Macrovascular Complications in Patients with Diabetes Mellitus: Incidence and Impact on Survival in Kazakhstan

Abstract

Background and aim: Diabetic patients are at an increased risk for the development of macrovascular complications such as acute myocardial infarction (AMI), stroke and lower-limb amputations (LLA). This study aimed to explore a. the incidence of hospital admission for macrovascular complications (AMI, stroke, and LLA); b. to assess the impact of hospital admission on survival in a large population with diabetes mellitus living in Kazakhstan.

Materials and methods: Retrospective observational study using a nationwide anonymized electronic database of 98.469 hospitalized diabetic patients from Kazakhstan between November 2013 and December 2019. The incidence of hospital admissions for AMI, stroke and LLA were obtained to calculate their all-time cumulative incidence, and survival rate at follow-up.

Results: The all-time cumulative incidence of hospital admissions was 1.30% for AMI, 1.94% for stroke and 2.94% for LLA. The incidence of macrovascular complications was statistically significantly higher in males compared to females (p-value<0.05). 29.03% of diabetic patients with AMI, 25.16% with stroke and 29.80% with LLA died during the follow-up period. Individuals with AMI had 3.58 (95% CI 3.20; 4.01) times, with stroke 3.86 (95% CI 3.52; 4.24) times and with LLA 3.63 (95% CI 3.38; 3.88) times higher hazard of 6-year death compared to diabetic patients free of these complications. The stratified survival analysis by sex indicated the lower survival in women than in men, and the lower survival in older age groups.

Conclusion: The results from this study shows that cumulative incidence of AMI and stroke among diabetic patients admitted in the hospitals in Kazakhstan between 2013-2019 years was similar to the estimates from other countries, but the incidence of LLA was significantly higher in Kazakhstan. Patients with diabetes mellitus (DM) in Kazakhstan are at high risk of excess mortality if they suffer from macro-vascular complications. More research is required to explore the reasons for the high incidence of those complications, in order to propose systematic solutions for lowering the incidence and improve survival.

Introduction

The prevalence of DM is increasing from year to year. Thus, if in 2017 DM cases reached staggering 451 million worldwide (among 18–99 years old), by 2045, it is projected to hit 693 million cases [1]. The mortality rate of DM was around 5 million (among 20–99 years old) in 2017 that is almost 10% of all deaths worldwide [1]. According to the International Diabetes Federation, the prevalence of DM in Kazakhstan was 6.2% (1.15 mln individuals) in 2019 [2]. The study NOMAD estimated a period prevalence between 2014–2016 of 8.2% [3]. High prevalence and mortality rates have a dramatic impact on healthcare expenditures. In 2017, the global expenditure on DM patients, aged 18–99 years, reached 850 billion USD, and it is expected to rocket up to 958 billion USD by 2045 [1].

Patients with diabetes mellitus are at high risk of cardiovascular complications with approximately a two-fold increased risk compared to non-diabetic subjects. These complications are also associated with an increased risk of death [4]. In particular, diabetic patients with acute cardiovascular diseases (CVD) such as acute myocardial infarction (AMI), stroke and lower limb amputation (LLA) have a 4-fold increase in mortality rate compared to diabetic patients without such complications [5, 6].

According to the Global Burden of Diseases, from 1990 through 2019, the disability adjusted life years (DALYs) for diabetic patients increased to 24.4%, ranking the disease at the 6th place among causes of the burden of disease [7]. In order to slow down the increasing public health impact of DM, it is crucial to explore complications of DM patients and address targeted measures against them [8].

Obviously, there are huge gaps in the valid knowledge about the incidence of DM-related complications, including acute cardiovascular and cardio-cerebral events, as well as lower limb amputations. Most research evidence comes from high-income countries that represent about 10% of the global population, while there are scanty data on the situation in Central Asia, particularly in Kazakhstan.

With these concepts in mind, we aimed to a. Determine the incidence of hospital admission for macrovascular complications (AMI, stroke, and LLA); b. Assess the impact of hospital admission on survival in a large population with DM living in Kazakhstan.

Methods

Results

Baseline characteristics

The population analyzed in this work consists of 98,469 patients with a mean follow-up period of 3.42±1.78 years (range 0 to 6.17 years). 37.28% were younger than 54 years, and 29.15% were older than 65 years. 59.82% were females. Ethnicity information was divided into three groups: Kazakhs (60.14%), Russians (19.29%) and Others (20.57%). In addition, 59.14% of the patients were from urban settings. Database also contained information about the regions of Kazakhstan, where the hospitalization took place. The 17 regions registered in the database were divided into five categories: North (24.30%), South (23.55%), East (29.01%), West (14.03%) and Central (9.11%) (Table 1).

Incidence of macrovascular complications

The all-time cumulative incidence of AMI, stroke and LLA was 1.30%, 1.94% and 2.94%, respectively. (Table 1).

Sex-stratified incidence of three complications was calculated. The incidence of AMI and stroke was higher in males compared to females (1.45% vs 1.19%, p<0.001, and 3.67% vs 2.45%, p<0.001, respectively, while the incidence of stroke was similar (1.95% in males vs 1.93% in females, p-value 0.06). (Figure 2a).

In addition, age-stratified incidence of AMI, stroke and LLA variables were calculated. The incidence of AMI was 0.57% in the younger than 54 years group, and it was 2.5 fold lower than in the 54-65 years group (1.43%), 3.6 times lower than in the older than 65 years group (2.08%), (p-value<0.001). The incidence of stroke showed the same trend and it was 0.93%, 2.26% and 2.85%, respectively. Almost the same situation in the LLA variable. Incidence of 1.26% of the younger than 54 years group was the lowest, and it was lower for 2.5 times than in the 54-65 years group (3.16%) and 3.8 times lower than in the older than 65 years group (4.85%), (p-value<0.001) (Figure 2b).

Survival analysis

Overall, 29.03% of patients with AMI, 25.16% of patients with stroke and 29.80% with LLA died during the follow-up period. Mortality after the first event of AMI and stroke at 1st, 7th and 28th days was: 8.76%; 16.0%; 19.72% for AMI and 2.52%; 9.33%; 14.36% for stroke.

According to the Kaplan-Meier survival curves (Figures 3a-3d), diabetic patients with any of these macrovascular complications had lower survival in comparison with individuals without these complications (p-value<0.001 for all graphs). Individuals with AMI had 3.58 (95% CI 3.20; 4.01) times, with stroke 3.86 (95% CI 3.52; 4.24) times and with LLA 3.63 (95% CI 3.38; 3.88) times higher hazard of 6-year death compared to diabetic patients free of complications.

Even though, the incidence of DM-related complications was higher in men than in women, the sex-stratified survival analysis showed that men had better survival than women, while age-stratified analysis demonstrated the patients older than 54 years showed lower survival than the same individuals younger than 54 years (Figures 4a-4c, Figures 5a-5c).

The stratified analysis by sex showed that survival after AMI was lower among women than in men (HRs of mortality 4.30 (95% CI 12.75; 4.94) vs. 2.78 (95% CI 2.30; 3.37)) (Figures 6a-6b). While stratified analysis of survival following AMI by age categories demonstrated that diabetics at younger age groups had higher survival after AMI than older groups. HRs of mortality among diabetics after AMI aged younger than 54 years were higher than HRs among individuals aged 54-65 and 65 years, 4.78 (95% CI 3.32; 6.93) vs. 2.85 (95% CI 2.30; 3.54) and 2.68 (95% CI 2.33; 3.08) respectively (Figures 6c-6e).

Additionally, the survival during this period after first hospitalization due to stroke was lower among women than in men with HRs 4.26 (95% CI 3.80; 4.77) vs. 3.25 (95% CI 2.76; 3.83) (Figures 6a-6b). Trend was similar with regard to age - 54-65 and older than 65-year old patients had lower survival after the first stroke event than individuals younger 54 years. HRs were 4.40 (95% CI 3.24; 5.98) among patients younger than 54 years, 3.48 (95% CI 2.92; 4.14) among those aged 54-65 years and 2.91 (95% CI 2.59; 3.28) among diabetics older than 65 years (Figures 6c-6e).

Sex-stratified cumulative survival analysis after first hospitalization due to LLA indicated that women had higher risk of mortality than men with HR 4.07 (95% CI 3.71; 4.46) vs. 3.26 (95% CI 2.93; 3.63) (Figures 6a-6b). In age-stratified analysis, 54-65 years old and older than 65 years diabetic individuals after LLA showed lower survival in comparison with the patients at age younger than 54. Stratified HRs were 3.75 (95% CI 2.92; 4.82) among patients younger than 54 years, 3.42 (95% CI 2.99; 3.89) among those aged 54-65 years and 2.46 (95% CI 2.25; 2.68) among diabetics older than 65 years (Figures 6c-6e).

Discussion

This is the first and largest observational retrospective study with electronic health data from all over Kazakhstan, shedding a light on the incidence of macrovascular complications and their impact on survival among diabetic patients and corroborating that the global un-meet need associated with macrovascular complications also affects the Kazakhstani diabetic patients.

According to the results, cumulative incidence of AMI, stroke, and LLA was 1.30%, 1.94%, and 2.94%, respectively. Those complications have a significant impact on survival of diabetic patients.

Ischemic heart disease and cerebrovascular disease represents the main causes of life lost to premature death in Kazakhstan [10]. Cardio-metabolic factors related with DM and their vascular complications, as dietary risks, high systolic blood pressure and high body mass index were the highest ranked risk factors for disease burden in Kazakhstan. Despite of progress due to reform over the past few years resulting in improvements in prevention and management of non-communicable disorders in the country [11], those health problems still have a significant public health impact and call for continuing strengthening of the health system to respond to their significant burden, including the evaluation of those interventions [12]. Along with increasing incidence and prevalence of DM in Kazakhstan, about 80% of diabetic patients are overweight or obese and uncontrolled elevated blood pressure is also highly prevalent, factors that contribute to the development of DM-related micro- and macrovascular complications [13–15].

The incidence of AMI found in this work is lower than has been reported in Africa, Americas, Europe and Eastern Mediterranean, but higher than in South-East Asia and Western Pacific; stroke was higher in Europe and Western Pacific, and lower in Africa, Americas, South-East Asia and Eastern Mediterranean. Studies from Spain and Israel with hospitalized diabetic patients reported a similar 2.0–3.0% incidence of AMI [16, 17].

LLA were significantly higher in Kazakhstan than in any of those regions [18]. LLA has shown incidence ranging from 0.02–2.48% [19–21]. The higher observed incidence of LLA in our study could be associated with high prevalence of risk factors among diabetic patients in Kazakhstan [19], resembling the trends in low- and middle-income countries (LMICs), where the incidence is increasing, possibly due to poor control of vascular risk factors among diabetic patients.

We observed a higher incidence of AMI, stroke and LLA in men [19–26], while mortality was higher in women compared to men [26–28]. Although there is still a gap in explanation of this observation, previously it was found that diabetic women had a higher overall CVD risk at baseline [29], including higher body fat percentage and higher abdominal fat, a factor that is associated with insulin-resistance, but also were less likely to reach recommended levels of low-density lipoprotein (LDL) and cholesterol [30, 31]: men may be treated more intensively [32]. But, there could be other socio-economic factors associated with sex-differences in mortality after macrovascular complications in diabetic patients [33]. Regarding LLA, men could seek less foot care and have a greater risk for development of fool ulcers, which is associated with higher incidence of LLA [20].

The incidence of all macrovascular complications in our study increased with age: factors like a higher presence of comorbidities, obesity, low level of physical activity, hyperglycemia and a longer duration of the disease are risk factors positively associated with CVDs and LLA [34]. Older age has been consistently associated with higher incidence of stroke and AMI [35]. However, fewer studies reported the incidence stratified by age categories for AMI, stroke and LLA [17, 20, 28].

Mortality rates for these complications were almost similar: 29.03% for AMI, 25.16% for stroke and 29.80% for LLA during the follow-up. The 5-year mortality rate due to AMI and stroke in other studies varied between 13.9%-50% [36–40] having been reported to be 62% for LLA [41].

Mortality reflects an increased risk of post-hospitalization mortality [37, 38, 42–44]. Overall, diabetic patients suffering from AMI, stroke or LLA have a significantly higher risk of death during 6 year of follow up [4, 45]. Some differences observed in the estimates from other studies could be partially explained by the diversity of data sources and methodologies applied in each study, by the heterogeneity in the characteristics of study populations, but may also be associated with the variations in care for diabetic patients in different countries.

Strengths and limitations.

Overall, this observational retrospective study has certain strengths. First, we have investigated the incidence of macro-vascular complications using a large database that covered all hospitalization cases with DM from all regions of Kazakhstan. We assume that the findings reflected the real situation of incidence and mortality after those events. To our knowledge, this is the first study in Kazakhstan and Central Asia to utilize such a large database, therefore representing an important contribution to understand the epidemiology of DM-related macrovascular complications in Kazakhstan.

Inevitably, this research has several limitations. Even though this study utilized a representative sample of diabetic patients, some major variables were not available for the analysis, including the type of DM, duration of DM, treatments, laboratory measures or comorbidities, including obesity, or health behaviors such as smoking or alcohol consumption, or lifestyle factors, such as level of physical activity and eating behavior. It is possible that the hospitalized population might be at a more progressed stage of the disease and have been prescribed different medications, which might affect consequent complications. Secondly, we used a probabilistic approach for imputations of missing RpnID, thus, our estimates of incidence could be underestimated. Third, there could be potential misclassification bias as diagnosis of DM and DM-related complications were defined by ICD-9 and ICD-10 codes. Fourth, the mortality rates for AMI and stroke could be underestimated as some cases could be coded with codes for main hospitalization reasons which might not be related to them.

Conclusion

This data demonstrates that patients with DM in Kazakhstan are at high risk of excess mortality if they suffer from macro-vascular complications, AMI, stroke and LLA. More research is required to characterize sub-populations of diabetic patients at higher risk for the incidence of those complications, but it is also important that Kazakhstan continues to improve the quality of care of its healthcare system to provide the integrated care required for managing a complex condition as DM.

Abbreviations

AMI: acute myocardial infarction; LLA: lower limb amputations; DM: diabetes mellitus; CVD: cardiovascular diseases; ICD-10: International Classification of diseases, Tenth Revision; ICD-9: International Classification of Diseases, Ninth Revision; LMICs: low- and middle-income countries; LDL: low-density lipoprotein.

Declarations

Ethics approval and consent to participate

The study was approved by the Institutional Research Ethics Committee (NU IREC #203/29112019).

Consent for publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from Republican Center for Electronic Health of the Ministry of Health of the Republic of Kazakhstan, but restrictions apply to the availability of these data, which were used under the contract-agreement for the current study, and so are not publicly available. Data is however available from the authors upon reasonable request and with permission of Ministry of Health of the Republic of Kazakhstan.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by grants from the Nazarbayev University Faculty Development Research Grant Program 240919FD3913 and 080420FD1916.

Authors' contributions

ASS contributed to conception, study design, data acquisition, analysis, interpretation of the data, literature search, wrote and drafted the first manuscript and provided final approval for the submission. BO, TM contributed to data analysis, interpretation of the data, literature search, wrote and drafted the first manuscript and provided final approval for the submission. AS, NG, AG: Analyzed and interpreted the data; Reviewed the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

Authors’ information

¹Department of Medicine, Nazarbayev University School of Medicine, Nur-Sultan, Kazakhstan. ²Department of Epidemiology, Evidence-Based Medicine and Biostatistics, Kazakhstan Medical University Higher School of Public Health, Almaty, Kazakhstan. ³Department of Medical Information Analysis, Republic Center of Electronic Healthcare, Ministry of Health, Nur-Sultan, Kazakhstan.

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Tables

Table 1. Demographic characteristics of the study population.