Timely reduction of triglyceride in patients with different severity of hypertriglyceridemia-associated acute pancreatitis：secondary analysis of a multicenter, prospective cohort study

doi:10.21203/rs.3.rs-4980789/v1

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Timely reduction of triglyceride in patients with different severity of hypertriglyceridemia-associated acute pancreatitis：secondary analysis of a multicenter, prospective cohort study

https://doi.org/10.21203/rs.3.rs-4980789/v1

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Objectives

It is controversial whether rapid lowering of triglyceride (TG) levels was associated with clinical benefits in patients with hypertriglyceridemia-associated acute pancreatitis (HTG-AP). Particularly, patients with different severity of disease may respond differently to TG-lowering therapy. In this study, we aimed to explore the association between timely reduction in serum TG levels and organ failure in patients with different severity of HTG-AP.

Methods

This is a secondary analysis of data from a multicenter, prospective registry recruiting HTG-AP patients (plasma TG levels > 11.3mmol/L at admission) admitted within 72 hours from the onset of symptoms. Patients were dichotomized into either target reaching (TG ≤ 5.65 mmol/L on study day 3) or not. The primary outcome was the presence of organ failure on day 14. The association between target-reaching and the primary outcome was modelled. Furthermore, subgroup analyses were conducted based on the disease severity of HTG-AP patients at enrollment (with vs. without organ failure, predicted severe vs. predicted non-severe based on APACHEII score).

Results

Overall, 413 patients were included for analysis, of whom 192 (46.5%) patients reached the target on day 3. For the overall study cohort, there was no significant difference in presence of organ failure at day 14 between patients reaching the target or not (3.1% vs. 6.8%, p = 0.091). In the subgroup of HTG-AP patients with organ failure at enrollment, compared to patients with TG > 5.65mmol/L on day 3, patients who reached the target had significantly lower presence of organ failure at day 14 (7.8% vs. 22%, p = 0.039), and the results remain unchanged after adjustment for potential confounders (p = 0.027). In the subgroup of more severe HTG-AP patients (APACHE II ≥ 8), there was also lower presence of organ failure at day 14 (5.8% vs. 17.7%, p = 0.044) and lower incidence of IPN within 60 days (1.4% vs. 11.3%, p = 0.036) in patients who reached the target.

Conclusion

Timely reduction of serum TG levels was associated with decreased presence of organ failure at day 14 in patients with more severe HTG-AP.

acute pancreatitis

hypertriglyceridemia

triglyceride

organ failure

Hypertriglyceridemia (HTG) is the third most common cause for acute pancreatitis (AP)(1), and compared with other causes, patients with HTG-AP are more likely to have severe disease courses characterized by organ failure and/or pancreatic necrosis(2). According to the latest Revised Atlanta Classification(3), organ failure is deemed as the key determinant of outcomes in AP, and a previous study indicated that the duration of organ failure was significantly related to mortality(4), implicating that shortening the duration of organ failure should be a primary therapeutic target in patients with severe AP characterized by persistent organ failure (POF).

During the pathogenesis of HTG-AP, it is believed that triglycerides (TG) are not inherently toxic to the pancreas, but it is the breakdown of TGs into free fatty acids (FFA), namely lipolysis, that causes toxicity(5). In addition, high levels of FFAs induce inflammatory response that, in combination with the damage caused by toxic FFAs, promotes the development of organ failure(6). In this context, aggressive lipid-lowering therapy has been called for to remove excess TGs and FFAs, thereby improving organ failure.

For the goal of TG-lowering therapy, previous studies showed that decreasing and maintaining serum TG levels below 5.65 mmol/L might be of clinical benefit (7, 8), like decreasing POF (9). While some other studies have demonstrated that rapid lowering of TG levels achieved by specific treatment modalities, such as plasmapheresis or high-volume hemofiltration, does not necessarily improve patient-centered outcomes(10–12). Considering that patients with different severity may have different extents of lipolysis(13), aggressive lipid-lowering therapy may have varying clinical impacts.

In this study, we aimed to explore the association between timely reduction in serum TG levels and the presence of organ failure at day 14 in patients with different severities of HTG-AP (with vs. without organ failure, Acute Physiologic Assessment and Chronic Health Evaluation II [APACHE II] score ≥ 8 or not, with vs. without pancreatic necrosis).

Study Design and Patient Characteristics

This study was an analysis of data from the PERFORM registry, which is a long-running, multicenter, prospective cohort study collecting clinical characteristics, treatments, and outcomes of patients with HTG-AP from the participating sites. The PERFORM registry was approved by the local ethics committees of all the participating sites and registered with the Chinese Clinical Trial Registry (ChiCTR2000039541) before enrollment commenced, and the study protocol was published previously(14).

In the original registry, patients diagnosed with AP aged 18–70 years admitted within 72h of the onset of abdominal pain were screened. The diagnosis of AP was based on the Revised Atlanta Classification criteria(3). Patients with plasma triglyceride > 11.3 mmol/L (1000 mmol/L) at admission, accompanied by any one or more of the clinical worrisome features (described by Gelrud et al. on the UpToDate(15)) were considered for inclusion. The list of worrisome features can be found in the published protocol(14). Patients were excluded if they were pregnant or lactating, if serum TG levels were not available on day 3, or if they were expected to die within 48h after enrollment.

Patient management

All patients received standardized management for HTG-AP according to the guidelines(16, 17). The initial treatment included intravenous hydration, analgesics, and early enteral nutrition. TG-lowering therapies that included fasting, insulin, heparin, and blood purification (e.g., plasma exchange, hemoperfusion, and hemofiltration) were applied at the discretion of the treating clinicians.

Data collection

In this study, all data were extracted from a secure web-based database (accessible via https://capctg.medbit.cn/) of the PERFORM registry, including data on demographic characteristics, daily treatment, and laboratory results, daily organ failure assessment score (SOFA), and the follow-up measures. The follow-up on day 60 was implemented through telephone.

Outcomes and Definitions

The primary outcome was a composite of death by day 14 or the presence of organ failure at day 14 of enrollment, defined as failure of respiration, renal, or cardiovascular organ systems. An individual SOFA score of 2 or more of the aforementioned organ systems was defined as organ failure(3).

Secondary outcomes included organ failure-free days (OFFD) to 14 days of enrollment, defined as the number of days alive without organ failure. For patients with recurrent organ failure, only the final period of OFFD was counted. Patients who had organ failure on day 14 or died before day 14 were assigned zero OFFD. Other secondary outcomes included incidence of new-onset organ failure to day 14, length of ICU and hospital stay, 28-day mortality, 60-day mortality, the incidence of infected pancreatic necrosis (IPN) within 60 days, prescription of blood purification during index admission, and in-hospital cost. New-onset organ failure was defined as organ failure that was not present in the first 24 hours after enrollment. IPN was diagnosed as the presence of extraluminal gas in the pancreatic and/or peripancreatic tissues on contrast-enhanced computed tomography (CECT) or a positive culture obtained during the first drainage and/or operative necrosectomy.

Statistical Analysis

The normality of continuous variables were evaluated by checking the Q–Q Plot. When continuous variables had a normal distribution, they were reported as mean ± standard deviations (SD); otherwise, they were reported as median (interquartile ranges, IQR). Categorical data are expressed as frequencies and percentages. Categorical variables were compared between groups using Fisher's exact test or Pearson's Chi-square test. Continuous variables were analyzed using the student t-test (normal distribution) or Mann-Whitney's test (non-normal distribution).

To detect potential heterogeneity in treatment effects depending on baseline disease severity, the subgroup × treatment interaction p value was generated by the logistic regression model that controlled for treatment and subgroups' main effects.

For the primary outcome, the generalized linear model [family = binomial (link = identity)] were employed to compare group differences. Both the results of crude and adjusted analyses were reported, with potential confounding factors [gender, age, body mass index (BMI), APACHE II, and baseline TG level] as covariates. Kaplan–Meier curves were used to compare the cumulative incidence of organ failure resolution to 14 days after enrollment tested by log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). For the secondary outcomes, the adjusted generalized linear models that included the abovementioned covariates were also used to compare group differences. For the categorical outcomes, we assumed they follow the binomial distribution, and the identity link function will be used. For the continuous outcomes, we assumed they follow the gaussian distribution, and the identity link function will be used. When the assumptions of models were not fulfilled, data conversions will be performed. Statistical tests were two-sided, and p values < 0.05 were considered statistically significant. All data analyses were done in R 4.2.3 and SPSS 26.0 software.

Cohort Characteristics

A total of 503 patients enrolled in the PERFORM registry between December 2020 and June 2023 were screened for inclusion. After excluding 90 patients without serum TG levels on day 3, 413 patients were included in this analysis (Fig. 1). The demographics and baseline characteristics were shown in Table 1. Overall, 74.1% (306/413) of the study patients were male. The mean (SD) age of the study cohort was 38 (8.9) years, and the median (IQR) TG level at baseline was 23.4 (17.3–35.9) mmol/L.

Table 1

Demographic and baseline characteristics.
Variables	All (n = 413)	Day3-TG ≤ 5.65 (n = 192)	Day3-TG > 5.65 (n = 221)	P value
Age, mean (SD)	38.0 (8.9)	39.5 (9.2)	37.9 (8.9)	0.062
Gender, n (%)				0.196
Female	107 (25.9)	44 (22.9)	63 (28.5)
Male	306 (74.1)	148 (77.1)	158 (71.5)
BMI, median (IQR)	27.4 (25.0-29.7)	27.1 (24.6–29.7)	27.4 (25.2–29.7)	0.362
Pre-existing Hyperlipidemia, n (%)				0.914
Yes	143 (34.6)	67 (34.9)	76 (34.4)
No or unknown	270 (65.4)	125 (65.1)	145 (65.6)
Familial hyperlipidemia, n (%)				1.00
Yes	6 (1.5)	3 (1.6)	3 (1.4)
No or unknown	407 (98.5)	189 (98.4)	218 (98.6)
Severity scores, median (IQR)
APACHE.II	6 (3–9)	6 (3–9)	6 (2–8)	0.551
SOFA	1 (0–2)	1 (0–2)	1 (0–3)	0.173
Baseline TG, median (IQR), mmol/L	23.4 (17.3–35.9)	22.0 (16.2–30.6)	24.5 (18.1–44.1)	0.002
Baeline HDL, median (IQR), mmol/L	0.59 (0.35–1.01)	0.60 (0.37–1.15)	0.59 (0.35-1.00)	0.566
Baseline LDL, median (IQR), mmol/L	2.23 (1.38–3.24)	2.16 (1.33–3.10)	2.33 (1.41–3.55)	0.236
Baseline CRP, median (IQR), mg/L	41.0 (9.3-145.7)	35.0 (7.9, 137.6)	48.2 (12.7-150.8)	0.319
Baseline creatinine, median (IQR), µmol/L	72.0 (53.6–102.0)	74.4 (56.0-101.8)	70.0 (49.0-103.0)	0.285

SD denotes standard deviation, IQR denotes interquartile range, BMI denotes body mass index, APACHE II denotes Acute Physiology and Chronic Health Evaluation II, SOFA denotes sequential organ failure assessment, TG denotes triglyceride, HDL denotes high density lipoprotein, LDL denotes low density lipoprotein, CRP denotes C-reacting protein.

By using the threshold of 5.65 mmol/L, 192 (46.5%) patients who reached the target on day 3 were classified as the target-reaching group, and 221 (53.5%) patients who did not, were classified as non-target-reaching group. There was no significant difference in age, BMI, prevalence of hyperlipidemia prior to AP attack, lipoproteins, C-reacting protein, creatinine, APACHE II, and SOFA scores at baseline between the two groups. Patients in the target-reaching group had lower baseline TG levels (22.0 [16.2–30.6] vs. 24.5 [18.1–44.1], p = 0.002) compared with patients that did not reach the target.

Impact of target reaching on organ failure

There was no significant difference in the presence of organ failure at day 14 between patients reaching the target or not in the overall study cohort (3.1% versus 6.8%, p = 0.091) (Table 2). Although no statistical interaction was shown between classification to an increased disease severity subgroup and the impact of target reaching on the presence of organ failure at day 14, the subgroup analysis found a significant association between target reaching and the presence of organ failure at day 14 across patients with either organ failure or APACHE II score ≥ 8 at enrollment (Fig. 2).

Table 2

The primary and secondary outcomes among the overall patients.
	Day3-TG ≤ 5.65 (n = 192)	Day3-TG > 5.65 (n = 221)	P value
Primary outcome
OF at day-14, n (%)	6 (3.1)	15 (6.8)	0.091
Secondary outcomes
OFFD, days, median (IQR)	11 (8–14)	11 (4–14)	0.619
New-onset organ failure to day 14, n (%)	18 (9.4)	31 (14.0)	0.145
Length of ICU stay, days, median (IQR)	5.0 (2.5, 9.0)	4.5 (0, 10.3)	0.065
Length of hospital stay, days, median (IQR)	13.0 (7.0, 17.0)	12.0 (7.0, 21.0)	0.627
28-day mortality, n (%)	3 (1.6)	4 (1.8)	1.00
60-day mortality, n (%)	4 (2.1)	7 (3.2)	0.555
60-day IPN, n (%)	3 (1.6)	13 (5.9)	0.038
Blood purification requirement during index admission, n (%)	56 (29.2)	51 (23.1)	0.159
In hospital cost, ¥10000, median (IQR)	5.3 (2.8–10.4)	4.7 (2.8–10.6)	0.159

TG denotes triglyceride, OF denotes organ failure, OFFD denotes organ failure free days to day 14, ICU denotes intensive care unit, IPN denotes infected pancreatic necrosis.

Impact of target reaching on clinical outcomes in patients with organ failure at enrollment

For the 123 patients who had organ failure at enrollment, 52% (64/123) patients reached the target (≤ 5.65mmol/L) on day 3. Compared to patients with TG > 5.65mmol/L on day 3, patients who reached the target had significantly lower presence of organ failure at day 14 (7.8% vs. 22%, p = 0.039). The results remain unchanged after adjustment for gender, age, BMI, APACHE II score, and baseline TG level (p = 0.027) (Table 3). The association between target reaching and organ failure was not shown in patients without organ failure at enrollment (Online Resource 1).

Table 3

Crude analysis of primary outcome and adjusted analyses of primary and secondary outcomes in patients with organ failure at enrollment.
	OF at enrollment
	Day3-TG ≤ 5.65 (n = 64)	Day3-TG > 5.65 (n = 59)	P value
Primary outcome
OF at day-14, n (%) ^*	5 (7.8)	13 (22.0)	0.039
OF at day-14, n (%) ^#	5 (7.8)	13 (22.0)	0.027
Secondary outcomes ^#
OFFD, days, median (IQR)	11 (8–14)	11 (4–14)	0.534
New-onset organ failure to day 14, n (%)	0	0	1.00
Length of ICU stay, days, median (IQR)	5.0 (2.5, 9.0)	4.5 (0, 10.3)	0.757
Length of hospital stay, days, median (IQR)	13.0 (7.0, 17.0)	12.0 (7.0, 21.0)	0.944
28-day mortality, n (%)	2 (3.1)	4 (6.8)	0.886
60-day mortality, n (%)	3 (4.7)	4 (6.8)	0.343
60-day IPN, n (%)	2 (3.1)	7 (11.9)	0.054
Blood purification requirement during index admission, n (%)	34 (53.1)	23 (39.0)	0.004
In hospital cost, ¥10000, median (IQR)	5.3 (2.8–10.4)	4.7 (2.8–10.6)	0.242

TG denotes triglyceride, OF denotes organ failure, OFFD denotes organ failure free days to day 14, ICU denotes intensive care unit, IPN denotes infected pancreatic necrosis. * Fisher's exact test. ^# adjusted for gender, age, BMI, APACHE II, and baseline TG level.

For secondary outcomes, there was no significant difference in OFFDs to day 14, new-onset organ failure to day 14, 28-day or 60-day mortality, length of ICU or hospital stay between groups after multivariable adjustment. Also, there was no difference in the cumulative incidence of organ failure resolution within 14 days of enrollment (HR, 1.35; 95%CI, 0.91 to 1.99; log-rank p = 0.11) between the two groups, as shown by Kaplan-Meier curves and Cox proportional hazards models (Fig. 3). However, the target-reaching group underwent significantly more blood purification (53.1% [34/64] vs. 39.0% [23/59], p = 0.004) compared to the non-target-reaching group.

Impact of target reaching on clinical outcomes in patients with APACHE II score ≥ 8 at enrollment

The multivariable analysis yielded similar findings as a significant association was found between target reaching and the presence of organ failure at day 14 (5.8% vs. 17.7%, p = 0.044) in patients with APACHE II score ≥ 8 at enrollment (Table 4), but not in patients with APACHE II score < 8 at enrollment (Online Resource 2). For secondary outcomes, the target reaching group had a lower incidence of IPN within 60 days of enrollment (1.4% vs. 11.3%, p = 0.036) and received more blood purification (44.9% [31/69] vs. 35.5% [22/62], p = 0.026). No significant difference was shown in other secondary outcomes (Table 4). Kaplan–Meier curves also showed no difference in the cumulative incidence of organ failure resolution within 14 days between the two groups (HR, 1.28; 95%CI, 0.89 to 1.86; log-rank p = 0.13) (Fig. 4).

Table 4

**Crude analysis of primary outcome and adjusted analyses of primary and secondary outcomes in patients with APACHE II score ≥ 8 at enrollment.**
Variables	APACHE II ≥ 8
Variables	Day3-TG ≤ 5.65 (n = 69)	Day3-TG > 5.65 (n = 62)	P value
Primary outcome
OF at day-14, n (%) ^*	4 (5.8)	11 (17.7)	0.052
OF at day-14, n (%) ^#	4 (5.8)	11 (17.7)	0.044
Secondary outcomes ^#
OFFD, days, median (IQR)	11 (8–14)	11 (4–14)	0.854
New-onset organ failure to day 14, n (%)	9 (13.0)	10 (16.1)	0.411
Length of ICU stay, days, median (IQR)	5.0 (2.5, 9.0)	4.5 (0, 10.3)	0.654
Length of hospital stay, days, median (IQR)	13.0 (7.0, 17.0)	12.0 (7.0, 21.0)	0.738
28-day mortality, n (%)	2 (2.9)	2 (3.2)	0.296
60-day mortality, n (%)	3 (4.3)	4 (6.5)	0.789
60-day IPN, n (%)	1 (1.4)	7 (11.3)	0.036
Blood purification requirement during index admission, n (%)	31 (44.9)	22 (35.5)	0.026
In hospital cost, ¥10000, median (IQR)	5.3 (2.8–10.4)	4.7 (2.8–10.6)	0.991

The main findings of this study were that timely reduction of serum TG levels (less than 5.65 mmol/L on day 3) was associated with decreased presence of organ failure at day 14 in patients with more severe HTG-AP, as determined by combined organ failure or high APACHE II score (≥ 8) at enrollment. While in HTG-AP patients without organ failure or with APACHE II score < 8 at enrollment, more rapid TG decline was not associated with improved clinical outcomes.

Currently, there is a lack of evidence-based recommendations for TG-lowering therapies in the mainstream guidelines, although different treatment modalities such as insulin, heparin, and blood purification therapies like plasmapheresis or hemoperfusion have been reported in the clinical practice. Plasmapheresis directly removes TGs and FFAs as well as inflammatory cytokines from the circulation(18), and a single session of plasmapheresis was reported to lower serum TG levels up to 50–80%(8). However, the measurement was not implemented immediately before and after the procedure, whether plasmapheresis will actually have such an effect remains doubtful. Moreover, most of the studies investigating the impact of plasmapheresis on the outcomes of HTG-AP were small, retrospective, and often included mild cases(19–22). The only randomized controlled trial (RCT) showed no effect of plasmapheresis on clinical outcomes despite a more rapid TG removal rate(11). Furthermore, the analysis of data from the PERFORM registry also found that the use of plasmapheresis was not associated with the incidence and duration of organ failure, but with increased ICU requirements(10).

Blood purification therapies are not without harm. They require central venous access and specific devices and commonly need to be implemented in ICU, which can be costly(10, 11). Our results showed that among patients with severe HTG-AP, early rapid TG decline was associated with less presence of organ failure at later stage, suggesting that patients with increased severity (e.g., with organ failure or APACHE II score ≥ 8) may be the right population to pursue rapid TG decline, and admission to ICU can also be better justified in these patients.

A combination of heparin and insulin can be an alternative strategy to achieve a rapid reduction in TG levels. Heparin and insulin can synergistically stimulate lipoprotein lipase (LPL) activity, increase the degradation of chylomicron, and thereby reduce serum TG levels(23). A retrospective study showed that the abilities of intravenous infusion of insulin and heparin therapy were not inferior to plasma exchange in lowering TG levels in the acute phase of HTG-AP(24). Nevertheless, blood glucose must be strictly monitored during insulin therapy and heparin also carries the additional risk of bleeding. The benefits and risks of combined use of insulin and heparin need to be explored in further well-designed prospective studies.

This study has several potential limitations. First, the observational nature of this study precludes a causal relationship analysis, therefore, the conclusions drawn in our study should be interpreted with caution. Second, the TG-lowering treatment modalities were at the treating physician's discretion, which may introduce selection bias into the results. Third, although subgroup analysis has been performed in patients with organ failure or APACHE II score ≥ 8 at enrollment, the benefits of early rapid TG decline are still unclear among patients with more severe HTG-AP, for instance, with APACHE II score ≥ 15 or multiple organ failure due to limited sample size. Last, we did not measure FFAs or other specific cytokines to clarify the effects of TG-mediated organ damage because of the difficulty of quality control in multiple laboratories.

In this secondary analysis of data from a multicenter large-scale registry, we found that timely reduction of serum TG levels to less than 5.65 mmol/L on day 3 was associated with decreased presence of organ failure at day 14 in patients with more severe HTG-AP. Further high-quality randomized controlled trials are warranted to confirm these results.

Author Contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed X. Luo, Y. Liu, X. Li, L. Fu and W. Mao. The first draft of the manuscript was written by L. Gao, X. Luo, X. Lai and L. Ke, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgement

This work was supported by National Natural Science Foundation of China (No. 82200722).

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No competing interests reported.

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Timely reduction of triglyceride in patients with different severity of hypertriglyceridemia-associated acute pancreatitis：secondary analysis of a multicenter, prospective cohort study

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Abstract

Objectives

Methods

Results

Conclusion

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INTRODUCTION

MATERIALS AND METHODS

Study Design and Patient Characteristics

Patient management

Data collection

Outcomes and Definitions

Statistical Analysis

RESULTS

Cohort Characteristics

Impact of target reaching on organ failure

Impact of target reaching on clinical outcomes in patients with organ failure at enrollment

Impact of target reaching on clinical outcomes in patients with APACHE II score ≥ 8 at enrollment

DISSCUSSION

CONCLUSION

Declarations

Author Contribution

Acknowledgement

References

Additional Declarations

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