The effect of blood glucose levels on serum triglyceride clearance in patients with hyperlipidemic acute pancreatitis

doi:10.21203/rs.3.rs-4330311/v1

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Research Article

The effect of blood glucose levels on serum triglyceride clearance in patients with hyperlipidemic acute pancreatitis

https://doi.org/10.21203/rs.3.rs-4330311/v1

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Background/Aims:

Preventing moderately severe and severe acute pancreatitis (MSAP & SAP) is the primary goal of the management of hyperlipidemic acute pancreatitis (HLAP). The main aim of this study was to investigate the factors affecting serum triglyceride (TG) clearance, particularly blood glucose (GLU) levels, which potentially help to prevent the development of MSAP & SAP.

Methods:

The clinical data from 181 patients with MSAP & SAP and 207 patients with mild acute pancreatitis (MAP) on days 1–6 after the onset were collected and analyzed by multivariate logistic regression to identify the factors that have an impact on the severity of HLAP, especially TG. The optimal TG threshold was obtained by receiver operating characteristic (ROC) analysis to differentiate TG fast-clearance patients from TG slow-clearance patients, as defined in this study. Metabolism-related factors that may interfere with TG clearance, such as GLU, diabetes mellitus (DM), obesity, and uric acid, were further analyzed.

Results:

Day 2 TG was an independent risk factor for MSAP & SAP in patients with HLAP (OR: 3.718, 95% CI: 2.042–6.77; P < 0.001). And patients with TG slow-clearance (day 2 TG ≥ 7.335 mmol/L) were more susceptible to MSAP & SAP, with a sensitivity of 0.932 and a specificity of 0.898.

DM (OR: 3.574, 95% CI: 1.13–11.308, P < 0.001) and day 2 GLU level (OR: 1.537, 95% CI: 1.292–1.675; P < 0.001) were independent risk factors for TG slow-clearance but not for HLAP severity (OR: 1.728, P= 0.253 and OR: 1.119, P = 0.059). Day 2 GLU decreased below 13.07 mmol/L and 6.575 mmol/L in patients with DM and non-diabetes mellitus (NDM), respectively, contributing to the reduction of day 2 TG to 7.335 mmol/L.

Conclusions:

Day 2 TG levels had the most impact on the severity of HLAP, which also accurately predicted the occurrence of MSAP & SAP. It is worth noting whether the GLU can reach the target value on day 2, as it can directly affect the TG clearance rate and indirectly affect the severity of HLAP.

serum triglyceride

blood glucose

hypertriglyceridemia

hyperglycemia

hyperlipidemic acute pancreatitis

diabetes mellitus

risk

Hyperlipidemic acute pancreatitis (HLAP) is associated with a more severe inflammatory response, more comorbidities, and higher risks of mortality and recurrence in acute pancreatitis (AP) compared to other etiologies, such as biliary stones and alcoholism (1–3). With the gradual increase in the incidence of HLAP (4, 5), hypertriglyceridemia (HTG) has now replaced alcoholism as the second major cause of AP in China (6–9), unlike in Western countries (10–13). The annual increase in mean serum triglycerides (TG) due to the westernization of the Chinese diet may explain this phenomenon (14, 15).

Serum TG not only causes HLAP episodes, it exacerbates the severity of HLAP in a concentration-dependent manner (16–18). Prior to this, Mosztbacher et al. divided patients with HLAP into 6 groups based on TG levels and demonstrated that TG ≥ 11.3 mmol/L within 48 hours of onset increased the odds of developing moderately severe and severe acute pancreatitis (MSAP & SAP) (16). Moreover, it has become a clinical guideline to reduce TG below 5.65 mmol/L as soon as possible after admission (19). Based on the previous work, the present study was further refined to analyze different TG cut-off values on different days after onset to predict the occurrence of MSAP & SAP.

Furthermore, it was supposed whether there are some metabolic factors that may interfere with the TG clearance rate in the early stages of HLAP, thus indirectly affecting the severity of HLAP. The components of metabolic syndrome proposed by the International Diabetes Federation in 2005 include elevated TG and blood glucose (GLU) concentrations, obesity, reduced high-density lipoprotein cholesterol (HDL-C) levels, and elevated blood pressure (20). It has been reported that 20–90% of diabetic patients have elevated blood lipid levels (21), and poorly controlled hyperglycemia could interfere with lipoprotein lipase (LPL) function, leading to secondary HTG (22). It has been speculated that the clearance rate of HTG is inseparable from diabetes mellitus (DM) and blood glucose (GLU) levels.

In patients with HLAP, could hyperglycemia affect the TG clearance in the early stage, especially days 1–3 after onset? For HLAP patients with DM or NDM, should there be different GLU target values that ultimately help to achieve a safer and more effective clinical management of HLAP patients?

2.1. Research population and criteria for inclusion and exclusion

The Ethics Committee of the Second Affiliated Hospital of Soochow University authorized this study (JD-LK-2021-001-1). A total of 388 HLAP patients who attended the Second Affiliated Hospital of Soochow University from September 14, 2009, to May 5, 2023, were retrospectively enrolled.

The diagnosis criteria for HLAP are as follows: (1) satisfying two of the three criteria for AP: persistent severe epigastric pain that frequently radiates to the back, serum lipase (or amylase) at least three times the upper limit of normal, and imaging evidence with typical AP features (23–27); (2) TG ≥ 11.3 mmol/L at the onset (28). The severity of AP was classified as mild acute pancreatitis (MAP), MSAP, and SAP according to the revised Atlanta Classification of Acute Pancreatitis (29). All patients received conventional treatment, including strict fasting, hydration, proton pump inhibitors, pancreatic enzyme secretion inhibitors, and antibiotics, etc. according to the latest Chinese guidelines for the diagnosis and treatment of AP (30).

Patients have been excluded according to the following standards: (1) insufficient clinical data; (2) chronic pancreatitis; and (3) younger than 18 years of age.

2.2. Clinical data

Clinical information was collected in detail, including age, gender, laboratory data, duration of hospitalization, and complications (ARDS, heart failure, renal failure, pseudocyst). Laboratory indicators such as uric acid, HDL-C, white blood cells (WBC), and C-reactive protein (CRP) were collected within 48–72 hours of the onset of abdominal pain, and the highest values were taken in this paper. Meanwhile, TG and GLU levels were recorded on days 1–6 of the disease.

2.3. Statistical methods

The statistical analyses were performed using SPSS version 25 (IBM, Armonk, NY, USA). All continuous variables were shown as mean ± standard deviation (SD), and all categorical variables were shown as numbers and percentages. For the purpose of comparing the two groups, appropriate tests (all two-tailed tests) were performed, with Pearson’s χ2 test and Fisher’s exact χ2 test used for categorical variables and Student’s t-test and the Mann-Whitney U test for numerical variables. Multivariate logistic regression analyses were utilized to report categorical outcome indicators and were expressed as odds ratios (OR), 95% confidence intervals (CI), and P values. Receiver operating characteristic (ROC) analysis was used to select the optimal cut-off values for diagnostic TG and GLU (31), with sensitivity, specificity, PLR (positive likelihood ratio), NLR (negative likelihood ratio), and Youden Index defined in the determination of MSAP & SAP and the TG slow-clearance group, as described by Greiner et al. (32). P values < 0.05 were considered statistically significant.

3.1. The clinical characteristics of all HLAP patients

The study included 388 HLAP patients with a mean age of 40.34 ± 10.03 years, and 306 (79%) of them were male.

There were 38 (10%) patients with SAP, 143 (37%) with MSAP, and 207 (53%) with MAP. In this study, 3 (1%) patients with SAP ultimately died. The majority of patients had comorbid DM (241, 62%) and fatty liver (321, 83%) (Detailed in Table 1).

Table 1

The clinical characteristics of 388 patients with HLAP
	HLAP (n = 388)
Male (n (%)	306 (79%)
Diabetes mellitus (n (%)	241 (62%)
Hypertension (n (%)	101 (26%)
Fatty liver (n (%)	321 (83%)
Death (n (%)	3 (1%)
ARDS (number (n (%)	55 (14%)
Heart failure (n (%)	8 (2%)
Renal failure (n (%)	16 (4%)
Pseudocyst (n (%)	47 (12%)
MAP	207 (53%)
MSAP number (n (%)	143 (37%)
SAP number (n (%)	38 (10%)
CTSI > 4 score number (n (%)	165 (43%)
Recurrence (n (%)	160 (41%)
Repeated recurrence (n (%)	96 (25%)
Age (years)	40.34 ± 10.03
Admission delay (hours)	26.61 ± 15.64
Hospital stay (days)	11.61 ± 10.90
BMI (kg/m²)	27.65 ± 3.20
WBC (×10ꝰ /L)	14.31 ± 4.28
CRP (mg/L)	203.68 ± 128.07
BUN (mmol/L)	5.02 ± 2.73
Ca²⁺ (mmol/L)	2.00 ± 0.34
GLU (mmol/L)	12.20 ± 6.14
TG (mmol/L)	18.51 ± 18.62
TC (mmol/L)	9.48 ± 5.57
HDL-C (mmol/L)	0.82 ± 0.35
Uric acid (µmol/L)	393.01 ± 125.21
HbA1c (%)	8.38 ± 2.51

ARDS: acute respiratory distress syndrome; MAP: mild acute pancreatitis; MSAP: moderately severe acute pancreatitis; SAP: severe acute pancreatitis; CTSI: computed tomography severity index; Repeated recurrence: at least two episodes of recurrence in one patient; BMI: body mass index. WBC: white blood cells; CRP: C-reactive protein; BUN: blood urea nitrogen; Ca²⁺: serum calcium; GLU: blood glucose; TG: serum triglyceride; TC: serum cholesterol; HDL-C: high-density lipoprotein cholesterol; HbA1c: hemoglobin A1c.

3.2. Comparison of clinical characteristics between MAP patients and MSAP & SAP patients

The results comparing the clinical characteristics of 207 patients with MAP and 181 patients with MSAP & SAP are presented in Table 2. The left side of Table 2 shows the detailed data and the P-values. Factors that were significant under univariate screening (P < 0.05) and likely to influence AP severity were analyzed by multivariate logistic regression, yielding odds ratios (OR), confidence intervals (CI), and P-values on the right side of Table 2.

Compared to the MAP group, the MSAP & SAP group had higher TG levels on days 1–6 (P < 0.001). This is the same as the previous studies showing that higher TG levels are associated with more severe symptoms (33). However, in multivariate logistic regression analyses in this study, only TG on day 2 was an independent risk factor for developing MSAP & SAP (OR: 3.718, 95% CI: 2.042–6.77; P < 0.001).

There were more patients with DM in the MSAP & SAP group (81% vs. 44%, P < 0.001). And the GLU levels on days 1–6 and HbA1c were significantly higher in the MSAP & SAP group than the MAP group (P < 0.001). However, after multivariate logistic regression analyses, these factors were not independent risk factors for HLAP severity (P > 0.05). This is not consistent with some previous studies on AP, which include multiple etiologies (34–36).

Ca²⁺ (OR: 0.15, 95% CI: 0.017–1.29, P < 0.001), and HDL-C (OR: 0, 95% CI: 0–0.002, P < 0.001) were independent predictive factors for the occurrence of MSAP & SAP, which is consistent with previous studies (37, 38). There was no difference between the two groups in terms of gender, body mass index (BMI), number of patients with comorbid hypertension, or fatty liver (P > 0.05).

Table 2

Comparison of clinical data in patients with MAP versus patients with MSAP & SAP
	MAP	MSAP & SAP	P	Estimate OR	P
	(n = 207)	(n = 181)		(95% CI)
Age (years)	41.68 ± 10.35	38.80 ± 9.45	0.014^*	0.982 (0.938–1.028)	0.435
Male, n (%)	166, 80%	140, 77%	0.493
BMI (kg/m²)	27.43 ± 3.49	27.89 ± 2.84	0.096
WBC (×10ꝰ/L)	13.91 ± 4.15	14.77 ± 4.39	0.089
CRP (mg/L)	119.74 ± 77.85	293.14 ± 109.19	< 0.001^***
BUN (mmol/L)	4.6139 ± 1.40414	5.4916 ± 3.6855	0.972
Ca²⁺ (mmol/L)	2.137 ± 0.30706	1.84 ± 0.30682	< 0.001^***	0.15 (0.017–1.29)	< 0.001^***
HDL-C (mmol/L)	0.91 ± 0.27	0.73 ± 0.39	< 0.001^***	0 (0–0.002)	< 0.001^***
Uric acid (µmol/L)	384.94 ± 121.05	402.20 ± 129.55	0.212
TC (mmol/L)	6.3237 ± 2.28724	12.6179 ± 6.08124	< 0.001^***	1.101 (0.94–1.29)	0.232
Day 1 TG (mmol/L)	16.77 ± 13.35	41.97 ± 24.15	< 0.001^***	1.017 (0.967–1.07)	0.515
Day 2 TG (mmol/L)	4.79 ± 2.44	20.95 ± 15.52	< 0.001^***	3.718 (2.042–6.77)	< 0.001^***
Day 3 TG (mmol/L)	3.68 ± 2.24	10.57 ± 8.78	< 0.001^***	1.185 (0.859–1.636)	0.3
Day 4 TG (mmol/L)	3.71 ± 2.12	7.14 ± 4.99	< 0.001^***	1.002 (0.715–1.403)	0.992
Day 5 TG (mmol/L)	3.08 ± 1.35	5.30 ± 3.28	< 0.001^***	0.752 (0.379–1.49)	0.413
Day 6 TG (mmol/L)	3.06 ± 1.57	4.47 ± 2.12	< 0.001^***	1.74 (0.502–6.025)	0.382
Day 1 GLU (mmol/L)	9.61 ± 4.51	15.07 ± 7.64	< 0.001^***	1.135 (0.97–1.328)	0.114
Day 2 GLU (mmol/L)	8.84 ± 3.59	13.78 ± 4.74	< 0.001^***	1.119 (0.996–1.258)	0.059
Day 3 GLU (mmol/L)	8.28 ± 3.40	12.01 ± 3.30	< 0.001^***	1.132 (0.977–1.312)	0.099
Day 4 GLU (mmol/L)	8.98 ± 4.23	11.25 ± 3.64	< 0.001^***	0.887 (0.742–1.059)	0.184
Day 5 GLU (mmol/L)	7.86 ± 3.57	11.16 ± 4.09	< 0.001^***	0.981 (0.812–1.185)	0.84
Day 6 GLU (mmol/L)	7.19 ± 3.22	10.38 ± 3.20	< 0.001^***	1.026 (0.827–1.274)	0.814
HbA1c (%)	7.53 ± 2.43	10.16 ± 12.58	< 0.001^***	1.074 (0.859–1.341)	0.532
DM, n (%)	92, 44%	147, 81%	< 0.001^***	1.728 (0.676–4.414)	0.253
Hypertension, n (%)	53, 26%	48, 27%	0.838
Fatty liver, n (%)	165, 80%	156, 86%	0.092
Recurrence, n (%)	97, 47%	63, 35%	0.016^*
Admission delay (hours)	26.44 ± 16.069	26.8 ± 15.172	0.862
Length of hospital stays (days)	8.04 ± 3.93	15.69 ± 14.37	< 0.001^***

MAP: mild acute pancreatitis; MSAP: moderately severe acute pancreatitis; SAP: severe acute pancreatitis; Estimate OR: odds ratio obtained by multivariate logistic regression analysis, CI: confidence interval.

WBC: white blood cells; CRP: C-reactive protein; BUN: blood urea nitrogen; Ca2+: serum calcium; HDL-C: high-density lipoprotein cholesterol; TC: serum cholesterol; GLU: blood glucose (The above laboratory results were taken from the highest values in the first 48 hours). BMI: body mass index; TG: serum triglyceride; HbA1c: hemoglobin A1c; DM: diabetes mellitus. ^*: P < 0.05; ^**: P < 0.01; ^***: P < 0.001.

3.3. The ROC analysis of TG levels to predict MSAP & SAP

Figure 1.A showed the ROC curves of the TG on days 1–3 for the prediction of MSAP & SAP. It was found that the area under the curve (AUC) of the TG was the largest on day 2 (0.968 ± 0.018), and the smallest on day 1 (0.854 ± 0.036).

Table 3 showed the optimal cutoffs, P-values, sensitivity, specificity, PLR, NLR, and Youden index of TG on days 1–3 and CRP on day 2 for predicting AP severity. The highest Youden index (0.83) appeared on day 2, when the cutoff value of TG was 7.335 mmol/L (sensitivity 0.932, specificity 0.898).

In this study, based on the optimal cutoff values of TG on day 2, HLAP patients were differentiated into a TG fast-clearance group (day 2 TG < 7.035 mmol/L) and a TG slow-clearance group (day 2 TG ≥ 7.035 mmol/L). Figure 1.B showed the differences in the proportions of MAP, MSAP, and SAP in the TG fast-clearance group and the TG slow-clearance group, respectively. There were more MSAP (72.2% vs. 3.2%) and SAP patients (17.6% vs. 1.6%) in the TG slow-clearance group, with statistically significant differences (P < 0.001).

Table 3

The cutoff points of TG on days 1–3 and CRP in the prediction of MSAP & SAP
	Cutoff Point (mmol/L)	AUC	Sensitivity	Specificity	PLR	NLR	P	Youden Index
Day 1 TG	23.5	0.854 ± 0.036	0.756	0.825	4.32	0.30	< 0.001^***	0.581
Day 2 TG	7.335	0.968 ± 0.018	0.932	0.898	9.14	0.08	< 0.001^***	0.83
Day 3 TG	4.615	0.891 ± 0.018	0.838	0.812	4.46	0.20	< 0.001^***	0.65
CRP	180.85	0.914 ± .016	0.908	0.802	4.59	0.11	< 0.001^***	0.71

AUC: area under the curve; PLR: positive likelihood ratio; NLR: negative likelihood ratio; TG: serum triglyceride; CRP: highest C-reactive protein level in the first 48 hours. ***: P < 0.001.

3.4 The metabolic-related factors affecting the TG clearance rate

Metabolic related factors that might affect TG clearance rates were compared between the TG fast-clearance group and the TG slow-clearance group in Table 4, which was formatted similarly to Table 2.

The independent risk factors for the occurrence of TG slow-clearance were DM (OR: 3.574, 95% CI: 1.13–11.308; P < 0.001) and day 2 GLU (OR: 1.537, 95% CI: 1.306–1.809; P = 0.028). Figure 2 (B) showed that there was a significant positive correlation between day 2 GLU and day 2 TG (r_s = 0.567, P < 0.001), which was slightly stronger than day 1 GLU (r_s = 0.486, P < 0.001) (Fig. 2.A).

Although HbA1c (7.55 ± 2.47 vs. 9.20 ± 2.30) and day 1 GLU (9.86 ± 4.62 vs. 14.73 ± 7.76) were significantly different between the two groups (P < 0.001), but they were not independent risk factors for TG slow-clearance.

Table 4

Comparison of metabolic factors that may affect TG clearance.
	TG Fast-Clearance Group	TG Slow-Clearance Group	P	Estimate OR	P
	(n = 185)	(n = 187)		(95% CI)
DM, n (%)	81, 44%	154, 82%	< 0.001^***	3.574 (1.13–11.308)	0.03^*
HbA1c (%)	7.55 ± 2.47	9.20 ± 2.30	< 0.001^***	0.997 (0.823–1.207)	0.972
Day 1 GLU (mmol/L)	9.86 ± 4.62	14.73 ± 7.76	< 0.001^***	1.07 (0.95–1.206)	0.262
Day 2 GLU (mmol/L)	8.78 ± 3.60	13.77 ± 4.70	< 0.001^***	1.537 (1.306–1.809)	< 0.001^***
BUN (mmol/L)	4.73 ± 1.73	5.37 ± 3.53	0.705
Ca²⁺ (mmol/L)	2.11 ± 0.34	1.88 ± 0.31	< 0.001^***	0.047 (0.006–0.345)	0.003^**
HDL-C (mmol/L)	0.93 ± 0.27	0.74 ± 0.39	< 0.001^***	0.268 (0.096–0.752)	0.012^*
Uric acid (µmol/L)	387.14 ± 122.40	402.42 ± 127.89	0.272
BMI (kg/m²)	27.51 ± 3.35	27.84 ± 2.98	0.090
Fatty liver, n (%)	147, 79%	162, 87%	0.065
Hypertension, n (%)	48, 26%	49, 26%	0.955
Fatty diet, n (%)	51, 28%	41, 22%	0.207

Estimate OR: odds ratio obtained by multivariate logistic regression analysis; CI: confidence interval. DM: diabetes mellitus; HbA1c: hemoglobin A1c; GLU: blood glucose; BUN: blood urea nitrogen; Ca²⁺: serum calcium; HDL-C: high-density lipoprotein cholesterol; BMI: body mass index; Fatty diet: a fatty diet before the onset. ^*: P < 0.05; ^**: P < 0.01; ^***: P < 0.001.

3. 5. The GLU cutoff values for the prediction of TG slow-clearance

Although DM and GLU on day 2 were the independent risk factors for TG slow-clearance (Table 4), GLU level was the factor that could be intervened in the clinic, so further research was conducted on GLU on day 2. Table 5 showed the results of days 1–2 GLU in predicting TG slow-clearance. When the cut-off value of GLU on day 2 was 9.045 mmol/L for all HLAP patients, the Youden index was the highest (0.465), with sensitivity 0.851 and specificity 0.614.

DM patients had higher GLU levels (P > 0.001) on days 1–6 of the onset, whereas the mean GLU value of NDM patients remained at 5 mmol/L (Fig. 3.A). NDM patients with TG slow-clearance had a little bit higher GLUs on days 2–3 compared with those with TG fast-clearance (Fig. 3.B), but neither had a significant downward trend, unlike patients with DM (Fig. 3.C). For patients with DM, the highest Youden index was 0.45 on day 2, with a cutoff point of 13.07 mmol/L (sensitivity 0.711, specificity 0.741). As for NDM patients, the highest Youden index (0.40) also appeared on day 2, with a cutoff point of 6.575 mmol/L of GLU.

Table 5

The cutoff points of GLU on days 1–2 in the prediction of TG slow-clearance
	Cutoff Point (mmol/L)	AUC	Sensitivity	Specificity	PLR	NLR	P	Youden Index
		ALL
Day1 GLU	11.955	0.748 ± 0.035	0.663	0.745	2.60	0.45	< 0.001^***	0.408
Day2 GLU	9.045	0.812 ± 0.025	0.851	0.614	2.20	0.24	< 0.001^***	0.465
		DM
Day1 GLU	13.31	0.62 ± 0.057	0.701	0.60	1.73	0.50	0.039	0.30
Day2 GLU	13.07	0.765 ± 0.038	0.711	0.741	2.75	0.39	< 0.001^***	0.45
		NDM
Day1 GLU	7.31	0.634 ± 0.087	0.6	0.75	2.40	0.53	0.109	0.35
Day2 GLU	6.575	0.733 ± 0.056	0.741	0.66	2.19	0.39	< 0.001^***	0.40

AUC: area under the curve; PLR: positive likelihood ratio; NLR: negative likelihood ratio; ALL: all HLAP patients; NDM: non-diabetic patients; DM; diabetic patients; GLU: blood glucose. ^***: P < 0.001.

The guideline proposes that reducing TG to below 5.65 mmol/L as soon as possible can prevent HLAP from deteriorating (39). In this study, the target value of TG has been further optimized by a retrospective analysis of 388 patients with HLAP (Table 1). It was found that the concentration of TG on day 2 had the most significant impact on the severity of HLAP. Moreover, several metabolic related factors affecting the clearance rate of TG were further studied, especially hyperglycemia.

As can be seen, the TG on day 2 was significantly lower than on day 1 (Table 2). The mean TG in patients with MAP was 16.77 ± 13.35 mmol/L on day 1 and decreased to 4.79 ± 2.44 mmol/L on day 2, a fall of approximately 12.07 mmol/L (72.0%). For MSAP & SAP patients, the mean TG level decreased by 21.02 mmol/L (50.1%). It is worthwhile to study the TG values according to the specific number of days after onset.

It was found that only TG on day 2 (OR: 3.718; P < 0.001) was an independent risk factor for MSAP & SAP on the first 1–6 days after onset, after excluding age as a confounding factor (Table 2). And the remaining 5 days appeared to have a slight effect on the severity of HLAP, such as TG on day 1 (OR: 1.017; P = 0.515) and TG on day 3 (OR: 1.185; P = 0.300). For every 1 mmol/L increase in TG on day 2, the probability of MSAP & SAP in patients with HLAP increased 3.718-fold (95% CI: 2.042–6.77; P < 0.001). TG on day 2 had the highest accuracy to predict MSAP & SAP (Fig. 1A). The Youden index for TG on day 2 was the highest at 0.83 (Table 3), even exceeding the CRP (0.71). CRP has been recognized as an important inflammatory indicator that reflects disease severity (40–42). Previous research had shown that day 2 CRP is a highly sensitive predictor of the severity of HLAP, with a Youden index of 0.72 (8).

In this study, the best cutoff point of TG on day 2 that can predict the severity of HLAP is 7.335 mmol/L, which might be a more powerful and detailed statement of “reducing TG to below 5.65 mmol/L as soon as possible” described in the present guideline. It can be seen that 3.2% and 1.6% of patients with day 2 TG < 7.335 mmol/L developed MSAP & SAP, respectively (Fig. 1.B), and only 10.2% of patients with TG ≥ 7.335 mmol/L on day 2 developed MAP.

Although several studies have suggested that DM may be an independent risk factor for AP severity (34–36), this is not the case in our study. It is apparent from Table 2 that GLU level and DM were not independent risk factors for HLAP severity (P < 0.05). However, they did have an interfering effect on the rate of TG clearance (Table 4). Patients with comorbid DM had a 3.574-fold higher rate of TG slow-clearance (95% CI: 1.13–11.308, P < 0.001). Insulin deficiency, resistance, and elevated counter-regulatory hormones impair the ability of LPL to hydrolyze lipids (22), which have been implicated as secondary factors in HTG (19, 43, 44). Brunzell et al. found (22) that patients with HTG and untreated DM had decreased LPL-TG affinity (K_m 390 mg/dl) and TG slow clearance (V_max 27.0 mg TG/kg/hr) when compared to ones with HTG and NDM (V_max 32.0;K_m 157) (P < 0.05). Fortunately, the clearance gradually recovers after two months of GLU-lowering therapy.

More importantly, it was found that GLU on day 2, which can be clinically intervened, was also an independent risk factor for TG clearance. For every 1 mmol/L increase in GLU levels on day 2, patients had a 1.537-fold increased risk of TG slow-clearance (95% CI: 1.306–1.809, P < 0.001). There was a moderate correlation (r_s = 0.567) between day 2 GLU and day 2 TG, and it was slightly better than day 1 GLU (Fig. 2).

The appropriate management of insulin is essential for patients with HLAP. Insulin combined with strict fasting has been used for more than a decade (45), with a positive efficacy no less than plasmapheresis (46). Promoting LPL function is the primary mechanism of insulin in the early stages of HLAP, which is widely accepted (47). This is true for patients with NDM who do not require GLU-lowering effects (48), as GLU fluctuates negligibly during the onset of the disease (Fig. 3.B).

However, it is speculated that insulin plays a more complicated role in patients with DM. Abnormally elevated GLU in patients with DM is associated with endogenous insulin deficiency (49, 50), and GLU must be lowered (Fig. 3.C), unlike in patients with NDM. The excess GLU at this time makes the body physiologically inclined to burn it first, resulting in TG slow-clearance. Therefore, in this case, supplementation with exogenous insulin promotes both consumption of excess GLU and hydrolysis of LPL.

An unresolved issue, however, is that appropriate and detailed GLU-lowering targets are not available in the early stages of HLAP, despite some positive results of insulin in clinical treatment (51, 52). Jing et al. found (53) that controlling the GLU in SAP patients to 6.1–8.3 mmol/L with insulin reduced the rate of concurrent infections and length of hospitalization. It is hypothesized that defined therapeutic target values and timeframes could be more beneficial for clinical implementation and broaden the scope of the applicable population.

Garg et al. suggested that lowering TG (> 5.65 mmol/L) should be the sole goal for insulin administration in patients with HLAP and that GLU should be checked frequently every hour (54). Continuous insulin therapy in the absence of appropriate GLU treatment targets may make patients more susceptible to hypoglycemia, which could be another serious blow to patients (55). Therefore, it would be better to find an accurate GLU-lowering target in order to promote the clearance of TG in the clinic.

It was found that for all HLAP patients, when the cutoff value of GLU on day 2 was 9.045 mmol/L, the Youden index (0.465) was higher than on day 1 (Table 5). This means that if it is uncertain whether the patient has comorbid DM, it would be advisable to keep the GLU value below 9.045 mmol/L on day 2, which will benefit the clearance of TG. Considering the huge difference in GLUs between DM and NDM patients (Fig. 3.A), further grouping analysis potentially would result in more accurate cutoff values of GLU on day 2. It is recommended to reduce the GLU of patients with DM to below 13.07 mmol/L on day 2, and that of patients with NDM to 6.575 mmol/L. According to the results of this study, it is possible to strictly control GLU, improve safety, and reduce difficulty by adopting different targets to reduce GLU in HLAP patients with DM or NDM.

Finally, HbA1c was neither an independent risk factor for HLAP severity (P = 0.532) nor TG clearance rate (P = 0.347). HbA1c showed a weak correlation (P < 0.01) with both day 1 (r_s = 0.363) and day 2 TG (r_s = 0.359), but a strong correlation (P < 0.01) with day 1 GLU (r_s = 0.805) and day 2 GLU (r_s = 0.719).

This study found that in HLAP patients, it was very important to control TG to be less than 7.335 mmol/L on day 2. It was also found for the first time that GLU level and DM might not be independent risk factors for the severity of HLAP, but indirectly contribute to MSAP & SAP by interfering with TG clearance. Moreover, different GLU control target points should be implemented in HLAP patients with DM or NDM to promote TG clearance. In the end, these data will hopefully be further refined in larger joint multicenter cohorts.

In patients with HLAP, TG on day 2 was not only an independent risk factor for MSAP & SAP but could also be utilized to predict the occurrence of MSAP & SAP. Keeping GLU within the safe range promotes TG clearance, and the safe ranges of GLUs are different for HLAP patients with DM or NDM. The findings of the study will make an appreciable contribution to the clinical management of HLAP and offer ideas for further research.

TG: serum triglyceride; HTG: hypertriglyceridemia; AP: acute pancreatitis; HLAP: hyperlipidemic acute pancreatitis; MAP: mild acute pancreatitis; MSAP: moderately severe acute pancreatitis; SAP: severe acute pancreatitis; GLU: blood glucose; DM: diabetes mellitus; NDM: non-diabetes mellitus; HDL-C: high-density lipoprotein cholesterol; WBC: white blood cells; CRP: C-reactive protein; Ca²⁺: serum calcium; ARDS: acute respiratory distress syndrome; HbA1c: hemoglobin A1c; BMI: body mass index; ROC: receiver operating characteristic; AUC: area under the ROC curve; OR: odds ratio; CI: confidence interval; positive likelihood ratio: PLR; negative likelihood ratio: NLR; LPL: lipoprotein lipase.

Data availability statement

The datasets generated and/or analyzed during this study are available upon request from the corresponding author.

Author contributions

Yuxin Liu, Shuqi Qin and Si Dai contributed equally to this study. Yuxin Liu: methodology, formal analysis, investigation, data curation, writing-original draft; Shuqi Qin: investigation, writing-original draft; Si Dai: investigation, writing-original draft; Guojian Yin*: methodology, validation, writing-review & editing, Funding; Jing Zhou: data curation; Zhendan Wang: data curation.

Financial support

The funding for technical support, data collection, and data analysis for this study came from the Suzhou Health and Wellness Commission (GSWS2022033).

Acknowledgements

We thank the Second Affiliated Hospital of Soochow University for providing case data for this study.

Ethical approval

The study was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University (JD-LK-2021-001-01) and was conducted in accordance with GCP principles.

Consent to participate

All subjects consented to participate in this study.

Consent for publication

All subjects and authors agreed to the final manuscript and its submission to the journal.

Conflicts of interest

The authors have no personal, financial, or other conflicts of interest to disclose.

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No competing interests reported.

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The effect of blood glucose levels on serum triglyceride clearance in patients with hyperlipidemic acute pancreatitis

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Abstract

Figures

1. Introduction

2. Patients and methods

2.1. Research population and criteria for inclusion and exclusion

2.2. Clinical data

2.3. Statistical methods

3. Results

3.1. The clinical characteristics of all HLAP patients

3.2. Comparison of clinical characteristics between MAP patients and MSAP & SAP patients

3.3. The ROC analysis of TG levels to predict MSAP & SAP

3.4 The metabolic-related factors affecting the TG clearance rate

3. 5. The GLU cutoff values for the prediction of TG slow-clearance

4. Discussion

5. Strengths and limitations of the study

6. Conclusions

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