First cardiovascular event in patients with type 2 diabetes mellitus of a cardiovascular risk management program of a poor Colombian population: a cohort study

Diabetes mellitus (DM) is responsible for high global mortality rates and high disability burden [1] and is a major risk factor for cardiovascular disease. The presence of both DM and cardiovascular disease (CVD) increases the risk of death [2‐5]. The global prevalence of DM has almost doubled in the adult population since 1980 (4.7 to 8.5%). In 2012, 1.5 million people died by DM. High blood glucose levels caused an additional 2.2 million deaths due to increased cardiovascular risk and other diseases. The percentage of deaths attributable to high blood glucose or diabetes that occurs prior to age 70 is higher in low- and middle-income countries (LMICs) than in high-income countries (HICs) [6].

In the world, 80% of cases of noncommunicable diseases (NCDs) occur in LMICs [7]. Most countries in Latin America, at least during the last 50 years, have experienced an epidemiological transition within a “prolonged polarized model”, presenting complex transformation of their conditions of health, with the existence of a double burden of disease or epidemiological superposition [8, 9]. In Colombia, DM is among the first 10 causes of general mortality and within the first 20 causes of years of healthy life lost (YHLL) in a population ≥ 45 years [10]. According to several studies in population of high-income countries (HIC), patients with Type 2 DM have a considerably higher risk of cardiovascular morbidity and mortality. However, it is not clear if the magnitude of this association can be widespread in other populations. This has been attributed to older age and a higher prevalence of cardiovascular risk factors among people with diabetes [11]. In observational studies of cases and controls that included participants from Latin America, including Colombia, an association between DM and AMI has been reported. In the INTERHEART study, a significant association between DM and AMI (Odds Ratio (OR) 2.59, 95% Confidence Interval (CI) 2.09–3.22) and a population risk attributable to DM of 17.2% was reported [12]. In the INTERSTROKE study, a significant association between DM and stroke (Relative Risk (RR) 1.36, 95% CI 1.10–1.68) and a population risk attributable to DM of 5% was reported [13]. In randomized clinical trials such as the NAVIGATOR study, Latin American participants with glucose intolerance had an increased risk of cardiovascular death (Hazard Risk (HR) 2.68, 95% CI 1.82–3.96) and composite cardiovascular outcome (HR 1.48, 95% CI 1.15–1.92) [14]. Traditional multivariate risk adjustment models may be limited by residual biases and questioned the reliability and when the data are recorded in the context of a clinical trial, they may not reflect the real characteristics of the population by the specified selection criteria. In addition, there may be variation in the management plans of cardiovascular risk programs even within a given region. Matching propensity scores allow balancing the covariates of baselines measured in the cohorts to obtain more robust results [15].

The objective of this study was to examine the association between Type 2 DM with first cardiovascular event in a cohort of type 2 DM Colombian Caribbean poor population with no previous records of cardiovascular events compared with a paired matched cohort of patients with no presence of DM.

The data from the Framingham Heart Study made it possible to identify DM as an important cardiovascular risk factor, mainly in women [17]. To the best of our knowledge, this is the first report of an association between Type 2 DM and first cardiovascular events in a propensity-matched cohort of poor population without a history of previous cardiovascular events in Latin America and Colombia. According to several studies, all patients with DM can be treated as if they had prior cardiovascular disease since the risk of fatal AMI in patients with DM without previous AMI is similar to that of patients without DM who have survived an AMI [11, 17]. In the study of Becker et al., 10-year follow-up, women with DM, but without prior cardiovascular disease have a risk of cardiovascular events that is similar to that of women without diabetes but with prior cardiovascular disease, whereas in men the presence of prior cardiovascular disease conferred a higher risk [11]. In our study, in the pre-matched cohort, the risk of the first cardiovascular event was significantly higher in women with Type 2 DM. In the post-matched cohort, these differences by sex disappeared for almost all outcomes, except for the stroke incidence that was significantly higher in women with Type 2 DM. In the Framingham Heart Study for stroke, women with DM had a higher incidence than men did with DM [17].

The findings of the current analysis demonstrate that in patients without a personal history of previous cardiovascular events, a history of Type 2 DM was associated with an increased risk of a first cardiovascular event, which was primarily driven by an increase in AMI. Type 2 DM was also associated with risk of all-cause hospitalization, cardiovascular death, stroke death and all-cause death, but had no independent association with cardiovascular hospitalization. In the Framingham Heart Study, an increased mortality due to CVD in patients with DM compared with patients without DM was reported [17]. In the INTERHEART study, a significant association between DM and AMI (OR 2.59, 95% CI 2.09–3.22) and a population risk attributable to DM of 17.2% was reported [12]. In the INTERSTROKE study, a significant association between DM and stroke (RR 1.36, 95% CI 1.10–1.68) and a population risk attributable to DM of 5% was reported [13]. These results should be interpreted considering the limitations and possible biases of a case-control study, in which the presence of exposure variables is determined after the onset of the disease [18]. In randomized clinical trials such as the NAVIGATOR study, Latin American participants with glucose intolerance had an increased risk of cardiovascular death (HR 2.68, 95% CI 1.82–3.96) and composite cardiovascular outcome (HR 1.48, 95% CI 1.15–1.92). When the data are recorded in the context of a clinical trial, they may not reflect the real characteristics of the population by the specified selection criteria [14]. In the PURE study identified that although risk-factor burden may be lower in LMIC, the risk of cardiovascular events was much higher [19]. In the current study, the risk of first cardiovascular event was significantly higher in the Type 2 DM group (HR 1.69; 95% CI 1.43–2.00).

In Colombia, DM is among the first 10 causes of general mortality and within the first 20 causes of years of healthy life lost (YHLL) in a population ≥ 45 years [10]. In Colombia, according to data from individual health care records (RIPS) and systematic reviews between 2010 and 2014, approximately 1,500,000 patients with type 2 DM were estimated [10]. According to the National Department of Statistics (DANE) of Colombia, between January 2016 and August 2018, 60,944 deaths from ischemic heart disease (17.1%), 24,548 deaths from cerebrovascular diseases (6.9%) and 11,743 deaths from DM (3.3%), were estimated. According to the cumulative incidence of first cardiovascular events (3.5%) and cardiovascular mortality (22.9%) in Type 2 DM group (+) estimated in the current study, approximately 52,500 first-time cardiovascular events and around 12,000 cardiovascular deaths per year would be expected to occur. These estimates are similar to the annual deaths due to DM estimated by the International Diabetes Federation (IDF) (11,400 deaths due to DM) [6] and the non-fetal death statistics of the DANE of Colombia (11,743 deaths due to DM).

Care of a patient with DM requires a multifactorial approach from the cardiovascular risk management program. All patients are at risk of developing vascular complications of DM, and these risks represents ultimately result in a doubled risk of mortality in patients with DM. Above and beyond targeted interventions, we now know that strict multifactorial interventions can result in a clinically significant reduction in both mortality and cardiovascular disease. These conclusions provide significant information on the importance of Type 2 DM in increasing the risk of first cardiovascular events in the poor population of the Colombian Caribbean region and the importance of an adequate diagnosis and treatment of Type 2 DM. However, evidence that an adequate metabolic control reduces the rates of cardiovascular events and death is not clear, although a discrete cardiovascular benefit may be observed after a prolonged follow-up period [20‐24]. Evidence from HICs indicates that multiple risk factor intervention programmes do not result in reductions in cardiovascular events but may be effective in reducing mortality in high-risk hypertensive and diabetic populations. Due to the differences in the structure of the communities and the target population, caution is needed to generalize the results to LMICs. In the systematic review of Uthman et al., evidence about effectiveness of multiple risk factor interventions (with or without pharmacological treatment) in LMICs was scarce and only one study reported cardiovascular outcomes and multiple risk factor interventions did not reduce the incidence of cardiovascular events and none of the included trials reported all-cause mortality [25]. For cardiovascular risk management programs it is important to evaluate the impact of their interventions over time to achieve optimal primary cardiovascular prevention in patients under the care of the program [26]. There may be variation in the management plans of cardiovascular risk programs even within a given region beyond differences in health budget and system characteristics [27]. The use of statins in the LMIC is low in comparison with the HIC [28]. In the NAVIGATOR study, was reported that patients in Latin America used fewer therapies for prevention of cardiovascular events, such as aspirin (32% versus 47% in North America and 35% in Europe), lipid-lowering therapies (28% versus 55% in North America and 35% in Europe), and ACEIs (4% versus 9% in North America and 8% in Europe) [14]. In the TECOS study, low use of statins and aspirin in Latin America compared to North America was reported [29]. Recently, trials evaluating anti-diabetic drugs (empagliflozin, liraglutide, pioglitazone and semaglutide) have shown improved cardiovascular outcomes in patients with Type 2 DM [30‐34]. The findings of the current analysis report a low use of statins, aspirin and new anti-diabetic drugs.

Our study has several strengths and limitations. More than 35 thousand of patients were included and, in spite of the nearly 1000 patients with type 2 DM lost, there were no differences in the incidences and incidence rates between the groups after propensity matching. We tried that the possibility of residual confounding, by the measured covariates and confounding by the unmeasured covariates that explain the associations between Type 2 DM and first cardiovascular event, were unlikely, considering that our patients were matched in 22 baseline characteristics and the conclusions of our analysis of sensitivity suggest that the association between Type 2 DM and a first cardiovascular event was quite insensitive to an unmeasured binary confounder.

Within limitations, we faced restrictions to access to sociodemographic data due to restrictions from the insurance company. In order to identify the diagnosis of cardiovascular outcomes we used the records of previous cardiovascular events and the ICD-10 hospital discharge code. However, we could not have data on confirmatory tests.

On the other hand, the exact date of death of patients and date of enrollment on the cardiovascular risk management program was not available.

We did not have access to information related to the treatment of cardiovascular events such as medications, thrombolysis, percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), etc. In conclusion, in the poor population of the Colombian Caribbean without a personal history of cardiovascular events receiving standard therapy, DM produces cardiovascular outcomes. It is not known if a more aggressive screening of DM, DM education at every level, quality care registries and taxes on sugary drinks can reduce the risk of a first cardiovascular event in these patients and should be determined prospectively in future studies in Latin America.