Cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM) was associated with disease duration and severity of hyperglycemia in many studies [
Additionally, duration of T2DM and severity of hyperglycemia are strong and consistent risk factors for the development and progression of microvascular diabetic complications—retinopathy (DR), neuropathy (DN), and nephropathy [
The association of diabetic nephropathy and increased risk of CVD has been revealed in multiple patient cohorts. Data from United States community-based study demonstrated that individuals with diabetic nephropathy were at four- and threefold higher risk for CV death and all-cause death, respectively, compared to those without [
Potential associations, of DR and DN with CV outcomes, whether causal or only predictive, have received less attention. We therefore investigated the association of DR and DN with increased risk of recurrent CV events, in patients with a recent acute coronary syndrome (ACS).
The ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) was a randomized, double-blind, placebo-controlled trial designed to assess the effects of lixisenatide added to current T2DM therapy on CV morbidity and mortality in 6068 patients with a recent ACS.
We examined the primary composite (CV death, nonfatal MI, stroke, or hospitalization for unstable angina), CV composite (CV death, nonfatal MI, stroke, and hospitalization for heart failure (HF)), each of its components, and all-cause mortality. Details of the trial design, entry criteria, and the main results have been reported previously [
For this post hoc analysis, all 6068 ELIXA participants were included. Self-reported historical data on DR and DN were collected at screening. Patients were asked to answer “yes,” “no,” or “unknown” on the presence of DR and/or DN. If DR was present, date of diagnosis was recorded, as well as information on photocoagulation and vitrectomy. However, these interventions were not analyzed further due to a small number of events. Presence of DN was defined as a report of either sensory/motor or autonomic neuropathy. Only “yes” responses were used to define the exposure variables for all subsequent analyses. Blood samples included in this analysis were done at screening by a central laboratory. Duration of T2DM was evaluated based on medical record review or self-report at the screening visit.
Baseline characteristics of patients were stratified by the presence of DR and/or DN. Descriptive data are presented as the mean ± standard deviation for normally distributed variables and as median (25–75th percentile) for nonnormally distributed variables. Categorical variables are expressed as proportions and were compared by the chi-square test, while continuous variables were compared using
Characteristics of all patients at baseline according to the presence of retinopathy and/or neuropathy.
Characteristic | All patients |
No retinopathy/neuropathy |
Retinopathy and/or neuropathy |
|
---|---|---|---|---|
Age (years) | 60.3 ± 9.7 | 59.7 ± 9.7 | 62.3 ± 9.2 | <0.001 |
Male sex ( |
4207 (69.3) | 3379 (71.8) | 828 (60.7) | <0.001 |
Body weight (kg) | 84.9 ± 19.4 | 84.1 ± 18.9 | 87.6 ± 20.9 | <0.001 |
Body mass index (kg/m2) | 30.2 ± 5.7 | 29.9 ± 5.6 | 31.2 ± 6.0 | <0.001 |
Duration of T2DM (years) | 7.4 (2.8, 13.6) | 6.0 (2.0, 11.7) | 12.4 (7.0, 20.2) | <0.001 |
Categories of T2DM duration ( | <0.001 | |||
≤1 year | 964 (15.9) | 914 (19.4) | 50 (3.7) | |
>1–≤5 years | 1294 (21.3) | 1130 (24.0) | 164 (12.0) | |
>5–≤10 years | 1359 (22.4) | 1076 (22.9) | 283 (20.8) | |
>10 years | 2451 (40.4) | 1585 (33.7) | 866 (63.5) | |
Race ( | <0.001 | |||
White | 4576 (75.4) | 3471 (73.8) | 1105 (81.1) | |
Black | 221 (3.6) | 171 (3.6) | 50 (3.7) | |
Asian | 771 (12.7) | 669 (14.2) | 102 (7.5) | |
Other | 500 (8.2) | 394 (8.4) | 106 (7.8) | |
Region ( | <0.001 | |||
Africa/Near East | 296 (4.9) | 228 (4.8) | 68 (5.0) | |
Asia Pacific | 703 (11.6) | 615 (13.1) | 88 (6.5) | |
Eastern Europe | 1587 (26.2) | 1115 (23.7) | 472 (34.6) | |
North America | 807 (13.3) | 564 (12.0) | 243 (17.8) | |
South and Central America | 1944 (32.0) | 1600 (34.0) | 344 (25.2) | |
Western Europe | 731 (12.0) | 583 (12.4) | 148 (10.9) | |
Smoking status ( | <0.001 | |||
Current | 709 (11.7) | 579 (12.3) | 130 (9.5) | |
Former | 2746 (45.3) | 2184 (46.4) | 562 (41.2) | |
Never | 2612 (43.1) | 1941 (41.3) | 671 (49.2) | |
Diastolic blood pressure (mmHg) | 77 ± 10 | 77 ± 10 | 76.3 ± 10 | <0.001 |
Systolic blood pressure (mmHg) | 130 ± 17 | 129 ± 17 | 131 ± 17 | <0.001 |
Heart rate (beats/min) | 70 ± 10 | 70 ± 10 | 71 ± 10 | 0.027 |
Fasting plasma glucose (mg/dl) | 148.3 ± 51.6 | 145.2 ± 49.1 | 159.3 ± 58.1 | <0.001 |
Glycated hemoglobin (%) | 7.7 ± 1.3 | 7.6 ± 1.3 | 8.0 ± 1.2 | <0.001 |
Glycated hemoglobin (mmol/mol) | 61 ± 14 | 60 ± 14 | 64 ± 13 | <0.001 |
Total cholesterol (mg/dl) | 153.5 ± 44.6 | 151.3 ± 43.5 | 161.1 ± 47.3 | <0.001 |
HDL cholesterol (mg/dl) | 42.9 ± 10.9 | 42.6 ± 10.6 | 44.1 ± 11.7 | <0.001 |
LDL cholesterol (mg/dl) | 78.5 ± 35.3 | 77.1 ± 34.7 | 83.4 ± 36.9 | <0.001 |
Triglycerides (mg/dl) | 137.2 (99.1, 195.6) | 136.3 (100.0, 192.9) | 141.6 (99.1, 208.0) | 0.021 |
eGFR (ml/min/1.73m2) | 76 ± 21 | 77 ± 21 | 71 ± 22 | <0.001 |
Albuminuria ( | <0.001 | |||
<30 mg/g | 4441 (74.3) | 3579 (77.2) | 862 (64.2) | |
≥30–<300 mg/g | 1148 (19.2) | 819 (17.7) | 329 (24.5) | |
≥300 mg/g | 389 (6.5) | 237 (5.1) | 152 (11.3) | |
Medical history at randomization ( | ||||
Hypertension | 4635 (76.4) | 3463 (73.6) | 1172 (86) | <0.001 |
Heart failure | 1358 (22.4) | 923 (19.6) | 435 (31.9) | <0.001 |
Stroke | 331 (5.5) | 204 (4.3) | 127 (9.3) | <0.001 |
Peripheral arterial disease | 393 (6.5) | 227 (4.8) | 166 (12.2) | <0.001 |
Atrial fibrillation | 366 (6.0) | 247 (5.2) | 119 (8.7) | <0.001 |
Percutaneous coronary intervention | 4079 (67.2) | 3263 (69.4) | 816 (59.9) | <0.001 |
Coronary artery bypass grafting | 507 (8.4) | 363 (7.7) | 144 (10.6) | <0.001 |
Qualifying ACS event ( | <0.001 | |||
STEMI | 2666 (44.0) | 2187 (46.5) | 479 (35.2) | |
NSTEMI | 2348 (38.7) | 1817 (38.6) | 531 (39.0) | |
Unstable angina | 1042 (17.2) | 693 (14.7) | 349 (25.6) | |
Missing | 9 (0.1) | 6 (0.1) | 3 (0.2) | |
Antihyperglycemic therapy ( | ||||
Metformin | 4243 (69.9) | 3367 (71.6) | 876 (64.3) | <0.001 |
Sulfonylureas | 2266 (37.3) | 1779 (37.8) | 487 (35.7) | 0.16 |
Insulin | 2891 (47.6) | 1948 (41.4) | 943 (69.2) | <0.001 |
Thiazolidinediones | 128 (2.1) | 92 (2.0) | 36 (2.6) | 0.12 |
Alpha-glucose inhibitor | 181 (3.0) | 150 (3.2) | 31 (2.3) | 0.08 |
Dipeptidyl peptidase 4 inhibitor | 226 (3.7) | 176 (3.7) | 50 (3.7) | 0.90 |
Other | 485 (8.0) | 384 (8.2) | 101 (7.4) | 0.37 |
Data is presented as means ± SD, median (25–75th percentile), or percentages. HDL: high-density lipoprotein; LDL: low-density lipoprotein; MI: myocardial infarction; ACS: acute coronary syndrome; eGFR: estimated glomerular filtration rate.
Demographic and clinical characteristics of the 6068 patients are shown in Table
Prevalence of retinopathy and/or neuropathy.
Patients who had DR and/or DN were significantly older (mean 62.3 vs. 59.7 years) and had longer known duration of T2DM (mean 12.4 vs. 6.0 years) than those with neither complication. Smaller proportions of patients with DR and/or DN reported shorter T2DM duration of <1 year (3.7% vs 19.4%) and ≤5 years (12.0% vs. 24.0%). The distribution of T2DM duration in all patients, as well as in those with and without retinopathy and/or neuropathy, is shown in Figure
Distribution of T2DM duration in all patients, patients with no retinopathy/neuropathy and patients with retinopathy and/or neuropathy.
In univariate analysis, DR was significantly associated with primary and CV composite endpoint, all-cause and CV death, and all CV events except stroke (
Multivariable modeling.
Hazard ratio (95% CI) | Primary composite endpoint |
CV composite endpoint |
Cardiovascular death |
Myocardial infarction |
Stroke |
Heart failure hospitalization |
Death | |
---|---|---|---|---|---|---|---|---|
Univariate |
Retinopathy | 1.44 (1.19–1.75) |
1.57 (1.31–1.88) |
1.58 (1.17–2.13) |
1.38 (1.08–1.76) |
1.56 (0.97–2.51) | 2.03 (1.48–2.78) |
1.65 (1.28–2.12) |
Neuropathy | 1.33 (1.12–1.57) |
1.38 (1.19–1.62) |
1.29 (0.99–1.68) | 1.26 (1.02–1.54) |
1.59 (1.07–2.37) |
1.71 (1.30–2.27) |
1.43 (1.15–1.78) | |
T2DM duration (per 5 years) | 1.17 (1.13–1.22) |
1.19 (1.15–1.23) |
1.22 (1.16–1.29) |
1.19 (1.14–1.25) |
1.08 (0.98–1.19) | 1.30 (1.23–1.38) |
1.22 (1.17–1.28) | |
Model 1 |
Retinopathy | 1.07 (0.86–1.32) | 1.13 (0.94–1.31) | 1.12 (0.80–1.56) | 1.00 (0.77–1.31) | 1.27 (0.74–2.16) | 1.21 (0.85–1.73) | 1.13 (0.85–1.50) |
Neuropathy | 1.10 (0.92–1.31) | 1.11 (0.94–1.31) | 1.01 (0.76–1.34) | 1.02 (0.82–1.28) | 1.43 (0.93–2.20) | 1.23 (0.90–1.66) | 1.12 (0.88–1.42) | |
T2DM duration (per 5 years) | 1.16 (1.12–1.21) |
1.18 (1.14–1.22) |
1.21 (1.14–1.29) |
1.19 (1.14–1.25) |
1.04 (0.94–1.16) | 1.28 (1.20–1.36) |
1.21 (1.15–1.27) | |
Model 2 |
Retinopathy | 1.07 (0.86–1.33) | 1.13 (0.92–1.38) | 1.12 (0.80–1.57) | 1.00 (0.76–1.32) | 1.28 (0.75–2.19) | 1.15 (0.81–1.65) | 1.15 (0.87–1.53) |
Neuropathy | 1.02 (0.85–1.23) | 0.99 (0.84–1.18) | 0.91 (0.68–1.22) | 1.00 (0.78–1.24) | 1.27 (0.82–1.99) | 0.96 (0.70–1.31) | 1.03 (0.81–1.31) | |
T2DM duration (per 5 years) | 1.10 (1.05–1.15) |
1.12 (1.07–1.16) |
1.14 (1.07–1.22) |
1.13 (1.08–1.20) |
0.95 (0.85–1.07) | 1.21 (1.13–1.30) |
1.13 (1.07–1.19) |
Primary composite endpoint: CV death, nonfatal MI, stroke, or hospitalization for unstable angina; CV composite endpoint: CV death, nonfatal MI, stroke, hospitalization for heart failure (HF);
In both univariate and multivariate analysis, the most significant predictors of both DR and DN were duration of T2DM and insulin use (Table
Predictors of retinopathy and neuropathy multivariate models.
Parameter | Retinopathy | Neuropathy | ||
---|---|---|---|---|
OR (95% CI) | OR (95% CI) | |||
Duration of diabetes (per 5 years) | 1.48 (1.41–1.56) | 14.64 | 1.31 (1.25–1.37) | 11.52 |
Insulin use | 2.77 (2.23–3.46) | 9.13 | 2.19 (1.86–2.58) | 9.36 |
Weight (per 5 kg) | — | — | 1.09 (1.07–1.11) | 8.83 |
Previous PCI | 0.75 (0.61–0.91) | 2.94 | 0.60 (0.51–0.70) | 6.32 |
Total cholesterol (per 10 mg/dl) | — | — | 1.05 (1.04–1.07) | 6.23 |
History of PAD | — | — | 1.88 (1.45–2.43) | 4.82 |
History of HF | 1.65 (1.35–2.02) | 4.82 | 1.32 (1.12–1.56) | 3.23 |
Previous stroke | 2.06 (1.51–2.82) | 4.54 | 1.86 (1.42–2.45) | 4.45 |
Diastolic blood pressure (per 10 mmHg) | — | — | 0.88 (0.82–0.95) | 3.25 |
Sulphonylurea use | — | — | 1.29 (1.11–1.51) | 3.24 |
Previous CABG | 0.72 (0.52–0.98) | 2.11 | 0.66 (0.51–0.86) | 3.06 |
Presence of hypertension | 1.46 (1.11–1.91) | 2.69 | 1.39 (1.12–1.72) | 3.00 |
Body mass index (per 5 kg/m2) | 1.12 (1.04–1.22) | 2.99 | — | — |
Glucose (per 10 mg/dl) | 1.02 (1.0-1.04) | 2.29 | 1.02 (1.01–1.03) | 2.87 |
eGFR (per 10 ml/min/1.73m2) | 0.94 (0.90–0.98) | 2.66 | — | — |
Male sex | — | — | 1.25 (1.06–1.47) | 2.60 |
HDL cholesterol (per 10 mg/dl) | 1.11 (1.02–1.20) | 2.53 | — | — |
Age (per 5 years) | — | — | 1.05 (1.01–1.10) | 2.20 |
HbA1c (per 1%) | 1.09 (1.00–1.19) | 1.98 | — | — |
Model AUC = 0.81 (retinopathy) and model AUC = 0.76 (neuropathy). HF: heart failure; PCI: percutaneous coronary intervention; eGFR: estimated glomerular filtration rate; HDL: high-density lipoprotein; CABG: coronary artery bypass grafting; HbA1c: glycated hemoglobin; PAD: peripheral artery disease.
In this post hoc analysis of a large population selected for having a recent ACS event, together with T2DM, less than one-fourth of patients reported a history of DR, DN, or both. This was a smaller proportion than found in other studies of CV outcomes in T2DM, in which many patients had CV risk factors but not necessarily a completed event. For example, the prevalence of DR in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study—which also relied on patient self-reports—was almost three times higher in a more severely compromised patient cohort with T2DM, chronic kidney disease, and anemia, but also twice as long T2DM duration [
The variability of previously reported associations between DR and/or DN and subsequent CV events could stem from variable T2DM duration and comorbidities of analyzed patient cohorts. The positive association of DR and CV events was observed in various patient cohorts [
Our findings on DN are partially in accordance with previously published studies that revealed an association between autonomic DN and CV events [
Consistent with prior reports, our analysis found that DR and/or DN were associated at baseline with longer T2DM duration, worse glycemic control, more insulin use, and history of prior manifest CV disease. Furthermore, both DR and DN were associated with increased risk of recurrent CV events, especially HF hospitalization. However, these associations were no longer statistically significant after adjustment for duration of T2DM, which remained a strong independent predictor of CV events [
While other relevant studies also adjusted clinical outcomes for the duration of T2DM—among other demographic characteristics and CV risk factors—none of them adjusted for only the known duration of the disease, which makes our findings unique. In a high-risk T2DM patient cohort used in the Veterans Affairs Diabetes Trial (VADT) (1791 subjects) [
There are several possible explanations for the duration of T2DM being a strong independent predictor of recurrent CV events in our analysis. Longer duration of the disease may have a direct effect on progression of atherosclerotic lesions, increasing the risk of a recurrent CV event. In addition, it might be associated with autonomic DN and reduced heart rate variability, increasing the risk of CV death, which was not the case in our cohort. A long-term increase in oxidative stress in T2DM patients may cause increased risk of CV death. Also, longer exposure to hyperglycemia may simply reflect greater exposure to other, perhaps unmeasured, CV risk factors.
The major limitation of our study was the assessment of DR and DN which was based on patients’ answers to self-report questionnaires. Therefore, the prevalence of both might have been underestimated. Such potential misclassification bias might have potentially weakened our results, and, therefore, the real association of DR and DN with recurrent CV events could be stronger than presented in this analysis. Another important limitation is the fact that T2DM duration was evaluated based on medical record or self-report and could therefore be underestimated, as patients often remain undiagnosed for many years. Also, having in mind that the study cohort included high-risk patients with T2DM and recent ACS, the results may not be applicable to other populations such as those without CV disease or with a less advanced stage of it. In addition, the design of this study was cross-sectional and therefore does not provide information on whether or not DR and DN developed before or after the onset of any CV disease antecedent to the qualifying ACS event. Finally, our findings should be considered post hoc and hypothesis-generating.
In a population with recent ACS together with T2DM, recurrent CV events, DR, and DN were all strongly associated with the T2DM duration. A history of either DR or DN was associated with increased risk of recurrent CV events. As these associations were eliminated by adjustment for the duration of T2DM, which remained a strong independent predictor of recurrent CV events, the link between DR and/or DN and these events is not likely to be a causal one. However, history of DR, DN, or both and longer duration of T2DM could be considered clinical markers for high risk of recurrent CV events. It is important to point out that the presence of both DN and DR is expected to positively correlate with patients’ level of interaction with healthcare providers. Furthermore, it is expected that their level of healthcare provider interaction would correlate negatively with the frequency and magnitude of adverse outcomes.
The data used to support the findings of this study are available from the corresponding author upon reasonable request.
The company, Sanofi, played no role in the design and execution of this analysis.
JPS has no competing interests. RBL is a consultant and research support of Sanofi and a research support and spouse/partner of Sanofi, Amgen Inc., and Novartis Pharmaceuticals Corporation. BC has no competing interests. RD is a research support of Sanofi. HCG is an advisory panel of Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Roche Pharmaceuticals, AstraZeneca Pharmaceuticals LP, GlaxoSmithKline, Bayer HealthCare, LLC, Merck, Boehringer Ingelheim Pharmaceuticals Inc., and Eli Lilly and Company; a consultant of Sanofi; and a research support of Sanofi and Eli Lilly and Company. LVK has a relationship with Sanofi and Novartis Pharmaceuticals Corporation. FL is an employee of Sanofi. EFL is a consultant and spouse/partner of Sanofi; a research support of Amgen Inc., Novartis Pharmaceuticals Corporation, and Sanofi; and a research support and spouse/partner of Sanofi. APM has a relationship with Sanofi, Oxford University, Eli Lilly and Company, and BMS. JMcM has a relationship with GlaxoSmithKline, PPD Development LP, Merck, Oxford University, Amylin Pharmaceuticals Inc., Eli Lilly and Company, Parexel, Bayer HealthCare, LLC, Abbvie, and Sanofi. JLP is an advisory panel of Sanofi, a consultant of Sanofi, and a research support of Sanofi. MCR is a consultant of Eli Lilly and Company, AstraZeneca Pharmaceuticals LP, Sanofi, Valeritas, LLC, and Elcelyx Therapeutics Inc.; a research support of AstraZeneca Pharmaceuticals LP, Eli Lilly and Company, Sanofi, and Novo Nordisk Inc.; and has a relationship with Sanofi. These dualities of interest have been reviewed and managed by Oregon Health & Science University. SDS is a consultant of Novartis Pharma AG and Amgen Inc. and a research support of Abbott Laboratories Inc., Amgen Inc., Daiichi-Sankyo Inc., Novartis Pharma AG, Theracos, Boston Scientific, NHLBI, Lone Star Heart, and Sanofi. JCT has no competing interests. MAP is a consultant of Aastrom Biosciences Inc., Abbott Laboratories Inc., Amgen Inc., FibroGen Inc., Cerenis Pharmaceuticals, Concert Pharmaceuticals, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Roche Pharmaceuticals, Servier, Teva Pharmaceuticals, and University of Oxford; a research support of Amgen Inc., Celladon, Novartis Pharma AG, and Sanofi; and has a relationship with Novartis Pharma AG.
The presented analysis was prepared jointly by all authors. The corresponding author and coauthors had full access to the data in the study, contributed to the writing of the manuscript, and had final responsibility for the decision to submit for publication.
The ELIXA trial was supported by Sanofi.
Supplementary Figure 1. Patient distribution by T2DM duration categories widely varies: 15.9 % of participants have known T2DM for less than 1 year, 21.3% ≤5 years, 22.4% >1–≤5 years, and 40.4% longer than 10 years. Supplementary Figures 2a–b. Relationship of retinopathy and neuropathy with T2DM duration.