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Circulating growth differentiation factor 15 levels and apolipoprotein B to apolipoprotein A1 ratio in coronary artery disease patients with type 2 diabetes mellitus



Clinical investigations have found that there was a close association between T2DM and adverse cardiovascular events, with possible mechanisms included inflammation, apoptosis, and lipid metabolism disorders. High serum GDF-15 concentration and the apolipoprotein B/apolipoprotein A1 ratio (ApoB/ApoA1) are involved in the above-mentioned mechanisms and are thought to be related to the occurrence of adverse cardiovascular events. However, it remains unclear whether circulating GDF-15 levels and the ApoB/ApoA1 ratio are related to T2DM patients with CAD.


T2DM patients with or without CAD were eligible for this study. According to the inclusion and exclusion criteria, 502 T2DM patients were enrolled between January 2021 and December 2021 and were then divided into T2DM group (n = 249) and CAD group (n = 253). The ApoB, ApoA1 and GDF-15 concentrations were measured at hospital admission and the ApoB/ApoA1 ratio was then calculated.


Compared with T2DM group, serum GDF-15 levels and ApoB/ApoA1 ratio increased in CAD group. Furthermore, a positive relationship between the occurrence of CAD in diabetic population and circulating GDF-15 concentrations and ApoB/ApoA1 ratio was observed in logistic regression analysis (p < 0.01). Restrictive cubic spline analysis after adjusted for multiple risky variables showed that serum GDF-15 or ApoB/ApoA1 ratio correlated positively with CAD.


Circulating GDF-15 levels and serum ApoB/ApoA1 ratio vary in CAD group and T2DM group. ApoB/ApoA1 and GDF-15 may be helpful for predicting the occurrence of CAD in patients with T2DM.


Type 2 diabetes mellitus (T2DM) is the most common form of diabetes. It is estimated that patients with diabetes mellitus in the world will reach 783.2 million in 2045, of which T2DM will account for more than 90% [1]. Despite the advent of insulin and exercise and dietary management largely controlling the progression of T2DM, comorbidities associated with the disorder, especially coronary artery disease (CAD), are still an important cause of death [2, 3]. Researchers have therefore turned their attention to novel biomarkers for predicting CAD in T2DM patients [4, 5].

GDF-15 is one of the new metrics and many recent studies have showed that its levels correlate closely with pancreatic β-cell apoptosis, vascular endothelial cell and adipocyte inflammatory damage and oxidative stress [6,7,8,9,10,11]. Possible mechanisms for this association are: 1) mediating vascular endothelial damage and atherosclerotic plaque formation via the TGFβRII pathway [12], 2) regulating apoptosis and IL − 6-related vascular damage [10], 3) combination with oxidized low-density lipoprotein(ox-LDL) to ruin macrophage autophagy then interfere with macrophage lipid homeostasis [11], and 4) maintaining the activity of the PI3K/Akt/eNOS pathway which regulates apoptosis of vascular endothelium caused by high glucose levels [13]. The above-mentioned mechanisms foster the development of CAD in T2DM.

It has been reported that elevated levels of low-density lipoprotein cholesterol (LDL-C) and decreased levels of high-density lipoprotein cholesterol (HDL-C) are vital risk factors for the increased risk of CAD in patients with T2DM [14, 15]. With apolipoprotein B (ApoB) as one of components, LDL-C is a cholesterol-rich lipoprotein that promotes the excessive lipid enter the arterial intima through pinocytosis and then participate in foam cell transformation and arterial plaque formation [16]. Apolipoprotein A1 (ApoA1) mainly exists in HDL-C. It plays an important role in balancing LDL-C function and promoting cholesterol’s reverse transport to the liver, followed by reducing LDL-C deposition in vascular walls and protecting against functional damage in islet beta cells [15, 17]. There was evidence that high ApoB/ApoA1 ratio may predict the severity of CAD [14]. Lp(a) has long been explored by many researchers for its novel function in cardiovascular diseases, and abnormal increase in Lp(a) has been seen as an established risk factor for CAD. It is genetically variable between individuals and is an atherogenic factor [18, 19]. However, unlike Lp(a), the ApoB/ApoA1 ratio has not been studied in detail in CAD patients. Given the increasingly important role of GDF-15 and lipoproteins in T2DM and CAD, this study aimed to evaluate and compare the ApoB/ApoA1 ratio and GDF-15 concentrations in T2DM patients with or without CAD and examine their ability to predict CAD.



All participants in this study were recruited from the Department of Cardiovascular Medicine and Endocrinology, Renmin Hospital of Wuhan University. Past medical history, lifestyle, and drug use of all patients were obtained before their admission. T2DM patients with or without CAD were all eligible for the study and consecutive patients were also included. The following are exclusion criteria: (1) malignancy and undergoing chemoradiotherapy, (2) history of contrast-induced acute renal failure after PCI and uremia or kidney transplantation, (3) receiving liver transplantation or other severe liver diseases, (4) infectious diseases, sepsis, autoimmune disease, pulmonary insufficiency, and cerebral infarction, (5) incomplete basic information such as medication history and previous disease history, (6) history of surgery within the past 14 days. According to inclusion and exclusion criteria, 502 diabetic subjects were included from January 2021 to December 20 and were divided into either a T2DM group (n = 249) or CAD group (n = 253) (Fig. 1).

Fig. 1
figure 1

Diagram of patients selection. Abbreviations: FPG, fasting blood glucose; 2hPG, 2 h postprandial blood glucose; HbA1c, glycosylated hemoglobin; T2DM, type 2 diabetes mellitus; CAD, coronary artery disease

Study definition

The diagnosis of T2DM was consistent with the standards issued by ADA [20]. Smokers and drinkers referred to those who had not quitted their smoking or drinking habits, respectively, from the past to the present. BMI was calculated as; “weight (kg) / height2(meters)”. Hypertension was defined by the WHO principles [21].

Coronary angiography and diagnosis of CAD

coronary angiography was performed to diagnose CAD and the latter was defined as greater than 50% stenosis of the major coronary arteries [22]. Coronary arteriography was performed by experienced interventional doctors and the results then analyzed and admitted by at least two cardiologists. The clinical materials were obtained from corresponding physicians who were unaware of the research’s methodology and objective. A new diagnosis of CAD was not made during the research.

Blood sampling and laboratory analysis

All patients fasted for at least 8 hours after admission. The blood sample was collected in tubes containing separating gel and EDTA-K2, and then centrifuged for serum collection, followed by storage until measurement. GDF-15 was quantified using a sandwich ELISA kit (R&D Systems, USA) with horseradish peroxidase involved in the color reaction. Hemolyzed specimens were strictly prohibited from measurement. Optical density was determined immediately in microplate reader (Autobio Instruments, PHOMO, Zhengzhou, Henan, China).

Leucocyte and its classification were counted on a Sysmex XN-20 (Kobe, Japan). HbA1c was determined in Trinity Biotech Premier Hb9210 kit (Kansas, USA). Total cholesterol (TC), triglycerides (TG), blood glucose (Glu), glycated albumin (GA), free fatty acids (FFA), HDL-C, LDL-C, ApoA1 and ApoB were measured on a Siemens automatic biochemical analyzer ADVIA 2400 (Erlangen, Germany). The CKD-EPICr formula recommended by the NKF-ASN Task Force was performed to compute the estimated glomerular filtration rate(eGFR) [23].

Statistical analysis

All data were analyzed in SPSS 23.0 and R 3.5.2. BMI obeyed normal distribution and was therefore presented as mean ± standard deviation with difference determination using Students t-test. Other continuous variables belonged to non-normally distributed data and they were given as interquartile range, then analyzed with the Mann-Whitney test. Categorical data including insulin, metformin, and anti-hypertensive treatment, drinking, smoking, hypertension and gender were expressed as percentages then analyzed by means of the chi-square test. Logistic regression was conducted and then analyzed in SPSS 23 software to examine the relationship between GDF-15 or ApoB/A1 and the prevalence of CAD in T2DM patients. Finally, further analysis of the fully adjusted model was performed using restricted cubic spline analysis.


Characteristic of subjects

The characteristics of 502 T2DM subjects were showed in Table 1. Diabetic duration, BMI, age, leukocyte, neutrophil, NLR, hs-CRP, 2hPG, GA, GA/ALB, GDF-15, AST, ApoB/ApoA1 ratio, Urea, Cr, FFA, and ApoB increased in the CAD group, while LYM, HDL-C, ApoA1 and eGFR were lower. The type, severity, and duration of CAD in the 253 patients were shown in Additional file (Table X1).

Table 1 Characteristic of T2DM patients with and without CAD

Logistic analysis of the prevalence of CAD in T2DM patients and serum GDF-15 concentrations and ApoB/ApoA1 ratio

To further analyze the correlation between CAD and GDF-15 or ApoB/ApoA1 ratio in the T2DM patients, the data were divided into quartiles of GDF-15 or ApoB/ApoA1 ratio, taking the first quartiles as the reference to calculate the odds ratio (OR) for CAD, and the results were shown in Tabless 2 and 3. GDF-15 and ApoB/ApoA1 ratio in T2DM patients presented a positive association with the prevalence of CAD in the Crude model (p < 0.01). After adjustment for insulin, metformin, and antihypertensive treatment, drinking, smoking, BMI, hypertension, diabetic duration, age, gender in Model 1, the results remained consistent with the Crude model (p < 0.01). The difference also remained statistically significant after further control of Urea, Cr, WBC, NEU, LYM, NLR, hs-CRP, UA, eGFR, HbA1c, FPG, 2hPG, GA, GA/ALB, FFA, LDL-C, HDL-C TC, TG, ALT, AST and GGT. The fully adjusted OR in Model 2 was 11.514(95%CI:4.586,28.909) for quartile 4 of circulating GDF-15 concentrations (the highest) versus quartile 1 (the lowest), and was 2.388(95%CI:1.891,10.245) for quartile 4 of ApoB/ApoA1 (the highest) versus quartile 1 (the lowest).

Table 2 Association of coronary heart diseases with serum GDF-15 in T2DM patients
Table 3 Association of coronary heart diseases with serum Apo B/Apo A1 ratios in T2DM patients

Restricted cubic spline analysis

Figure 2a and b indicated the association between the prevalence of CAD in T2DM population and GDF-15 and ApoB/ApoA1 ratio. The grey area in these graphs showed the 95% confidence interval. The analysis was adjusted for insulin, metformin, anti-hypertensive treatment, drinking, smoking, BMI, hypertension, diabetic duration, age, gender, ALT, AST, GGT, WBC, NEU, LYM, NLR, hs-CRP, FFA, TC, TG, HDL-C, LDL-C, Urea, Cr, HbA1c, FPG, 2hPG, GA, GA/ALB, UA and eGFR. The results indicated that serum GDF-15 or ApoB/ApoA1 ratio correlated positively with the prevalence of CAD.

Fig. 2
figure 2

Restricted cubic spline model of the odds ratios of CAD with serum GDF-15 and ApoB to ApoA1 ratio in T2DM patients. The dashed lines represent the 95% confidence intervals. GDF-15: serum growth differentiation factor 15; Apo B, apolipoproteins B; Apo A1, apolipoproteins A1. Both serum GDF-15 levels and ApoB/ApoA1 ratio were positively correlated with CAD


To the best of our knowledge, this is the first study to investigate the association between GDF-15 and ApoB/ApoA1 ratio and the prevalence of CAD in T2DM patients.

CAD is one of terrible comorbidities of T2DM, as well as the leading cause of death in T2DM patients [2]. Investigations have indicated that the risk of CAD in diabetic men is up to 2 times higher than that in normal men, while CAD in women with diabetes is appropriately 3 times higher than that of normal women [24]. As an inflammatory factor, serum GDF-15 is up-regulated when inflammatory damage occurs in vascular endothelial cells, pancreatic islet β cells, and cardiomyocytes, a process possibly involving TGFβRII and IL-6. The formation of atherosclerotic plaque is essentially the inflammation of vascular wall, and GDF-15 involved in this process [10, 12, 25, 26]. Consistent with previous reports, findings in this research showed that subjects with diabetes and CAD had higher levels of WBC, NEU, NLR, hs-CRP and GDF-15 than those with T2DM alone, indicating a more severe inflammatory state. GDF-15 is secreted from endothelial cells under high glucose conditions through ROS- and p53-dependent pathways, and acts in the occurrence and development of CAD [13]. Furthermore, another study pointed that the increase in circulating GDF-15 levels predicted the severity of coronary atherosclerosis and CAD, as well as raised the mortality of adverse cardiovascular events [27]. These findings suggest that the activation of hyperglycaemia-endothelial-GDF15-inflammation pathway may lead to myocardial damage. However, it should be noted that there is insufficient evidence supporting that controlling GDF-15 concentrations effectively leads to low incidence rate of CAD [28].

Results in this study showed that T2DM patients with CAD had significantly higher GDF-15 levels than those with T2DM only. Being a novel biomarker, however, not all studies showed that circulating GDF-15 levels increased in diabetics [25, 28]. Recent literatures found that GDF-15 predicted the ventricular remodeling in healthy individuals and diabetic patients [26, 29, 30]. In the heart, GDF-15 might activate the ALK receptor and phosphorylate smad protein, and inhibit the NF-κB related pathway and EGFR trans-activation to contribute to cardiac inflammation and ventricular remodeling [31]. In macrophages, GDF-15 induces the expression of ABCA1 by triggering the PI3-K related pathway, and then indirectly results in atherosclerosis [32]. Furthermore, the up-regulated GDF-15 also involves in the damage on endothelial cell mediated by the increased glucose levels via attenuating NF-1 and activating the PI3K/AKT/eNOS signaling pathway [33]. Despite the mechanism by which GDF-15 acts remains unclear, we speculate that it is the existence of above-mentioned signaling pathways or signaling molecules that makes GDF-15 a potential inflammatory factor connecting T2DM with CAD.

Both T2DM and CAD exist lipid metabolism disorders, with a large number of studies having shown that dyslipidemia acts as a crucial part in the occurrence of CAD in T2DM patients [34, 35]. A retrospective study conducted in Romanian T2DM populations found that abnormal blood lipids were an important cause of CAD and up to 91.48% of subjects had both CAD and a history of receiving lipid-lowering drugs such as atorvastatin [34]. Another observational study in Swedes with T2DM indicated that serum non-HDL-C to HDL-C ratio might predict CAD [36]. According to existing literature, it can be assumed that dyslipidemia acts as a vital role in T2DM and CAD.

ApoB/ApoA1 ratio is elevated in diabetics with CAD in this study, but the mechanism is unclear. Voluminous literature revealed that the development of CAD in diabetic patients was a long-term process involving increased LDL-C levels and decreased HDL-C levels, accompanied by the continuous formation of subintimal foam cells [36, 37]. A multivariate Mendelian randomization study showed that the ApoB in LDL may be a major feature of the serum lipid profile and etiology of CAD [16, 38]. Thomas et al. found that administration of ApoB synthesis inhibitors significantly reduced the risk of CAD [39], indicating the potential value of ApoB. ApoA1 is a constituent of HDL-C and participates in hepatic cholesterol metabolism. Another study from a large-scaled population indicated that the combination of HDL-C and ApoA1 predicted the occurrence of CAD, as well as presenting a close association between ApoA1 and the risk factors of CAD, including high BMI, CRP, and ApoB [40]. Serum ApoB/ApoA1 ratio was also reportedly associated with first myocardial infarction [41]. These findings suggest that ApoB/ApoA1 ratio might act as a potential marker, providing novel perspectives for explaining the associations between CAD and T2DM.

Study strength and limitations

The current research indicated, for the first time, that the ApoB/ApoA1 ratio and concentrations of serum GDF-15 were predictive indicators of CAD in Chinese patients with T2DM, independent of potential risk factors such as hyperglycemia, diabetic duration, hypertension and age. Therefore, dynamically monitoring variations in the ApoB/ApoA1 ratio and GDF-15 concentration has high value for clinical management of T2DM.

However, several limitations in this study should be considered. First, the serum samples were collected from Chinese, which means the generalizability of the study findings to different regions or ethnicities requires further verification. In addition, statistical power in this research was limited by the small sample size. Third, despite adjustments for medication and other confounders, it was not possible to rule out potential elements such as the effect of other drugs on GDF-15, ApoB and ApoA1 that were not recorded in this study. Fourth, follow-up data applicable to long-term prognosis was missing in the patients with T2DM.


All in all, circulating GDF-15 levels and serum ApoB/ApoA1 ratio in T2DM patients with CAD were higher than those who with T2DM only. Serum GDF-15 levels and the ApoB/ApoA1 ratio may therefore be helpful in T2DM patients for predicting CAD and preventing adverse cardiovascular events.

Availability of data and materials

The datasets generated during and analyzed during the current study are not publicly available due to privacy or ethical restrictions but are available from the corresponding author on reasonable request.



Growth differentiation factor 15


Apolipoprotein B


Apolipoprotein A1


Coronary artery disease


Type 2 diabetes mellitus


Diabetes mellitus


Body mass index


White blood cell






Neutrophil to lymphocyte ratios


High-sensitivity C-reactive protein


Glycated hemoglobin A1c


Fasting plasma glucose


2 h-plasma glucose


Glycated albumin


Glycated albumin ratio


Alanine aminotransferase


Aspartate aminotransferase


γ-glutamyl transpeptidase




Uric acid


Estimated glomerular filtration rate


Free fatty acid


Total cholesterol




High-density lipoprotein cholesterol


Low-density lipoprotein cholesterol


Receiver operating curve


  1. Sun H, Saeedi P, Karuranga S, et al. IDF diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2021;109119. published online ahead of print, 2021 Nov 24.

  2. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88–98.

    Article  PubMed  Google Scholar 

  3. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018;17(1):83.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hirata A, Kishida K, Nakatsuji H, Hiuge-Shimizu A, Funahashi T, Shimomura I. High serum S100A8/A9 levels and high cardiovascular complication rate in type 2 diabetics with ultrasonographic low carotid plaque density. Diabetes Res Clin Pract. 2012;97(1):82–90.

    Article  CAS  PubMed  Google Scholar 

  5. Wu HK, Zhang Y, Cao CM, et al. Glucose-sensitive Myokine/Cardiokine MG53 regulates systemic insulin response and metabolic homeostasis. Circulation. 2019;139(7):901–14 published correction appears in circulation. 2019 Jul 16;140(3):e160.

    Article  CAS  Google Scholar 

  6. Hörbelt T, Tacke C, Markova M, et al. The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes. Diabetologia. 2018;61(9):2054–65.

    Article  CAS  PubMed  Google Scholar 

  7. He X, Su J, Ma X, et al. The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes. Cardiovasc Diabetol. 2020;19(1):40. Published 2020 Mar 28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol. 2021;17(10):592–607.

    Article  CAS  PubMed  Google Scholar 

  9. Nakayasu ES, Syed F, Tersey SA, et al. Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention. Cell Metab. 2020;31(2):363–374.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bonaterra GA, Zügel S, Thogersen J, et al. Growth differentiation factor-15 deficiency inhibits atherosclerosis progression by regulating interleukin-6-dependent inflammatory response to vascular injury. J Am Heart Assoc. 2012;1(6):e002550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ackermann K, Bonaterra GA, Kinscherf R, Schwarz A. Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages. Atherosclerosis. 2019;281:128–36.

    Article  CAS  PubMed  Google Scholar 

  12. Wang J, Wei L, Yang X, Zhong J. Roles of growth differentiation factor 15 in atherosclerosis and coronary artery disease. J Am Heart Assoc. 2019;8(17):e012826.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Li J, Yang L, Qin W, Zhang G, Yuan J, Wang F. Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus. PLoS One. 2013;8(6):e65549. Published 2013 Jun 14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Du Y, Chen J, Chen MH, et al. Relationship of lipid and lipoprotein ratios with coronary severity in patients with new on-set coronary artery disease complicated with type 2 diabetics. J Geriatr Cardiol. 2016;13(8):685–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Raj R, Bhatti JS, Badada SK, Ramteke PW. Genetic basis of dyslipidemia in disease precipitation of coronary artery disease (CAD) associated type 2 diabetes mellitus (T2DM). Diabetes Metab Res Rev. 2015;31(7):663–71.

    Article  CAS  PubMed  Google Scholar 

  16. Khatana C, Saini NK, Chakrabarti S, et al. Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis. Oxidative Med Cell Longev. 2020;2020:5245308. Published 2020 Sep 15.

    Article  CAS  Google Scholar 

  17. Ouimet M, Barrett TJ, Fisher EA. HDL and reverse cholesterol transport. Circ Res. 2019;124(10):1505–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cesaro A, Schiavo A, Moscarella E, et al. Lipoprotein(a): a genetic marker for cardiovascular disease and target for emerging therapies. J Cardiovasc Med (Hagerstown). 2021;22(3):151–61.

    Article  CAS  Google Scholar 

  19. Gragnano F, Fimiani F, Di Maio M, et al. Impact of lipoprotein(a) levels on recurrent cardiovascular events in patients with premature coronary artery disease. Intern Emerg Med. 2019;14(4):621–5.

    Article  PubMed  Google Scholar 

  20. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S15–33. published correction appears in Diabetes Care. 2021 Sep;44(9):2182.

    Article  Google Scholar 

  21. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the task force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–219.

    Article  PubMed  Google Scholar 

  22. Winther S, Schmidt SE, Rasmussen LD, et al. Validation of the European Society of Cardiology pre-test probability model for obstructive coronary artery disease. Eur Heart J. 2021;42(14):1401–11.

    Article  PubMed  Google Scholar 

  23. Delgado C, Baweja M, Crews DC, et al. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. Am J Kidney Dis. 2021;S0272–6386(21)00828–3. published online ahead of print, 2021 Sep 23.

  24. Wilson PW. Diabetes mellitus and coronary heart disease. Am J Kidney Dis. 1998;32(5 Suppl 3):S89–S100.

    Article  CAS  PubMed  Google Scholar 

  25. Adela R, Banerjee SK. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res. 2015;2015:490842.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Echouffo-Tcheugui JB, Daya N, Ndumele CE, et al. Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study. Diabetologia. 2022;65(6):955–63.

    Article  CAS  PubMed  Google Scholar 

  27. Skau E, Henriksen E, Wagner P, Hedberg P, Siegbahn A, Leppert J. GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction. Eur J Prev Cardiol. 2017;24(15):1576–83.

    Article  PubMed  Google Scholar 

  28. Au Yeung SL, Luo S, Schooling CM. The impact of GDF-15, a biomarker for metformin, on the risk of coronary artery disease, breast and colorectal cancer, and type 2 diabetes and metabolic traits: a Mendelian randomisation study. Diabetologia. 2019;62(9):1638–46.

    Article  CAS  PubMed  Google Scholar 

  29. Elsewify WAE, Ashry MA, Elsaied AA, Hassan MH, Ahmed MA, Mahmoud HEM. Validity of B-type natriuretic peptide, growth differentiation factor 15, and high-sensitivity troponin I levels in ischemic heart failure. Clin Lab. 2022;68(5).

  30. Girerd N, Cleland J, Anker SD, et al. Inflammation and remodeling pathways and risk of cardiovascular events in patients with ischemic heart failure and reduced ejection fraction. Sci Rep. 2022;12(1):8574. Published 2022 May 20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ago T, Sadoshima J. GDF15, a cardioprotective TGF-beta superfamily protein. Circ Res. 2006;98(3):294–7.

    Article  CAS  PubMed  Google Scholar 

  32. Wu JF, Wang Y, Zhang M, et al. Growth differentiation factor-15 induces expression of ATP-binding cassette transporter A1 through PI3-K/PKCζ/SP1 pathway in THP-1 macrophages. Biochem Biophys Res Commun. 2014;444(3):325–31.

    Article  CAS  PubMed  Google Scholar 

  33. Ho FM, Lin WW, Chen BC, et al. High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-kappaB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway. Cell Signal. 2006;18(3):391–9.

    Article  CAS  PubMed  Google Scholar 

  34. Găman MA, Cozma MA, Dobrică EC, Bacalbașa N, Bratu OG, Diaconu CC. Dyslipidemia: a trigger for coronary heart disease in Romanian patients with diabetes. Metabolites. 2020;10(5):195. Published 2020 May 14.

    Article  CAS  PubMed Central  Google Scholar 

  35. Garber AJ. Implications of cardiovascular risk in patients with type 2 diabetes who have abnormal lipid profiles: is lower enough? Diabetes Obes Metab. 2000;2(5):263–70.

    Article  CAS  PubMed  Google Scholar 

  36. Eliasson B, Gudbjörnsdottir S, Zethelius B, Eeg-Olofsson K, Cederholm J. National Diabetes Register (NDR). LDL-cholesterol versus non-HDL-to-HDL-cholesterol ratio and risk for coronary heart disease in type 2 diabetes. Eur J Prev Cardiol. 2014;21(11):1420–8.

    Article  PubMed  Google Scholar 

  37. Wang M, Wang D, Zhang Y, Wang X, Liu Y, Xia M. Adiponectin increases macrophages cholesterol efflux and suppresses foam cell formation in patients with type 2 diabetes mellitus. Atherosclerosis. 2013;229(1):62–70.

    Article  CAS  PubMed  Google Scholar 

  38. Richardson TG, Sanderson E, Palmer TM, et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis. PLoS Med. 2020;17(3):e1003062. Published 2020 Mar 23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013;62(23):2178–84.

    Article  CAS  PubMed  Google Scholar 

  40. van Capelleveen JC, Bochem AE, Boekholdt SM, et al. Association of High-Density Lipoprotein-Cholesterol Versus Apolipoprotein A-I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer-Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women’s Health Study. J Am Heart Assoc. 2017;6(8):e006636. Published 2017 Aug 3.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Bodde MC, Hermans MPJ, Jukema JW, et al. Apolipoproteins A1, B, and apoB/apoA1 ratio are associated with first ST-segment elevation myocardial infarction but not with recurrent events during long-term follow-up. Clin Res Cardiol. 2019;108(5):520–38.

    Article  CAS  PubMed  Google Scholar 

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We are grateful to all participants in charge with data collection, laboratory measurement and statistical analysis and all authors have agreed with the content of this study.


This research was supported by the National Natural Science Foundation of China (Grant Numbers: 81772265).

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Authors and Affiliations



Yufeng M carried out most of the experimental work and wrote the paper. Yan L directed the research and provided funding supports. Yufeng Mei, Zhiming Zhao and Yongnan Lyu collected the samples and performed data analysis. Zhiming Zhao contributed greatly to the statistical analysis and revision of this manuscript. Grammar and syntax errors in the whole study has been checked by Zhiming Zhao. All authors read and approved the final manuscript.

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Correspondence to Yan Li.

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This study was approved by the Medical Ethics Review Committee of Renmin Hospital of Wuhan University, China, and complies with the Declaration of Helsinki and all participants signed informed consent.

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Supplementary Information

Additional file 1: Table X1.

Characteristic of 253 CAD patients

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Mei, Y., Zhao, Z., Lyu, Y. et al. Circulating growth differentiation factor 15 levels and apolipoprotein B to apolipoprotein A1 ratio in coronary artery disease patients with type 2 diabetes mellitus. Lipids Health Dis 21, 59 (2022).

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