Type 2 Diabetes Mellitus and Cardiovascular Disease in Spain: A Narrative Review
a Department of Cardiology. Hospital General Universitario Gregorio Marañón. Madrid. Spain.
b Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health. Baltimore. MD. USA.
c Department of Quantitative Health Sciences. Cleveland Clinic. Cleveland. OH. USA. and Clinical Epidemiology Unit. Department of Cardiology. Thoraxcentre. Erasmus Medical Centre. Rotterdam. The Netherlands.
KeywordsDiabetes mellitus. Cardiovascular disease. Prevention. Epidemiology. Spain.
AbstractIntroduction. In spite of having a high prevalence of diabetes mellitus the prevalence of ischemic heart disease is low in Spain. Methods. A narrative review of the bibliography was performed to search for potential particularities in the epidemiology, pathogenecity, and care of diabetes mellitus in Spain. Results. The age-adjusted prevalence of diabetes in Spain is close to 10% (90% type 2) ranging from 6.1% to 13.3% (higher in Canary Islands), with an increased North-to-South gradient. Men have a 27%-42% higher prevalence than women. The incidence ranges from 5 to 8 cases per 1000 inhabitants-year. Spanish patients with diabetes have similar incidences and prevalences of cardiovascular complications and related mortality compared with those reported in other countries. Several studies have shown a consistent underuse of preventive therapies both in patients with and without cardiovascular diseases, and low rates of achievement of therapeutic goals. Despite their much worse prognosis, and contrary to current recommendations, diabetic patients with acute vascular events are not treated differently compared with non-diabetics. Conclusions. The age-adjusted prevalence and incidence estimates of diabetes mellitus in Spain appear to be similar to those in high-incidence countries. Diabetic patients show a high cardiovascular risk profile but the control of risk factors is poor, particularly in women and in patients with established cardiovascular disease. Initial and later care of diabetic patients with acute vascular events in Spain is far away from optimal. There is a huge opportunity for improving cardiovascular prevention and care in diabetic patients with and without cardiovascular disease in Spain.
Type 2 diabetes mellitus (DM) is a strong cardiovascular risk factor. Spain is a country with a high prevalence of DM1 but one of the lowest of ischemic heart disease in the Western world.2 Due to this apparent paradox, we tried to address whether there is any specific feature in the epidemiology, pathogenecity or care of type 2 DM in Spain, the most common phenotype of diabetes. Type 1 diabetes is beyond the scope of this paper and can be reviewed elsewhere.3-5
Prevalence and incidence of type 2 diabetes mellitus in Spain
DM is among the diseases with the greatest impact on the Spanish population and healthcare system due to its high prevalence, the frequency of chronic complications and its high mortality. According to the World Health Organization (WHO), diabetes prevalence is expected to increase in Spain 40% by 2025 compared to year 2000.6
A number of epidemiological studies have shown that Spain is a country with an intermediate to high prevalence of DM compared with other nations.7-10 However, prevalence comparisons within and between populations must be made with caution due to the potential use of different diagnostic criteria (eg, American Diabetes Association, WHO), screening tests (eg, self reported, physician based, prescription records), populations (eg, general population, population at risk for type 2 diabetes, different population structure), designs and sampling techniques. As a result, eight studies using similar methodology were identified in the literature to assess the prevalence of diabetes in Spain (Table 1).11-18 The age-adjusted prevalence ranged from 6.1% to 13.3% showing an increased North-to-South gradient, with higher prevalence in men compared to women (27%-42% higher). Overall, these data are consistent with the 2003 IDF estimations, in which Spain was ranked as the tenth country with the highest prevalence of diabetes in the 20-79 age group in the world.1 According to the same report, the overall prevalence of diabetes is 9.9% (90% of whom were type 2 diabetes mellitus). This implied that Spain had to spend in 2003 the 6% of total healthcare budget (2.4-2.6 million euros) to treat nearly 3 million patients with DM.1 Although not strictly comparable due to the use of different standard populations and ethnic differences, the total prevalence of diabetes in the US was 9.3% between 1999 and 2002 (7.9% for non-Hispanic whites), suggesting that Spain and the U.S. probably have similar prevalences of DM.19 As far as incidence of type 2 DM is concerned, of the published papers providing an estimate,9,20-23 only a few accounted for age structure in Spain.20-23 Vázquez et al.22 showed an annual age-adjusted cumulative incidence of 8 cases per 1000 inhabitants-year, using WHO-1985 criteria after 10 years of follow-up.22 Another study, using similar diagnostic criteria and methodology in the Basque Country, found an age-standardized cumulative incidence of 5 per 1000 inhabitants-year.22 Finally, Valdes et al.23 showed that incidence of type 2 diabetes adjusted for the age and sex structure of Asturias was 10.8 cases/1,000 persons years (95% CI 7.8-14.6) after 6.3 years of mean follow-up, using WHO 1999 criteria. These results are also comparable with the United States for similar populations, where an estimated age-adjusted annual cumulative incidence of 6.0 per 1000.24
Type 2 diabetes mellitus and cardiovascular disease
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among individuals with diabetes. Adults with DM have a two- to fourfold higher risk of CVD compared with those without diabetes.25 In Spain, published longitudinal studies reporting the incidence of cardiovascular events in individuals with diabetes are scarce. Tomas et al.26 (n=1059 men) showed in the Manresa Study that the estimated age-adjusted 28-years cumulative incidence for coronary heart disease (CHD) was 17.6% for individuals with basal glycemia greater than 110 mg/dL or previously diagnosed diabetes. Rius et al27 reported an outpatient-based clinic longitudinal study (6.3 years of mean follow-up) with 176 patients free of CVD. They observed a cumulative incidence of macroangiopathy, defined as CHD, stroke and intermittent claudication of 15.9% and, specifically, 6.3% of CHD, 8% of cerebrovascular disease and 4% of peripheral arterial disease. Cañón-Barroso et al28 retrospectively identified in a general practice clinic a cohort of patients with type 2 DM free of CVD at baseline. They observed a 14.7%, 10-year cumulative incidence of CHD (angina, fatal, and non-fatal myocardial infarction), 13.3% for men and 16.0% for women. Using a similar design, Jimeno et al29 found a 17% cumulative incidence of CHD (18.5% in men and 15.2% in women) after 10 years of follow-up. Overall, these data are consistent with Morrish et al,30 who showed in a cohort (n=497) over a period of 8.33 years of follow-up for patients with type 2 DM a 18.8 incidence of myocardial infarction, 5.9 of cerebrovascular disease, and 5.2 of peripheral arterial disease.
On the other hand, several cross-sectional studies reported crude prevalence estimates of macrovascular complications in Spain.31-38 These studies reported a wide prevalence range for peripheral arterial disease (5.6%-24.5%). Estimates for CHD ranged between 10.5% and 19.8%, and between 3.3% and 11.8% for stroke. Obviously, prevalence rates vary according to different methodologies and clinical characteristics of the population such as the duration of the disease. Arteagoitia et al20 studied 2920 diabetic patients in the Basque Country using a sentinel practice network during year 2000. They found a 21.6% prevalence of macroangiopathy in new onset cases (12.4% of CHD, 9.8% of stroke, and 14.1% of peripheral vascular disease), and 33% among cases of known diabetes (7% CHD, 4% stroke, and 14% peripheral artery disease). They showed that macrovascular disease was more likely to be reported in men compared to women (odds ratio [OR] for incident DM, 2.3; 95% confidence interval, 1.2-4.6; OR for prevalent DM, 1.5; 95% CI, 1.5-2.1).
Type 2 diabetes mellitus, cardiovascular risk factors and risk of coronary heart disease
The prevalence of CHD disease in Spain is among the lowest in the Western countries2 despite the high prevalence of risk factors.39,40 However, individuals with type 2 DM usually have higher prevalence of traditional risk factors posing them into the highest risk category for CVD and, particularly for ischemic heart disease, in the "coronary risk equivalence."41,42 In terms of cardiovascular risk estimation, several Spanish authors28,29,35,43 examined the risk of coronary events using available risk engines in order to predict the most common complication in this population.44 For the Framingham-REGICOR risk engine45, the 10-year likelihood of coronary events were between 5.6% and 15% in men, and between 6% and 10% in women. Using the diabetes-specific risk engine UKPDS,46 they found that men had a 10-year risk of CHD between 19% and 38%, while the risk ranged from 11% and 28% for women. Finally, when the SCORE calculator to estimate 10-year risk of fatal coronary disease47 was applied, Lahoz35 found that women had a 2% compared to 4% in men.
Mortality and impact of type 2 diabetes mellitus in Spain
In Spain, CVD are the cause of death in at least half of type 2 DM,30,48 although other reports find it up to 75%-80%.9 In 2005, CVD was the leading cause of death, accounting in Spain for 32.8% of the deaths.49 Diabetes constituted the seventh cause of death, raking the 8th-9th for men and 5th-6th for women depending on the year.49,50 These estimates are also very similar to the United States, where diabetes was the sixth leading cause of death.51 However, it must be acknowledged that direct comparison of these mortality rates is incorrect due to the lack of standardization to the same population.
According to the Spanish National Institute of Statistics, ischemic heart disease accounted for 90.98 deaths and cerebrovascular disease 80.23 per 100 000 habitants-year compared to the diabetes-specific death rate of 23.3 deaths per 100 000 inhabitants-year. Concordantly with the prevalence estimates for DM, diabetes-related mortality showed an increasing North-South gradient.49,50,52 Locally, Ruiz et al53 analyzed the trends of mortality due to diabetes in Andalusia during 1975-1994. Using age standardization (direct method) from European population, they found that mortality due to DM decreased from 24.45 to 19.15 deaths per 100 000 persons-year in men, and from 33.55 to 22.43 in women, in that time period. Compared to the United States, the diabetes-specific age standardized mortality rate for whites, using U.S. population as standard, was 27.0 for males and 19.9 for females per 100 000 habitants/year.51 In the U.K. a recent study showed that for the period of 1993-1999, the specific age-standardized mortality rate (using European population as the reference), was 32.0 for women and 38.7 per 100 000 habitants-years for men.54 Considering the important limitations of the population attributable fraction,55 Banegas et al56 suggested that the attributable population fraction for diabetes is approximately 8.3% for CHD and 3.7% for cerebrovascular disease. They estimated that 2% of coronary mortality and 1.6% of cerebrovascular mortality was attributable to diabetes in men, but as much as 10.4% and 3.9%, respectively, in women.
Whereas CHD mortality is decreasing among diabetic men over the last three decades, it seems to be increasing among women.57 In Spain, available data suggest a similar pattern. However, while the prevalence of diabetes is slightly superior in men, Spanish women tend to have a worse control of their risk factors compared to men.58 Moreover, women have a worse prognosis once they are affected by cardiovascular diseases.59 According to an Andalusian study, unadjusted mortality rate is higher in women compared to men, especially when cohorts become older.53 These results are comparable with those reported in other countries.30
CARDIOVASCULAR PREVENTION IN DIABETIC PATIENTS IN SPAIN
Glycemic control, detection, and treatment of associated co-morbidities are essential to prevent future macrovascular complications. A number of Spanish studies have addressed the health status of diabetic patients at a national31,32,60 and local level.35,61,62 They consistently showed a suboptimal control of cardiovascular risk factors in this patient population. In average, one quarter of patients had glycosilated hemoglobin (A1C) levels >8%; at least half of the individuals were diagnosed of hypertension and between 50%-70% were above optimal levels (>130/85 mm Hg); LDL-C levels were elevated (>115 mg/dL)63 in up to 90% of patients; current smokers accounted for 9%-17%; obesity, defined as a body mass index >30 kg/m2, was present in 30%-60% of subjects; and when physical activity was reported,31,60 between 60%-80% of patients had a sedentary lifestyle. These data are consistent with other European64 and American studies.65,66
In primary prevention, a subanalysis of the 316 diabetic and 345 non-diabetic patients without prior CVD enrolled in the Trans-STAR study--a Spanish national prospective case-control study performed in 326 primary care centers during a week in October 2001 that recruited 776 patients (388 diabetics and 388 non-diabetics)32--has shown a low rate of use of pharmacological preventive therapies (Table 2) in spite of the high prevalence of known dyslipidemia (50%) and hypertension (51%) among diabetics. In addition, a low proportion of these patients had their risk factors measured during the year previous to the interview (Table 3). When the control of risk factors was ascertained in the diabetic group according to the JNC VI and NCEP III recommendations, extremely low rates of LDL-C and systolic blood pressure control were found (Table 3). Interestingly, fewer patients (7%) with known high LDL levels reached established goals in comparison to those without high LDL levels (10%). Similarly, fewer patients with known systolic or diastolic hypertension (6% vs 33%) reached goals in comparison to those without known hypertension (28% and 45%, P<.001). Underuse of lipid-lowering and antihypertensive therapies in diabetic patients as well as low proportions of patients reaching therapeutic goals have been described throughout the world.67-70
The degree of control of cardiovascular risk factors in patients with established cardiovascular disease is particularly disturbing. González-Juanatey et al71 in a nationwide sample of clinics involving 1275 patients showed that blood pressure was controlled (<130/80 mm Hg) in less than 30%, LDL-C levels were above 100 mg/dL in more than 90% of patients, and use of current established therapies for secondary prevention were underused in 60%-74% depending on the drug. The DIETRIC study72 showed similar results among 628 patients. Although more than 60% of patients presented 3 or more related risk factors, only 15% had adequate control of blood pressure (<139/80 mm Hg), 7.5% had adequate control of plasma lipids (LDL-C<100 mg/dL, and triglycerides <150 mg/dL), and 57.2% had A1c> 6.5%. The same direction showed a major study in the field. Mostaza et al73 included 8,817 patients from primary care clinics who were hospitalized for a coronary event. They found that only 7% had optimum control of all their risk factors. Specifically, "the percentage of diabetic subjects attaining objectives for smoking habit, low-density lipoprotein cholesterol, blood pressure, and glycated hemoglobin were 90.7%, 29%, 38.2%, and 49.7%, respectively." Even more, recent data suggests that Spanish women have worse control of cardiovascular risk factors compared to men.59
MANAGEMENT OF ACUTE VASCULAR EVENTS IN DIABETIC PATIENTS
There is scarce information about the management of acute vascular events in Spanish diabetic patients. A small study performed in the Canary Islands showed that the subgroup of diabetic patients with for non ST-segment elevation acute coronary syndromes (ACS) were older, had a higher prevalence of risk factors and had higher incidences of heart failure, 28-day, and 6-month mortality. Despite these facts, they did not find different patterns of use of coronary angiography, angioplasty or surgical revascularization.74 DESCARTES (Descripción del Estado de los Síndromes Coronarios Agudos en un Registro Temporal ESpañol), a Spanish nation-wide registry of patients hospitalized for suspected ACS performed by the Working Group on Ischemic Heart Disease of the Spanish Society of Cardiology, recruited 1877 consecutive patients with ACS in 45 randomly selected hospitals in Spain stratified by 3 different levels of care between April and May, 2002.75 The results of DESCARTES have shown a significative underutilisation of evidence-based therapies among patients with ACS in Spain, particularly those at higher risk.75,76 Diabetes mellitus is considered as a high-risk feature in patients with ACS by the 2002 European Society of Cardiology task force, and an intermediate risk by the contemporary Spanish guidelines. According to these recommendations, diabetic patients with ACS should undergo an aggressive pharmacological management including upstream use of glycoprotein IIb/IIIa inhibitors and an early (within 48 hours) invasive strategy. When the baseline clinical characteristics, hospital management and outcomes of the diabetic patients enrolled in DESCARTES with those without DM were compared (data not shown), diabetic patients were found at a significantly higher predicted risk regardless the way it was addressed (clinical characteristics, TIMI risk score, ESC criteria), and actually showed a higher short-term incidence of heart failure and death (figure 1). Despite this features, during hospitalization diabetic patients only received clopidogrel and angiotensin-converting enzyme inhibitors slightly more frequently than non diabetics, and the latter difference was attributed to the higher prevalence of hypertension among diabetics. On the contrary, none of the interventions recommended specifically for high-risk patients, i.e. glycoprotein IIb/IIIa inhibitors, early coronary angiography, and coronary revascularization were not used more frequently in diabetic patients. At 6 months, diabetic patients showed nearly a 3-fold increase in mortality compared with non-diabetics.77 A small angiographic study on diabetic ACS confirmed the lack of use of early coronary angiography among these patients, despite the high prevalence of severe diffuse coronary artery disease.78 Diabetic patients hospitalised for stroke do not receive a different treatment compared with non-diabetics, although DM seems not to have an impact on prognosis in stroke patients.79
Fig. 1. Survival according to diabetes status in patients with non ST-segment elevation acute coronary syndromes in Spain (year 2002). Despite their worse prognosis, diabetic patients did not receive a more aggressive treatment than non-diabetics.
In summary, the age-adjusted prevalence and incidence estimates of type 2 diabetes mellitus in Spain appear to be similar to those in the United States. Diabetes mellitus is one of the leading causes of death, but most patients die as a consequence of cardiovascular disease. Diabetic patients in Spain show a high cardiovascular risk profile, and furthermore, the control of risk factors is poor, particularly in women, and in patients with established cardiovascular disease. Acute care of diabetic patients with acute vascular events in Spain is far away from optimal, There is a huge opportunity for improving cardiovascular prevention and care in diabetic patients with and without cardiovascular disease is Spain.
We appreciate the contribution the DESCARTES and TranSTAR steering committee members and investigators, of BMS and of Gemma Gambús of NOVARTIS, for sharing the results of the studies.
ACS: acute coronary syndromes
ADA: American Diabetes Association
CHD: coronary heart disease
CVD: cardiovascular disease
DM: diabetes mellitus
IDF: International Diabetes Federation
WHO: World Health Organization
Dr. Hernáez was a scholar of the Fundación Caja Madrid and is a current postdoctoral fellow of the American Diabetes Association.
Correspondence: Dr. H.Bueno.
Servicio de Cardiología.
Hospital General Universitario Gregorio Marañón.
Dr. Esquerdo, 46. 28007-Madrid, Spain.
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