Impact of longer diabetes duration and lower estimated glomerular filtration rate on cardiovascular complications and mortality: A nationwide population-based study

Abstract

BACKGROUND

Decreased renal function is a well-known risk factor for cardiovascular diseases (CVD) and death. However, the impact of diabetes duration and the glomerular filtration rate (GFR) on cardiovascular complications in patients with type 2 diabetes has not been well studied.

AIM

To investigate the complex impact of longer diabetes duration and GFR on CVD and mortality.

METHODS

Subjects with diabetes age ≥ 20 years, who underwent health check-ups from 2015 to 2016 were identified in the Korean National Health Insurance Service database. Based on diabetes duration, subjects were grouped into new-onset, < 5 years, 5–9 years, or ≥ 10 years. The new-onset diabetes group [estimated GFR (eGFR): ≥ 90 mL/min/1.73 m²] was the reference group. A Cox proportional hazards model adjusted for potential confounders was used to estimate the risk for myocardial infarction (MI), ischemic stroke (IS), and mortality.

RESULTS

During a 3.9-year follow-up of 2105228 patients, 36003 (1.7%) MIs, 46496 (2.2%) ISs, and 73549 (3.5%) deaths were documented. Both longer diabetes duration and lower eGFR were independently associated with higher risks of MI, IS, and mortality, which were further amplified when these factors coexisted. Even patients with new-onset diabetes had elevated MI and IS risk at mildly reduced eGFR (60–90 mL/min/1.73 m²). Mortality risk rose appreciably once eGFR declined below 60 mL/min/1.73 m², particularly in those with longer diabetes duration. eGFR ≥ 90 mL/min/1.73 m² subgroups had higher death risk than eGFR 60–90 mL/min/1.73 m² subgroups regardless of diabetic duration.

CONCLUSION

Increasing diabetes duration and decreasing eGFR are associated with increased risk of MI, IS, and mortality. For cardiovascular risk estimation, diabetes duration should be considered an important risk factor.

Key Words: Diabetes mellitus; Duration; Cardiovascular disease; Myocardial infarction; Stroke; Mortality

Core Tip: This study investigated the complex impact of longer diabetes duration and glomerular filtration rate (GFR) on cardiovascular diseases and mortality. We reveal an association between longer diabetes duration and an increased risk of myocardial infarction and ischemic stroke, even when the GFR is within the normal range. With increasing diabetes duration, mortality increased in subjects with GFR < 60 mL/min/1.73 m². These findings highlight that for cardiovascular risk estimation, diabetes duration should be considered an important risk factor.

INTRODUCTION

Diabetes mellitus (DM) accounts for a large portion of the global disease burden, and as of 2022, its worldwide prevalence was approximately 14% in the adult population, double the prevalence about 30 years ago[1]. DM causes various complications, including diabetic kidney disease, diabetic foot, and cardiovascular disease (CVD)[2], the leading cause of morbidity and mortality in people with diabetes[3]. Diabetes is the most common cause of chronic kidney disease (CKD) in adults, with 20%–40% of people with diabetes developing kidney disease[4]. In people with DM, CKD markedly increases CV risk and socioeconomic burden[5]. Like DM, CKD increases future coronary risk and their coexistence leads to greater risk[5].

With the recent emphasis on individualized DM treatment, interest in each patient’s characteristics is increasing. A previous study reported that in patients with DM, adding diabetic duration to classic risk factors improves CV risk assessment[6]. Additionally, some society guidelines suggest diabetes-duration-based CV risk categories[7]. However, current kidney disease guidelines do not consider diabetes duration as a CV risk factor[8]. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines assess the risk of complications based on albuminuria and glomerular filtration rate (GFR)[9], an indicator of renal function. It is well known that in patients with CKD, the risk of death and CV events increases gradually with decreasing GFR[10]. However, the impact of diabetes duration on CV complications and its combined effect with GFR in diabetic patients have not been well studied.

Here, we aimed to investigate the impact of diabetes duration on the association between GFR and the risk of CVD and mortality. We analyzed large-scale nationally representative data from the Korean National Health Insurance System (NHIS).

MATERIALS AND METHODS

Data source and study population

Information on the Korean NHIS has been published previously[11]. Figure 1 provides an overview of the patient selection process. Among 2613026 individuals with diabetes, who had undergone health examination provided by the Korean NHIS between January 1, 2015, and December 31, 2016, those aged < 20 years (n = 322), those with missing variables (n = 28030), and those with prior myocardial infarction (MI) and ischemic stroke (IS) diagnoses (n = 150728 and 299502, respectively) were excluded. To avoid confounding by pre-existing disease and to minimize possible reverse causality effects, individuals with newly diagnosed MI or IS in the first year of follow-up, or those who died during the first year of follow-up were excluded (n = 29216). Finally, 2105228 individuals with type 2 DM (1291933 men and 813295 women), who had estimated GFR (eGFR) monitoring at baseline and data on diabetes duration, were enrolled for analyses and follow-up until the date of death or end of follow-up (December 31, 2020; mean follow-up duration: 3.9 years).

Figure 1 Flow diagram of the study population.

Definition of type 2 diabetes, diabetes duration, and covariates

Type 2 diabetes was defined based on the following criteria: at least one claim per year under International Classification of Disease, 10^th Revision (ICD-10) codes E11–14 and at least one claim per year for antidiabetic medication prescription or fasting serum glucose levels of ≥ 126 mg/dL in the health examination database. Based on diabetes duration, subjects were categorized into the new-onset (those with no previously recorded disease code or history of antidiabetic drug prescription, but with a fasting blood glucose (FBG) level ≥ 126 mg/dL at health examination), < 5 years, 5–9 years, or ≥ 10 years groups. This categorization of diabetes duration is based on observations from previous studies[12-14].

Covariate definitions were based on data from health examination of the index years (2015–2016), and they included age, sex, socioeconomic status, body mass index (BMI; kg/m²), and systolic/diastolic blood pressure (mmHg). Smoking status, alcohol consumption, and physical activity data were obtained from a health examination questionnaire. Standardized self-reported questionnaires were used for alcohol consumption [categorized as none, mild (< 30 g of alcohol/day), or heavy (≥ 30 g of alcohol/day)] and smoking status (never, former, or current smoker). Regular physical activity was defined as high-intensity activity ≥ 1 time/wk or moderate-intensity activity ≥ 1 time/wk. BMI was calculated by dividing the subject’s weight (kg) by the square of their height (m²). Blood samples for serum creatinine, glucose, and lipid profile [total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein (LDL) cholesterol levels] measurements were drawn after overnight fasting. The above variables were extracted from the health examination data provided biennially to the NHIS by the participants. Hospitals that performed health examinations were NHIS-certified and subject to regular quality control evaluations. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration’s equation[15]. Income level was divided into quartiles, with the lowest quartile being defined as low income. Hypertension presence was defined based on at least one claim per year under ICD-10 codes I10–I13 and I15, at least one claim per year for an antihypertensive agent prescription, or a systolic/diastolic blood pressure of ≥ 140/90 mmHg in the health examination database. The presence of dyslipidemia was defined based on the presence of at least one claim per year under ICD-10 code E78 and at least one claim per year for a lipid-lowering agent prescription or a total cholesterol level of ≥ 240 mg/dL.

Study endpoints definitions

The study endpoints were newly diagnosed MI, IS, or death after a 1-year lag period. MI was defined by ICD-10 codes I21 or I22, with more than one diagnosis during hospitalization. IS was defined as the recording of ICD-10 codes I63 or I64 during hospitalization, and concomitant brain imaging studies using magnetic resonance imaging or computed tomography. Participants without MI, IS, or death during follow-up, were considered to have completed the study at the date of death or the end of the follow-up period, whichever came first. The study population was followed from baseline to the date of CV events or death, or until December 31, 2020, whichever came first.

Statistical analyses

Continuous and categorical variables are presented as mean ± SD and n (%), respectively. Intergroup differences were estimated using a χ² test or analysis of variance. MI, IS, or death incidence rates are presented per 1000 person-years. The hazard ratios (HRs) and 95% confidence intervals (CIs) of the risk of CV events or death were estimated using multivariable Cox proportional hazard regression analysis, with adjustment for age, sex, smoking, alcohol consumption, regular physical activity, income status, BMI, hypertension and dyslipidemia history, FBG level, insulin use, and ≥ 3 oral glucose-lowering drugs. Cox regression analysis using restricted cubic splines was used to examine the association between diabetes duration and eGFR with outcomes on a continuous scale. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, United States). P < 0.05 indicated statistical significance.

Ethical approval

The Institutional Review Board of Chonnam National University Hospital (No. CNUH-EXP-2024-136) waived the ethical approval and informed consent requirements for this study. Hence, consent was not obtained because the participants’ records and information were anonymized and de-identified before analysis.

RESULTS

Baseline characteristics of the study population

Table 1 shows the patients’ baseline characteristics based on diabetes duration. A total of 2 105 228 individuals with type 2 diabetes were enrolled. Of these, 33.6% had new-onset diabetes, 24.2% had diabetes for < 5 years, 20.1% had diabetes for 5–9 years, and 22.2% had diabetes for ≥ 10 years. Patients with longer duration were older, had higher hypertension and dyslipidemia prevalences, and were more likely to be non- or ex-smokers, nondrinkers, and to have regular physical activity. The longer the diabetes duration, the higher the likelihood that subjects were taking > 3 antidiabetic medications or using insulin. FBG was lowest in the < 5 years diabetes duration group and gradually increased with duration. However, total cholesterol, LDL cholesterol, and triglycerides decreased with diabetes duration. In particular, as diabetes duration increased, the proportion of patients with eGFR ≥ 90 mL/min/1.73 m² decreased, while the number of patients with eGFR < 90 mL/min/1.73 m² increased gradually (Table 1).

Table 1 Baseline characteristics of the study population based on diabetes duration, n (%)/mean ± SD.

	New-onset (n = 706461)	< 5 yr (n = 508600)	5–9 yr (n = 423032)	≥ 10 yr (n = 467135)	P
Age (yr)	52.98 ± 11.9	57.52 ± 11.1	60.56 ± 10.6	63.93 ± 9.9	< 0.0001
Sex (male)	481589 (68.2)	299076 (58.8)	246708 (58.3)	264560 (56.6)	< 0.0001
Smoking					< 0.0001
Non-smokers	332142 (47.01)	276207 (54.31)	238244 (56.32)	281535 (60.27)
Ex-smokers	157675 (22.32)	112509 (22.12)	95514 (22.58)	105528 (22.59)
Current smokers	216644 (30.67)	119884 (23.57)	89274 (21.1)	80072 (17.14)
Alcohol consumption					< 0.0001
None	300444 (42.53)	291682 (57.35)	253053 (59.82)	308113 (65.96)
Mild	311423 (44.08)	170781 (33.58)	134214 (31.73)	128087 (27.42)
Heavy	94594 (13.39)	46137 (9.07)	35765 (8.45)	30935 (6.62)
Regular exercise	140064 (19.83)	111534 (21.93)	96503 (22.81)	114805 (24.58)	< 0.0001
Low income	154498 (21.87)	116919 (22.99)	100476 (23.75)	105547 (22.59)	< 0.0001
Hypertension	310325 (43.93)	286258 (56.28)	258243 (61.05)	302440 (64.74)	< 0.0001
Dyslipidemia	272583 (38.58)	317279 (62.38)	260692 (61.62)	286680 (61.37)	< 0.0001
No. of oral GLD ≥ 3	133 (0.02)	85760 (16.86)	130444 (30.84)	226545 (48.5)	< 0.0001
Insulin use	623 (0.09)	29453 (5.79)	29086 (6.88)	84052 (17.99)	< 0.0001
BMI (kg/m2)	25.74 ± 3.74	25.74 ± 3.62	25.25 ± 3.41	24.52 ± 3.23	< 0.0001
WC (cm)	86.34 ± 9.27	86.63 ± 9.12	86.02 ± 8.82	85.02 ± 8.61	< 0.0001
Systolic BP (mmHg)	129.33 ± 15.22	127.23 ± 14.38	127.75 ± 14.69	128.15 ± 15.19	< 0.0001
Diastolic BP (mmHg)	80.45 ± 10.3	78.24 ± 9.53	77.5 ± 9.46	75.9 ± 9.51	<.0001
Fasting glucose (mg/dL)	151.14 ± 41.23	136.54 ± 43.02	144.22 ± 47.37	150.1 ± 52.12	< 0.0001
Total cholesterol (mg/dL)	209.39 ± 41.85	181.72 ± 41.28	177.47 ± 40.03	171.98 ± 38.99	< 0.0001
HDL-C (mg/dL)	52.46 ± 16.27	50.72 ± 14.25	50.69 ± 13.83	50.37 ± 14.08	< 0.0001
LDL-C (mg/dL)	121.35 ± 38.42	100.06 ± 36.78	97.02 ± 35.69	93.73 ± 34.61	<.0001
Triglyceride (mg/dL)	158.94 (158.72–159.16)	137.31 (137.1–137.52)	131.6 (131.39–131.82)	122.67 (122.48–122.86)	< 0.0001
eGFR (mL/min/1.73 m2)					< 0.0001
≥ 90	427078 (60.45)	291515 (57.32)	219064 (51.78)	201984 (43.24)
60-90	259089 (36.67)	193292 (38)	173265 (40.96)	200657 (42.95)
30-60	18770 (2.66)	21810 (4.29)	27807 (6.57)	55283 (11.83)
< 30	767 (0.11)	904 (0.18)	1442 (0.34)	5010 (1.07)
ESKD	757 (0.11)	1079 (0.21)	1454 (0.34)	4201 (0.9)

GLD: Glucose-lowering drugs; BMI: Body-mass index; WC: Waist circumference; BP: Blood pressure; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; eGFR: Estimated glomerular filtration rate; ESKD: End-stage kidney disease.

Diabetes duration, GFR, and risk of MI or IS

During 3.9 years of follow-up, 36 003 (1.7%) MI cases and 46 496 (2.2%) IS cases were identified. The new-onset diabetes group with eGFR ≥ 90 mL/min/1.73 m² was used as the reference group. Incidence rates and risk of MI and IS increased gradually with increasing diabetes duration (Figure 2, Tables 2 and 3). In each diabetes duration group, the lower the eGFR, the higher the risk of MI or IS. In each diabetes duration group, MI or IS risk in the groups with eGFR of 60–90 mL/min/1.73 m², which implies preserved renal function, was higher than in those with eGFR ≥ 90 mL/min/1.73 m². (Tables 2 and 3, Supplementary Table 1). Even in the new-onset diabetes group, MI or IS risk began to increase at an eGFR of 60–90 mL/min/1.73 m² (adjusted HR: 1.067 or 1.111; 95%CI: 1.02–1.117 or 1.066–1.158, respectively). In the same eGFR subgroup, longer diabetes duration was associated with higher MI or IS risk. Even patients with eGFR ≥ 90 mL/min/1.73 m² in the < 5 years, 5–9 years, and > 10 years groups had a significantly higher risk of MI or IS than those in the reference group. Patients with the longest diabetes duration and the lowest eGFR experienced the highest rates of MI and IS, indicating an amplified risk when these factors coexisted. Similar trends were revealed by the associations between eGFR on a continuous scale and the risk of MI or IS according to diabetes duration (Supplementary Figure 1). As the duration of diabetes increased, the increase in MI or IS risk due to a decrease in eGFR tended to be steeper.

Figure 2 Incidence rate, hazard ratios, and 95% confidence intervals based on diabetes duration and glomerular filtration rate. A: Myocardial infarction; B: Ischemic stroke; C: Death. The new-onset diabetes group (estimated glomerular filtration rate: > 90 mL/min/1.73 m²) was used as the reference group. Adjusted for age, sex, smoking, alcohol consumption, regular physical activity, income status, body mass index, hypertension and dyslipidemia history, fasting blood glucose level, insulin use, and ≥ 3 oral glucose-lowering drugs.

Table 2 Impact of estimated glomerular filtration rate on myocardial infarction based on diabetes duration.

Diabetes duration	eGFR, mL/min/1.73 m2	n	Events (n)	Incidence rate (per 1000 person-years)	HR (95%CI)
					Model 11	Model 22	Model 33
New-onset	≥ 90	427078	4191	2.56	1 (Ref.)	1 (Ref.)	1 (Ref.)
	60–90	259089	3530	3.54	1.384 (1.323-1.447)	1.076 (1.028-1.126)	1.067 (1.020-1.117)
	30–60	18770	525	7.46	2.916 (2.663-3.193)	1.520 (1.385-1.668)	1.466 (1.336-1.609)
	< 30	767	19	6.96	2.726 (1.737-4.278)	1.523 (0.970-2.391)4	1.474 (0.939-2.314)4
	ESKD	757	18	6.44	2.519 (1.585-4.002)	1.916 (1.205-3.044)	1.909 (1.201-3.034)
< 5 yr	≥ 90	291515	3744	3.28	1.279 (1.224-1.336)	1.103 (1.055-1.154)	1.077 (1.029-1.126)
	60–90	193292	3264	4.31	1.679 (1.604-1.758)	1.150 (1.096-1.206)	1.125 (1.072-1.180)
	30–60	21810	661	7.95	3.104 (2.86-3.369)	1.590 (1.461-1.730)	1.522 (1.398-1.656)
	< 30	904	40	12.47	4.888 (3.58-6.674)	2.657 (1.945-3.629)	2.431 (1.779-3.322)
	ESKD	1079	48	12.25	4.805 (3.615-6.386)	3.655 (2.749-4.860)	3.262 (2.452-4.338)
5–9 yr	≥ 90	219064	3290	3.84	1.498 (1.432-1.568)	1.176 (1.122-1.232)	1.098 (1.047-1.151)
	60–90	173265	3538	5.23	2.039 (1.949-2.132)	1.285 (1.226-1.347)	1.207 (1.150-1.266)
	30–60	27807	941	8.89	3.469 (3.232-3.724)	1.716 (1.594-1.848)	1.584 (1.470-1.706)
	< 30	1442	77	15.11	5.926 (4.73-7.424)	3.140 (2.504-3.937)	2.756 (2.197-3.457)
	ESKD	1454	59	11.13	4.359 (3.371-5.636)	3.282 (2.537-4.245)	2.764 (2.135-3.577)
≥ 10 yr	≥ 90	201984	3803	4.87	1.904 (1.822-1.989)	1.356 (1.296-1.419)	1.158 (1.104-1.215)
	60–90	200657	5104	6.62	2.585 (2.482-2.693)	1.505 (1.440-1.573)	1.283 (1.224-1.344)
	30–60	55283	2410	11.75	4.597 (4.373-4.834)	2.240 (2.122-2.366)	1.835 (1.733-1.943)
	< 30	5010	422	24.65	9.695 (8.772-10.716)	5.039 (4.550-5.582)	3.858 (3.476-4.281)
	ESKD	4201	319	22.18	8.731 (7.792-9.784)	5.721 (5.099-6.419)	4.202 (3.737-4.725)

¹Unadjusted for age and sex.

²Adjusted for age, sex, smoking, alcohol consumption, regular exercise, low-income status, body mass index, and history of hypertension or dyslipidemia.

³Adjusted for age, sex, smoking, alcohol consumption, regular exercise, low-income status, body mass index, history of hypertension or dyslipidemia, use of insulin, and ≥ 3 oral glucose-lowering drugs.

⁴Insignificant values.

eGFR: Estimated glomerular filtration rate; ESKD: End-stage kidney disease; HR: Hazard ratio; CI: Confidence interval.

Table 3 Impact of estimated glomerular filtration rate on ischemic stroke based on diabetes duration.

Diabetes duration	eGFR, mL/min/1.73 m2	n	Events (n)	Incidence rate (per 1000 person-years)	HR (95%CI)
					Model 11	Model 22	Model 33
New-onset	≥ 90	427078	4615	2.82	1 (Ref.)	1 (Ref.)	1 (Ref.)
	60–90	259089	4627	4.65	1.650 (1.584-1.718)	1.123 (1.077-1.170)	1.111 (1.066-1.158)
	30–60	18770	826	11.83	4.196 (3.897-4.519)	1.578 (1.462-1.702)	1.505 (1.395-1.624)
	< 30	767	41	15.21	5.413 (3.980-7.361)	2.215 (1.628-3.013)	2.114 (1.553-2.876)
	ESKD	757	23	8.21	2.913 (1.934-4.389)	2.048 (1.360-3.086)	2.057 (1.365-3.099)
< 5 yr	≥ 90	291515	4185	3.67	1.297 (1.244-1.353)	1.092 (1.047-1.139)	1.087 (1.042-1.134)
	60–90	193292	4344	5.75	2.031 (1.949-2.117)	1.205 (1.154-1.258)	1.200 (1.149-1.253)
	30–60	21810	1020	12.35	4.374 (4.087-4.681)	1.694 (1.580-1.817)	1.651 (1.539-1.771)
	< 30	904	48	14.93	5.312 (3.997-7.059)	2.289 (1.721-3.043)	2.150 (1.617-2.860)
	ESKD	1079	34	8.63	3.072 (2.192-4.305)	2.251 (1.606-3.155)	2.105 (1.502-2.951)
5–9 yr	≥ 90	219064	4171	4.88	1.726 (1.655-1.800)	1.257 (1.204-1.311)	1.188 (1.138-1.240)
	60–90	173265	4720	7.00	2.474 (2.376-2.577)	1.293 (1.239-1.349)	1.228 (1.176-1.282)
	30–60	27807	1373	13.07	4.625 (4.355-4.913)	1.704 (1.600-1.815)	1.597 (1.499-1.702)
	< 30	1442	104	20.53	7.309 (6.018-8.877)	3.012 (2.478-3.661)	2.730 (2.246-3.319)
	ESKD	1454	71	13.39	4.758 (3.764-6.015)	3.403 (2.691-4.303)	2.986 (2.361-3.778)
≥ 10 yr	≥ 90	201984	5058	6.50	2.304 (2.214-2.398)	1.445 (1.387-1.505)	1.245 (1.193-1.300)
	60–90	200657	7305	9.53	3.375 (3.253-3.502)	1.561 (1.500-1.624)	1.342 (1.287-1.399)
	30–60	55283	3170	15.55	5.520 (5.276-5.776)	1.988 (1.894-2.088)	1.647 (1.565-1.733)
	< 30	5010	405	23.57	8.412 (7.599-9.311)	3.416 (3.081-3.787)	2.689 (2.422-2.985)
	ESKD	4201	356	24.79	8.863 (7.957-9.871)	5.208 (4.672-5.807)	3.948 (3.535-4.409)

¹Unadjusted for age and sex.

²Adjusted for age, sex, smoking, alcohol consumption, regular exercise, low-income status, body mass index, and history of hypertension or dyslipidemia.

³Adjusted for age, sex, smoking, alcohol consumption, regular exercise, low-income status, body mass index, history of hypertension or dyslipidemia, use of insulin, and ≥ 3 oral glucose-lowering drugs.

eGFR: Estimated glomerular filtration rate; ESKD: End-stage kidney disease; HR: Hazard ratio; CI: Confidence interval.

Diabetes duration, GFR, and risk of death

A total of 73 549 (3.5%) deaths were identified during follow-up. Incidence rates and risk of death increased gradually with increasing diabetes duration (Figure 2, Table 4). In each diabetes duration groups, the risk of death in the groups with eGFR of 60–90 mL/min/1.73 m² was significantly lower than in the reference group. When the group with eGFR ≥ 90 mL/min/1.73 m² in each diabetes duration group was set as the reference, the risk of MI or IS was higher in the groups with eGFR 60–90 mL/min/1.73 m² than in the groups with eGFR ≥ 90 mL/min/1.73 m² only in the new-onset and < 5 years groups (Supplementary Table 1). The risk of death began to increase at eGFR of 30–60 mL/min/1.73 m² in each diabetes duration group and the risk gradually increased as GFR decreased. The association between eGFR on a continuous scale and the risk of death according to diabetes duration exhibited a U shape in all duration groups (Supplementary Figure 1).

Table 4 Impact of estimated glomerular filtration rate on death based on diabetes duration.

Diabetes duration	eGFR, mL/min/1.73 m2	n	Events (n)	Incidence rate (per 1000 person-years)	HR (95%CI)
					Model 11	Model 22	Model 33
New-onset	≥ 90	427078	7135	4.33	1 (Ref.)	1 (Ref.)	1 (Ref.)
	60–90	259089	7509	7.49	1.724 (1.669-1.780)	0.957 (0.926-0.989)	0.943 (0.913-0.975)
	30–60	18770	1765	24.78	5.695 (5.406-5.999)	1.406 (1.332-1.483)	1.345 (1.275-1.420)
	< 30	767	133	48.28	11.150 (9.392-13.236)	2.800 (2.357-3.326)	2.673 (2.250-3.176)
	ESKD	757	64	22.63	5.215 (4.077-6.670)	2.839 (2.219-3.631)	2.814 (2.200-3.600)
< 5 yr	≥ 90	291515	6400	5.57	1.276 (1.234-1.320)	1.056 (1.020-1.092)	1.013 (0.979-1.048)4
	60–90	193292	6614	8.66	1.980 (1.915-2.047)	0.971 (0.938-1.005)4	0.932 (0.900-0.965)
	30–60	21810	1881	22.33	5.110 (4.857-5.376)	1.439 (1.365-1.516)	1.339 (1.270-1.412)
	< 30	904	137	41.82	9.651 (8.15-11.429)	2.787 (2.352-3.302)	2.444 (2.063-2.897)
	ESKD	1079	96	24.01	5.565 (4.550-6.807)	3.307 (2.703-4.046)	2.716 (2.220-3.324)
5–9 yr	≥ 90	219064	5639	6.54	1.498 (1.446-1.551)	1.000 (0.965-1.036)4	0.913 (0.881-0.947)
	60–90	173265	7305	10.70	2.445 (2.367-2.526)	1.003 (0.969-1.037)4	0.921 (0.889-0.953)
	30–60	27807	2683	24.99	5.714 (5.466-5.974)	1.514 (1.445-1.586)	1.362 (1.300-1.428)
	< 30	1442	275	52.80	12.192 (10.808-13.753)	3.548 (3.143-4.005)	2.942 (2.605-3.322)
	ESKD	1454	187	34.57	7.978 (6.900-9.224)	4.685 (4.051-5.419)	3.717 (3.213-4.301)
≥ 10 yr	≥ 90	201984	6632	8.43	1.936 (1.872-2.002)	1.006 (0.972-1.041)4	0.816 (0.787-0.845)
	60–90	200657	11112	14.26	3.270 (3.174-3.368)	1.091 (1.057-1.126)	0.885 (0.856-0.915)
	30–60	55283	6091	29.16	6.706 (6.480-6.939)	1.688 (1.627-1.752)	1.300 (1.250-1.351)
	< 30	5010	1081	60.88	14.153 (13.276-15.087)	4.115 (3.854-4.393)	2.926 (2.738-3.128)
	ESKD	4201	810	54.56	12.711 (11.820-13.669)	5.540 (5.147-5.963)	3.629 (3.367-3.912)

¹Unadjusted for age and sex.

²Adjusted for age, sex, smoking, alcohol consumption, regular exercise, low-income status, body mass index, and history of hypertension or dyslipidemia.

³Adjusted for age, sex, smoking, alcohol consumption, regular exercise, low-income status, body mass index, history of hypertension or dyslipidemia, use of insulin, and ≥ 3 oral glucose-lowering drugs.

⁴Insignificant values.

eGFR: Estimated glomerular filtration rate; ESKD: End-stage kidney disease; HR: Hazard ratio; CI: Confidence interval.

DISCUSSION

This study investigated the association between diabetes duration, GFR, and the risk of CVD and mortality in individuals with type 2 diabetes. Our findings indicate that prolonged diabetes duration is a significant predictor of increased MI, IS, and all-cause mortality risk. Notably, even among individuals with normal or near-normal GFR (≥ 90 mL/min/1.73 m²), extended diabetes duration correlated with increased MI and IS risk. Additionally, a GFR decline to < 60 mL/min/1.73 m² was associated with a marked increase in mortality risk. These results highlight that the coexistence of diminished renal function and prolonged diabetes duration amplifies adverse CV outcomes. In other words, patients with long-standing diabetes and reduced eGFR bore the greatest burden of CV risk, underscoring a potentially synergistic interaction between these risk factors.

Our results are consistent with existing literature emphasizing the pivotal role of diabetes duration in CVD risk prediction. For instance, using United Kingdom Biobank data, a study demonstrated that participants with diabetes durations of 10–15 years had a 1.5-fold risk increase, and those with durations of ≥ 15 years had a 2.22-fold increase in fatal and nonfatal CVD event risk when compared with those with durations of < 5 years[6]. Similarly, the Atherosclerosis Risk in Communities study revealed that compared with nondiabetic counterparts, individuals with diabetes duration ≥ 15 years exhibited a 2.82-fold increase in heart failure risk and each 5-year increase in duration was associated with a 17% relative increase in heart failure risk, independent of traditional risk factors[16]. Collectively, these findings highlight the need to integrate diabetes duration into routine CV risk assessments to enhance predictive accuracy and guide therapeutic interventions. In the same context as diabetes duration, age at diabetes onset has also emerged as a crucial determinant of disease trajectory and complication risk. Individuals diagnosed with type 2 diabetes before the age of 40 years face a higher CVD risk and cardiac 10-year expected risk than those diagnosed later[17]. A prospective study by Chan et al[18] found that compared with patients with late-onset diabetes, young-onset patients diagnosed with type 2 diabetes before 40 years of age had a higher risk for CV and renal events[18]. However, after adjustment for diabetes duration, the association between young-onset type 2 diabetes and CVD was not significant[18]. Since complications, including retinopathy and nephropathy, progress rapidly, these demographic characteristics highlight the need for early, aggressive management strategies and ongoing monitoring to mitigate long-term adverse effects.

A notable observation from our study is the U-shaped association between GFR and mortality risk. While reduced GFR (< 60 mL/min/1.73 m²) is traditionally linked to higher mortality, our findings indicate that those with preserved or high normal GFR also face increased mortality rates. This paradox may be attributed to several factors. First, individuals with low muscle mass, malnutrition, or frailty may present with artificially elevated GFR because of lower serum creatinine levels, masking underlying health issues and leading to actual renal impairment underestimation; a phenomenon known as reverse epidemiology[19]. Second, early diabetic nephropathy stages often involve glomerular hyperfiltration, which, despite normal or elevated GFR readings, signifies renal pathology and correlates with increased CV events and mortality[5]. These insights suggest that GFR alone may be an insufficient renal function marker and highlight the need to include additional parameters, such as albuminuria, for a more reasonable risk assessment. Current CKD guidelines, including by KDIGO, primarily use GFR and albuminuria levels to stratify CV risk. Albuminuria is one of the important indicators of renal damage, and it is well known that the amount of albuminuria shows a linear relationship with not only renal prognosis but also CVD risk[20]. GFR and albuminuria are currently the main markers used for risk estimation of CKD[9]. However, our study advocates for the incorporation of diabetes duration as an independent risk factor in these models. Although diabetes duration cannot be changed, it is a crucial indicator of cumulative glycemic exposure and vascular damage, much like age reflects accumulated risk. Therefore, incorporating diabetes duration into risk assessments can identify high-risk patients who might otherwise appear at moderate risk if only current modifiable factors are considered. In clinical practice, recognizing a patient with long-standing diabetes as higher risk can prompt earlier and more aggressive interventions on modifiable factors, such as stricter blood pressure or lipid control and timely initiation of cardiorenal protective therapies.

The mechanism of CVD development due to renal dysfunction represented by low GFR is well known. This includes mechanisms involving traditional risk factors such as hypertension, hyperglycemia, and dyslipidemia, and nontraditional factors such as vascular calcification, chronic systemic inflammation, and uremic milieu[21]. However, the mechanism by which longer diabetes duration increases CV complications is unclear. However, through previous studies, several causes can be hypothesized. A prospective cohort study involving patients with diabetes undergoing diagnostic coronary angiography and intravascular ultrasound revealed that a longer diabetes duration was associated with intravascular ultrasound-defined thin-cap fibroatheroma, which is believed to be associated with plaque rupture and events related to coronary heart disease [22]. Oxidized LDL is a key factor in atherosclerosis progression, and compared with newly diagnosed patients and healthy participants, oxidized LDL cholesterol levels were significantly higher in patients with diabetes duration > 5 years, while total LDL cholesterol was significantly lower in patients with prolonged diabetes when compared with newly diagnosed patients[23]. In the Northern Manhattan Study, a prospective population-based cohort study designed to determine stroke incidence, risk factors, and prognosis in an urban multiethnic population, diabetes duration was associated with an increased risk of IS (adjusted HR: 1.03, 95%CI: 1.02–1.04). Patients with a diabetes duration of > 10 years showed a 3.2-fold higher IS risk (adjusted HR: 3.2, 95%CI: 2.4–4.5)[24]. The authors suggest that in longstanding diabetes, endothelial dysfunction and fibrinogen and clotting mechanism abnormalities may contribute to ischemic vascular complications.

To our knowledge, this is the first study to demonstrate in a nationwide cohort that prolonged diabetes duration magnifies the CV risks associated with CKD. These findings build upon prior evidence of diabetes duration as a risk factor and extend it by illustrating the interactive impact of diabetes duration and renal function on CVD and mortality risk. Despite the strengths of our large population-based study, several limitations warrant consideration. First, diabetes duration was determined using claims data, which may introduce misclassification bias. Diabetes duration calculation may have some errors, especially in patients with late diagnoses or those who did not visit the hospital. However, because of the characteristics of the Korean NHIS, in which most citizens are enrolled, and biennial mandatory free health check-ups, it seems a fairly accurate calculation was made. Second, the lack of albuminuria measurements, a pivotal diabetic kidney disease marker, limits the renal risk assessment’s comprehensiveness. If we had known the albuminuria level of the patients in our study, we could have observed the joint association of diabetes duration and CVD according to more detailed risk status including albuminuria as well as GFR. In future research, incorporating albuminuria data might enhance the understanding of the interplay between renal function and CV outcomes. Third, because this was a retrospective cohort study, causal inferences cannot be definitively established. Future studies will need to evaluate diabetes duration as one of the major risk factors for complications and design interventions based on this risk stratification. Additionally, evaluating the potential benefits of modifying risk assessment frameworks to include diabetes duration may inform clinical practice and guideline development. For example, diabetes duration can be used to adjust baseline risk or coefficients in multivariable models, or to guide the timing of using specific classes of drugs, such as sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide-1 receptor agonists, based on risk assessment using diabetes duration.

CONCLUSION

Our study elucidated a profound impact of diabetes duration on CV risk and mortality, independent of GFR status. In all diabetes duration groups, lower eGFR was associated with higher risk of MI or IS. The association between eGFR and mortality revealed a U shape, especially in new-onset diabetes and diabetes duration < 5 years. These findings highlight the need for considering diabetes duration as an essential factor in CV risk assessment and CKD management. Diabetes duration integration into clinical guidelines may facilitate the identification of high-risk individuals early, enabling more personalized and effective interventions.