Triglyceride-glucose index and the risk of heart failure: evidence from two large cohorts and a Mendelian randomization analysis

BackgroundThe relationship between triglyceride-glucose (TyG) index, an emerging marker of insulin resistance, and the risk of incident heart failure (HF) was unclear. This study thus aimed to investigate this relationship.

MethodsSubjects without prevalent cardiovascular diseases from the prospective Kailuan cohort (recruited during 2006-2007) and a retrospective cohort of family medicine patients from Hong Kong (recruited during 2000-2003) were followed up until December 31st, 2019 for the outcome of incident HF. Separate adjusted hazard ratios (aHRs) summarizing the relationship between TyG index and HF risk in the two cohorts were combined using a random-effect meta-analysis. Additionally, a two-sample Mendelian randomization (MR) of published genome-wide association study data was performed to assess the causality of observed associations.

ResultsIn total, 95,996 and 19,345 subjects from the Kailuan and Hong Kong cohorts were analyzed, respectively, with 2,726 cases (2.8%) of incident HF in the former and 1,709 (7.0%) in the latter. Subjects in the highest quartile of TyG index had the highest risk of incident HF in both cohorts (Kailuan: aHR 1.23 (95% confidence interval: 1.09-1.39), PTrend <0.001; Hong Kong: aHR 1.21 (1.04-1.40), PTrend =0.007; both compared with the lowest quartile). Meta-analysis showed similar results (highest versus lowest quartile: HR 1.22(1.11-1.34), P<0.0001). Findings from MR analysis, which included 47,309 cases and 930,014 controls, supported a causal relationship between higher TyG index and increased risk of HF (odds ratio 1.27(1.15-1.40), P<0.001).

ConclusionA higher TyG index is an independent and causal risk factor for incident HF in the general population.

Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIn 115,341 subjects from two large cohorts in China, an elevated triglyceride-glucose (TyG) index was independently associated with an increased risk of incident heart failure (HF).
C_LIO_LITwo-sample Mendelian randomization analysis based on published genome-wide association studies found significant association between genetically determined TyG index and the risk of HF.
C_LIO_LITogether, these findings suggest that a higher TyG index is an independent and causal risk factor of incident HF in the general population.
C_LI

What are the clinical implications?O_LIThe TyG index may facilitate recognition of individuals at elevated risk of incident HF and allow early preventive interventions.
C_LIO_LIThe demonstrated causal effect of TyG index on incident HF warrants further research to fully understand the underlying mechanisms.
C_LI


Introduction
Heart failure (HF) is associated with significant morbidity and mortality, with 86 contemporary five-year survival rates of less than 50% 1 . The prevalence of HF has been 87 estimated to be 1-2% in developed countries and is projected to double by 2060 2, 3 . 88 Given the enormous public health and socioeconomic burden caused by HF, it is 89 critically important to identify individuals at high risk of HF and to implement 90 preventive interventions as early as possible 4 .

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Recently, the role of metabolic disorders in the development of HF has been 93 increasingly investigated 5 . Insulin resistance, a hallmark of type II diabetes mellitus and 94 metabolic syndrome, has been observed to be associated with adverse cardiac 95 remodeling and dysfunction 6 . Molecular studies have provided ample evidence for the 96 etiological role of insulin resistance in the development of HF 7, 8 . However, the gold 97 standard method for measuring insulin sensitivity, the hyperinsulinaemic-euglycaemic 98 clamp test, is time-consuming and invasive 9 , which has impeded its widespread use in 99 clinical practice. The triglyceride-glucose (TyG) index, a simple, dimensionless marker derived from 102 fasting blood triglyceride and glucose levels as measured in routine biochemical tests, 103 has been proposed and validated as a surrogate marker of insulin resistance 10 . Previous 104 studies have found a positive association between TyG index and the risk of various 105 metabolic and atherosclerotic cardiovascular diseases 11,12 . However, few studies have 106 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted https://doi.org/10.1101https://doi.org/10. /2022 7 been conducted to investigate the association between TyG index and the risk of 107 incident HF, and whether the association is causal remains undetermined. wide association studies (GWAS), MR is highly suited and has been used for 114 investigating the causal association between TyG index and HF 15, 16 .

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As such, the present study aimed to assess the association between the TyG index and 117 the risk of incident HF, as well as using a two-sample MR study to determine whether 118 such associations were causal in nature. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted https://doi.org/10.1101https://doi.org/10. /2022 The Kailuan Study is a prospective cohort that based on a community in the Tangshan   129 City. Details of the study has been published elsewhere 17   10 has not been implemented in CDARS to date. The ICD-9 codes used for identifying 148 comorbid conditions and the outcome (HF) were summarized in Table S1. CDARS has 149 been extensively used in prior studies and has been shown to have good diagnostic 150 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted https://doi.org/10.1101https://doi.org/10. /2022 In the Hong Kong cohort, all patients were followed up from inclusion until the first 173 recorded diagnosis of HF, death, or the end of follow-up (December 31 st , 2019), 174 whichever came first. HF was identified using ICD-9 codes as summarized in Table S1.  TyG index-associated variants that reached genome-wide significance (P < 5 × 10 -8 ) 184 were retrieved from a previous GWAS 16 . In brief, the identified GWAS included 185 273,368 subjects from the United Kingdom Biobank, who were aged 40-69 and free 186 from diabetes mellitus and lipid metabolism disorders 16 . These SNPs were further 187 pruned by linkage disequilibrium with R 2 < 0.01 and those that were significantly 188 associated with TG or glucose were also excluded. In total, 192 IVs were selected for (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Continuous variables were presented as mean ± standard deviation (SD)  (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. To combine the results from the two cohorts, we extracted hazard ratios from the fully 222 adjusted model and performed a meta-analysis using the inverse variance method with 223 random effects to estimate the association between TyG index, both as categorical and 224 continuous variables, and the risk of incident HF.

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In the MR analysis, the summary exposure and outcome data were first harmonized, 227 and SNPs significantly associated with incident HF were excluded. Causal effects of 228 TyG index on HF were estimated by the inverse-variance weighted (IVW) method.  To test the validity of causal effects estimates, multivariable MR (MVMR) using the 235 IVW method was conducted to further investigate the direct causal effect of TyG index 236 on HF after adjusting for confounders including BMI 27 , SBP 28 , DBP 28 , LDL-c 29 , and 237 HDL-c 29 . An additional sensitivity analysis was performed by excluding any SNP 238 All rights reserved. No reuse allowed without permission.
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Of the 101,510 subjects who took part in the Kailuan study, 95,996 subjects were 249 analyzed after applying the exclusion criteria ( Figure S1). For the Hong Kong cohort, 250 24,338 patients were identified for inclusion, and 19,345 patients were analyzed after 251 applying the exclusion criteria ( Figure S2). Table 1 and Table 2 shows the baseline 252 characteristics of subjects according to the baseline TyG index quartiles of two cohorts.

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In the Kailuan cohort, there were 2,726 cases (2.8%) of incident HF over a mean follow-255 up of 12.3±2.2 years, with an overall incidence rate of 2.3 (95% CI 2.2-2.4) cases per 256 1000 person years. In the Hong Kong cohort, there were 1,709 cases (7.0%) of incident 257 HF over a mean follow-up of 16.2±4.3 years, with an overall incidence rate of 5.5 (95% 258 CI 5.3-5.8) cases per 1000 person years. Over the study duration, 10,825 subjects 259 (11.3%) in the Kailuan cohort died (9,985 (10.1%) without developing HF), while 6,372 260 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  Table 3 and Table 4 show the associations between the TyG index, assessed both as a  (Tables 3 and 4). Sensitivity analyses produced consistent and 282 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted June 29, 2022. ; https://doi.org/10.1101/2022.06.28.22277033 doi: medRxiv preprint similar results (Tables 3 and 4).  A random-effect meta-analysis combining the results from the two cohorts showed that 295 the risk of incident HF of subjects in the highest quartile of the TyG index was 22% 296 higher (95% CI 11% -34%, P<0.0001; Figure 3A) than those in the lowest quartile, 297 with every unit increment of the TyG index being associated with a 15% increase in the 298 risk of incident HF (95% CI 10% -21%, P<0.00001; Figure 3B). Similarly, subjects in 299 the highest quartile of the TyG index had a 25% (95% CI 13% -37%) increase in the 300 sub-hazard of incident HF.

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Two-Sample MR analysis 303 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The associations between genetically determined TyG index and the risk of incident HF 304 as estimated by two-sample MR are presented in Figure 4. Analysis using the IVW 305 method demonstrated that genetic predisposition to increased TyG index was 306 significantly associated with an increased risk of incident HF (OR 1.27, 95% CI 1.15 -307 1.40, P<0.001). The Cochran's Q statistic indicated significant heterogeneity across 308 SNPs, while no indication of directional pleiotropy was found by MR-Egger intercept 309 ( Table S3). The association remained consistent when using complementary methods 310 for analysis, including weighted median, MR-Egger and MRPRESSO (Figure 4).

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To verify the causal effect of TyG index on HF, we performed multivariable MR 313 analysis by adjusting for HF risk factors, including BMI, blood pressure, and lipids.

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The association remained stable after adjusting for single risk factors (Table S4)   (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. TyG and HF was causal by nature. Although the exact underlying mechanism for the 340 association between TyG index and HF remains to be confirmed by further molecular 341 studies, the well-established relationship between TyG index and insulin resistance 342 suggests that insulin resistance may at least be an important driver of such association 10 .

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This was further reinforced by the results from the Kailuan cohort showing that the 344 association between TyG index and HF was independent of chronic inflammation, as 345 well as previous studies observing associations between insulin resistance and higher 346 risks of incident HF independent of myocardial ischaemia 32-34 . Insulin resistance may 347 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 29, 2022. ; https://doi.org/10.1101/2022.06.28.22277033 doi: medRxiv preprint lead to excessive circulating free fatty acids and triglycerides, which induces cardiac 348 lipotoxicity by generating toxic lipid intermediates, and decreases cardiac efficiency by 349 increasing fatty acid oxidation 35,36 . Insulin resistance is also associated with  Another major finding of the present study is that the association between TyG index 362 and the risk of HF was stronger in females than in males. Between-gender differences 363 are common in cardiovascular medicine. Previous studies have shown that women with 364 disorders of glucose metabolism have a greater risk of coronary heart disease than 365 men 30, 39 . HF caused by obesity, diabetes, or metabolic syndrome was also found to be 366 more common in women 40 . These suggest that between-gender differences in molecular 367 mechanisms, particularly those in hormonal axes, may not only influence glucose and 368 lipid metabolism, but also energy metabolism in the heart and, thereby, cardiac function. 369 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 29, 2022. ; https://doi.org/10. 1101 Females are known to be less likely than males to develop insulin resistance 41 but are 370 at higher risk of diabetic cardiomyopathy 42 , implying that females may be more Having derived consistent findings from two geographically distinct regions in China, 386 our results suggest that the TyG index, as a surrogate marker of insulin resistance, may 387 be widely applicable and prognostically useful regardless of geographical region and 388 ethnicity. As subjects with prevalent major cardiovascular diseases were excluded from 389 the present study, the analyzed cohorts had relatively low cardiovascular risks. Our 390 results supported the TyG index as a potentially viable and effective tool for 391 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. TyG index and higher risk of incident HF. Nonetheless, some limitations must be noted.

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First, we were unable to compare the predictive power of different methods for 413 All rights reserved. No reuse allowed without permission.
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The copyright holder for this preprint this version posted June 29, 2022. ; https://doi.org/10.1101/2022.06.28.22277033 doi: medRxiv preprint assessing insulin resistance in our observational study, since fasting insulin levels were 414 unavailable for most subjects. Second, inherent to all observational studies, there may 415 be residual or unmeasured confounders that we were not able to address. Nonetheless, 416 we have included multiple important risk factors for incident HF in the multivariable 417 regression models, and the numerous sensitivity analyses yielded consistent results 418 which reinforced the validity of our findings. Third, the MR analysis was restricted to 419 patients of European descent to reduce bias from population stratification, which may As observed from two large, geographically distinct Chinese cohorts, a higher TyG 435 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The authors appreciate all the subjects involved in this study, their families, and the 442 members of the survey team from the Kailuan community.   (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
458 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  of the health care system in Hong Kong and its referential significance to mainland 524 All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted https://doi.org/10.1101https://doi.org/10. /2022  (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted https://doi.org/10.1101https://doi.org/10. /2022  (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted https://doi.org/10.1101https://doi.org/10. /2022  (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.