高脂血症与新型冠状病毒肺炎住院患者28天全因死亡率的关系

doi:10.24920/003866

摘要/Abstract

摘要：

目的本研究旨在确定高脂血症与COVID-19住院患者的临床终点之间的关联,尤其是那些伴随心血管疾病（cardiovascular diseases, CVDs）和糖尿病的COVID-19患者。

方法这项多中心回顾性队列研究搜集2019年12月31日至2020年4月21日期间中国湖北省21家医院全部确诊COVID-19的住院患者。我们排除了年龄<18岁或≥85岁、处于妊娠期间、患有急性致死性器官损伤（如急性心肌梗塞,严重的急性胰腺炎或急性中风）、甲状腺功能减退、恶性疾病、严重的营养不良以及因服用降脂药物（如他汀类,烟酸,非诺贝特或吉非贝齐,依泽替米贝）而血脂正常的患者。采用1:1倾向性评分匹配（Propensity score matching,PSM）控制高脂血症组和非高脂血症组的患者的基线特征差异,并以相同的PSM策略对不同高脂血症参数亚组进行匹配, 包括甘油三酸酯（triglyceride,TG）升高组,低密度脂蛋白胆固醇(low-density lipoprotein cholesterol, LDL-C)升高组和高密度脂蛋白胆固醇（high-density lipoprotein cholesterol, HDL-C）降低组。采取混合效应Cox模型分析总体以及各亚组内高脂血症与COVID-19患者28天全因死亡率之间的相关性,并分别在男性、女性、伴有CVDs及伴有2型糖尿病患者的亚组中对结果进行验证分析。

结果在10 945例住院的COVID-19患者中,共9822例纳入研究,包括6309例（64.2%）血脂升高患者和3513例（35.8%）血脂正常患者。按1:1的倾向性评分匹配后经混合效应Cox模型分析显示,与血脂正常组相比,高脂血症不显著增加或减少COVID-19患者28天全因死亡风险（HR=1.17, 95% CI,0.95~1.44, P=0.151）。COVID-19患者预后与血脂各参数异常亦无显著关联,包括TG升高(HR=1.23,95% CI,0.98~1.55,P=0.075),LDL-C升高（HR=0.78;95% CI,0.57~1.07,P=0.123）,以及HDL-C降低（HR=1.12,95% CI,0.90~1.39,P=0.299）。在伴有心血管疾病、伴有糖尿病的COVID-19患者亚组中,以及在男性或女性COVID-19患者亚组中,高脂血症与COVID-19全因死亡率均无显著相关性。

结论我们的研究表明,即使在伴有心血管疾病和伴有糖尿病的患者中,脂质分布失衡与COVID-19的28天全因死亡率也无显着相关性。分别对TG,HDL-C及LDL-C脂质参数的高脂血症亚组分析也获得了相似的结果。因此,脂质失衡可能不是导致与心血管代谢性疾病相关的COVID-19不良预后的主要原因。该结果为COVID-19流行期间住院患者的干预提供了参考。

关键词: 新型冠状病毒肺炎, 血脂异常, 死亡率, 心血管疾病, 糖尿病

Abstract:

Objective This study aimed to determine the association of hyperlipidemia with clinical endpoints among hospitalized patients with COVID-19, especially those with pre-existing cardiovascular diseases (CVDs) and diabetes.

Methods This multicenter retrospective cohort study included all patients who were hospitalized due to COVID-19 from 21 hospitals in Hubei province, China between December 31, 2019 and April 21, 2020. Patients who were aged < 18 or ≥ 85 years old, in pregnancy, with acute lethal organ injury (e.g., acute myocardial infarction, severe acute pancreatitis, acute stroke), hypothyroidism, malignant diseases, severe malnutrition, and those with normal lipid profile under lipid-lowering medicines (e.g., statin, niacin, fenofibrate, gemfibrozil, and ezetimibe) were excluded. Propensity score matching (PSM) analysis at 1:1 ratio was performed to minimize baseline differences between patient groups of hyperlipidemia and non-hyperlipidemia. PSM analyses with the same strategies were further conducted for the parameters of hyperlipidemia in patients with increased triglyceride (TG), increased low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C). Mixed-effect Cox model analysis was performed to investigate the associations of the 28-days all-cause deaths of COVID-19 patients with hyperlipidemia and the abnormalities of lipid parameters. The results were verified in male, female patients, and in patients with pre-existing CVDs and type 2 diabetes.

Results Of 10 945 inpatients confirmed as COVID-19, there were 9822 inpatients included in the study, comprising 3513 (35.8%) cases without hyperlipidemia and 6309 (64.2%) cases with hyperlipidemia. Based on a mixed-effect Cox model after PSM at 1:1 ratio, hyperlipidemia was not associated with increased or decreased 28-day all-cause death [adjusted hazard ratio (HR), 1.17 (95% CI, 0.95-1.44), P =0.151]. We found that the parameters of hyperlipidemia were not associated with the risk of 28-day all-cause mortality [adjusted HR, 1.23 (95% CI, 0.98-1.55), P = 0.075 in TG increase group; 0.78 (95% CI, 0.57-1.07), P = 0.123 in LDL-C increase group; and 1.12 (95% CI, 0.9-1.39), P = 0.299 in HDL-C decrease group, respectively]. Hyperlipidemia was also not significantly associated with the increased mortality of COVID-19 in patients accompanied with CVDs or type 2 diabetes, and in both male and female cohorts.

Conclusion Our study support that the imbalanced lipid profile is not significantly associated with the 28-day all-cause mortality of COVID-19 patients, even in those accompanied with CVDs or diabetes. Similar results were also obtained in subgroup analyses of abnormal lipid parameters. Therefore, hyperlipidemia might be not a major causative factor for poor outcome of COVID-19, which provides guidance for the intervention of inpatients during the epidemic of COVID-19.

Key words: coronavirus disease 2019 (COVID-19), lipid disorder, mortality, cardiovascular diseases, diabetes

基金资助: 国家重点研发计划重大科学仪器设备开发重点专项2016年度项目基金(2016YFF0101500);国家自然科学基金。(81970364);国家自然科学基金。(81770053)

Bin Wu,Jianghua Zhou,Wenxin Wang,Huilin Yang,Meng Xia,Binghong Zhang,Zhigang She,Hongliang Li. Association Analysis of Hyperlipidemia with the 28-Day All-Cause Mortality of COVID-19 in Hospitalized Patients[J].Chinese Medical Sciences Journal, 2021, 36(1): 17-26.

图/表 4

Characteristics	Study cohort			Cohort after matching (1:1)^b
Characteristics	Hyperlipidemia^a (n=6309)	Normal (n=3513)	SD	Hyperlipidemia ^a (n=3506)	Normal (n=3506)	SD
Age [years, median (IQR)]	59(48-68)	59(45-68)	0.083	58(47-67)	59(45-68)	-0.001
Gender-male [n (%)]	3387(53.69)	1450(41.28)	0.250	1597(45.55)	1450(41.36)	0.085
Heart rate [bpm, median (IQR)]	85(78-97)	84(78-96)	0.049	85(78-96)	84(78-96)	0.005
Respiratory [bpm, median(IQR)]	20(19-21)	20(19-21)	0.104	20(19-21)	20(19-21)	-0.018
SBP [mmHg, median (IQR)]	129(120-141)	128(118-139)	0.087	128(119-140)	128(118-139)	0.025
DBP [mmHg, median (IQR)]	80(72-88)	79(72-86)	0.101	79(72-87)	79(72-86)	0.038
SpO₂ [%, median(IQR)]	97(95-98)	97(96-98)	-0.06	98(96-98)	97(96-98)	0.024
Comorbidities on admission [n (%)]
Chronic obstructive pulmonary disease	67(1.06)	47(1.34)	-0.025	45(1.28)	45(1.28)	0.000
Diabetes	1095(17.36)	408(11.61)	0.164	386(11.01)	408(11.64)	-0.020
Heart failure	40(0.63)	23(0.65)	-0.003	20(0.57)	23(0.66)	-0.011
Coronary heart disease	603(9.56)	195(5.55)	0.152	204(5.82)	195(5.56)	0.011
Cerebrovascular diseases	196(3.11)	81(2.31)	0.049	89(2.54)	81(2.31)	0.015
Chronic liver disease	151(2.39)	76(2.16)	0.015	75(2.14)	76(2.17)	-0.002
Chronic renal diseases	266(4.22)	103(2.93)	0.002	112(3.19)	103(2.94)	0.015
Medications [n (%)]
Insulin	975(15.45)	320(9.11)	0.194	332(9.47)	320(9.13)	0.012
Oral hypoglycemic drugs	1352(21.43)	456(12.98)	0.225	474(13.52)	456(13.01)	0.015
non-ACEI/ARB antihypertensive drug	1907(30.23)	873(24.85)	0.121	814(23.22)	872(24.87)	-0.039
ACEI/ARB	628(9.95)	233(6.63)	0.121	215(6.13)	233(6.65)	-0.021
Antiplatelet	533(8.45)	110(3.13)	0.229	89(2.54)	110(3.14)	-0.036
Chest CT on admission [n (%)]
Bilateral lesions	5154(87.05)	2808(83.60)	0.098	2718(83.35)	2807(83.74)	-0.011
Lab tests on admission [n (%), or median(IQR)]
Leukocyte count > 9.5×10⁹/L	697(11.08)	270(7.71)	0.116	313(8.98)	270(7.73)	0.045
Neutrophil count > 6.3×10⁹/L	1062(16.89)	412(11.77)	0.146	455(13.05)	412(11.80)	0.038
Lymphocyte< 1.1×10⁹/L	2595(41.26)	1400(40.00)	0.026	1405(40.28)	1394(39.91)	0.008
RBC < 3.5×10¹²/L (female) or 4.0×10¹²/L (male)	2568(40.83)	1579(45.14)	-0.087	1441(41.32)	1574(45.09)	-0.076
CRP > ULN ^c	2103(52.65)	821(46.10)	0.131	1257(51.52)	819(46.11)	0.108
PCT > ULN ^c	2479(45.06)	1021(34.95)	0.207	954(31.39)	1020(34.99)	-0.076
ALT > 40 U/L	1679(26.63)	640(18.23)	0.202	611(17.45)	640(18.27)	-0.021
eGFR value (mL/min)	103.57 (87.61-120.50)	105.30 (89.21-122.61)	-0.073	107.34 (91.14-125.22)	105.29 (89.21-122.55)	0.043
D-dimer > ULN ^c	3024(52.06)	1351(42.26)	0.197	1479(46.88)	1351(42.32)	0.092
cTnI > ULN^c	446(10.96)	160(7.35)	0.125	153(7.65)	160(7.36)	0.013

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Categories	Number of patients (n)	Deaths (n)	Adjusted HR (95% CI)	P value ^a
All patients of matched cohort ^b
Hyperlipidemia group vs. non-hyperlipidemia group	3506 vs. 3506	231 vs. 193	1.17 (0.95, 1.44)	0.151
TG ≥1.7 mmol/L group vs. TG<1.7 mmol/L group	2409 vs. 2409	180 vs. 137	1.23 (0.98, 1.55)	0.075
LDL-C ≥3 mmol/L group vs. LDL-C<3 mmol/L group	2083 vs. 2083	67 vs. 95	0.78 (0.57, 1.07)	0.123
HDL-C <1.0 mmol/L group vs. HDL-C ≥1.0 mmol/L group	2855 vs. 2855	213 vs. 157	1.12 (0.90, 1.39)	0.299
Male patients in matched cohort ^c
Hyperlipidemia group vs. non-hyperlipidemia group	1449 vs. 1449	135 vs. 112	1.24 (0.91, 1.70)	0.176
TG ≥1.7 mmol/L group vs. TG<1.7 mmol/L group	1145 vs. 1145	114 vs. 81	1.23 (0.92, 1.66)	0.170
LDL-C ≥3 mmol/L group vs. LDL-C<3 mmol/L group	988 vs. 988	43 vs. 46	1.00 (0.65, 1.52)	0.983
HDL-C <1.0 mmol/L group vs. HDL-C ≥1.0 mmol/L group	1499 vs. 1499	131 vs. 86	1.27 (0.94, 1.72)	0.113
Female patients in matched cohort ^d
Hyperlipidemia group vs. non-hyperlipidemia group	2014 vs. 2014	92 vs. 81	0.91 (0.66, 1.25)	0.547
TG ≥1.7 mmol/L group vs. TG<1.7 mmol/L group	1233 vs. 1233	62 vs. 50	1.14 (0.78, 1.66)	0.509
LDL-C ≥3 mmol/L group vs. LDL-C<3 mmol/L group	1099 vs. 1099	24 vs. 33	0.82 (0.48, 1.39)	0.456
HDL-C <1.0 mmol/L group vs. HDL-C ≥1.0 mmol/L group	1326 vs. 1326	79 vs. 66	1.00 (0.71, 1.40)	0.993

Categories	Number of Patients (n)	Deaths (n)	Adjusted HR (95% CI)	P value ^a
Cardiovascular diseases ^b
Hyperlipidemia group vs. non-hyperlipidemia group	1242 vs. 1242	128 vs. 114	0.96 (0.73,1.26)	0.765
TG ≥1.7 mmol/L group vs. TG<1.7 mmol/L group	1004 vs. 1004	115 vs. 81	1.19 (0.88,1.60)	0.253
LDL-C ≥3 mmol/L group vs. LDL-C<3 mmol/L group	814 vs. 814	42 vs. 59	0.78 (0.52,1.17)	0.235
HDL-C <1.0 mmol/L group vs. HDL-C ≥1.0 mmol/L group	1131 vs. 1131	124 vs. 90	1.00 (0.75,1.33)	0.991
Type 2 diabetes ^c
Hyperlipidemia group vs. non-hyperlipidemia group	473 vs. 473	52 vs. 54	0.74 (0.49,1.13)	0.164
TG ≥1.7 mmol/L group vs. TG<1.7 mmol/L group	515 vs. 515	56 vs. 40	1.07 (0.70,1.64)	0.752
LDL-C ≥3 mmol/L group vs. LDL-C<3 mmol/L group	364 vs. 364	20 vs. 29	0.72 (0.40,1.30)	0.279
HDL-C <1.0 mmol/L group vs. HDL-C ≥1.0 mmol/L group	492 vs. 492	56 vs. 43	1.17 (0.76,1.81)	0.468

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