Diabetes and chronic coronary syndrome (CCS) are closely related: approximately one third of patients with CCS are diabetic,1–3 and these patients have had a worse prognosis than patients without diabetes in prior studies.1–3 However, information on long-term follow-up of this population is very limited in Spain. Our objective was to investigate very long-term prognosis in a cohort of patients with diabetes and CCS in day-to-day clinical practice.
The Cardiopatía Isquémica Crónica en CÓRdoba [Chronic Ischaemic Heart Disease in Córdoba] (CICCOR) registry was an observational, prospective, single-centre cohort study with the objective of researching CCS prognosis.3 From 01/02/2000 to 31/01/2004, 1268 consecutive patients with CCS who attended two general cardiology appointments at a tertiary hospital, referred by primary care physicians, from the emergency department or for review following hospitalisation in cardiology or internal medicine were prospectively selected. All CICCOR registry patients with a diagnosis of diabetes mellitus at their baseline visit were selected for this analysis. The primary objective of the study was to investigate the very long-term incidence of major adverse cardiovascular events (MACEs) (combined event: infarction, stroke or cardiovascular death), that of each element of the primary objective, the incidence of admissions due to heart failure and overall mortality, as well as factors associated with MACE onset. The study was approved by the local Independent Ethics Committee, and the patients consented to inclusion in the study.
A total of 394 patients were included in the study. Table 1 shows the baseline characteristics of the series. None of the patients received dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide agonists at the baseline visit, as they were not on the market at that time in Spain. After a maximum follow-up of 17 years (median: 9 years; p25−75: 4–14 years), with just two patients lost to follow-up and 3517 patients per year of observation, 207 patients experienced a MACE. Of them, 55 patients had a stroke, 66 patients had an infarction and 165 patients died due to a cardiovascular cause. One hundred and one patients were admitted for heart failure; 238 patients died. The annual incidence of MACEs was 6.5 per 100 patient-years, with 1.64 corresponding to stroke, 1.97 to infarction, 3.12 to admission for heart failure, 4.69 to cardiovascular death and 6.77 to total mortality per 100 patient-years. The probability of survival free from each of these events after 12 years were 47%, 85%, 80%, 68%, 56% and 45%, respectively. In multivariate models, variables independently associated with MACEs were age (hazard ratio [HR] 1.06 [1.04–1.08], p < 0.0005), being a former smoker (HR 1.43 [1.02–1.99], p = 0.04) or an active smoker (HR 2.23 [1.16–4.30], p = 0.02), having angina in a functional class ≥ II (HR 1.57 [1.14–2.16], p = 0.006), baseline heart rate (HR 1.04 [1.00–1.08], p = 0.04) and treatment with diuretics (HR 1.71 [1.26–2.30], p = 0.001).
Baseline characteristics of the sample and univariate predictors of major adverse cardiovascular events in follow-up.
| Variable | Total | Major adverse CV events | No major adverse CV events | Hazard ratio (95% CI) | p |
|---|---|---|---|---|---|
| N = 394 | n = 207 | n = 187 | |||
| Age (years) | 68.7 ± 8.3 | 69.9 ± 7.2 | 66.4 ± 9.8 | 1.05 (1.04−1.07) | <0.0005 |
| Male sex, n (%) | 241 (61.2) | 121 (58.4) | 120 (64.2) | 0.90 (0.68−1.18) | 0.45 |
| Hypertension, n (%) | 246 (62.6) | 129 (62.3) | 117 (62.9) | 1.04 (0.78−1.37) | 0.80 |
| Active smoker, n (%) | 21 (5.4) | 13 (6.3) | 8 (4.4) | 1.21 (0.69−2.15) | 0.51 |
| Former smoker, n (%) | 116 (29.9) | 59 (28.6) | 57 (31.3) | 0.96 (0.71−1.30) | 0.79 |
| Dyslipidaemia, n (%) | 294 (82.6) | 160 (83.3) | 134 (81.7) | 0.90 (0.61−1.31) | 0.57 |
| Prior ACS, n (%) | 332 (84.3) | 176 (85) | 154 (83.4) | 1.18 (0.80−1.72) | 0.40 |
| Prior revasc., n (%) | 172 (43.8) | 91 (44) | 81 (43.5) | 0.88 (0.67−1.16) | 0.36 |
| Percutaneous revasc., n (%) | 118 (30) | 60 (29) | 58 (31.2) | 1.00 (0.98−1.00) | 0.32 |
| Surgical revasc., n (%) | 61 (15.5) | 33 (15.9) | 28 (15.1) | 0.93 (0.64−1.35) | 0.69 |
| Atrial fibrillation, n (%) | 23 (5.9) | 12 (5.8) | 11 (6) | 1.39 (0.77−2.49) | 0.30 |
| Prior CHF, n (%) | 27 (6.9) | 19 (9.2) | 8 (4.3) | 2.01 (1.25−3.23) | 0.004 |
| Angina FG ≥ II, n (%) | 92 (23.4) | 59 (28.5) | 33 (17.6) | 1.71 (1.27−2.32) | 0.001 |
| Baseline SBP (mmHg) | 132.7 ± 15 | 133.2 ± 14.2 | 132.1 ± 16.5 | 1.00 (1.00−1.01) | 0.45 |
| Baseline DBP (mmHg) | 74.5 ± 8.6 | 74.7 ± 8.7 | 74.6 ± 8.6 | 1.01 (0.99−1.02) | 0.41 |
| Baseline HR (bpm) | 70.5 ± 12.3 | 71.2 ± 12.2 | 69 ± 11.4 | 1.01 (1.00−1.02) | 0.02 |
| Blood glucose (mg/dl) | 165.1 ± 53.3 | 167.5 ± 58.3 | 161.8 ± 46.0 | 1.00 (0.99−1.01) | 0.98 |
| Baseline blood glucose <108 mg/dl, n (%) | 14 (8.8) | 10 (10.9) | 4 (5.9) | 1.76 (0.91−3.40) | 0.09 |
| Total cholesterol (mg/dl) | 191.2 ± 38.7 | 195 ± 39.3 | 189.4 ± 37.9 | 1.00 (0.99−1.00) | 0.51 |
| HDL-C (mg/dl) | 50.3 ± 12.3 | 50.8 ± 12.3 | 49.2 ± 12.7 | 1.01 (1.00−1.02) | 0.12 |
| LDL-C (mg/dl) | 114.5 ± 32.4 | 114 ± 33.5 | 114.3 ± 31.3 | 0.99 (0.99−1.00) | 0.77 |
| LDL-C <70 mg/dl, n (%) | 25 (8.2) | 17 (10.1) | 8 (5.9) | 1.47 (0.89−2.43) | 0.13 |
| LDL-C <55 mg/dl, n (%) | 3 (1) | 3 (1.8) | 0 (0) | 6.96 (2.18−22.23) | 0.001 |
| Triglycerides (mg/dl) | 135.3 ± 75.9 | 144.1 ± 86.7 | 126 ± 58.6 | 1.00 (1.00−1.00) | 0.63 |
| Creatinine (mg/dl) | 1.1 ± 0.3 | 1.2 ± 0.3 | 1.1 ± 0.3 | 1.78 (0.94−3.36) | 0.1 |
| GFR (ml/min) | 63.7 ± 16.0 | 63.6 ± 16.1 | 63.9 ± 16.1 | 0.99 (0.98−1.00) | 0.16 |
| Haemoglobin (g/dl) | 14.1 ± 2.7 | 14.2 ± 3.2 | 13.9 ± 1.7 | 0.98 (0.92−1.06) | 0.64 |
| Leukocytes (103/μl) | 8.0 ± 1.7 | 7.9 ± 1.6 | 8.0 ± 1.9 | 1.02 (0.90−1.16) | 0.79 |
| Platelets (103/μl) | 231.3 ± 75.0 | 239.1 ± 82.6 | 220.8 ± 62.4 | 1.00 (1.00−1.00) | 0.10 |
| Abnormal ECG, n (%) | 268 (70.5) | 139 (69.2) | 129 (72.1) | 1.13 (0.84−1.52) | 0.43 |
| Cardiomegaly n (%) | 51 (14.3) | 29 (15.2) | 22 (13.3) | 1.42 (0.95−2.11) | 0.10 |
| LVEF (%) | 53.8 ± 14.8 | 53.7 ± 15.4 | 54 ± 14.1 | 1.00 (0.98−1.00) | 0.32 |
| Antiplatelet therapy, n (%) | 359 (91.3) | 187 (90.3) | 172 (92.5) | 0.67 (0.42−1.06) | 0.10 |
| Oral anticoagulation, n (%) | 23 (5.9) | 12 (5.8) | 11 (5.9) | 1.48 (0.83−2.66) | 0.21 |
| Beta blockers, n (%) | 280 (71.1) | 140 (67.6) | 140 (74.9) | 0.79 (0.59−1.05) | 0.11 |
| Statins, n (%) | 258 (65.5) | 137 (66.2) | 121 (64.7) | 0.77 (0.58−1.03) | 0.08 |
| Nitrates, n (%) | 285 (72.5) | 152 (73.4) | 133 (71.5) | 1.07 (0.78−1.45) | 0.69 |
| ACE inhibitors/ARBs, n (%) | 240 (60.9) | 128 (61.8) | 112 (59.9) | 1.03 (0.78−1.36) | 0.86 |
| Diuretics, n (%) | 148 (37.7) | 88 (42.5) | 60 (32.3) | 1.68 (1.27−2.22) | <0.0005 |
95% CI: 95% confidence interval; ACE inhibitors: angiotensin converting enzyme inhibitors; ACS: acute coronary syndrome; ARBs: angiotensin II receptor blockers; CHF: congestive heart failure; CV: cardiovascular; DBP: diastolic blood pressure; ECG: electrocardiogram; FG: functional grade; GFR: glomerular filtration rate; HDL-C: cholesterol bound to high-density lipoproteins; HR: heart rate; LDL-C: cholesterol bound to low-density lipoproteins; LVEF: left ventricular ejection fraction; revasc.: revascularisation; SBP: systolic blood pressure.
The major clinical trials that have studied new antidiabetic drugs in populations at high cardiovascular risk have generally found lower incidences of MACEs compared to our study.4 Other observational studies5,6 have shown rates of events that were lower than or similar to those of our study. Differences in baseline characteristics, history of cardiovascular disease, baseline kidney function, management of risk factors, rates of prior revascularisation and medical treatment might account for these differences. However, studies with a follow-up beyond five years are very limited. Hence, our study adds valuable information regarding these patients' very long-term course. This study also showed the impact on prognosis of simple clinical variables, which, though reported in general populations of patients with CCS,1–3 had not been widely validated in the subgroup of patients with diabetes. The limitations of the study included the unavailability of information on type of diabetes, baseline glycosylated haemoglobin or other variables of prognostic interest, such as frailty, depression or social support; the impossibility of accurately describing changes in treatment over time, including the addition of drugs of prognostic interest such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide agonists; and the study's single-centre nature.
Finally, the main clinical implication of our study was the accurate picture it painted for the scientific community of the nature of the very long-term course of diabetic patients in the early decades of the 21 st century. The high rates of events found could represent an incentive to both optimise the management of classic cardiovascular risk factors and extend the use of new antidiabetic drugs which have demonstrated prognostic benefits.
FundingThis study was funded by the Sociedad Andaluza de Cardiología [Andalusian Society of Cardiology] through a research grant from the Boehringer Ingelheim–Lilly alliance.