.0) 85.2 (20.4) 0.001 BMI (kg/m ) 29.4 (5.3) 31.5 (4.3) 32.2 (5.4) 31.7 (4.8) 29.6 (6.5) < 0.001 Smoking (%) 56.6 58.3 53.1 56.4 37.1 0.007 Co-morbidities [n (%)] 69 (35.2) 48 (44.4) 36 (56.3) 84 (48.8) 74 (87.1) < 0.001 Complications [n (%)] 5 (8.2) 7 (9.1) 8 (16.3) 15 (11.9) 26 (30.6) < 0.001 SBP (mmHg) 119.3 (18.5) 129.5 (16.2) 128.0 (16.1) 128.9 (16.1) 134.9 (18.9) < 0.001 DBP (mmHg) 75.9 (12.0) 78.9 (11.5) 77.4 (11.5) 78.3 (11.5) 74.9 (10.4) NS Cholesterol (mmol/L) 5.47 (0.97) 5.70 (0.97) 5.82 (1.01) 5.75 (0.99) 4.24 (1.08) < 0.001 Triglycerides (mmol/L) 1.18 (0.57) 1.49 (0.88) 1.57 (0.71) 1.52 (0.36) 1.43 (0.74) < 0.001 HDL-C (mmol/L) 1.20 (0.21) 1.22 (0.23) 1.25 (0.19) 1.23 (0.22) 1.22 (0.28) NS LDL-C (mmol/L) 3.72 (0.88) 3.82 (0.84) 3.86 (0.94) 3.84 (0.88) 2.35 (0.91) < 0.001 DM duration (years) –– –– 17.0 (10.0) – HbA1c (%) –– –– 7.2 (1.2) – NGT Normal Glucose Tolerance, DM Diabetes mellitus, SBP Systolic blood pressure, DBP Diastolic blood pressure, BMI Body mass index, NS Non- significant, Co-morbidities Hypertension and/or dyslipidemia, Complications Any combination of coronary heart disease, stroke, peripheral arterial disease, nephropathy, retinopathy, neuropathy *P = Comparison among the 4 groups (NGT, IFG, IGT, DM) by Chi-squared or Kruskal-Wallis analysis Table 2 Comparison of the HRQOL-15D score and its components among the DM patients, people with pre-DM (IFG – IGT) and NGT NGT Pre-diabetes DM P* IFG IGT All pre-DM Mobility 0.9179 0.9122 0.8711 0.8969 0.8264 < 0.001 Vision 0.8688 0.8963 0.8938 0.8954 0.8333 NS Hearing 0.9487 0.9562 0.9455 0.9522 0.9152 NS Breathing 0.9150 0.8849 0.8862 0.8854 0.8473 0.044 Sleeping 0.8335 0.8385 0.8256 0.8338 0.8172 NS Eating 0.9983 1.0000 0.9945 0.9980 0.9901 NS Speech 0.9887 0.9880 0.9844 0.9867 0.9676 NS Excretion 0.9433 0.9511 0.9234 0.9410 0.9048 NS Usual activities 0.9214 0.9329 0.8956 0.9191 0.8226 < 0.001 Mental function 0.9153 0.9095 0.9068 0.9085 0.9007 NS Discomfort and symptoms 0.8841 0.8779 0.8683 0.8743 0.8694 NS Depression 0.8601 0.8627 0.8472 0.8569 0.8574 NS Distress 0.7561 0.7333 0.6971 0.7205 0.7657 0.019 Vitality 0.8474 0.8150 0.8424 0.8246 0.8112 NS Sexual activity 0.9000 0.8838 0.8895 0.8858 0.6642 < 0.001 Total score 0.9092 0.9043 0.8946 0.9008 0.8605 < 0.001 NGT Normal Glucose Tolerance, IFG Impaired Fasting Glucose, IGT Impaired Glucose Tolerance, DM Diabetes mellitus, NS Non-significant *P = Comparison among the 4 groups (NGT, IFG, IGT, DM) by Kruskal-Wallis analysis Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 5 of 10 Fig. 1 HRQOL-15D scores in NGT, pre-diabetes (IFG-IGT) and diabetes persons In a multifactorial analysis of covariance (ANCOVA), shown in Table 2, there were statistically significant after controlling for age, gender, BMI and smoking differences for the components of “mobility”, “breath- (model 1, Table 3), the HRQOL-15D score was signifi- ing”, “usual activities”, “distress” and “sexual activity” cantly associated with the glycemic status (NGT, among the groups as a whole. In post-hoc analyses, a pre-diabetes [IFG/IGT] or diabetes) (p < 0.001). Male statistically significant difference was found between gender (p < 0.001) and higher BMI (p = 0.003) were also the NGT and IGT groups as regarded to the compo- significantly associated with a lower HRQOL score, and nents of “mobility” (p = 0.042) and “distress” (p = 0.01) this model explained the variance of HRQOL score by (lower values for the IGT group), as well as between 14% (R = 0.14). When the presence, however, of the IGT and DM groups as regarded to the compo- co-morbidities and vascular complications were added nents of “distress” (p = 0.029) (lower for the IGT to the model (model 2, Table 4), the relationship of the group) and “sexual activity” (p < 0.001) (lower for the glycemic status with the HRQOL-15D score was attenu- DM group). These associations were attenuated but ated and lost significance. Male gender still had a signifi- persisted after adjustment for age, gender, BMI, pres- cant contribution to the model (p < 0.001), whereas the ence of co-morbidities and complications. There were independent effect of vascular complications (p = 0.004) no differences in any component of the HRQOL-15D negated the effects of the glycemic status and of BMI score between the two groups of the pre-diabetes par- (the model now explained the overall variance of the ticipants (IFG and IGT), or the NGT vs. the IFG HRQOL score by 21.8% [R = 0.218]). group (Fig. 2). The different components of the HRQOL-15D score were evaluated separately among the groups. As Discussion There is a lot of interest in the past few decades in stud- Table 3 Analysis of covariance (ANCOVA) for the relationship ies of health-related quality of life (HRQOL) and the im- between the HRQOL-15D score with glycemic status, controlling pact of various diseases and disease-states upon it, for age, gender, BMI and smoking (persons with pre-diabetes which has led to the development and refinement of a were considererd separately as IFG - IGT) (Model 1) number of generic and disease-specific HRQOL mea- Variable F P sures [24, 25]. It should be emphasized also that clinical Age 0.72 NS variables alone do not comprehensively capture patients’ Gender (male) 20.05 < 0.001 perceptions of their health, which is in part due to the BMI 8.53 0.003 fact that HRQOL is influenced by many other factors, Smoking (yes) 0.26 NS such as the existence of other health problems, social relationships, marital status, patient knowledge, treat- Glycemic status 3.62 < 0.001 2 ment satisfaction and perceived ability to control R 0.14, BMI Body mass index Glycemic status: 1 = NGT, 2 = IFG, 3 = IGT, 4 = Diabetes one’sdisease [26]. Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 6 of 10 Table 4 Analysis of covariance (ANCOVA) for the relationship (owing mainly to the presence of vascular complica- between the HRQOL-15D score with glycemic status, controlling tions), while there were no significant differences in the for age, gender, BMI, smoking, presence of co-morbidities and overall HRQOL score between the NGT and the vascular complications (persons with pre-diabetes were considererd pre-diabetes groups. Examination, however, of the indi- separately as IFG - IGT) (Model 2) vidual components of the HRQOL score showed signifi- Variable F P cant differences between the NGT and the pre-diabetes Age 2.08 NS group in certain aspects. In particular, the IGT group Gender (male) 19.07 < 0,001 had lower scores compared to the NGT, as regarded to the components of “mobility” and “distress”. No differ- BMI 3.48 NS ence was noted in any of the 15 dimensions of the score Smoking (yes) 1.28 NS between the NGT and IFG group, nor between the two Co-morbidities 0.37 NS groups of the pre-diabetes subjects (IFG vs. IGT). Complications 6.39 0.004 The deterioration of the HRQOL in people with DM Glycemic status 0.53 NS [4] and the contribution of vascular complications to R 0.218, Co-morbidities arterial hypertension and/or dyslipidemia, that effect found in the present study is in line with pre- Complications any combination of coronary heart disease, stroke, peripheral vious reports in the literature [27, 28]. For people with arterial disease, nephropathy, retinopathy or neuropathy pre-diabetes, however, there are only few published stud- Glycemic status: 1 = NGT, 2 = IFG, 3 = IGT, 4 = Diabetes ies examining the relationship of their quality of life as In the present study, the HRQOL of patients with dia- regards to physical [5, 12] or psychological/mental betes was compared with that of pre-diabetes (IFG/IGT) parameters [7, 8, 10], sometimes with conflicting results, and persons with normal glucose tolerance (NGT), using either because of the use of different HRQOL measure- the HRQOL-15D questionnaire. It was found, that, in ment methods (e.g. by recording only the physical health general, the HRQOL of patients with diabetes was sig- condition and not the psychological-mental), or because nificantly worse than that of the other two groups of the use of small sample sizes or because of focusing Fig. 2 Profiles of the HRQOL-15D components among the NGT, Pre-DM (IFG – IGT) and DM participants Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 7 of 10 on specific population groups (e.g. the elderly) [6, 9, 29]. physical dimensions of quality of life, especially bodily Specifically using the HRQOL-15D questionnaire, stud- pain and physical functioning, and in general health sta- ies in people with pre-diabetes are extremely sparse [22]. tus [32]. On the contrary, in a population study in Since these people (with pre-diabetes) usually have Western Finland (the Harmonica Project) in 1383 sub- no symptoms and no major complications and very jects, aged 45–70 years, no differences in HRQOL were often no knowledge of their condition [10], their detected (with the same questionnaire SF-36) in partici- HRQOL should not be expected to be affected. The pants with pre-diabetes compared with non-diabetes fact, however, that around 10–20% of them may subjects [6]. In this study, people with known cardiovas- already have some mild micro- or macro- vascular cular disease were excluded in advance, which limits the complications [11], could explain the findings of their generalization and validity of the results. In the largest affected HRQOL in some aspects of it. For example, population study to date [8], that included 55,882 people limited joint action, prayer’ssign and Dupuytren’s of the general population in Sweden (Västerbotten contracture were more common in elderly IGT per- Intervention Program), using the Health Utility Weight sons compared to controls [12]. [HUW] SF-6D questionnaire (that included the dimen- In the present study, ‘mobility’ was found to be im- sions of physical functioning, role limitations, social paired in the group of pre-diabetes subjects with IGT function, bodily pain, mental health, and vitality), there (compared to those of the control group), which is was also a gradual decrease in HUWs with a progressive broadly in line with findings in the literature [22, 30]. It deterioration of the glycemic status from normal glucose is possible that mild, even subconscious abnormalities in tolerance to pre-diabetes and overt diabetes. physical functioning could explain this finding. In a re- Another significant finding in the present study was cently published prospective study [22] using 3 different that the “psychological distress” appeared to be highly assessment tools of HRQOL (SF-36, SF-6D and 15D), affected in the group of pre-diabetes individuals with and dividing the subjects into 5 groups (normal glucose IGT (relative to normal, and surprisingly even to people tolerance, IFG, IGT, newly diagnosed diabetes and with diabetes). Of note, the recording of this fact in the known diabetes), it was found that the deterioration of HRQOL-15D questionnaires was done before the partic- the glycemic status from the stage of normal glucose ipants were informed about the results of the OGTT tolerance to the pre-diabetes and overt diabetes was as- tests that they belonged to the pre-diabetes group. Sev- sociated with a worsening of HRQOL scores, as mea- eral studies in the literature have reported worsening of sured with all three questionnaires. Specifically for the the psychological state in people with diabetes [2, 33], 15D questionnaire, decreases in the components of “mo- which may be caused by the impact of the diagnosis of bility” (similar to the present study), “breathing”, “usual diabetes itself, the psychological stress associated with activities”, “discomfort and symptoms”, “vitality” and the management of diabetes or the burden of diabetic “sexual activity” were found, but not for the psycho- complications [34], or even through physiological path- logical dimensions of the questionnaire. These reduc- ways, including inflammatory processes and reductions tions - similar to the present study – did not occur in in neurotrophic function [35], which in turn may lead to subjects with IFG but only in those with IGT or diabetes reduced plasticity of neuronal networks and subse- who exceeded the limits of minimal clinical significance quently depression [36]. For pre-diabetes, however, the [minimal (clinically) important differences (MIDs)] the correlations that have been found are less robust. In ini- study had set (i.e. the smallest change a patient or health tial studies, it was observed that depressive symptoms professional can notice - for the 15D questionnaire MID were more frequent in women with pre-diabetes [37], was proposed at ≥0.02–0.03 units of the total score). A but a recent meta-analysis concluded that the risk for similar population study from Spain (Di@bet.es Study) depression was not increased in impaired glucose me- [30], in 5047 individuals of the general population, using tabolism compared to normal glucose metabolism or the SF-12 questionnaire, showed that women had wors- even undiagnosed diabetes subjects [38]. In the present ening quality of life scores (relating both to physical and study, “depression” did not differ between the groups of psychological parameters) with the deterioration of the NGT, pre-diabetes or diabetes subjects. glycemic status towards the pre-diabetes and diabetes The relationship between mental disorder and the states, while in men only physical parameters were affected glucose metabolism is likely to be bidirectional, affected (similarly in the present study male gender was as depressive symptoms or psychological distress may independently associated with worsening HRQOL). also lead to a higher risk of developing pre-diabetes Other population studies from Australia (AusDiab (especially in men) [39] or diabetes [40]. Higher work study), using the quality of life short form-36 (SF-36) distress has also been associated with prevalent diabetes questionnaire, showed that people with IFG (especially and especially pre-diabetes in a German cohort, espe- women) [5] or IGT [31], had reduced values in mainly cially in men [41], which could also explain the findings Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 8 of 10 of increased “distress” of participants with pre-diabetes the states of pre-diabetes and diabetes strengthens the in the present study, although no etiology of distress findings of the study. (e.g. work-related, social, family, etc) was elucidated. There are several limitations of the present study. Conclusions They include the relatively small sample size examined In conclusion, the quality of life of individuals with and the fact that it is a cross-sectional study, and thus pre-diabetes was overall not significantly different from cannot demonstrate cause and effect or the time frame that of normal glucose tolerance subjects, whereas for par- in which indices of the HRQOL deteriorate. For this ticipants with diabetes it was lower (mainly due to the purpose, prospective studies are required, with a signifi- presence of vascular complications). However, certain cant population sample and sufficient monitoring time. components of the quality of life were already affected in In such a relatively small study from Germany [7], there the pre-diabetic state of IGT (compared to the control was a trend for a decline in the quality of life (only for group), specifically “mobility” and “psychological distress”. physical parameters, as measured by the SF-12 question- Providing an understanding of the stages of diabetes naire) within 7 years from the transition of NGT to where health status is diminished will allow prioritization pre-diabetes, but the association was statistically signifi- of intervention efforts, and enable more effective targeting cant only for the subjects converting from NGT to of policy and strategic interventions to improve health diabetes. outcomes. Thus, quality of life issues (in particular phys- Another limitation of this study is that the population ical and psychological-emotional issues) should be investi- examined is not necessarily representative of the general gated when people with pre-diabetes are diagnosed in population, since the participants without diabetes every-day routine clinical practice, since their identifica- selected themselves to participate in the study, while tion could potentially lead to more effective overall man- people with diabetes were derived from a large Diabetes agement of their condition. University Center (Laiko Hospital), and thus the findings are not necessarily applicable to the general population. Abbreviations DM: Diabetes mellitus; HRQOL: Health related quality of life; IFG: Impaired Also, the fact that the HRQOL-15D questionnaire is not fasting glucose; IGT: Impaired glucose tolerance specific for diabetes [25], may probably have as a result that the responses to it reflect problems associated with Acknowledgements other conditions. The fact that it was applied only once We would like to thank the following Health Centers/individuals for helping may additionally preclude its ability to find fluctuations implement the present study: the medical staff of the Health Center of Alimos (especially Dr. Ourania Zacharopoulou), the staff of the Center for the of HRQOL over time. Elderly Agioi Anargyroi, the medical and nursing staff of the Health Center of It has to be emphasized also, that there were many miss- Markopoulo (especially Mrs. R. Salonikioti), the medical and nursing staff of ing data regarding presence of vascular complications in the Hellenic Telecommunications Company (especially Drs C. Pietris and C. Alexopoulos), the medical and nursing staff of the Hellenic Radiotelevision the group of individuals with pre-diabetes (46 persons) (especially Dr. M. Katsorida), the medical and nursing staff of the Bank of and NGT (137 persons), which may have influenced the Greece (especially Drs V. Spandagos and P. Konstantopoulou), the medical aforementioned comparisons. staff of the Olympic Village complex (especially Dr. S. Tigas), the staff of the electrical equipment manufacturer “Pitsos-Bosch”, the medical and nursing On the other hand, strengths of the present study staff of the Health Center of Vari (especially Dr. M. Dandoulakis) and the include the fact that the determination of the glycemic medical and nursing staff of the Health Center of Vyronas (especially Dr. K. status was performed with a glucose tolerance test Kyriakopoulos). (OGTT) and was not self-reported, which enhances the Funding reliability of the reported correlations. Also the This project was partly funded by the Commission of the European HRQOL-15D questionnaire was completed by the par- Communities, Directorate C – Public Health, grant agreement No. 2004310. ticipants of the DEPLAN cohort before they had learned Under the rules of the agreement, it was also partly co-funded by the private sector and in this case it was supported by an unrestricted educational grant the results of the OGTT, and thus their answers were from Bristol-Myers-Squibb, Greece. not affected by the knowledge of their glycemic status. In addition, in a comparative evaluation of the Availability of data and materials HRQOL-15D questionnaire with other HRQOL assess- The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. ment questionnaires in the Greek population [42], the 15D was found to be superior as regards to the assess- Authors’ contributions ment of vascular complications in diabetes (particularly KM designed the study, obtained the data, analyzed and interpreted the for coronary heart disease and diabetic retinopathy). Fur- patient data and wrote the manuscript; SL designed the study, obtained the thermore, the exclusion of the few newly diagnosed data and reviewed the first draft of the manuscript; AT, CS, EP obtained the data; DP analyzed the data; NK, NK and DN designed the study and provided (screen-detected) people with diabetes from the analysis, critical revisions of important intellectual content to the manuscript. All whose participation could cause distortion of the associ- authors revised the manuscript and approved the final version prior to the ations found, because of their actual position in-between submission. Makrilakis et al. BMC Endocrine Disorders (2018) 18:32 Page 9 of 10 Ethics approval and consent to participate 16. Cos FX, Barengo NC, Costa B, Mundet-Tudurí X, Lindström J, Tuomilehto JO. The study was approved by the cooperating hospital’s ethics committee DEPLAN study group. Screening for people with abnormal glucose (Laiko General Hospital Ethics Review Board), and the Hellenic National Drug metabolism in the European DE-PLAN project. Diabetes Res Clin Pract. 2015; Organization. All participants signed an informed consent according to the 109(1):149–56. general recommendations of the Declaration of Helsinki. 17. Makrilakis K, Liatis S, Grammatikou S, Perrea D, Katsilambros N. Implementation and effectiveness of the first community lifestyle intervention programme to prevent type 2 diabetes in Greece. The DE- Competing interests PLAN study. Diabet Med. 2010;27(4):459–65. The authors declare that they have no competing interests. 18. Sintonen H. The 15D instrument of health-related quality of life: properties and applications. Ann Med. 2001;33(5):328–36. 19. Lindström J, Tuomilehto J. The diabetes risk score: a practical tool to predict Publisher’sNote type 2 diabetes risk. Diabetes Care. 2003;26(3):725–31. Springer Nature remains neutral with regard to jurisdictional claims in 20. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of published maps and institutional affiliations. low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502. Author details 21. Anagnostopoulos F, Yfantopoulos J, Moustaki I, Niakas D. 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Journal

BMC Endocrine DisordersSpringer Journals

Published: May 29, 2018

References

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