强化降脂对血糖管理困难的2型糖尿病合并慢性肾脏病患者死亡风险的缓冲作用：基于双代谢轨迹的队列研究

doi:10.12122/j.issn.1673-4254.2026.07.17

摘要/Abstract

摘要：

目的探究2型糖尿病合并慢性肾脏病（T2DM-CKD）患者低密度脂蛋白（LDL-C）与糖化血红蛋白（HbA1c）的纵向协同演变特征，解析双代谢轨迹对全因死亡的交互影响及风险修饰作用。方法基于天津市医保数据平台纳入7991例T2DM-CKD患者。采用群体基础轨迹模型（GBTM）识别LDL-C和HbA1c的长期演变模式，并据此构建双代谢轨迹联合组以评估其协同效应。采用 LASSO回归进行特征选择，利用多变量Cox回归及双参照组交互分析策略，系统量化双轨迹的联合风险，并重点评估深度降脂在不同血糖背景下的风险修饰价值。结果中位随访5.10（3.15~7.52）年，共记录死亡事件405例（5.1%）。研究识别出3种LDL-C轨迹（深度控制、标准控制、高位回归）及3种HbA1c轨迹（控制良好、中度改善、控制不良）。双重代谢紊乱呈现显著的剂量-反应梯度，“脂差糖差组”死亡风险最高（HR=5.550，95% CI： 3.322~9.274，P<0.001），远超单一指标异常的风险叠加。即便HbA1c控制良好，LDL-C高位回归仍独立增加死亡风险（HR=2.015，P=0.039）；反之，在LDL-C深度控制下，HbA1c 控制不良的额外风险不再显著（P=0.480）。交互分析证实，对于HbA1c控制不良（血糖管理困难）的患者，相较于标准降脂，将LDL-C强化至深度控制水平（<1.8 mmol/L）发挥了显著的缓冲保护作用，使死亡风险降低 51%（HR=0.49，95% CI： 0.26~0.92，P=0.026）。相反，从深度控制降至标准控制则使风险增加99%（HR=1.99，95%CI： 1.07~3.69，P=0.029）。结论本研究首次揭示了T2DM-CKD患者糖脂代谢轨迹的协同演变规律及其对预后的叠加影响。深度降脂（LDL-C<1.8 mmol/L）对血糖管理困难患者具有显著保护作用。当血糖控制面临挑战时，强化血脂管理是改善患者预后的有效补偿策略，为个体化精准治疗提供了新的循证依据。

关键词: 2型糖尿病, 慢性肾脏病, 低密度脂蛋白胆固醇, 糖化血红蛋白, 群体基础轨迹模型, 全因死亡率, 交互效应

Abstract:

Objective To investigate the longitudinal synergistic evolution of low-density lipoprotein cholesterol (LDL-C) and glycated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), and analyze the interaction effects and risk-modifying effect of dual metabolic trajectories on all-cause mortality. Methods This study included 7991 patients with T2DM and CKD based on the Tianjin medical insurance data platform. Group-based trajectory modeling (GBTM) was employed to identify longitudinal trajectory patterns of LDL-C and HbA1c, and dual metabolic trajectory groups were constructed to evaluate their synergistic effects. LASSO regression was applied for feature selection. Multivariable Cox proportional hazards regression with a dual-reference group strategy was utilized to systematically quantify the combined risks of dual trajectories and specifically assess the risk modification value of intensive lipid lowering across different glycemic backgrounds. Results During a median follow-up of 5.10 (3.15-7.52) years, 405 deaths (5.1%) were recorded. Three LDL-C trajectories (Intensive Control, Standard Control, and High-Regression) and 3 HbA1c trajectories (Well-Controlled, Moderate Improvement, and Poorly Controlled) were identified. Dual metabolic disturbances demonstrated a significant dose-response gradient, with the "Lipid-Poor/Glucose-Poor" group exhibiting the highest mortality risk (HR=5.550, 95% CI: 3.322-9.274, P<0.001), far exceeding the additive risk of single-indicator abnormalities. Even with well-controlled HbA1c, the high-regression LDL-C trajectory independently increased mortality risk (HR=2.015, P=0.039). Conversely, under intensive LDL-C control, the excess risk associated with poorly controlled HbA1c was no longer significant (P=0.480). Interaction analysis confirmed that for patients with poorly controlled HbA1c, intensifying LDL-C to a deep control level (<1.8 mmol/L) had a significant buffering protective effect compared to standard lipid lowering, reducing the mortality risk by 51% (HR=0.49, 95% CI: 0.26-0.92, P=0.026); in contrast, de-escalating from intensive to standard control increased the risk by 99% (HR=1.99, 95% CI: 1.07-3.69, P=0.029). Conclusion This study reveals for the first time the longitudinal synergistic evolution of glucose and lipid metabolic trajectories in patients with T2DM and CKD and their superimposed impact on prognosis. Intensive lipid lowering (LDL-C<1.8 mmol/L) confers a significant protective effect in patients with difficulty in glycemic management and serves as an effective compensatory strategy to improve patient prognosis.

Key words: type 2 diabetes mellitus, chronic kidney disease, low-density lipoprotein cholesterol, glycated hemoglobin, group-based trajectory modeling, all-cause mortality, interaction effect

王小龙, 杨建, 梁爽, 董哲毅. 强化降脂对血糖管理困难的2型糖尿病合并慢性肾脏病患者死亡风险的缓冲作用：基于双代谢轨迹的队列研究[J]. 南方医科大学学报, 2026, 46(7): 1634-1647.

Xiaolong WANG, Jian YANG, Shuang LIANG, Zheyi DONG. Buffering effect of intensive lipid lowering on mortality risk in type 2 diabetic patients with chronic kidney disease and challenging glycemic management: a cohort study based on dual metabolic trajectories[J]. Journal of Southern Medical University, 2026, 46(7): 1634-1647.

图/表 14

参考文献 34

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Trajectory cohort	Number of patients [n (%)]	Mean indicator values
Trajectory cohort	Number of patients [n (%)]	Baseline	Endpoint	Overall
HbA1c
Good control	3378 (42.3)	5.50	4.88	5.11
Moderatel improvement	3254 (40.7)	7.12	6.16	6.64
Poor control	1359 (17.0)	8.96	8.27	8.74
LDL-C
Deep control	3970 (49.7)	1.82	1.58	1.65
Standard control	3231 (40.4)	2.59	2.25	2.41
High-level regression	790 (9.9)	3.88	3.04	3.54

Trajectory cohort	Number of patients [n (%)]	Mean indicator values
Trajectory cohort	Number of patients [n (%)]	Baseline	Endpoint	Overall
HbA1c
Good control	3378 (42.3)	5.50	4.88	5.11
Moderatel improvement	3254 (40.7)	7.12	6.16	6.64
Poor control	1359 (17.0)	8.96	8.27	8.74
LDL-C
Deep control	3970 (49.7)	1.82	1.58	1.65
Standard control	3231 (40.4)	2.59	2.25	2.41
High-level regression	790 (9.9)	3.88	3.04	3.54

Item	Survival (n=7586)	Death (n=405)	Total (n=7991)	P
Age (year)	58.21 (50.47, 64.55)	65.46 (58.89, 71.69)	58.58 (50.83, 65.04)	<0.001
Male [n (%)]	4300(56.7)	240 (59.3)	4540 (56.8)	0.333
BMI (kg/m²)	25.78 (23.67, 28.37)	25.51 (23.51, 28.58)	25.78 (23.66, 28.38)	0.431
SBP (mmHg)	130.00 (122.00, 140.00)	130.00 (126.00, 140.00)	130.00 (122.00, 140.00)	0.002
DBP (mmHg)	80.00 (76.00, 85.00)	80.00 (78.00, 86.00)	80.00 (76.00, 85.00)	0.247
Laboratory tests
Hemoglobin (g/L)	139.00 (127.00, 152.00)	126.00 (112.00, 141.00)	139.00 (126.00, 151.00)	<0.001
White blood cells (10⁹/L)	6.79 (5.68, 8.12)	7.00 (5.93, 8.53)	6.79 (5.69, 8.14)	0.017
Neutrophils (10⁹/L)	4.14 (3.28, 5.27)	4.59 (3.61, 5.89)	4.15 (3.30, 5.30)	<0.001
Lymphocytes (10⁹/L)	1.92 (1.51, 2.38)	1.68 (1.26, 2.12)	1.90 (1.50, 2.37)	<0.001
Platelets (10⁹/L)	226.00 (189.00, 270.00)	210.00 (169.00, 258.00)	226.00 (187.70, 269.00)	<0.001
ALT (U/L)	19.70 (14.00, 29.60)	15.90 (11.40, 23.00)	19.50 (14.00, 29.10)	<0.001
AST (U/L)	18.90 (15.00, 24.50)	16.60 (13.50, 22.00)	18.70 (15.00, 24.30)	<0.001
Total protein (g/L)	69.80 (64.50, 74.50)	66.30 (60.60, 71.30)	69.60 (64.20, 74.40)	<0.001
Albumin (g/L)	42.20 (38.70, 45.30)	37.90 (34.10, 42.00)	42.00 (38.50, 45.10)	<0.001
Direct bilirubin (μmol/L)	2.90 (2.00, 4.19)	2.55 (1.60, 3.50)	2.90 (1.98, 4.13)	<0.001
Total bilirubin (μmol/L)	7.90 (5.74, 10.70)	5.90 (4.20, 8.65)	7.85 (5.63, 10.61)	<0.001
Total cholesterol (mmol/L)	5.12 (4.31, 6.04)	5.09 (4.20, 6.18)	5.12 (4.30, 6.05)	0.922
Triglycerides (mmol/L)	1.78 (1.23, 2.71)	1.77 (1.21, 2.60)	1.78 (1.23, 2.70)	0.464
HDL-C (mmol/L)	1.13 (0.96, 1.35)	1.09 (0.91, 1.33)	1.13 (0.95, 1.35)	0.001
LDL-C( mmol/L)	2.15 (1.70, 2.80)	2.29 (1.74, 3.13)	2.16 (1.70, 2.81)	0.009
Glucose (mmol/L)	8.55 (6.84, 11.43)	8.67 (6.44, 11.88)	8.57 (6.83, 11.46)	0.934
Blood urea nitrogen (mmol/L)	5.90 (4.73, 7.50)	7.60 (5.89, 10.60)	5.96 (4.76, 7.61)	<0.001
Uric acid (μmol/L)	335.00 (275.00, 410.00)	352.00 (283.10, 445.90)	336.00 (275.00, 411.00)	<0.001
Serum creatinine (μmol/L)	70.90 (57.00, 92.00)	100.40 (74.00, 148.00)	71.80 (57.30, 94.00)	<0.001
eGFR [mL·min^-1·(1.73 m²)^-1]	93.21 (71.11, 104.60)	60.73 (38.36, 85.72)	92.40 (68.84, 104.09)	<0.001
INR	0.94 (0.89, 1.00)	0.96 (0.90, 1.03)	0.94 (0.89, 1.00)	<0.001
D-dimer (μg/mL)	0.36 (0.22, 0.60)	0.61 (0.33, 1.11)	0.37 (0.22, 0.63)	<0.001
Phosphorus (mmol/L)	1.18 (1.06, 1.31)	1.19 (1.05, 1.37)	1.18 (1.06, 1.32)	0.251
Potassium (mmol/L)	4.14 (3.86, 4.43)	4.20 (3.85, 4.60)	4.14 (3.86, 4.44)	0.013
Sodium (mmol/L)	140.08 (138.00, 142.00)	140.00 (137.40, 142.10)	140.07 (138.00, 142.00)	0.250
Calcium (mmol/L)	2.29 (2.19, 2.38)	2.18 (2.05, 2.30)	2.28 (2.18, 2.38)	<0.001
24-hour UTP (g/24 h)	0.24 (0.11, 0.83)	0.95 (0.26, 4.03)	0.25 (0.11, 0.94)	<0.001
CKD stage [n (%)]				<0.001
G1	4237 (55.8)	81 (20.0)	4318 (54.0)
G2	2057 (27.1)	123 (30.4)	2180 (27.3)
G3	1063 (14.0)	131 (32.3)	1194 (14.9)
G4	163 (2.1)	46 (11.4)	209 (2.6)
G5	66 (0.9)	24 (5.9)	90 (1.1)
Comorbidities
Hypertension [n (%)]	4629 (61.0)	279 (68.9)	4908 (61.4)	0.002
Duration of hypertension (year)	0.84 (0.00, 3.69)	0.75 (0.00, 3.19)	0.84 (0.00, 3.64)	0.332
Duration of diabetes (year)	2.43 (0.41, 5.12)	2.06 (0.46, 4.76)	2.40 (0.41, 5.09)	0.215
Dyslipidemia [n (%)]	3208 (42.3)	150 (37.0)	3358 (42.0)	0.042

Item	Survival (n=7586)	Death (n=405)	Total (n=7991)	P
Age (year)	58.21 (50.47, 64.55)	65.46 (58.89, 71.69)	58.58 (50.83, 65.04)	<0.001
Male [n (%)]	4300(56.7)	240 (59.3)	4540 (56.8)	0.333
BMI (kg/m²)	25.78 (23.67, 28.37)	25.51 (23.51, 28.58)	25.78 (23.66, 28.38)	0.431
SBP (mmHg)	130.00 (122.00, 140.00)	130.00 (126.00, 140.00)	130.00 (122.00, 140.00)	0.002
DBP (mmHg)	80.00 (76.00, 85.00)	80.00 (78.00, 86.00)	80.00 (76.00, 85.00)	0.247
Laboratory tests
Hemoglobin (g/L)	139.00 (127.00, 152.00)	126.00 (112.00, 141.00)	139.00 (126.00, 151.00)	<0.001
White blood cells (10⁹/L)	6.79 (5.68, 8.12)	7.00 (5.93, 8.53)	6.79 (5.69, 8.14)	0.017
Neutrophils (10⁹/L)	4.14 (3.28, 5.27)	4.59 (3.61, 5.89)	4.15 (3.30, 5.30)	<0.001
Lymphocytes (10⁹/L)	1.92 (1.51, 2.38)	1.68 (1.26, 2.12)	1.90 (1.50, 2.37)	<0.001
Platelets (10⁹/L)	226.00 (189.00, 270.00)	210.00 (169.00, 258.00)	226.00 (187.70, 269.00)	<0.001
ALT (U/L)	19.70 (14.00, 29.60)	15.90 (11.40, 23.00)	19.50 (14.00, 29.10)	<0.001
AST (U/L)	18.90 (15.00, 24.50)	16.60 (13.50, 22.00)	18.70 (15.00, 24.30)	<0.001
Total protein (g/L)	69.80 (64.50, 74.50)	66.30 (60.60, 71.30)	69.60 (64.20, 74.40)	<0.001
Albumin (g/L)	42.20 (38.70, 45.30)	37.90 (34.10, 42.00)	42.00 (38.50, 45.10)	<0.001
Direct bilirubin (μmol/L)	2.90 (2.00, 4.19)	2.55 (1.60, 3.50)	2.90 (1.98, 4.13)	<0.001
Total bilirubin (μmol/L)	7.90 (5.74, 10.70)	5.90 (4.20, 8.65)	7.85 (5.63, 10.61)	<0.001
Total cholesterol (mmol/L)	5.12 (4.31, 6.04)	5.09 (4.20, 6.18)	5.12 (4.30, 6.05)	0.922
Triglycerides (mmol/L)	1.78 (1.23, 2.71)	1.77 (1.21, 2.60)	1.78 (1.23, 2.70)	0.464
HDL-C (mmol/L)	1.13 (0.96, 1.35)	1.09 (0.91, 1.33)	1.13 (0.95, 1.35)	0.001
LDL-C( mmol/L)	2.15 (1.70, 2.80)	2.29 (1.74, 3.13)	2.16 (1.70, 2.81)	0.009
Glucose (mmol/L)	8.55 (6.84, 11.43)	8.67 (6.44, 11.88)	8.57 (6.83, 11.46)	0.934
Blood urea nitrogen (mmol/L)	5.90 (4.73, 7.50)	7.60 (5.89, 10.60)	5.96 (4.76, 7.61)	<0.001
Uric acid (μmol/L)	335.00 (275.00, 410.00)	352.00 (283.10, 445.90)	336.00 (275.00, 411.00)	<0.001
Serum creatinine (μmol/L)	70.90 (57.00, 92.00)	100.40 (74.00, 148.00)	71.80 (57.30, 94.00)	<0.001
eGFR [mL·min^-1·(1.73 m²)^-1]	93.21 (71.11, 104.60)	60.73 (38.36, 85.72)	92.40 (68.84, 104.09)	<0.001
INR	0.94 (0.89, 1.00)	0.96 (0.90, 1.03)	0.94 (0.89, 1.00)	<0.001
D-dimer (μg/mL)	0.36 (0.22, 0.60)	0.61 (0.33, 1.11)	0.37 (0.22, 0.63)	<0.001
Phosphorus (mmol/L)	1.18 (1.06, 1.31)	1.19 (1.05, 1.37)	1.18 (1.06, 1.32)	0.251
Potassium (mmol/L)	4.14 (3.86, 4.43)	4.20 (3.85, 4.60)	4.14 (3.86, 4.44)	0.013
Sodium (mmol/L)	140.08 (138.00, 142.00)	140.00 (137.40, 142.10)	140.07 (138.00, 142.00)	0.250
Calcium (mmol/L)	2.29 (2.19, 2.38)	2.18 (2.05, 2.30)	2.28 (2.18, 2.38)	<0.001
24-hour UTP (g/24 h)	0.24 (0.11, 0.83)	0.95 (0.26, 4.03)	0.25 (0.11, 0.94)	<0.001
CKD stage [n (%)]				<0.001
G1	4237 (55.8)	81 (20.0)	4318 (54.0)
G2	2057 (27.1)	123 (30.4)	2180 (27.3)
G3	1063 (14.0)	131 (32.3)	1194 (14.9)
G4	163 (2.1)	46 (11.4)	209 (2.6)
G5	66 (0.9)	24 (5.9)	90 (1.1)
Comorbidities
Hypertension [n (%)]	4629 (61.0)	279 (68.9)	4908 (61.4)	0.002
Duration of hypertension (year)	0.84 (0.00, 3.69)	0.75 (0.00, 3.19)	0.84 (0.00, 3.64)	0.332
Duration of diabetes (year)	2.43 (0.41, 5.12)	2.06 (0.46, 4.76)	2.40 (0.41, 5.09)	0.215
Dyslipidemia [n (%)]	3208 (42.3)	150 (37.0)	3358 (42.0)	0.042

Risk factor	Model 1		Model 2		Model 3
Risk factor	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Lipid optimal glucose optimal	1.0 (Reference)		1.0 (Reference)		1.0 (Reference)
Lipid optimal glucose moderate	1.840 (1.269-2.668)	0.001	1.239 (0.847-1.814)	0.270	1.160 (0.792-1.700)	0.445
Lipid optimal glucose poor	2.302 (1.492-3.552)	<0.001	1.394 (0.890-2.184)	0.146	1.177 (0.748-1.852)	0.480
Lipid moderate glucose optimal	0.891 (0.566-1.402)	0.616	1.061 (0.667-1.686)	0.803	1.002 (0.630-1.593)	0.994
Lipid moderate glucose moderate	1.813 (1.248-2.634)	0.002	1.506 (1.023-2.218)	0.038	1.454 (0.987-2.142)	0.058
Lipid moderate glucose poor	3.392 (2.292-5.018)	<0.001	2.619 (1.745-3.933)	<0.001	2.343 (1.554-3.533)	<0.001
Lipid poor glucose optimal	1.989 (1.049-3.772)	0.035	2.147 (1.104-4.173)	0.024	2.015 (1.036-3.918)	0.039
Lipid poor glucose moderate	2.471 (1.535-3.979)	<0.001	2.162 (1.287-3.631)	0.004	2.142 (1.273-3.606)	0.004
Lipid poor glucose poor	5.457 (3.467-8.591)	<0.001	5.551 (3.323-9.273)	<0.001	5.550 (3.322-9.274)	<0.001
Age (year)			1.061 (1.048-1.074)	<0.001	1.060 (1.047-1.073)	<0.001
Hypertension duration (year)			1.036 (0.989-1.085)	0.140	1.017 (0.969-1.067)	0.492
MI/Stroke			1.672 (1.339-2.090)	<0.001	1.589 (1.270-1.988)	<0.001
DBP (mmHg)			1.015 (1.004-1.027)	0.010	1.011 (1.000-1.023)	0.049
Platelets (10⁹/L)			0.998 (0.997-1.000)	0.021	0.998 (0.997-1.000)	0.031
Neutrophils (10⁹/L)			1.058 (1.016-1.101)	0.006	1.051 (1.010-1.095)	0.015
Hemoglobin (g/L)			0.994 (0.989-1.000)	0.059	0.996 (0.991-1.002)	0.226
INR			1.244 (0.627-2.469)	0.532	1.379 (0.706-2.692)	0.347
Albumin (g/L)			0.909 (0.887-0.932)	<0.001	0.916 (0.893-0.940)	<0.001
Total protein (g/L)			1.038 (1.021-1.055)	<0.001	1.042 (1.025-1.060)	<0.001
Direct bilirubin (μmol/L)			1.004 (0.983-1.025)	0.730	1.010 (0.988-1.032)	0.376
Indirect bilirubin (μmol/L)			0.999 (0.972-1.027)	0.962	0.996 (0.970-1.022)	0.740
HDL-C (mmol/L)			0.678 (0.481-0.954)	0.026	0.734 (0.522-1.033)	0.076
Potassium (mmol/L)			0.852 (0.698-1.039)	0.113	0.862 (0.708-1.050)	0.140
Sodium (mmol/L)			0.987 (0.964-1.011)	0.282	0.993 (0.969-1.018)	0.573
Calcium (mmol/L)			0.905 (0.617-1.327)	0.609	0.882 (0.597-1.303)	0.528
Blood urea nitrogen (mmol/L)			1.027 (1.001-1.054)	0.042	1.024 (0.997-1.052)	0.077
Serum creatinine (μmol/L)			1.000 (0.998-1.001)	0.807	1.000 (0.998-1.002)	0.819
24-hour UTP (g/24 h)			1.124 (1.088-1.160)	<0.001	1.107 (1.071-1.144)	<0.001
Glucose (mmol/L)			1.048 (1.026-1.072)	<0.001	1.046 (1.023-1.071)	<0.001
eGFR (mL/min/1.73 m²)			0.981 (0.976-0.987)	<0.001	0.984 (0.978-0.991)	<0.001
Proton pump inhibitors					1.068 (0.854-1.337)	0.563
β-blockers					1.131 (0.912-1.404)	0.262
Calcium channel blockers					1.345 (1.056-1.713)	0.017
Diuretics					1.715 (1.352-2.175)	<0.001
Biguanides					0.898 (0.715-1.128)	0.354
CPM					1.112 (0.856-1.445)	0.426
ARB/ACEI					1.123 (0.884-1.426)	0.342
DPP4 inhibitors					1.135 (0.833-1.547)	0.423
SGLT2 inhibitors					1.064 (0.592-1.912)	0.836
Insulin					1.346 (0.953-1.901)	0.092