Next Article in Journal
Potential of MMP-2 and MMP-9 Gelatinase Blockade as a Therapeutic Strategy in Fibrosarcoma Treatment: A Decadal Review
Previous Article in Journal
SK-03-92 Treatment Causes Release of a Lethal Factor Protein That Kills Staphylococcus aureus Cells
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Non-Fasting Plasma Triglycerides Are Positively Associated with Diabetes Mortality in a Representative US Adult Population

1
Discipline of Life Science, Institute of Innovation, Science and Sustainability, Federation University Australia, Ballarat, VIC 3350, Australia
2
Department of Urology, The Second Hospital of Shandong University, Jinan 250033, China
3
Cardiometabolic Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100037, China
*
Author to whom correspondence should be addressed.
Targets 2024, 2(2), 93-103; https://doi.org/10.3390/targets2020006
Submission received: 17 April 2024 / Revised: 19 May 2024 / Accepted: 22 May 2024 / Published: 24 May 2024

Abstract

:
This study aimed to investigate whether non-fasting plasma triglycerides were associated with diabetes mortality. It included 7312 US adult participants. Diabetes mortality data were obtained via the linkage to National Death Index (NDI) records. Hazard ratios of non-fasting plasma triglycerides for diabetes mortality were assessed using Cox proportional hazards models, adjusting for age, gender, ethnicity, obesity, poverty–income ratio, education levels, physical activity, alcohol consumption, cigarette smoking status, survey period, hypercholesterolemia, hypertension, diabetes, and family history of diabetes. Among these participants, 1180 had diabetes. A total of 420 diabetes-caused deaths were recorded during a mean follow-up of 16.8 years. A 1-natural-log-unit increase in non-fasting plasma triglycerides was associated with a 41% higher diabetes mortality risk (hazard ratio, 1.41; 95% confidence interval, 1.19–1.67). Participants with non-fasting plasma triglycerides in the highest quintile, versus those in the lowest quintile, had a 141% higher diabetes mortality risk (hazard ratio, 2.41; 95% confidence interval, 1.46–3.97). The positive association of non-fasting plasma triglycerides with diabetes mortality was independent of diabetes status at the baseline. In conclusion, this study demonstrated that non-fasting plasma triglycerides were positively associated with diabetes mortality, independent of diabetes status at baseline. Non-fasting triglycerides may be a therapeutic target for diabetes-related complications.

1. Introduction

According to the World Health Organization, diabetes affects 422 million individuals worldwide and causes 1.5 million deaths per year [1]. The diabetes mortality rate has increased over time. The age-standardized mortality rate from diabetes is increased by 3% from 2000 to 2019 worldwide, whereas the increase is 13% in lower-middle-income countries [1]. In the US, diabetes leads to 30.4 deaths per 100,000 population per year and is the eighth leading cause of death [2]. Therefore, it is important to investigate the modifiable risk factors for diabetes mortality.
High triglycerides have been linked to cardiovascular events [3,4], cardiovascular mortality [5], and all-cause mortality [6]. Recently, baseline fasting plasma triglycerides have been shown to be positively associated with diabetes mortality [7], suggesting that triglycerides may play a crucial role in glycemic control. However, whether non-fasting triglycerides are associated with diabetes mortality is unknown.
Some guidelines have started to recommend the use of non-fasting triglycerides for general screening and risk evaluation [8,9]. This shift from fasting to non-fasting triglyceride tests is supported by various reasons. Non-fasting tests are more comfortable and convenient than fasting tests, and they may be safer as certain people may experience hypoglycemia when fasting [8,9]. In addition, non-fasting triglyceride levels are ~27 mg/dL above their fasting counterpart [8], and this difference is thought to be not clinically significant for most people [8]. Most importantly, non-fasting triglycerides seem to a have similar or better prognostic value for general risk screening compared with their fasting counterpart [6,8]. Therefore, it is clinically relevant to investigate whether non-fasting triglycerides are associated with diabetes mortality.
This study aimed to investigate the association of non-fasting plasma triglycerides with diabetes mortality using US adults who attended the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2014.

2. Materials and Methods

2.1. Study Participants

A total of 7490 adults aged ≥ 20 years attended the NHANES from 1988 to 2014 and had their non-fasting (fasting time < 8 h) plasma triglycerides available. The following participants with missing data were excluded from this study: follow-up time (n = 14), blood hemoglobin A1c (HbA1c, n = 38), plasma glucose (n = 31), serum insulin (n = 45), cigarette smoking status (n = 1), or education (n = 49). The remaining 7312 participants were included in the final analysis. The study was conducted following the ethical standards laid down in the Declaration of Helsinki. It was approved by the National Center for Health Statistics Research Ethics Review Board. All procedures were performed following the guidelines of the Declaration of Helsinki. The participants’ records were anonymized before being accessed by the author.

2.2. Definitions of Comorbidities

Diabetes was defined as HbA1c ≥ 6.5%, fasting plasma glucose ≥ 126 mg/dL, taking hypoglycemic drugs, or self-reported diagnosis [10]. Hypercholesterolemia was defined as total cholesterol ≥ 240 mg/dL or self-reported diagnosis of hypercholesterolemia [11]. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg or prior diagnosis or treatment of hypertension [12].

2.3. Diabetes Mortality

Diabetes mortality was obtained from NHANES-linked mortality files and was defined as diabetes being listed as underlying cause of death [7]. Follow-up time was defined as the time (in months) from the time when the blood was drawn at the Mobile Examination Center until death, or until the end of follow-up (i.e., 31 December 2015), whichever occurred first.

2.4. Covariates

Confounding covariates of this study included age, gender, ethnic background (Hispanic, non-Hispanic black, non-Hispanic white, or other), obesity (underweight, normal, overweight, obese, or unknown) [13], education (<high school, high school, or >high school) [14], poverty–income ratio (<130%, 130%–349%, ≥350%, or unknown) [15], and survey periods [16]. Lifestyle confounders included physical activity (inactive, insufficiently active, or active) [7], alcohol consumption (never, <1 drink per week, 1–6 drinks per week, ≥7 drinks per week, or unknown), and cigarette smoking (smoker or non-smoker). Clinical confounding factors included hypercholesterolemia, hypertension, diabetes, and family history of diabetes [7].

2.5. Statistical Analyses

Data were presented as mean and standard deviation for continuous variables or percentages for categorical variables. The difference in the baseline variables between participants with and without diabetes was analyzed by T-test (for continuous variables) or chi-squared test (for categorical variables) [17]. Associations of non-fasting plasma triglycerides with diabetes markers (glucose, HbA1c, and insulin) were analyzed using scatter plots and linear regression. The association of plasma triglycerides with diabetes diagnosis was analyzed by binary logistic regression [18].
The performance of non-fasting triglycerides for classifying diabetes mortality was analyzed using receiver operating characteristic (ROC) curve analysis [19,20]. The optimal cutoff was determined by the Youden Index [21]. Hazard ratios (HRs) and 95% confidence intervals (CIs) of non-fasting plasma triglycerides for diabetes mortality were analyzed using Cox proportional hazards models [22], with or without adjustment for the following confounders: age, gender, ethnicity, obesity, poverty–income ratio, education levels, physical activity, alcohol consumption, cigarette smoking status, survey period, hypercholesterolemia, hypertension, diabetes, and family history of diabetes. Triglycerides, glucose, HbA1c, and insulin were natural-log-transformed to improve the data distribution in all the regression analyses. Sensitivity analyses were conducted by further adjustment for total cholesterol and HDL cholesterol. All the analyses were conducted using SPSS (version 27.0). A two-sided p value of <0.05 was considered as statistically significant.

3. Results

3.1. Baseline Characteristics

This cohort included 7312 US adult participants, among which 1180 had diabetes. The baseline characteristics are described in Table 1.

3.2. Association of Non-Fasting Triglycerides with Plasma Glucose, Blood Hemoglobin A1c, Serum Insulin, and Diabetes

Scatter plots showed that non-fasting plasma triglycerides were positively associated with glucose, HbA1c, and insulin, independent of diabetes diagnosis at baseline (Figure 1). The positive associations remained after adjustment for all the tested confounders (Table 2). A 1-natural-log-unit increase in non-fasting plasma triglycerides (e.g., from 80 to 217 mg/dL) was associated with a 130% higher diabetes diagnosis risk (adjusted odds ratio, 2.30; 95% CI, 2.01–2.63; p < 0.001).

3.3. Association of Non-Fasting Triglycerides with Diabetes Mortality

During 122,940 person-years of follow-up (mean follow-up 16.8 years), 420 diabetes-caused deaths were documented. A 1-natural-log-unit increase in non-fasting plasma triglycerides was associated with a 41% higher risk of diabetes mortality, which was independent of diabetes status at baseline (Table 3).
An ROC curve analysis showed that non-fasting triglycerides classified diabetes mortality with an optimal cutoff of 135.5 mg/dL (p < 0.001) (Figure 2). The optimal cutoff was lower in participants without diabetes (103.5 mg/dL) than in participants with diabetes (135.5 mg/dL, Figure 2).
A Kaplan–Meier analysis was conducted to assess the association of triglycerides with diabetes mortality. In this analysis, triglyceride was treated as a dichotomous categorical variable using the optimal cutoffs determined in Figure 2. The results showed that participants with triglycerides above the cutoff had worse survival compared with those with triglycerides below the cutoff in the whole cohort (Figure 3). Similar results were obtained in the sub-cohorts of participants with or without diabetes (Figure 3). A Cox proportional hazards models analysis confirmed that triglycerides above the cutoff remained an independent risk factor for diabetes mortality after adjusting for all the tested confounders (Table 4).

3.4. Sensitivtiy Analyses

Further analysis showed that similar results were obtained when triglycerides were stratified as quintiles: participants with non-fasting plasma triglycerides in the highest quintile, versus those in the lowest quintile, had a 141% higher risk of diabetes mortality (adjusted HR, 2.41; 95% CI, 1.46–3.97, Table 5). The positive association remained in those with or without diabetes at baseline (Table 6 and Table 7). Sensitivity analyses showed that the positive association remained after a further adjustment for total cholesterol and HDL cholesterol (Table 5, Table 6 and Table 7).

4. Discussion

Using a representative cohort of US adults, this study found, for the first time, that non-fasting plasma triglycerides were positively associated with diabetes mortality. This study extended the previous finding that triglycerides are positively associated with diabetes mortality from the fasting state [7,23] to the non-fasting state. Similar to the previous finding [7], such an association was independent of diabetes status at the baseline. Therefore, non-fasting triglycerides might be used to detect those with a high risk of diabetes mortality.
The mechanism underlying the positive association between triglycerides and diabetes mortality is unclear. A few hypotheses have been put forward. For example, triglycerides promote inflammation [24]. Additionally, a higher number of triglycerides may co-exist with other morbidities, such as hypercholesterolemia and hypertension, and diabetes [25]; however, after adjusting for these co-morbidities, our results showed that triglycerides remained positively associated with diabetes mortality.
Some guidelines have started to recommend the use of non-fasting triglycerides for general screening and risk evaluation [8,9]. The results of the study also support the use of non-fasting triglycerides for risk prediction, which is consistent with previous reports [6,8].
Many studies have shown a positive relationship between triglycerides and diabetes prevalence [7] and incidence [26,27,28,29,30]. In addition, fibrates, triglyceride-lowering medications, protect against diabetes in both mice [31] and humans [32,33,34]. Moreover, elevated triglyceride levels contribute to insulin resistance [35,36,37] and pancreatitis [37,38], key factors in diabetes development, with insulin resistance accounting for 49% of the link between high triglycerides and diabetes [39]. These results suggest that high triglycerides may be a causal factor for diabetes; however, the reverse causality cannot be ruled out.
This study found that the optimal cutoff of non-fasting triglycerides for diabetes mortality was 135.5 mg/dL. This cutoff is supported by the mortality data: those with non-fasting triglycerides above the cutoff had a 37% higher multivariable-adjusted risk of diabetes mortality compared with those below the cutoff. However, this cutoff is lower than the current hypertriglyceridemia threshold of 150 mg/dL [40,41]. The lower threshold of triglycerides for cardiovascular incidence [42,43], all-cause mortality [6,44], and diabetes mortality [23] have been reported previously. Therefore, whether the hypertriglyceridemia cutoff of 150 mg/dL should be lowered needs to be further investigated in the future.
The present study has a number of strengths, e.g., a large sample size (n = 7312) derived from a nationally representative adult sample, prospective study design, and adjustment for many confounders.
This study has some limitations. Firstly, it lacked multiple triglyceride measurements throughout the study [45]. Secondly, mortality outcomes were ascertained by the linkage to National Death Index (NDI) records with a probabilistic match, which might result in misclassification, although this matching method had a high accuracy of 98.5% [46,47].

5. Conclusions

Non-fasting triglycerides were positively associated with diabetes mortality, suggesting that non-fasting triglycerides might be used to detect those with a high risk of diabetes mortality.

Author Contributions

Conceptualization, Y.W.; formal analysis, Y.W.; data curation, Y.F.; writing—original draft preparation, Y.W., X.Z. and N.-Q.W.; writing—review and editing, Y.W., Y.F., X.Z. and N.-Q.W.; and funding acquisition, Y.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Health and Medical Research Council of Australia, grant number 1062671.

Institutional Review Board Statement

The National Center for Health Statistics Research Ethics Review Board (ERB) approved all the study protocols (ERB Numbers: NHANES III, NHANES Protocol #98–12, NHANES Protocol #2005–06, and NHANES Protocol #2011–17).

Informed Consent Statement

All participants provided their written informed consent.

Data Availability Statement

The datasets supporting the conclusions of this article are publicly available on the NHANES website, https://www.cdc.gov/nchs/nhanes/index.htm (accessed on 10 May 2020).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. World Health Organization. Diabetes. 2023. Available online: https://www.who.int/news-room/fact-sheets/detail/diabetes (accessed on 31 August 2023).
  2. Centers for Disease Control and Prevention. Diabetes. 2024. Available online: https://www.cdc.gov/nchs/fastats/diabetes.htm (accessed on 17 May 2024).
  3. Nordestgaard, B.G.; Varbo, A. Triglycerides and cardiovascular disease. Lancet 2014, 384, 626–635. [Google Scholar] [CrossRef] [PubMed]
  4. Raposeiras-Roubin, S.; Rosselló, X.; Oliva, B.; Fernández-Friera, L.; Mendiguren, J.M.; Andrés, V.; Bueno, H.; Sanz, J.; Martínez de Vega, V.; Abu-Assi, E.; et al. Triglycerides and Residual Atherosclerotic Risk. J. Am. Coll. Cardiol. 2021, 77, 3031–3041. [Google Scholar] [CrossRef] [PubMed]
  5. Wang, Y.; Fang, Y.; Magliano, D.J.; Charchar, F.J.; Sobey, C.G.; Drummond, G.R.; Golledge, J. Fasting triglycerides are positively associated with cardiovascular mortality risk in people with diabetes. Cardiovasc. Res. 2023, 119, 826–834. [Google Scholar] [CrossRef]
  6. Fang, Y.; Wang, Y. Fasting status modifies the association between triglyceride and all-cause mortality: A cohort study. Health Sci. Rep. 2022, 5, e642. [Google Scholar] [CrossRef] [PubMed]
  7. Wang, Y. Higher fasting triglyceride predicts higher risks of diabetes mortality in US adults. Lipids Health Dis. 2021, 20, 181. [Google Scholar] [CrossRef] [PubMed]
  8. Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; et al. ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur. Heart J. 2019, 41, 111–188. [Google Scholar] [CrossRef] [PubMed]
  9. Pearson, G.J.; Thanassoulis, G.; Anderson, T.J.; Barry, A.R.; Couture, P.; Dayan, N.; Francis, G.A.; Genest, J.; Grégoire, J.; Grover, S.A.; et al. Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can. J. Cardiol. 2021, 37, 1129–1150. [Google Scholar] [CrossRef] [PubMed]
  10. American Diabetes Association, 2. 10. American Diabetes Association, 2. Classification and diagnosis of diabetes: Standards of medical care in diabetes. Diabetes Care. [CrossRef]
  11. Liu, L.; Miura, K.; Kadota, A.; Fujiyoshi, A.; Gracely, E.J.; Xue, F.; Liu, Z.; Takashima, N.; Miyagawa, N.; Ohkubo, T.; et al. The impact of sex on risk of cardiovascular disease and all-cause mortality in adults with or without diabetes mellitus: A comparison between the U.S. and Japan. J. Diabetes Complicat. 2019, 33, 417–423. [Google Scholar] [CrossRef] [PubMed]
  12. Chobanian, A.V.; Bakris, G.L.; Black, H.R.; Cushman, W.C.; Green, L.A.; Izzo, J.L., Jr.; Jones, D.W.; Materson, B.J.; Oparil, S.; Wright, J.T., Jr.; et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003, 42, 1206–1252. [Google Scholar] [CrossRef] [PubMed]
  13. Urrutia, I.; Martín-Nieto, A.; Martínez, R.; Casanovas-Marsal, J.O.; Aguayo, A.; Del Olmo, J.; Arana, E.; Fernandez-Rubio, E.; Castaño, L.; Gaztambide, S. Incidence of diabetes mellitus and associated risk factors in the adult population of the Basque country, Spain. Sci. Rep. 2021, 11, 3016. [Google Scholar] [CrossRef]
  14. Al-Mawali, A.; Al-Harrasi, A.; Jayapal, S.K.; Morsi, M.; Pinto, A.D.; Al-Shekaili, W.; Al-Kharusi, H.; Al-Balushi, Z.; Idikula, J. Prevalence and risk factors of diabetes in a large community-based study in the Sultanate of Oman: STEPS survey 2017. BMC Endocr. Disord. 2021, 21, 42. [Google Scholar] [CrossRef] [PubMed]
  15. Alam, M.S.; Dyck, R.; Janzen, B.; Karunanayake, C.; Dosman, J.; Pahwa, P. Risk factors, incidence, and prevalence of diabetes among rural farm and non-farm residents of Saskatchewan, Canada; A population-based longitudinal cohort study. J. Diabetes Metab. Disord. 2020, 19, 1563–1582. [Google Scholar] [CrossRef]
  16. Wang, Y. Stage 1 hypertension and risk of cardiovascular disease mortality in United States adults with or without diabetes. J. Hypertens. 2022, 40, 794–803. [Google Scholar] [CrossRef]
  17. Turner, N. Chi-squared test. J. Clin. Nurs. 2000, 9, 93. [Google Scholar] [PubMed]
  18. Elkahwagy, D.; Kiriacos, C.J. Logistic regression and other statistical tools in diagnostic biomarker studies. Clin. Transl. Oncol. 2024. [Google Scholar] [CrossRef] [PubMed]
  19. Brancato, D.; Saura, G.; Fleres, M.; Ferrara, L.; Scorsone, A.; Aiello, V.; Di Noto, A.; Spano, L.; Provenzano, V. Prognostic accuracy of continuous glucose monitoring in the prediction of diabetes mellitus in children with incidental hyperglycemia: Receiver operating characteristic analysis. Diabetes Technol. Ther. 2013, 15, 580–585. [Google Scholar] [CrossRef]
  20. Wang, Y.; Fang, Y. Postabsorptive homeostasis model assessment for insulin resistance is a reliable biomarker for cardiovascular disease mortality and all-cause mortality. Diabetes Epidemiol. Manag. 2021, 6, 100045. [Google Scholar] [CrossRef]
  21. Perkins, N.J.; Schisterman, E.F. The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am. J. Epidemiol. 2006, 163, 670–675. [Google Scholar] [CrossRef] [PubMed]
  22. Tao, C.; Hu, N.; Liu, Y.; Wang, H.; Wang, Z.; Zhang, K.; Wang, L.; Chen, B.; Wu, F.; Rong, W.; et al. Long-term outcome of adjuvant radiotherapy upon postoperative relapse of centrally located hepatocellular carcinoma: A real-world study. Sci. Rep. 2024, 14, 8506. [Google Scholar] [CrossRef]
  23. Wang, Y. Fasting triglycerides in the upper normal range are independently associated with an increased risk of diabetes mortality in a large representative US population. J. Cardiovasc. Dev. Dis. 2024, 11, 128. [Google Scholar] [CrossRef]
  24. Aung, H.H.; Lame, M.W.; Gohil, K.; An, C.I.; Wilson, D.W.; Rutledge, J.C. Induction of ATF3 gene network by triglyceride-rich lipoprotein lipolysis products increases vascular apoptosis and inflammation. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 2088–2096. [Google Scholar] [CrossRef]
  25. Pradhan, A.D. A New Beginning for Triglyceride-Lowering Therapies. Circulation 2019, 140, 167–169. [Google Scholar] [CrossRef]
  26. Tirosh, A.; Shai, I.; Bitzur, R.; Kochba, I.; Tekes-Manova, D.; Israeli, E.; Shochat, T.; Rudich, A. Changes in triglyceride levels over time and risk of type 2 diabetes in young men. Diabetes Care 2008, 31, 2032–2037. [Google Scholar] [CrossRef]
  27. Zhao, J.; Zhang, Y.; Wei, F.; Song, J.; Cao, Z.; Chen, C.; Zhang, K.; Feng, S.; Li, W.-D. Triglyceride is an independent predictor of type 2 diabetes among middle-aged and older adults: A prospective study with 8-year follow-ups in two cohorts. J. Transl. Med. 2019, 17, 403. [Google Scholar] [CrossRef] [PubMed]
  28. Beshara, A.; Cohen, E.; Goldberg, E.; Lilos, P.; Garty, M.; Krause, I. Triglyceride levels and risk of type 2 diabetes mellitus: A longitudinal large study. J. Investig. Med. 2016, 64, 383–387. [Google Scholar] [CrossRef]
  29. Guo, R.; Wei, L.; Cao, Y.; Zhao, W. Normal triglyceride concentration and the risk of diabetes mellitus type 2 in the general population of China. Front. Endocrinol. 2024, 15, 1330650. [Google Scholar] [CrossRef]
  30. Szili-Torok, T.; Bakker, S.J.L.; Tietge, U.J.F. Normal fasting triglyceride levels and incident type 2 diabetes in the general population. Cardiovasc. Diabetol. 2022, 21, 111. [Google Scholar] [CrossRef] [PubMed]
  31. Araki, M.; Nakagawa, Y.; Oishi, A.; Han, S.I.; Kumagai, K.; Ohno, H.; Mizunoe, Y.; Iwasaki, H.; Sekiya, M.; Matsuzaka, T.; et al. The peroxisome proliferator-activated receptor α (PPARα) agonist pemafibrate protects against diet-induced obesity in mice. Int. J. Mol. Sci. 2018, 19, 2148. [Google Scholar] [CrossRef] [PubMed]
  32. Tenenbaum, A.; Motro, M.; Fisman, E.Z.; Schwammenthal, E.; Adler, Y.; Goldenberg, I.; Leor, J.; Boyko, V.; Mandelzweig, L.; Behar, S. Peroxisome proliferator–activated receptor ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary artery disease. Circulation 2004, 109, 2197–2202. [Google Scholar] [CrossRef]
  33. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 2010, 362, 1563–1574. [Google Scholar] [CrossRef]
  34. Keech, A.C.; Mitchell, P.; Summanen, P.A.; O’Day, J.; Davis, T.M.; Moffitt, M.S.; Taskinen, M.R.; Simes, R.J.; Tse, D.; Williamson, E.; et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): A randomised controlled trial. Lancet 2007, 370, 1687–1697. [Google Scholar] [CrossRef]
  35. Hoy, A.J.; Brandon, A.E.; Turner, N.; Watt, M.J.; Bruce, C.R.; Cooney, G.J.; Kraegen, E.W. Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation. Am. J. Physiol. Endocrinol. Metab. 2009, 297, E67–E75. [Google Scholar] [CrossRef] [PubMed]
  36. Høeg, L.D.; Sjøberg, K.A.; Jeppesen, J.; Jensen, T.E.; Frøsig, C.; Birk, J.B.; Bisiani, B.; Hiscock, N.; Pilegaard, H.; Wojtaszewski, J.F.P.; et al. Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. Diabetes 2010, 60, 64–73. [Google Scholar] [CrossRef] [PubMed]
  37. Lee, J.; Jeon, S.; Lee, M.; Yoon, M. Fenofibrate alleviates insulin resistance by reducing tissue inflammation in obese ovariectomized mice. Nutr. Diabetes 2023, 13, 19. [Google Scholar] [CrossRef] [PubMed]
  38. Grundy, S.M.; Stone, N.J.; Bailey, A.L.; Beam, C.; Birtcher, K.K.; Blumenthal, R.S.; Braun, L.T.; Ferranti, S.d.; Faiella-Tommasino, J.; Forman, D.E.; et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: A report of the american college of cardiology/american heart association task force on clinical practice guidelines. Circulation 2019, 139, e1082–e1143. [Google Scholar] [CrossRef] [PubMed]
  39. Wang, Y.; Fang, Y.; Vrablik, M. Homeostasis model assessment for insulin resistance mediates the positive association of triglycerides with diabetes. Diagnostics 2024, 14, 733. [Google Scholar] [CrossRef] [PubMed]
  40. Yuan, G.; Al-Shali, K.Z.; Hegele, R.A. Hypertriglyceridemia: Its etiology, effects and treatment. CMAJ 2007, 176, 1113–1120. [Google Scholar] [CrossRef]
  41. Simha, V. Management of hypertriglyceridemia. BMJ 2020, 371, m3109. [Google Scholar] [CrossRef] [PubMed]
  42. Jeppesen, J.ø.; Hein, H.O.; Suadicani, P.; Gyntelberg, F. Triglyceride concentration and ischemic heart disease. Circulation 1998, 97, 1029–1036. [Google Scholar] [CrossRef] [PubMed]
  43. Tikhonoff, V.; Casiglia, E.; Virdis, A.; Grassi, G.; Angeli, F.; Arca, M.; Barbagallo, C.M.; Bombelli, M.; Cappelli, F.; Cianci, R.; et al. Prognostic value and relative cutoffs of triglycerides predicting cardiovascular outcome in a large regional-based italian database. J. Am. Heart Assoc. 2024, 13, e030319. [Google Scholar] [CrossRef]
  44. Klempfner, R.; Erez, A.; Sagit, B.-Z.; Goldenberg, I.; Fisman, E.; Kopel, E.; Shlomo, N.; Israel, A.; Tenenbaum, A. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease. Circ. Cardiovasc. Qual. Outcomes 2016, 9, 100–108. [Google Scholar] [CrossRef]
  45. MacMahon, S.; Peto, R.; Cutler, J.; Collins, R.; Sorlie, P.; Neaton, J.; Abbott, R.; Godwin, J.; Dyer, A.; Stamler, J. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet 1990, 335, 765–774. [Google Scholar] [CrossRef] [PubMed]
  46. National Center for Health Statistics; Office of Analysis and Epidemiology. The Linkage of National Center for Health Statistics Survey Data to the National Death Index—2015 Linked Mortality File (LMF): Methodology Overview and Analytic Considerations. 2019. Available online: https://www.cdc.gov/nchs/data-linkage/mortality-methods.htm (accessed on 9 July 2021).
  47. Menke, A.; Muntner, P.; Batuman, V.; Silbergeld, E.K.; Guallar, E. Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. Circulation 2006, 114, 1388–1394. [Google Scholar] [CrossRef]
Figure 1. Scatter plots of non-fasting triglycerides with plasma glucose, blood hemoglobin A1c, and serum insulin. The plots on the left were from all the participants, the plots in the middle were from participants without diabetes, and the plots on the right were from participants with diabetes. B values represented correlation coefficients. p < 0.05 for all the associations.
Figure 1. Scatter plots of non-fasting triglycerides with plasma glucose, blood hemoglobin A1c, and serum insulin. The plots on the left were from all the participants, the plots in the middle were from participants without diabetes, and the plots on the right were from participants with diabetes. B values represented correlation coefficients. p < 0.05 for all the associations.
Targets 02 00006 g001
Figure 2. ROC curves of non-fasting triglycerides to classify diabetes mortality. The optimal cutoff was 135.5 mg/dL in the whole cohort, with a sensitivity of 69%, a specificity of 57%, and an area under the curve (AUC) of 0.674. The optimal cutoff was 103.5 mg/dL for participants without diabetes, with a sensitivity of 80%, a specificity of 42%, and an AUC of 0.644. The optimal cutoff was 135.5 mg/dL for participants with diabetes, with a sensitivity of 73%, a specificity of 36%, and an AUC of 0.547. The blue line represented the ROC curve, and the red line represented the reference line.
Figure 2. ROC curves of non-fasting triglycerides to classify diabetes mortality. The optimal cutoff was 135.5 mg/dL in the whole cohort, with a sensitivity of 69%, a specificity of 57%, and an area under the curve (AUC) of 0.674. The optimal cutoff was 103.5 mg/dL for participants without diabetes, with a sensitivity of 80%, a specificity of 42%, and an AUC of 0.644. The optimal cutoff was 135.5 mg/dL for participants with diabetes, with a sensitivity of 73%, a specificity of 36%, and an AUC of 0.547. The blue line represented the ROC curve, and the red line represented the reference line.
Targets 02 00006 g002
Figure 3. Kaplan–Meier curves of triglycerides for diabetes mortality. The blue line (the top line) represented participants with triglycerides below the optimal cutoff, and the red line (the bottom line) represented participants with triglycerides above the optimal cutoff.
Figure 3. Kaplan–Meier curves of triglycerides for diabetes mortality. The blue line (the top line) represented participants with triglycerides below the optimal cutoff, and the red line (the bottom line) represented participants with triglycerides above the optimal cutoff.
Targets 02 00006 g003
Table 1. Baseline characteristics of the study cohort.
Table 1. Baseline characteristics of the study cohort.
AllWithout DiabetesWith Diabetesp Value
Participant number731261321180NA
Non-fasting triglycerides, mg/dL, mean (SD)159 (126)147 (108)220 (180)<0.001
Age, y, mean (SD)50 (19)48 (19)62 (14)<0.001
PG, mg/dL, mean (SD)107 (49)94 (13)176 (93)<0.001
HbA1c, %, mean (SD)5.7 (1.3)5.3 (0.5)7.8 (1.9)<0.001
Insulin, µU/mL, mean (SD)17.5 (39.6)13.4 (15.3)39.2 (89.1)
Gender (male), %46.746.946.00.58
Ethnicity, %
   Hispanic27.527.229.6<0.001
   Non-Hispanic white44.345.736.9
   Non-Hispanic black25.924.931.2
   Other2.32.32.3
Obesity, %
   Underweight2.22.50.6<0.001
   Normal35.338.617.8
   Overweight35.034.736.4
   Obese26.723.543.4
   Unknown0.80.71.8
Poverty–income ratio, %
   <130%29.928.735.7<0.001
   130%–349%38.538.737.4
   ≥350%22.323.615.3
   Unknown9.48.911.7
Education status, %
   <High School40.737.656.9<0.001
   High School29.030.024.0
   >High School30.232.419.1
Physical activity, %
   Inactive32.334.123.3<0.001
   Insufficiently active38.939.535.6
   Active28.826.541.1
Alcohol consumption, % <0.001
   0 drink/week18.716.530.2
   <1 drink/week12.212.98.3
   1–6 drinks/week17.719.67.8
   ≥7 drinks/week12.113.35.9
   Unknown39.437.847.8
Cigarette smoker, %51.451.153.50.13
Hypercholesterolemia, %33.530.748.2<0.001
Hypertension, %41.636.369.6<0.001
Diabetes, %16.10100<0.001
Family diabetes history, %44.040.363.3<0.001
Abbreviations: HbA1c, hemoglobin A1c; NA, not applicable; PG, plasma glucose; SD, standard deviation. Obesity was defined by body mass index (BMI) values: underweight, BMI < 18.5 kg/m2; normal weight, BMI between 18.5 and 24.9 kg/m2; overweight, BMI between 25.0 and 29.9 kg/m2; and obese, BMI ≥ 30 kg/m2.
Table 2. Association of non-fasting plasma triglycerides 1 with plasma glucose, 1 blood hemoglobin A1c, 1 and serum insulin, 1 analyzed by linear regression.
Table 2. Association of non-fasting plasma triglycerides 1 with plasma glucose, 1 blood hemoglobin A1c, 1 and serum insulin, 1 analyzed by linear regression.
All Participants
(n = 7312)
Without Diabetes
(n = 6132)
With Diabetes
(n = 1180)
βp Valueβp Valueβp Value
Unadjusted
   Plasma glucose0.258<0.0010.170<0.0010.191<0.001
   Hemoglobin A1c0.257<0.0010.145<0.0010.151<0.001
   Serum insulin0.396<0.0010.362<0.0010.267<0.001
Adjusted 2
   Plasma glucose0.106<0.0010.087<0.0010.235<0.001
   Hemoglobin A1c0.067<0.0010.051<0.0010.163<0.001
   Serum insulin0.286<0.0010.318<0.0010.247<0.001
1 Triglycerides, glucose, hemoglobin A1c, and serum insulin were natural-log-transformed. 2 The analysis was adjusted for age, sex, ethnicity, obesity, poverty–income ratio, education, survey period, physical activity, alcohol consumption, smoking status, hypercholesterolemia, hypertension, diabetes, and family history of diabetes.
Table 3. Non-fasting plasma triglycerides 1 and risk for diabetes mortality.
Table 3. Non-fasting plasma triglycerides 1 and risk for diabetes mortality.
All
(n = 7312)
Without Diabetes
(n = 6132)
With Diabetes
(n = 1180)
HR95% CIp ValueHR95% CIp ValueHR95% CIp Value
Model 12.502.17–2.87<0.0012.291.69–3.11<0.0011.201.01–1.420.038
Model 22.321.98–2.72<0.0011.871.32–2.65<0.0011.311.08–1.570.005
Model 32.211.87–2.61<0.0011.681.17–2.430.0061.371.13–1.650.001
Model 42.141.81–2.53<0.0011.651.15–2.390.0071.351.12–1.640.002
Model 51.411.19–1.67<0.0011.621.10–2.380.0141.331.10–1.610.004
Abbreviations: CI, confidence interval; HR, hazard ratio. 1 Triglycerides were natural-log-transformed. Model 1: unadjusted; Model 2: adjusted for age, sex, and ethnicity; Model 3: adjusted for all the factors in Model 2 plus obesity, poverty–income ratio, education, and survey period; Model 4: adjusted for all the factors in Model 3 plus physical activity, alcohol consumption, and smoking status; Model 5: adjusted for all the factors in Model 4 plus hypercholesterolemia, hypertension, diabetes, and family history of diabetes.
Table 4. Non-fasting plasma triglycerides for diabetes mortality, stratified according to dichotomous triglycerides (above versus below the optimal cutoff).
Table 4. Non-fasting plasma triglycerides for diabetes mortality, stratified according to dichotomous triglycerides (above versus below the optimal cutoff).
All
(n = 7312)
Without Diabetes
(n = 6132)
With Diabetes
(n = 1180)
HR95% CIp ValueHR95% CIp ValueHR95% CIp Value
Model 13.072.50–3.78<0.0013.241.94–5.43<0.0011.331.05–1.700.020
Model 22.261.83–2.79<0.0012.181.28–3.690.0041.311.02–1.680.035
Model 32.041.64–2.54<0.0011.931.12–3.330.0171.391.07–1.800.014
Model 42.001.61–2.48<0.0011.931.12–3.320.0181.401.08–1.820.011
Model 51.371.10–1.720.0061.861.07–3.230.0281.381.06–1.790.017
Abbreviations: CI, confidence interval; HR, hazard ratio. Model 1: unadjusted; Model 2: adjusted for age, sex, and ethnicity; Model 3: adjusted for all the factors in Model 2 plus obesity, poverty–income ratio, education, and survey period; Model 4: adjusted for all the factors in Model 3 plus physical activity, alcohol consumption, and smoking status; Model 5: adjusted for all the factors in Model 4 plus hypercholesterolemia, hypertension, diabetes, and family history of diabetes.
Table 5. Non-fasting plasma triglycerides in quintiles and adjusted risk for diabetes mortality in the whole cohort 1.
Table 5. Non-fasting plasma triglycerides in quintiles and adjusted risk for diabetes mortality in the whole cohort 1.
Model 1Model 1 with Further Adjustment for Total Cholesterol 2Model 1 with Further Adjustment for Total Cholesterol + HDL 2
HR95% CIp ValueHR95% CIp ValueHR95% CIp Value
Q1HR = 1 (reference)HR = 1 (reference)HR = 1 (reference)
Q21.721.03–2.870.0401.721.02–2.880.0401.721.02–2.890.041
Q31.901.13–3.190.0161.901.13–3.190.0161.901.12–3.220.017
Q41.921.16–3.180.0111.921.16–3.190.0111.931.14–3.240.014
Q52.411.46–3.97<0.0012.411.45–4.01<0.0012.421.40–4.170.001
Abbreviations: CI, confidence interval; HR, hazard ratio; Q, quintile (Q1 = lowest quintile and Q5 = highest quintile). 1 44 out of 7312 participants had missing HDL cholesterol values and were excluded. Therefore, the remaining 7268 participants were included in the analysis. 2 Total cholesterol and HDL cholesterol were natural-log-transformed. Model 1: adjusted for age, sex, ethnicity, obesity, poverty–income ratio, education, survey period, physical activity, alcohol consumption, smoking status, hypercholesterolemia, hypertension, diabetes, and family history of diabetes.
Table 6. Non-fasting plasma triglycerides in quintiles and adjusted risk for diabetes mortality in the sub-cohort of participants without diabetes 1.
Table 6. Non-fasting plasma triglycerides in quintiles and adjusted risk for diabetes mortality in the sub-cohort of participants without diabetes 1.
Model 1Model 1 with Further Adjustment for Total Cholesterol 2Model 1 with Further Adjustment for Total Cholesterol + HDL 2
HR95% CIp ValueHR95% CIp ValueHR95% CIp Value
Q1HR = 1 (reference)HR = 1 (reference)HR = 1 (reference)
Q22.960.84–10.390.0902.870.82–10.080.1001.330.89–1.970.160
Q34.141.22–14.060.0233.901.15–13.290.0301.250.84–1.880.275
Q43.220.92–11.230.0672.970.85–10.400.0891.591.05–2.420.030
Q54.841.42–16.540.0124.261.23–14.780.0221.821.16–2.850.009
Abbreviations: CI, confidence interval; HR, hazard ratio; Q, quintile (Q1 = lowest quintile and Q5 = highest quintile). 1 27 out of 6132 participants had missing HDL cholesterol values and were excluded. Therefore, the remaining 6105 participants were included in the analysis. 2 Total cholesterol and HDL cholesterol were natural-log-transformed. Model 1: adjusted for age, sex, ethnicity, obesity, poverty–income ratio, education, survey period, physical activity, alcohol consumption, smoking status, hypercholesterolemia, hypertension, and family history of diabetes.
Table 7. Non-fasting plasma triglycerides in quintiles and adjusted risk for diabetes mortality in the sub-cohort of participants with diabetes 1.
Table 7. Non-fasting plasma triglycerides in quintiles and adjusted risk for diabetes mortality in the sub-cohort of participants with diabetes 1.
Model 1Model 1 with Further Adjustment for Total Cholesterol 2Model 1 with Further Adjustment for Total Cholesterol + HDL 2
HR95% CIp ValueHR95% CIp ValueHR95% CIp Value
Q1HR = 1 (reference)HR = 1 (reference)HR = 1 (reference)
Q21.320.89–1.940.1641.320.89–1.940.1671.330.89–1.970.160
Q31.230.83–1.810.2991.240.84–1.820.2871.250.84–1.880.275
Q41.541.05–2.260.0291.561.06–2.300.0261.591.05–2.420.030
Q51.741.18–2.550.0051.771.19–2.620.0051.821.16–2.850.009
Abbreviations: CI, confidence interval; HR, hazard ratio; Q, quintile (Q1 = lowest quintile and Q5 = highest quintile). 1 17 out of 1180 participants had missing HDL cholesterol values and were excluded. Therefore, the remaining 1163 participants were included in the analysis. 2 Total cholesterol and HDL cholesterol were natural-log-transformed. Model 1: adjusted for age, sex, ethnicity, obesity, poverty–income ratio, education, survey period, physical activity, alcohol consumption, smoking status, hypercholesterolemia, hypertension, and family history of diabetes.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wang, Y.; Fang, Y.; Zhang, X.; Wu, N.-Q. Non-Fasting Plasma Triglycerides Are Positively Associated with Diabetes Mortality in a Representative US Adult Population. Targets 2024, 2, 93-103. https://doi.org/10.3390/targets2020006

AMA Style

Wang Y, Fang Y, Zhang X, Wu N-Q. Non-Fasting Plasma Triglycerides Are Positively Associated with Diabetes Mortality in a Representative US Adult Population. Targets. 2024; 2(2):93-103. https://doi.org/10.3390/targets2020006

Chicago/Turabian Style

Wang, Yutang, Yan Fang, Xiulin Zhang, and Na-Qiong Wu. 2024. "Non-Fasting Plasma Triglycerides Are Positively Associated with Diabetes Mortality in a Representative US Adult Population" Targets 2, no. 2: 93-103. https://doi.org/10.3390/targets2020006

APA Style

Wang, Y., Fang, Y., Zhang, X., & Wu, N.-Q. (2024). Non-Fasting Plasma Triglycerides Are Positively Associated with Diabetes Mortality in a Representative US Adult Population. Targets, 2(2), 93-103. https://doi.org/10.3390/targets2020006

Article Metrics

Back to TopTop