The article selection process is shown in Fig. 1. The initial search identified 114 papers of possible interest, and 52 met the selection criteria after systematic and detailed examination of the full article. Table 1 lists these studies along with their methodological characteristics and main outcomes. In total, 22 studies had a cross-sectional design, 20 were retrospective and ten were prospective cohort studies. Electronic Supplementary Material (ESM) Table S1 provides detailed descriptions of the definitions of CVD in each article and shows that most studies used codes from the International Statistical Classification of Diseases and Related Health Problems, Ninth or Tenth Revision (ICD-9 or ICD-10) to identify the presence of CVD or the occurrence of CV events.
Regarding epidemiological parameters, this review included 31 articles published between 2009 and 2019 that analysed the prevalence of CVD overall or a type of CVD in patients with T2DM in Spain [15, 16, 19, 20, 23,24,25, 28,29,30,31,32,33,34,35, 37, 42, 43, 45, 52, 54,55,56,57, 59,60,61,62,63, 65, 66], 20 articles that analysed incidence [15, 21,22,23, 27, 36, 38,39,40,41, 44, 46, 48,49,50,51, 53, 56, 58, 64], and 18 articles that analysed mortality [16, 18, 21, 22, 25, 27, 30, 31, 38,39,40,41, 44, 46, 56, 57, 60, 66].
Of the articles reporting epidemiology data, 20 included countrywide (national) data, 17 were regional (autonomous communities) and 11 were local (specific hospitals, cities, or districts). Catalonia was the region with the most studies (18 articles), followed by Madrid (five), Valencia (four), the Basque Country (two) and Asturias (one).
Five studies reported on HRU and/or costs associated with CVD in patients with T2DM [17, 26, 37, 40, 62].
Prevalence of CVD in Patients with T2DM
Table 2 summarizes the prevalence or frequency of CV comorbidities in the samples of patients with T2DM described in the articles. Seven studies analysed the overall prevalence of CVD at the national level [28, 34, 52, 54, 55, 59, 66]. A recent countrywide study analysed the prevalence of CVD in 619,188 patients with T2DM hospitalized in Spain in 2015 and is the largest study to date on this topic .
The regional studies included in this systematic review analysed evaluated patients from Catalonia (nine studies), the Basque Country (two studies), Madrid (two studies) and Valencia (one study). Of these, the studies including the largest number of patients with T2DM were those from Catalonia (373,185 patients) , Valencia (350,015 patients) , the Basque Country (149,015 patients)  and Madrid (3407 patients) .
Considering studies of the general population with T2DM, the overall prevalence/frequency of CVD ranged from 6.9 to 40.8% in the 14 studies reporting this value (Table 2; Fig. 2). In these studies, the range of prevalence was 17.0–40.8% at the national level and 6.9–30.4% at the regional level.
Most studies detailed the type of CVD (Table 2). For the general diabetic population, prevalence was 4.7–37.0% for CHD (17 studies) [15, 19, 20, 28, 34, 37, 43, 45, 47, 52, 55, 56, 59, 60, 63, 65, 66]; 3.5–19.6% for CVA (stroke; 16 studies) [15, 19, 20, 28, 34, 43, 45, 47, 52, 55, 56, 59, 60, 63, 65, 66]; 2.5–13.0% for PAD (15 studies) [15, 19, 20, 28, 34, 37, 43, 45, 52, 55, 56, 59, 60, 65, 66]; and 4.3–20.1% for HF (eight studies) [15, 19, 20, 42, 43, 55, 60, 66].
Consistently, in the five studies that provided data on sex, men had a higher prevalence than women of CHD, CVA and PAD [15, 20, 37, 56, 65].
The literature review identified several studies that reported the prevalence of CVD or a type of CVD in patients with T2DM in special populations, such as those of a predetermined age range or with additional comorbidities (Table 2). These studies focused on elderly patients [29, 31, 35, 61], patients with HF [30, 31, 33, 35] and patients with kidney disease [59, 60]. Several studies reported age as one of the main risks for CVD in patients with T2DM. The prevalence of ischaemic heart disease, stroke and HF increased sharply with age in patients with T2DM . Also, a large regional study in Catalonia showed that the prevalence of CVD was 32.3% in patients aged ≥ 75 years and about 10 points lower in the overall population . Two studies analysed the prevalence of CVD specifically in patients aged 85 and ≥ 90 years, respectively [29, 61]: in one study, the prevalence of stroke was slightly higher among patients with T2DM aged 85 years (14.0%) than in studies of the general population ; in the other study, the prevalence of CHD and PAD among nonagenarians with diabetes in the community of Madrid was higher in males than in females (21.5 vs. 12.6% and 8.5 vs. 2.3%, respectively; both p < 0.01) . However, the prevalence of stroke in the latter study was similar in both sexes (16.5 vs. 16.0%; p = 0.44) .
Two studies analysed the prevalence of CVD in patients with T2DM and kidney disease [59, 60]. The prevalence of CVD was high among patients with chronic kidney disease (30.2%)  and increased dramatically with worsening estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) parameters. Decreases in eGFR and increases in UACR are independent risk factors that increase the prevalence of CVD. The authors of the other study  suggested that both parameters should be determined at the time of T2DM diagnosis to identify patients at increased risk of CVD. The conclusion drawn in both studies was that patients with chronic kidney disease had an increased risk of CV mortality compared with patients without kidney disease [59, 60]. A population-based study of comorbidities showed that the co-prevalence of chronic kidney disease and CVD among patients with T2DM was 19.3% .
Incidence of CV Events in Patients with T2DM
The incidence of CVD or a type of CVD in patients with T2DM was analysed in 20 studies (Table 1). Several studies used the Spanish National Hospital Discharge Database (Registro de Altas de los Hospitales del Sistema Nacional de Salud [CMBD]) and other national databases to analyse the incidence of a specific CVD associated with patients with T2DM. These studies reported data on the incidence of acute myocardial infarction [27, 39, 40], thoracic aortic aneurysm [27, 36], ischaemic stroke [27, 50], haemorrhagic stroke , HF  and acute lower limb ischaemia  among patients with T2DM. Table 3 shows the incidence of CVD reported in studies among patients with T2DM in Spain. Most studies reported the incidence as rate per 100,000 inhabitants, but other formats were also used, which meant comparisons between studies were difficult.
The study with the most consistent and comprehensive data across all macrovascular comorbidities was that of de Miguel-Yanes et al. , which used data from the Spanish National Hospital Discharge Database. It also provided a time series for age-adjusted incidence from 2002 to 2014. For 2014, the most recent datapoint, this study reported an age-adjusted incidence of 145.13 per 100,000 inhabitants for all CVD combined .
De Miguel-Yanes et al.  reported a trend of increasing incidence of stroke from 2002 to 2014 (56.27–71.98 per 100,000 inhabitants), whereas the incidence of CHD remained stable or declined slightly (63.69–51.07 per 100,000 inhabitants in that period) . The regional studies by Mata Cases et al.  in Catalonia and Piniés et al.  in the Basque Country, for the periods 1991–2006 and 1998–2000, respectively, showed that the incidence of CHD was higher than that of stroke about two decades ago.
Recurrence of CV Events in Patients with T2DM with Established CVD
Information on the occurrence of subsequent CV events in patients with T2DM was specifically mentioned in 7 of the 20 studies reporting incidence [22, 23, 30, 31, 33, 35, 60].
Camafort et al.  analysed the incidence of recurrent ischaemic events in a countrywide sample of 974 patients with T2DM prospectively enrolled in a registry of symptomatic artery disease. Over a mean follow-up of 14 months, 13% of the patients had a second ischaemic event. In patients with HbA1c levels > 7%, the incidence rate was 4.4 (range 2.9–6.4) per 100 patient-years for myocardial infarction, 2.6 (1.5–4.2) for acute ischemic stroke, and 6.7 (4.8–9.1) for critical limb ischaemia. Overall, the incidence rate of subsequent ischaemic events was 14 (11–17) per 100 patient-years . This study concluded that for patients with coronary artery disease and HbA1c levels < 7.0%, the incidence of subsequent ischaemic events was significantly reduced compared with patients with HbA1c levels > 7.0%.
Salinero-Fort et al.  detailed the number of CV events in patients with T2DM from Madrid primary health care centres: 74.6% were free of CVD, 17.8% had one CV event, 6.8% had two CV events, and 1.3% had more than two CV events. Three studies reported previous CVD associated with patients with T2DM hospitalized for HF [23, 30, 31]. In patients with T2DM hospitalized for HF, 34% had previous CHD, 15% had stroke, and 21% had PAD . A second study in the same population showed that 79.8% had a previous episode of HF and 27.8% an episode of myocardial infarction .
Two studies studied subsequent CV events in elderly patients with T2DM [31, 35]. A study of 240 patients aged ≥ 75 years first admitted for acute HF reported that 28.8% had a previous diagnosis of CHD and 19.2% had a previous stroke . Gual et al.  studied cases of acute coronary syndrome in patients aged ≥ 80 years and found that a large proportion of patients had previous comorbid CVDs.
Mortality for CVD in Patients with T2DM
Mortality associated with CVD in patients with T2DM in Spain was analysed in 18 studies (Table 1). All used hospital registry data, and six of the seven studies at the national level reported data for CV-related mortality in patients with T2DM from the Spanish National Hospital Discharge Database [27, 38,39,40, 46, 48, 66]. Therefore, all of these studies presented data from hospitalized patients with T2DM.
Six studies analysed CV-related mortality in patients with T2DM in regional or local settings [16, 30, 31, 44, 57, 60]. For these studies, the data sources were more diverse, with three population-based studies [16, 57, 60], two studies based on hospital admissions [30, 31] and one study based on data from primary healthcare centres .
Table 4 shows the mortality rates obtained in 13 of the 18 studies analysing mortality (data from the remaining five studies were not tabulated as they only reported hazard ratios or mortality in a subpopulation). Mortality ranged from 5.6%  to 10.8% . A recent study found that CVD-related in-hospital mortality in patients with T2DM declined significantly in the years analysed (2002–2014) . However, multivariate analysis showed that, compared with matched controls without diabetes, patients with T2DM had a 15, 6 and 6% higher mortality when admitted for myocardial infarction, CVA and CVD, respectively .
Costs Associated with CVD in Patients with T2DM
Five studies analysed the costs of CV complications in patients with T2DM (Table 1). All studies identified in this review reported only direct costs from CV comorbidity in patients with T2DM.
Two studies analysed economic costs at the national level [26, 40], and three analysed costs at the regional level in Madrid , Catalonia , and Valencia . Costs reported in these studies referred to the years 2006–2012.
Table 5 shows data from the five studies included in this review. Mata-Cases et al.  estimated the annual cost per patient with T2DM as €3110 (year 2011 values), but the presence of CVD increased costs to €4814. The largest increase in costs was generated by HF, which reached €6866 per year in patients with T2DM, followed by PAD (€5858), CHD (€5006), and stroke (€4720) . A study of the costs of complications of T2DM in Madrid found a mean overall cost of €4121, of which two-thirds was due to macrovascular complications (especially heart revascularization and acute myocardial infarction) .
None of these studies analysed CVD cost components comprehensively, as some studies only evaluated hospitalization costs [26, 40] and others only medication costs . Generally, costs were driven mainly by hospitalizations and medications, and CVD caused an increase in both components .