The association between hemoglobin A1c (HbA1c) and stroke risk along with its subtypes is rarely reported. We aimed to investigate the association between HbA1c and the risk of incident stroke in patients with type 2 diabetes based on real world data from three healthcare systems.
We performed a retrospective cohort study of 27,113 African Americans and 40,431 whites with type 2 diabetes. Demographic, anthropometric, laboratory, and medication information were abstracted from the National Patient-Centered Clinical Research Network common data model. Incident stroke events including both ischemic and hemorrhagic stroke were defined.
During a mean follow-up period of 3.79±1.68 years, 7,735 patients developed stroke (6,862 ischemic and 873 hemorrhagic). Multivariable-adjusted hazard ratios across levels of HbA1c at baseline (<6.0%, 6.0% to 6.9% [reference group], 7.0% to 7.9%, 8.0% to 8.9%, 9.0% to 9.9%, and ≥10%) were 1.07, 1.00, 1.13, 1.23, 1.27, and 1.37 (
These data suggest that diabetes management may have to be individualized according to the guideline recommendations rather than intensively attempting to lower HbA1c.
Type 2 diabetes has emerged as a pandemic globally, with very high rates in the United States. For example, estimated cases of diabetes increased by 9 million in the United States between 2003–2004 and 2013–2014, affecting 30.2 million (13%) adults in 2013–2014 [
Data on patients with type 2 diabetes in the Louisiana Experiment Assessing Diabetes outcomes (LEAD) cohort study were obtained through the Research Action for Health Network (REACHnet) [
The definition of type 2 diabetes in the present study was formulated according to the Surveillance, PREvention, and Management of Diabetes Mellitus (SUPREME-DM) criteria [
The study and analysis plan were approved by the Pennington Biomedical Research Center, Tulane University, and Ochsner Health System Institutional Review Boards. Registrations of this study at clinicaltrials.gov (
The National Patient-Centered Clinical Research Network (PCORnet) common data model is a specification that defines a standard organization and representation of data for the PCORnet distributed research network [
We created the follow-up database in electronic form by using the number assigned to each patient who visited the health system with a unique patient identifier. The updated mean value of HbA1c was calculated for each participant from baseline to each year of follow-up. For example, after 1 year, the updated mean was the average of the baseline and 1-year values, and after 3 years it was the average of baseline, 1-, 2-, and 3-year values. In the case of an event occurring during followup, the period for estimating the updated mean value was from baseline to the year before the event occurred. The average number of HbA1c measurements during the follow-up period was 6.64. Stroke (ischemic or hemorrhagic) was the primary outcome in the present analysis. ICD-9-CM and ICD-10-CM codes were used to identify hemorrhagic stroke (ICD-9-CM codes 430–432 and ICD-10-CM codes I60–I62), ischemic stroke (ICD-9-CM codes 433–436 and ICD-10-CM codes I63–I64), and any stroke (ICD-9-CM codes 430–436 and ICD-10-CM codes I60–I64) events. The distributions of all ICD-9 and ICD-10 codes were: 430 (1.8%), 431 (3.4%), 432 (1.7%), 433 (39.4%), 434 (23.1%), 435 (5.5%), 436 (0.6%), I60 (1.9%), I61 (2.4%), I62 (1.5%), and I63 (18.7%). These diagnoses were recorded in the course of routine patient care by the patients’ treating clinicians. Incident stroke events were defined only when they occurred after the first record of diabetes diagnosis. The duration of follow-up for each cohort member (personyears) was tabulated from the date of the first documented diabetes diagnosis to the date of diagnosis of the outcome, death of inpatients or July 31, 2018. Either the admission date, the visiting date of emergency room or the visiting date of outpatient clinic was used when the ICD codes for stroke were first recorded. Diagnosis of stroke events could be made in either outpatient, inpatient or emergency encounters. Encounter types including ambulatory visit and other ambulatory visit were considered as outpatient encounters, while encounter types including inpatient, emergency department, emergency admission to inpatient, institutional stay, observation stay and institutional consult were considered as either inpatient or emergency encounters.
Cox proportional hazards regression was used to estimate hazard ratios (HRs) for incident stroke according to levels of HbA1c. HbA1c was evaluated in the following two ways: (1) as categories (<6.0%, 6.0% to 6.9% [reference group], 7.0% to 7.9%, 8.0% to 8.9%, 9.0% to 9.9%, and ≥10%); and (2) as a continuous variable when restricted cubic spline curves were performed. HbA1c levels were included in the models as dummy variables, and the significance of the trend across categories of HbA1c was tested in the same models by giving an ordinal numeric value for each dummy variable. The proportional hazards assumption in the Cox model was assessed with graphical methods and with models including time-by-covariate interactions. In general, all proportionality assumptions were appropriate. All analyses were first carried out adjusting for age and sex, and further for race, BMI, systolic blood pressure, LDL-C, HDL-C, triglycerides, eGFR, smoking, insurance type, use of antihypertensive drugs, use of glucose lowering drugs, use of lipid-lowering drugs, use of antiplatelet or anticoagulant drugs, and presence of atrial fibrillation. Sensitivity analyses were performed among patients who were diagnosed with stroke only in inpatient or emergency encounters. Statistical significance was considered to be
The data that support the findings of this study are available from REACHnet but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of REACHnet.
The baseline characteristics of patients in all categories of baseline HbA1c level are presented in
During a mean follow-up period of 3.79±1.68 years, 7,735 patients developed stroke (6,862 ischemic and 873 hemorrhagic). A total of 2,604 inpatient deaths occurred including 554 cardiovascular deaths during the follow-up visits. Multivariable-adjusted HRs across levels of HbA1c at baseline (<6.0%, 6.0% to 6.9% [reference group], 7.0% to 7.9%, 8.0% to 8.9%, 9.0% to 9.9%, and ≥10%) were 1.07, 1.00, 1.13, 1.23, 1.27, and 1.37 (
We performed two sensitivity analysis to confirm our findings. Using diagnoses associated with inpatient or emergency encounters was applied in the first sensitivity analysis. During a mean follow-up period of 3.95±1.58 years, 2,946 patients developed stroke (2,623 ischemic and 323 hemorrhagic). Multivariable-adjusted HRs across levels of HbA1c at baseline (<6.0%, 6.0% to 6.9% [reference group], 7.0% to 7.9%, 8.0% to 8.9%, 9.0% to 9.9%, and ≥10%) were 1.31, 1.00, 1.35, 1.43, 1.56, and 1.72 (
When HbA1c level was considered as a continuous variable by using restricted cubic splines, a U-shaped association of HbA1c with the risk of stroke was observed (
When subgroup analyses were utilized (including sensitivity analysis), the U-shaped association between HbA1c and the risk of total stroke was consistent among patients of different ages, races, sexes, BMI, never and past or current smokers (
In this large health system-based cohort, we found that both lower HbA1c and higher HbA1c levels were associated with higher risks of incident stroke, which formed a U-shaped curve. In the analysis restricted to stroke cases only diagnosed by inpatient or emergency, the U-shape association appears more pronounced. These results indicate that both intensive and poor glycemic control might be associated with an increased risk of stroke in patients with type 2 diabetes.
Diabetes is a leading cause of stroke, especially ischemic stroke. Patients with type 2 diabetes have an increased risk of stroke estimated to range from 150% to 400% compared with those without diabetes [
However, the previous data source was totally different from the present one. The data from the Louisiana State University Health Care Services Division were used previously, which compromised over 75% poor patients without any type of insurance covered and over 50% African Americans. Between-study differences in the population characteristics might account for the discrepant findings between the earlier and current studies. However, it is not always true that lower HbA1c can result in a better quality of life or health outcomes, because some studies [
Very few studies have thus far focused on the association between HbA1c level and hemorrhagic stroke among patients with diabetes (both type 1 and type 2). Data from the multi-ethnic Women’s Health Initiative Observational Study [
Poor glycemic control has been shown to be well correlated with macrovascular events in many studies and trials including the UKPDS [
A major strength of this study was the large sample size, which allowed for high statistical power and the ability to perform stratified analyses. Further, the relatively rich clinical data and numerous events also make the results robust. The data we used was derived from administrative databases, avoiding the problem of differential recall bias. Data in this study were extracted from three partners of REACHnet, which minimizes the influence of low accessibility of health care. Inevitably, the study has several limitations. First, some socioeconomic variables were missing in the EMR data including education level, family income etc. Second, the stroke diagnoses in the present study were based on physician diagnosis and no chart review was performed. However, most American and European cohort studies, such as the Framingham Study [
The present study found a U-shaped association between HbA1c levels and the risk of total, ischemic and hemorrhagic stroke among patients with type 2 diabetes, and the lowest risk was found among patients with HbA1c at 6.0% to 7.0%. Our findings supported the perspective that clinical diabetes management should be individualized according to the guideline recommendations rather than intensively seeking to lower HbA1c.
Supplementary materials related to this article can be found online at
Risk of total stroke, ischemic stroke, and hemorrhagic stroke diagnosed only by inpatient or emergency encounters according to baseline and mean follow-up hemoglobin A1c level in patients with type 2 diabetes
Subgroup analyses for the risk of total stroke by baseline hemoglobin A1c in patients excluding those who died during the follow-up
Subgroup analyses for the risk of total stroke diagnosed only by inpatient and emergency according to baseline hemoglobin A1c levels in patients with type 2 diabetes
The authors have no financial conflicts of interest.
The LEAD study would like to acknowledge the contributions of our partners. The success of this study depended on their ongoing support and expertise. These partners include Ochsner Health System and the Ochsner Patient Research Advisory Board; Tulane Medical Center; University Medical Center New Orleans; REACHnet (a PCORnet CDRN) and their multi-stakeholder Diabetes Advisory Groups; Pennington Biomedical Research Center; Blue Cross and Blue Shield of Louisiana; and our patient and community partners Patricia Dominick, Catherine Glover, and Peggy Malone.
This work was supported by a Patient-Centered Outcomes Research (PCORI) cooperative agreement (NEN-1508-32257) as part of Natural Experiments for Translation in Diabetes 2.0 (NEXT-D2). All statements in this manuscript, including findings and conclusions, are solely those of the authors and do not necessarily represent the views of PCORI, its Board of Governors, or Methodology Committee. Drs. Shen, Hu, and Katzmarzyk were partly supported by a grant from the National Institute of General Medical Sciences (U54GM104940) of the National Institutes of Health.
Hazard ratios of total stroke risks among patients with type 2 diabetes diagnosed in all encounters (A) and only in inpatients/emergency encounters (B) by different hemoglobin A1c (HbA1c) levels at baseline. Models were adjusted for age, sex, race, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate, smoking, insurance type, use of antihypertensive drugs, use of glucose lowering drugs, use of lipid-lowering drugs, use of antiplatelet or anticoagulant drugs, and presence of atrial fibrillation.
Baseline characteristics of patients with type 2 diabetes by baseline hemoglobin A1c level
Characteristic | Hemoglobin A1c (%) |
||||||
---|---|---|---|---|---|---|---|
<6.0 | 6.0–6.9 | 7.0–7.9 | 8.0–8.9 | 9.0–9.9 | ≥10 | ||
No. of participants | 11,487 | 25,160 | 12,934 | 6,516 | 3,839 | 7,608 | |
Age (yr) | 67.4±12.6 | 68.2±12.0 | 67.6±11.7 | 65.7±11.5 | 63.2±11.3 | 60.0±10.5 | <0.001 |
Male sex (%) | 45.9 | 45.2 | 48.2 | 49.8 | 52.2 | 52.0 | <0.001 |
Race (%) | <0.001 | ||||||
African American | 34.4 | 39.0 | 38.7 | 40.5 | 44.6 | 52.5 | |
White | 65.6 | 61.0 | 61.3 | 59.5 | 55.4 | 47.5 | |
Body mass index (kg/m2) | 31.4±7.7 | 32.8±7.5 | 33.2±7.3 | 33.5±7.5 | 33.7±7.4 | 33.2±7.4 | <0.001 |
Body mass index categories (%) | |||||||
<25 kg/m2 | 19.6 | 11.9 | 10.1 | 9.1 | 8.9 | 10.9 | <0.001 |
25–29.9 kg/m2 | 29.0 | 28.0 | 26.8 | 26.2 | 25.4 | 25.3 | |
30.0–34.9 kg/m2 | 25.3 | 27.9 | 29.3 | 28.3 | 27.6 | 28.4 | |
≥35 kg/m2 | 26.2 | 32.2 | 33.9 | 36.4 | 38.1 | 35.4 | |
Blood pressure (mm Hg) | |||||||
Systolic | 132±14 | 133±13 | 134±13 | 135±13 | 135±13 | 135±14 | <0.001 |
Diastolic | 74±9 | 75±8 | 75±8 | 76±8 | 77±8 | 78±8 | <0.001 |
Total cholesterol (mg/dL) | 167±41.0 | 170±37.2 | 167±37.8 | 169±40.0 | 173±41.4 | 183±46.0 | <0.001 |
LDL-C (mg/dL) | 95.7±32.4 | 98.1±30.8 | 95.1±31.5 | 96.4±32.6 | 99.6±34.1 | 108±37.6 | <0.001 |
HDL-C (mg/dL) | 46.0±14.5 | 45.2±12.2 | 43.3±11.7 | 42.3±11.8 | 42.1±11.8 | 42.2±12.1 | <0.001 |
Triglycerides (mg/dL) | 129±77.3 | 136±70.7 | 148±81.9 | 156±93.3 | 164±133 | 173±122 | <0.001 |
Estimated GFR (%) | |||||||
≥90 mL/min/1.73 m2 | 14.7 | 13.8 | 13.4 | 12.6 | 14.6 | 16.1 | <0.001 |
60–89 mL/min/1.73 m2 | 51.6 | 58.7 | 56.5 | 55.8 | 55.4 | 55.2 | |
30–59 mL/min/1.73 m2 | 23.0 | 23.3 | 25.2 | 25.9 | 25.0 | 24.5 | |
15–29 mL/min/1.73 m2 | 4.5 | 2.4 | 3.2 | 3.2 | 3.1 | 2.9 | |
<15 mL/min/1.73 m2 | 6.3 | 1.7 | 1.7 | 2.4 | 2.0 | 1.3 | |
Current smoker (%) | 10.0 | 8.5 | 8.2 | 8.6 | 9.7 | 10.2 | <0.001 |
Insurance type (%) | <0.001 | ||||||
Commercial/private | 31.2 | 35.6 | 36.8 | 38.4 | 42.2 | 47.8 | |
Medicare | 59.6 | 57.1 | 55.6 | 52.5 | 45.5 | 35.2 | |
Medicaid | 5.9 | 4.3 | 4.2 | 5.1 | 7.5 | 10.1 | |
Self-pay | 1.5 | 1.6 | 1.7 | 2.2 | 2.9 | 4.7 | |
Others | 1.8 | 1.4 | 1.7 | 1.8 | 1.9 | 2.2 | |
Use of medications (%) | |||||||
Lipid-lowering | 49.5 | 63.4 | 64.5 | 64.1 | 62.6 | 60.2 | <0.001 |
Antihypertensive | 74.8 | 78.4 | 78.9 | 78.9 | 77.1 | 74.2 | <0.001 |
Glucose-lowering | 49.9 | 65.6 | 82.5 | 85.9 | 87.0 | 90.5 | <0.001 |
Antiplatelet or anticoagulant | 42.7 | 42.3 | 41.1 | 40.3 | 39.3 | 37.2 | <0.001 |
Atrial fibrillation | 19.7 | 14.1 | 13.0 | 12.3 | 10.8 | 8.3 | <0.001 |
Values are presented as mean±standard deviation.
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; GFR, glomerular filtration rate.
Risk of total stroke, ischemic stroke and hemorrhagic stroke by baseline and mean follow-up hemoglobin A1c level
Variable | Hemoglobin A1c (%) |
||||||
---|---|---|---|---|---|---|---|
<6.0 | 6.0–6.9 | 7.0–7.9 | 8.0–8.9 | 9.0–9.9 | ≥10 | ||
Baseline hemoglobin A1c level | |||||||
No. of patients | 11,487 | 25,160 | 12,934 | 6,516 | 3,839 | 7,608 | |
Total stroke | |||||||
No. of cases | 1,316 | 2,702 | 1,607 | 830 | 458 | 822 | |
Person-years | 39,331 | 96,393 | 51,510 | 25,284 | 14,618 | 27,575 | |
Age- and sex-adjustment | 1.12 (1.05–1.21) | 1.00 | 1.21 (1.14–1.29) | 1.39 (1.28–1.51) | 1.42 (1.28–1.58) | 1.55 (1.42–1.69) | <0.001 |
Multivariable adjustment | 1.07 (1.01–1.14) | 1.00 | 1.13 (1.06–1.21) | 1.23 (1.13–1.33) | 1.27 (1.14–1.40) | 1.37 (1.26–1.49) | <0.001 |
Ischemic stroke | |||||||
No. of cases | 1,103 | 2,420 | 1,451 | 736 | 410 | 742 | |
Person-years | 39,042 | 95,856 | 51,217 | 25,100 | 14,530 | 27,437 | |
Age-and sex-adjustment | 1.08 (1.01–1.17) | 1.00 | 1.22 (1.14–1.30) | 1.39 (1.28–1.51) | 1.43 (1.28–1.59) | 1.55 (1.42–1.70) | <0.001 |
Multivariable adjustment | 1.02 (1.01–1.05) | 1.00 | 1.13 (1.06–1.21) | 1.20 (1.10–1.31) | 1.24 (1.12–1.39) | 1.35 (1.24–1.48) | <0.001 |
Hemorrhagic stroke | |||||||
No. of cases | 213 | 282 | 156 | 94 | 48 | 80 | |
Person-years | 37,957 | 93,207 | 49,537 | 24,299 | 14,034 | 36,469 | |
Age-and sex-adjustment | 1.65 (1.31–2.07) | 1.00 | 1.10 (0.90–1.33) | 1.49 (1.18–1.88) | 1.50 (1.10–2.04) | 1.60 (1.24–2.07) | <0.001 |
Multivariable adjustment | 1.40 (1.16–1.69) | 1.00 | 1.14 (0.93–1.39) | 1.47 (1.16–1.87) | 1.47 (1.07–2.01) | 1.51 (1.16–1.98) | 0.002 |
Mean follow-up hemoglobin A1c level | |||||||
No. of patients | 8,630 | 22,172 | 22,977 | 6,808 | 3,491 | 3,466 | |
Total stroke | |||||||
No. of cases | 1,169 | 2,431 | 2,383 | 887 | 444 | 421 | |
Person-years | 31,222 | 86,500 | 82,936 | 27,132 | 13,772 | 13,149 | |
Age- and sex-adjustment | 1.24 (1.15–1.33) | 1.00 | 1.04 (0.98–1.11) | 1.47 (1.36–1.59) | 1.62 (1.46–1.80) | 1.76 (1.57–1.96) | <0.001 |
Multivariable adjustment | 1.18 (1.10–1.27) | 1.00 | 1.07 (1.01–1.13) | 1.25 (1.16–1.35) | 1.42 (1.28–1.58) | 1.52 (1.36–1.69) | <0.001 |
Ischemic stroke | |||||||
No. of cases | 983 | 2,191 | 2,107 | 806 | 402 | 373 | |
Person-years | 30,927 | 86,041 | 82,511 | 26,953 | 13,693 | 13,057 | |
Age-and sex-adjustment | 1.18 (1.09–1.27) | 1.00 | 1.04 (0.98–1.10) | 1.48 (1.36–1.60) | 1.63 (1.46–1.82) | 1.73 (1.54–1.94) | <0.001 |
Multivariable adjustment | 1.12 (1.04–1.21) | 1.00 | 1.05 (0.99–1.12) | 1.24 (1.14–1.35) | 1.40 (1.26–1.56) | 1.46 (1.30–1.64) | <0.001 |
Hemorrhagic stroke | |||||||
No. of cases | 186 | 240 | 276 | 81 | 42 | 48 | |
Person-years | 29,929 | 83,506 | 80,367 | 25,964 | 13,141 | 12,595 | |
Age-and sex-adjustment | 2.04 (1.61–2.59) | 1.00 | 1.12 (0.90–1.40) | 1.39 (1.03–1.89) | 1.54 (1.03–1.89) | 2.16 (1.46–3.20) | 0.001 |
Multivariable adjustment | 1.67 (1.36–2.04) | 1.00 | 1.19 (1.00–1.42) | 1.33 (1.03–1.72) | 1.60 (1.14–2.24) | 2.07 (1.50–2.87) | <0.001 |
Values are presented as hazard ratio (95% confidence interval) unless otherwise indicated. Multivariable adjustment included age, sex, race, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate, smoking, insurance type, use of antihypertensive drugs, use of glucose lowering drugs, use of lipid-lowering drugs, use of antiplatelet or anticoagulant drugs, and presence of atrial fibrillation.
Subgroup analyses for the risk of total stroke by baseline hemoglobin A1c level
Variable | No. of patients | Hemoglobin A1c (%) |
||||||||
---|---|---|---|---|---|---|---|---|---|---|
<6.0 | 6.0–6.9 | 7.0–7.9 | 8.0–8.9 | 9.0–9.9 | ≥10 | |||||
Age (yr) | ||||||||||
<60 | 20,512 | 1.01 (0.82–1.24) | 1.00 | 1.05 (0.86–1.29) | 1.16 (0.92–1.46) | 1.36 (1.07–1.73) | 1.43 (1.19–1.72) | 0.001 | ||
≥60 | 47,032 | 1.02 (0.95–1.10) | 1.00 | 1.12 (1.05–1.20) | 1.18 (1.09–1.29) | 1.15 (1.03–1.29) | 1.18 (1.07–1.30) | <0.001 | ||
Sex | ||||||||||
Men | 32,073 | 1.02 (0.88–1.08) | 1.00 | 1.14 (1.04–1.24) | 1.17 (1.04–1.32) | 1.14 (0.99–1.33) | 1.35 (1.19–1.53) | <0.001 | ||
Women | 35,471 | 1.15 (1.05–1.26) | 1.00 | 1.12 (1.02–1.22) | 1.27 (1.14–1.41) | 1.38 (1.20–1.59) | 1.37 (1.22–1.54) | <0.001 | ||
Race | ||||||||||
African Americans | 27,113 | 1.12 (1.00–1.26) | 1.00 | 1.11 (1.00–1.24) | 1.24 (1.09–1.40) | 1.44 (1.25–1.67) | 1.39 (1.23–1.57) | <0.001 | ||
Whites | 40,431 | 1.04 (0.95–1.13) | 1.00 | 1.14 (1.06–1.24) | 1.23 (1.11–1.36) | 1.13 (0.98–1.31) | 1.35 (1.20–1.52) | <0.001 | ||
Body mass index (kg/m2) | ||||||||||
<30 | 26,747 | 1.13 (1.04–1.24) | 1.00 | 1.11 (1.01–1.21) | 1.20 (1.07–1.35) | 1.17 (1.00–1.36) | 1.30 (1.15–1.48) | <0.001 | ||
≥30 | 40,797 | 1.00 (0.99–1.02) | 1.00 | 1.14 (1.04–1.24) | 1.23 (1.10–1.37) | 1.33 (1.16–1.52) | 1.42 (1.27–1.59) | <0.001 | ||
Smoking status | ||||||||||
Never smoking | 53,959 | 1.04 (0.96–1.13) | 1.00 | 1.05 (0.91–1.20) | 1.16 (0.98–1.38) | 1.12 (0.89–1.40) | 1.33 (1.10–1.59) | 0.037 | ||
Past and current smoking | 13,585 | 1.14 (0.99–1.31) | 1.00 | 1.17 (1.09–1.25) | 1.26 (1.15–1.38) | 1.33 (1.18–1.49) | 1.39 (1.26–1.53) | <0.001 | ||
Using glucose-lowering drugs |
||||||||||
No | 18,810 | 1.08 (0.97–1.20) | 1.00 | 1.09 (0.93–1.28) | 1.16 (0.92–1.46) | 1.12 (0.81–1.56) | 1.22 (0.91–1.65) | 0.451 | ||
Yes | 48,734 | 1.06 (0.97–1.16) | 1.00 | 1.14 (1.06–1.22) | 1.24 (1.14–1.35) | 1.29 (1.16–1.44) | 1.40 (1.28–1.53) | <0.001 | ||
Insulin or sulfonylurea | 20,573 | 1.04 (0.93–1.16) | 1.00 | 1.02 (0.94–1.11) | 1.11 (1.01–1.22) | 1.10 (0.98–1.23) | 1.16 (1.06–1.28) | 0.017 | ||
Others | 28,161 | 1.10 (1.01–1.20) | 1.00 | 1.09 (0.98–1.22) | 1.00 (0.83–1.20) | 1.12 (0.86–1.45) | 1.09 (0.86–1.39) | 0.491 | ||
Using lipid-lowering drugs |
||||||||||
No | 26,396 | 1.04 (0.92–1.18) | 1.00 | 1.21 (1.06–1.38) | 1.18 (1.00–1.40) | 1.31 (1.07–1.62) | 1.28 (1.08–1.52) | 0.005 | ||
Yes | 41,148 | 1.07 (1.01–1.16) | 1.00 | 1.12 (1.04–1.20) | 1.25 (1.14–1.37) | 1.26 (1.12–1.42) | 1.41 (1.28–1.55) | <0.001 | ||
Using antihypertensive drugs |
||||||||||
No | 15,278 | 1.19 (0.98–1.44) | 1.00 | 1.12 (0.92–1.36) | 1.27 (0.99–1.63) | 1.10 (0.79–1.52) | 1.21 (0.94–1.56) | 0.333 | ||
Yes | 52,266 | 1.05 (0.97–1.13) | 1.00 | 1.13 (1.06–1.21) | 1.22 (1.12–1.33) | 1.28 (1.15–1.43) | 1.39 (1.27–1.52) | <0.001 | ||
Using antiplatelet or anticoagulant drugs |
||||||||||
No | 52,949 | 1.08 (0.99–1.18) | 1.00 | 1.13 (1.04–1.23) | 1.31 (1.19–1.45) | 1.33 (1.16–1.52) | 1.36 (1.22–1.53) | <0.001 | ||
Yes | 14,595 | 1.04 (0.94–1.16) | 1.00 | 1.12 (1.01–1.24) | 1.09 (0.96–1.24) | 1.17 (1.00–1.36) | 1.31 (1.16–1.48) | 0.001 | ||
Presence of atrial fibrillation |
||||||||||
No | 58,200 | 1.13 (1.04–1.23) | 1.00 | 1.13 (1.05–1.22) | 1.27 (1.16–1.40) | 1.27 (1.12–1.42) | 1.40 (1.27–1.54) | <0.001 | ||
Yes | 9,344 | 1.01 (0.85–1.08) | 1.00 | 1.13 (1.01–1.27) | 1.07 (0.91–1.25) | 1.24 (1.01–1.52) | 1.26 (1.06–1.51) | 0.031 |
Values are presented as hazard ratio (95% confidence interval) unless otherwise indicated. All hazard ratios were adjusted for age, sex, race, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate, smoking, insurance type, use of antihypertensive drugs, use of glucose lowering drugs, use of lipid-lowering drugs, use of antiplatelet or anticoagulant drugs, and presence of atrial fibrillation other than the variable for stratification.
Summary of the findings of previous population-based studies since 2009
Year | Country | Data source | Sample size | No. of cases | Age (yr) | Mean or median follow-up | HR or RR (95% CI) | |
---|---|---|---|---|---|---|---|---|
Cederholm et al. (2009) [ |
Sweden | Swedish National Diabetes Register | 4,753 | 238 | 30–70 | 5.7 years | 7.5%–9.0%: reference | |
<7.5%: 0.47 (0.36–0.63) | ||||||||
Camafort et al. (2011) [ |
Spain | FRENA Registry | 974 | 29 | 68±9.5 | 14 months | >7%: reference | |
<7%: 0.9 (0.4–1.8) | ||||||||
Skriver et al. (2012) [ |
Denmark | Electronic medical records | 11,747 | 287 | HbA1c <7%: 67 (57–77) | 730 days | <7%: reference | |
HbA1c ≥7%: 65 (56–74) | ≥7%: 1.00 (0.78–1.27) | |||||||
Hayashi et al. (2013) [ |
Japan | JCDM cohort | 4,014 | 104 | 67.4±9.5 years old | 5.5 years | Per 1% increase: 1.171 (1.001–1.356) | |
Lin et al. (2014) [ |
Taiwan, China | NDCMP cohort | 63,084 | 2,250 | ≥30 | 7.5 years | <7.0%: reference | |
7.0%–8.0%: 1.27 (1.13–1.43) | ||||||||
8.0%–9.0%: 1.55 (1.37–1.75) | ||||||||
≥9.0%: 2.06 (1.85–2.31) | ||||||||
Zhao et al. (2014) [ |
USA | Electronic medical records | 30,154 | 2,949 | Men: 50.9±10.1 | 6.7 years | Men | |
Women: 51.5±10.1 | <6.0%: 1.05 (0.88–1.26) | |||||||
6.0%–6.9%: reference | ||||||||
7.0%–7.9%: 1.12 (0.94–1.33) | ||||||||
8.0%–8.9%: 1.20 (0.98–1.46) | ||||||||
9.0%–9.9%: 1.23 (0.98–1.54) | ||||||||
≥10.0%: 1.08 (0.86–1.36) | ||||||||
Women | ||||||||
<6.0%: 1.06 (0.93–1.21) | ||||||||
6.0%–6.9%: reference | ||||||||
7.0%–7.9%: 1.11 (0.97–1.27) | ||||||||
8.0%–8.9%: 1.30 (1.12–1.52) | ||||||||
9.0%–9.9%: 1.41 (1.19–1.68) | ||||||||
≥10.0%: 1.33 (1.11–1.59) | ||||||||
Kranenburg et al. (2015) [ |
The Netherlands | SMART cohort | 1,687 | 62 | 60.2±10.2 | 6.1 years | Per 1% increase: | |
Patients with vascular disease: 1.03 (0.81–1.31) | ||||||||
Patients without vascular disease: 1.40 (1.01–1.94) | ||||||||
Bots et al. (2016) [ |
The Netherlands | SMART cohort | 1,096 | 48 | 62.6±8.8 | 6.9 years | Per 1% increase: 1.09 (0.84–1.41) | |
Freemantle et al. (2016) [ |
International | CREDIT cohort | 2,999 | 57 | >40 | 54 months | Per 1% increase: 1.363 (1.168–1.591) | |
Morita et al. (2017) [ |
Japan | Community-dwelling cohort | 184 | 7 | 65–94 | 5 years | ≥6.0%: reference | |
<6.0%: non-significant | ||||||||
Hwang et al. (2017) [ |
Korea | Electronic medical records | 980 | 31 | HbA1c <7.0%: 62.9±10.0 | 717.6 days | <7.0%: reference | |
HbA1c ≥7.0%: 62.7±10.1 | ≥7.0%: 1.22 (0.66–2.27) | |||||||
Heller et al. (2017) [ |
International | EXAMINE trial | 5,380 | 61 | 61.0 | 18 months | <7.0%: reference | |
7.0%–8.0%: 1.73 (0.81–3.71) | ||||||||
8.0%–9.0%: 2.36 (0.99–5.61) | ||||||||
≥9.0%: 1.68 (0.56–5.01) | ||||||||
Alatorre et al. (2018) [ |
UK | Electronic medical records | 82,151 | 2,127 | ≥18 | 5 years | <6.0%: 1.29 (1.02–1.63) | |
6.0%–6.49%: NA | ||||||||
6.5%–6.99%: reference | ||||||||
7.0%–7.49%: 1.49 (1.24–1.79) | ||||||||
7.5%–8.0%: 4.67 (2.92–7.45) | ||||||||
Rawshani et al. (2018) [ |
Sweden | Swedish National Diabetes Register | 271,174 | 14,474 | 60.6±10.9 | 5.7 years | Levels below the guideline target levels for glycated hemoglobin was associated with lower risks of stroke. | |
Fangel et al. (2019) [ |
Denmark | Electronic medical records | 5,386 | 253 | 72.7±9.7 | 1.9 years | <48 mmol/mol: reference | |
49–58 mmol/mol: 1.49 (1.09–2.05) | ||||||||
>58 mmol/mol: 1.59 (1.13–2.22) | ||||||||
Present study (2019) | USA | Electronic medical records | 67,544 | 7,735 | 66.5±12.1 | 3.8 years | <6.0%: 1.10 (1.02–1.18) | |
6.0%–6.9%: reference | ||||||||
7.0%–7.9%: 1.16 (1.08–1.23) | ||||||||
8.0%–8.9%: 1.27 (1.17–1.37) | ||||||||
9.0%–9.9%: 1.30 (1.17–1.45) | ||||||||
≥10%: 1.40 (1.28–1.53) |
HR, hazard ratio; RR, relative risk; CI, confidence interval; FRENA, Factores de Riesgo y ENfermedad Arterial; HbA1c, hemoglobin A1c; JCDM, Japan Cholesterol and Diabetes Mellitus Study; NDCMP, National Diabetes Case Management Program; SMART, the Second Manifestations of ARTerial Disease; CREDIT, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy; EXAMINE, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; NA, not applicable.