Abstract
Objective: The aim of the present study was to evaluate the relationship between vitamin D (25[OH]D) status and the risk of cardiovascular disease as assessed by various cardiovascular risk scoring systems such as QRISK2, BNF, ASSING, SCORE, and Framingham in patients with type 2 diabetes mellitus(T2DM).
Methods: The study included 108 patients with vitamin D insufficiency (25[OH]D ≥ 10–30 ng/mL) and 100 patients with vitamin D deficiency (25[OH]D < 10 ng/mL), who were admitted to the diabetes outpatient clinics due to T2DM and who were aged 45–65 years. QRISK2, BNF, ASSING, SCORE, and Framingham were calculated and compared between the two groups.
Results: HbA1c levels were significantly higher in patients with vitamin D deficiency. Patients with vitamin D deficiency had significantly higher Framingham risk score (p < .001) and significantly lower BNF score (p < .001), whereas other scores did not significantly differ between the groups. There was a moderate, statistically significant correlation between 25[OH]D levels and Framingham risk score in negative direction (r = 0.537) and a weak but statistically significant correlation between 25[OH]D levels and BNF score (r = 0.295). 25[OH]D levels were significantly higher and HbA1c levels were significantly lower in patients with Framingham cardiovascular risk score ≤10%.
Conclusion: We found a close relationship with Framingham cardiovascular risk score in diabetic patients with very low serum vitamin D levels. Cardiovascular risk as assessed by the Framingham’s scale increases with decreasing 25[OH]D levels. BNF score was negatively correlated with 25[OH]D levels.
Introduction
Vitamin D controls production of pro-inflammatory cells by controlling immunity and prevents the development of inflammatory diseases [Citation1]. Therefore, lack of vitamin D has been shown to be involved in etiopathology of chronic inflammatory diseases such as obesity, hypertension, and diabetes [Citation2]. There is some evidence that the epigenetic mechanisms of vitamin D may play a role in the suppression of Toll-like receptor mediated inflammation [Citation3]. Some studies have shown that vitamin D metabolites play a role in pathways that are integrated in cardiovascular function and disease, including chronic inflammation, thrombosis, and the renin-angiotensin system [Citation4]. The studies have reported a relationship between vitamin D status and pancreatic cell dysfunction [Citation5]. Also, it has been shown that vitamin D has direct and indirect effects on various mechanisms related to the pathophysiology of type 2 diabetes such as impaired insulin effect and systemic inflammation [Citation6]. In addition, there are also studies reporting an association between vitamin D deficiency and increased cardiovascular risk in the healthy population as well as in patients with type 2 diabetes mellitus [Citation7,Citation8]. Studies have shown that chronic inflammation markers and vitamin D deficiency play an important role in the pathogenesis of cardiovascular disease [Citation9]. Clinical trials have shown that vitamin D deficiency is independent of all risk factors on many systems, including the cardiovascular system [Citation10–12]. Various markers of atherosclerosis have been found to be elevated in patients with type 2 diabetes mellitus and concurrent vitamin D deficiency [Citation13]. Also, severe vitamin D deficiency in patients with type 2 diabetes mellitus was shown to be associated with increased all-cause and cardiovascular mortality independent from all conventional risk factors [Citation14]. Vitamin D deficiency has been shown to increase the severity of coronary stenosis in hypertensive patients [Citation15]. Vitamin D and metabolites suppress the development and activation of TH1 and TH17 cells [Citation16]. These cytotoxic T cells have been shown to cause arterial plaque formation in mice with apoE deficiency [Citation17]. The regulatory role of vitamin D on the cardiovascular system has been shown to be an activation of the systemic and local renin-angiotensin system in studies [Citation18]. There has been growing interest in the relationship between vitamin D deficiency and type 2 diabetes mellitus. There is, however, no study in the literature that evaluated cardiovascular risk scores together with vitamin D deficiency in patients with type 2 diabetes mellitus. The present study evaluated the relationship between vitamin D levels and the risk of cardiovascular disease as assessed by various cardiovascular risk scoring systems such as QRISK2, BNF, ASSING, SCORE, and Framingham in patients with type 2 diabetes mellitus.
Materials and methods
Design, setting, and recruitment
This was a cross-sectional study. As a result of power analysis, the study included 208 consecutive patients with type 2 diabetes mellitus (DM) aged between 45 and 65 years, who were admitted to diabetes outpatient clinics of our hospital and who had no abnormal kidney (glomerular filtration rate >30 ml/min/1.73m2) and had liver functions (alanine aminotransferase <45 U/L and aspartate transferase <34 U/L) and normal lifestyle engaging regular physical activity. The study was approved by University of Health Sciences Umraniye Education and Research Hospital local ethics committee. All procedures performed and studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The first group comprised of 108 patients with vitamin D insufficiency (30–10 ng/mL) and second group comprised of 100 patients with vitamin D deficiency (<10 ng/mL). Blood samples were collected in December, January, and February, as vitamin D levels are known to show seasonal variations. Patients with type I diabetes mellitus, liver disease, acute infections, thyroid disorders, hyperparathyroidism, severe cardiovascular, and neurologic disease, acute cerebrovascular accident, acute or chronic infection, uncontrolled diabetes, and those who have received or are currently receiving vitamin D replacement and supplement therapy were excluded from the study. The study was approved by the local ethics committee. The patients gave their written informed consent according to the Institutional Review Board guidelines and the Declaration of Helsinki.
Measures and methods
A detailed medical history was obtained and all patients underwent physical examination. Weight, height, body mass index (BMI, kg/m2), and waist circumference were measured. Blood pressure was measured twice according to the standard protocol. Hypertension was defined as systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg or presence of antihypertensive drug use. Presence of coronary artery disease in the past medical history was evaluated from the medical records of the patients. 25-(OH) vitamin D, fasting blood glucose, Glycated hemoglobin A1c (HbA1c), alkaline phosphatase, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, urea, and creatinine levels were measured after at least 8 h of fasting period. Blood samples were collected into SST II, LH PST II, and EDTA tubes and all samples were analyzed at the same time. Various cardiovascular risk scores were calculated such as QRISK2, BNF, ASSING, SCORE, and Framingham risk score. By comparing the risk scores with vitamin D levels, relationship between vitamin D status and different cardiovascular risk scores was evaluated. Blood glucose levels were studied in whole blood by enzymatic calorimetric methods using commercial devices with an intra-assay coefficient variance of 6% and an inter-assay coefficient variance of 8%. Total cholesterol, HDL, triglyceride, calcium, and phosphate levels were measured by using enzymatic colorimetric test using a Hitachi 747 autoanalyser (Mito, Ibaragi, Japan). LDL cholesterol levels were calculated using the formula of Friedewald. HbA1c levels were measured by boronate affinity high-performance liquid chromatography (HPLC) as described in the NHANES Laboratory Procedure Manual, Glycohemoglobin. Measurement of 25-OH vitamin D was performed by means of a chemiluminescence assay (Liaison XL, DiaSorin, Stillwater, MN) (intra-assay coefficients of variation were 3.8% at a vitamin D concentration of 7.85 ng/ml, 2.3% at 19.6 ng/ml and 2% at 51.9 ng/ml). Concentration of vitamin d < 10,0 ng/mL is adopted as “deficient’’ and between 10.0 and 30.0 ng/ml as “insufficient’’ [Citation19].
Cardiovascular risk scores
Qrisk 2 score calculated using parameters such as age, sex, ethnicity, smoking status, diabetes status, angina or heart attack status, chronic kidney disease status, atrial fibrillation status, blood pressure treatment status, rheumatoid arthritis status, cholesterol/HDL ratio, systolic blood pressure, and body mass index [Citation20].
BNF score calculated using parameters such as age, years, sex, smoking status, blood pressure, total cholesterol, and HDL [Citation21].
ASSING score calculated using parameters such as age, sex, diabetes status, rheumatoid arthritis status, smoking status, systolic blood pressure, total cholesterol, and HDL cholesterol [Citation21].
SCORE score calculated using parameters such as age, sex, smoking status, systolic blood pressure, and total cholesterol. In SCORE system; >10% points: very high risk, ≥5% and ≤10% points: high risk group, ≥1% and ≤5% points: moderate risk group, ≤1% low risk group [Citation22].
Framingham risk score calculated using parameters such as age, gender, total cholesterol, HDL cholesterol, smoking status, diabetes status, systolic blood pressure, and blood pressure treatment status. In Framingham risk score system; ≤10% points: low risk group, >10% and ≤20% points: moderate risk group, >20% points: high risk group [Citation23].
Statistical analysis
Continuous variables were expressed using descriptive statistics such as mean, standard deviation, minimum, median, and maximum. The Student’s t-test was used to compare two independent continuous variables with normal distribution, and Mann–Whitney U-test was used to compare two independent variables without normal distribution. Chi-square test (or Fisher’s Exact test, where appropriate) was used to evaluate the relationship between categorical variables. Spearman’s rho correlation coefficient was used to evaluate the correlation between two continuous variables without normal distribution. The level of statistical significance was set at p < .05. The statistical analysis was performed using MedCalc Statistical Software version 12.7.7 (MedCalc Software bvba, Ostend, Belgium).
Results
The mean age of the study patients was 55.5 ± 6,1 years, and of these patients, 91 (43.8%) were males and 117 (56.3%) were females. The mean height was 164.2 ± 9.1 cm, the mean weight was 85.3 ± 15 kg, the mean waist circumference was 102.2 ± 12.3 cm, and the mean BMI was 31.7 ± 5.7 kg/m2 (). There were 16 patients with coronary artery disease. The mean vitamin D level was 11.8 ± 5.5 ng/mL and the mean HbA1c level was 9.1 ± 2.5% (76 mmol/mol). Of the study participants, 20.7% were smokers. When the patients were divided into two groups according to gender, there was difference between the scores of SCORE of the two groups (). There were statistically significant differences between patients with vitamin D levels below 10 ng/ml and those with vitamin D level at or above 10 ng/ml with respect to HbA1c levels (9.5 ± 2.5% (80 mmol/mol) versus 8.7 ± 2.5%(72 mmol/mol), p = .019), cholesterol levels (218.9 ± 50.1 versus 205.1 ± 44.8 mg/dl, p = .038), and SBP and DBP (138.7 ± 16.7 versus 131.8 ± 15.6 mmHg, p = .001; 83 ± 13.2 versus 78.8 ± 10.6 mmHg, p = .004) ().
Table 1. Comparison of demographic, antropometric and clinical data according to vitamin D levels.
Table 2. Comparison of various cardiovascular risk scores according to gender.
Table 3. Comparison of the parameters between patients with vitamin D insufficiency and patients with vitamin D deficiency.
Framingham risk score was significantly higher (29.3 ± 11.4 versus 11.7 ± 11.2, p < .001) and BNF score was significantly lower (15 ± 8.4 versus 21.8 ± 10.3, p < .001) in patients with vitamin D concentrations less than 10 ng/mL when compared with patients with vitamin D levels at or above 10 ng/mL. The scores in other risk scoring systems did not significantly differ according to vitamin D concentrations. There was a moderate, statistically significant negative correlation between 25[OH]D concentrations and Framingham risk score (r = 0.537) and a weak but statistically significant correlation between 25[OH]D concentrations and BNF score (r = 0.295).
When patients were grouped according to Framingham risk score, vitamin D concentrations were significantly higher (14.8 ± 4.7 versus 10.3 ± 5.4, p < .001), HbA1c levels were significantly lower (8.8 ± 2.6% versus 9.2 ± 2.5%, p = .019), total cholesterol levels were significantly lower (203.2 ± 46.1 versus 216 ± 48.2, p = .038), BMI was significantly lower (31.4 ± 6.4 versus 31.9 ± 5.5, p = .018), and the levels of SBP and DBP were significantly lower (131.5 ± 16.8 versus 137 ± 16, p = .001 and 79.7 ± 12.4 and 81.3 ± 11.9, p = .004) in patients with a score of 10 points or lower and those with a score of higher than 10 points in Framingham risk score ().
Table 4. Comparison of the parameters between patients grouped according to the Framingham risk score.
Discussion
Our study was interesting because it was the first study to evaluate the association between vitamin D status and the risk of cardiovascular disease as assessed by various cardiovascular risk scoring systems in patients with type 2 diabetes mellitus. The present study found a close relationship between Framingham cardiovascular risk score and serum vitamin D concentrations in patients with type 2 diabetes mellitus. In addition, Framingham risk score increased with decreasing 25(OH)D concentrations. We think that this effect may be due to the fact that Vitamin D deficiency causes maladaptive cardiac remodeling due to myocyte hypertrophy and interstitial fibrosis.
There was an inverse relationship between vitamin D concentration and BNF score, while QRISK, ASSING, and SCORE did not show an association with vitamin D status. It is interesting to increase the level of vitamin D at the level of BNF score but we cannot make a clear statement of it. However, the Framingham score also includes diabetes and left ventricular hypertrophy, unlike BNF. The relationship between Framingham risk score and low vitamin D can be explained by these two factors. In the literature, there is no recommended test for use in evaluating cardiovascular risk in type 2 diabetic patients but our study showed that Framingham risk scoring system could be used in this patient group. Our study suggests that the activation of the vitamin D receptor levels by epigenetic pathways of vitamin D metabolites leads to the formation of specific sub-clusters of microRNAs resulting in post-translational effects.
Vitamin D plays a classical hormonal role in musculoskeletal health by regulating calcium and phosphorus metabolism [Citation24]. It also has physiological functions through the paracrine and autocrine mechanisms of vitamin D metabolites, especially in non-skeletal tissues such as the cardiovascular system [Citation25]. The interest in the role of vitamin D in cardiovascular disease has been due to evidence of adverse cardiovascular effects of vitamin D deficiency and to epidemiological studies of increases in cardiovascular events and eccentricity in winter [Citation26]. The active metabolite of vitamin D has been shown to have direct effects on innumerable genes involved in cell proliferation and differentiation, apoptosis, oxidative stress, matrix homeostasis and cell adhesion in physiopathology of many cardiovascular diseases [Citation27]. It has been shown that most cardiovascular and inflammatory cells excrete CYP27B1, providing local synthesis of vitamin D [Citation28]. Vitamin D receptors are found in all major cardiovascular cell types including cardiomyocytes, arterial wall cells, and immune cells [Citation27].
Vitamin D insufficiency was defined as serum 25(OH)D concentration of 10–30 ng/mL and vitamin D deficiency was defined as serum 25(OH)D concentration of less than 10 ng/mL. The studies to date have used various cut-off levels to evaluate vitamin D status. A study from Italy reported a prevalence rate of 34% for vitamin D deficiency in patients with type 2 diabetes mellitus by taking a cut-off level of ≤37.5 nmol/L (15 ng/mL) for vitamin D concentration [Citation13]. Another study from the same country reported a prevalence rate of 60.8% by considering a cut-off level of <20 ng/mL (∼50 nmol/L) [Citation29]. The studies taking the same cut-off level reported a prevalence rate of 70.6% in Japan, 63.5% in the US, and one study conducted on South Asians in the UK reported a rate of 83% [Citation30–32]. Another study used a cut-off level of <5 ng/mL for vitamin D concentration and reported a prevalence rate of 39% for vitamin D deficiency in women with type 2 diabetes mellitus [Citation33]. Although studies have used different cut-off levels and reported different results, increased prevalence of vitamin D deficiency in patients with type 2 diabetes mellitus highlights the importance of evaluating vitamin D status in this particular group of patients.
Vitamin deficiency is seen in 9 of 10 people in our country [Citation34]. For this reason, we could not include patients with optimal vitamin D concentration (>30 ng/ml) as group 3.
Vitamin D is known to suppress the expression of calcineurin inhibitor protein, which modulates chronic inflammation [Citation35]. Therefore, it is thought that this vitamin deficiency is related to chronic inflammation and insulin resistance. In a prospective 10-year follow-up study, a significant relationship was reported between 25(OH) vitamin D concentrations and insulin and HOMA-IR [Citation36]. Jung Re et al. reported higher HbA1c, CRP, triglyceride, low-density lipoprotein cholesterol, ferritin, and fibrinogen levels in diabetic patients with vitamin D deficiency [Citation37]. Also in the present study, patients with vitamin D deficiency had significantly higher HbA1c level (9.5 ± 2.5%, p = .019). However, some recent studies have found no significant effect of high-dose vitamin D supplementation on glycemic control [Citation38]. As a result, further studies are needed to establish actual relationship between vitamin D status and glycemic control in patients with type 2 diabetes mellitus.
It is indicated that both vitamin D and its active metabolite inhibit tumor necrosis factor-α and IL-6 production by targeting monocyte/macrophage mitogen-activated protein kinase phosphatase-1, which suppresses chronic inflammation [Citation39]. Therefore, vitamin D deficiency has been shown to play a role in the pathophysiology of diseases with chronic inflammation such as obesity. Vitamin D level is also closely associated with MPV, another chronic inflammatory marker [Citation40]. There may be a relationship between obesity and vitamin D concentrations. Previous studies conducted on this subject have reported low vitamin D concentrations in individuals with a BMI ≥30 kg/m2 and decreased bioavailability of vitamin D in these subjects [Citation41]. In addition, a study conducted in recent years found lower vitamin D concentrations with increasing body fat percentage [Citation42]. In the present study, the mean BMI was significantly higher in patients with serum vitamin D concentrations of 10 ng/mL or lower when compared to patients with vitamin D concentrations at or above 10 ng/mL (32.6 ± 5.7 versus 30.9 ± 5.8, p = .018).
Vitamin D has been shown to suppress endoplasmic reticulum stress and the formation of foam cells by macrophages in patients with type 2 diabetes mellitus [Citation43]. Vitamin D deficient group had higher total cholesterol levels compared to vitamin D insufficient group. In relation to this subject, one study in the literature reported a relationship between low vitamin D concentrations and low HDL cholesterol levels and that HDL levels increased with increasing vitamin D concentration [Citation44]. For this reason, it is considered that vitamin D status might play a role in the development of atherosclerosis through its relationship with HDL cholesterol levels in patients with type 2 diabetes mellitus.
Cardiovascular diseases are among the leading causes of morbidity and mortality [Citation45]. As atherosclerotic cardiovascular diseases often develop in relation to multiple risk factors, predicting the risk of cardiovascular events in the near future, particularly in asymptomatic individuals is of great importance in terms of prevention. All risk calculation systems have been developed to evaluate total risk imposed by joint effects of classical risk factors. However, the question is not which risk scoring system among all is superior, but which scoring system should be used in a particular situation in daily practice. The present study showed that Framingham risk score is more logical cardiovascular risk scoring system to be used in diabetic patients with vitamin D deficiency. Therefore, diabetics patients with D vitamin level of <30 ng/mL should be treated with 800–1500 lU of vitamin D per day for cardiovascular protection [Citation19].
Conclusion
In conclusion, our study showed a close relationship between vitamin D status and Framingham risk score in patients with type 2 diabetes mellitus. In addition, cardiovascular risk assessed by Framingham risk calculator increases with decreasing 25(OH) vitamin D concentrations. Whether the correction of vitamin D deficiency is beneficial on inflammatory markers and cardiovascular outcomes should be investigated by controlled clinical trials.
Study limitations
The limitation of our study is this was a cross-sectional study and do not obtain direct evidence of causal relationship.
Disclosure statement
The authors report no conflicts of interest in this work.
Related Research Data
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