Burden of comorbidities among older Malaysians with stroke: Associations with diabetes mellitus and frailty

Background and aims The increasing prevalence of diabetes and the growing population of older people further adds to the complexities of stroke care. This study aimed to describe (1) prevalence of diabetes in older persons with stroke and (2) compare the burden of comorbidities and cardiovascular risk factors among patients with diabetes and frailty compared to those without these conditions. Methods We conducted an analysis of older patients aged ≥ 65 years. Comorbidities were assessed using the Charlson Comorbidity Index (CCI). Frailty assessments were performed using the Clinical Frailty Scale (CFS) version 2. Results A total of 384 participants were included for analysis, mean age of 81.11 ± 6.373. Diabetes was present in 45.1%. The prevalence of frailty was 81.3% in those with diabetes and 70.5% in those without diabetes. The mean CCI was highest for the frail and diabetic group (6.97 ± 1.97). Participants with diabetes also had a signi�cantly higher prevalence of risk factors like hypertension (90.8% versus 74.4%, p <0.001) and cardiovascular disease like ischemic heart disease (27.2% versus 14.8%, p =0.003).


Introduction
Stroke continues to be a major contributor to mortality and disability. 1 Due to the nature of the disease, stroke patients experience loss of brain function that affects motor and cognitive function resulting in disabilities.Recent advancements have allowed improved care resulting in a growing number of stroke survivors. 2These stroke survivors may regain some motor capability depending on recovery. 3Factors in uencing the prognosis of stroke recovery include, age, stroke severity, subtypes of stroke and comorbidities like diabetes. 4,5e prevalence of diabetes has increased considerably over recent decades. 6,7 8This has implications when considering management and prevention strategies for stroke.The high prevalence of diabetes among stroke in-patients speci cally can increase complexities and healthcare utilization.Some studies have reported how diabetes in uences mortality and recurrent stroke, although this is usually limited to the younger population. 9,10th most studies focusing on patients aged less than 65 years 11 , there is currently limited data on inhospital and long-term outcomes for older stroke patients with diabetes.This is partly contributed by the age limit set in some clinical trials. 12The growing number of older people and the fact that age is an irreversible risk factor for stroke, studies in this speci c age group are needed to help guide future care.Especially when age-speci c prevalence rates of diabetes are noted to be growing faster in the older population (≥ 65 years of age) when compared to those younger. 13Research prioritization exercises have also highlighted the lack of evidence to guide care for older people with diabetes and the need for more studies to explore how it relates to other comorbidities. 14,15The additional in uence of frailty on health outcomes for an older person 12,16 further increases the complexity but also shows the necessity for further studies.
Like many other regions, stroke and diabetes are growing public health concerns in Malaysia. 17Malaysia, has one of the highest rates of diabetes in the Western Paci c region. 18For broader stroke management strategies, this is critical as the prevalence of diabetes in hospitalized patients with strokes in Malaysia has been reported to be highest among Southeast Asian and East Asian countries. 8Stroke is also the second major cause of premature mortality among older adults in Malaysia. 19The growth of the older population has overtaken the younger population and it is estimated that the older population will make up almost 20% of the population by 2040. 20The continuous rise of diabetes and the growing ageing population in Malaysia further adds to challenges for broader stroke management. 21In 2016, more than 40% of hospital admissions for stroke in Malaysia were those 65 years and older. 17In this study of Malaysian older patients hospitalised with strokes, we aimed to: (1) describe the prevalence of diabetes and (2) compare the burden of comorbidities and cardiovascular risk factors among patients with diabetes and frailty compared to those without these conditions.

Methods
This study was conducted using data from an observational study on the prevalence of pre-stroke frailty and its impact on outcomes in older patients hospitalised with strokes in Malaysia.Details of this study were published in 2023. 22In brief, patients from Universiti Malaya Medical Centre, a teaching hospital in Kuala Lumpur, Malaysia were included for analysis.The study period was from January 2016 to January 2020.Older patients aged ≥ 65 years admitted to the Geriatric Medicine Unit with acute stroke were eligible for the study.Patients underwent a Comprehensive Geriatric Assessment (CGA) at the point of admission where medical history and functional abilities before their stroke were recorded.Ethics approval was obtained from the Medical Research Ethics Committee of the University Hospital (MEC No: 201312-0636).

Variable de nitions
Comorbidities were assessed using the Charlson Comorbidity Index, (CCI).The CCI is a widely used index and is considered to be the gold standard measure in predicting patient survivability in patients with multiple comorbidities in clinical research. 23rticipants' history of cardiovascular disease was collected using a prede ned list of eight conditions, namely hypertension, previous stroke/transient ischemic attack, dyslipidaemia, chronic kidney disease (eGFR < 60mL/min), atrial brillation, ischemic heart disease, congestive heart failure and peripheral vascular disease.
Participants' frailty status before their admission with stroke was assessed using the Clinical Frailty Scale (CFS) version 2. The CFS is a 9-point scale that can be used to summarize the level of frailty in an older person. 24,25,26The CFS score ranges from 1-9, and a score of 4 or greater indicates a frailty status. 25,27Brie y, scoring were as follows: 1 -very t, 2 -well, 3 -managing well, 4 -living with very mild frailty, 5-living with mild frailty, 6-living with moderate frailty, 7-living with severe frailty, 8-living with very severe frailty, 9-terminally ill.For this study, the frail category includes CFS 4-8 and the non-frail category includes CFS 1-3.CFS 9 was excluded as it describes patients with limited life expectancy.

Statistical analysis
Data analysis was conducted using IBM SPSS Statistics version 26.0 (IBM Corp, Armonk, NY, USA).
Comparisons between participants with and without diabetes were conducted using independent samples t-test for continuous variables and Chi-square tests or Fisher's exact tests for categorical variables.P-value < 0.05 was deemed signi cant.
Participants were also classi ed into 4 groups according to their frailty status and whether they had diabetes or not: Group 1 -frail and diabetic, Group 2 -non-frail and diabetic, Group 3 -frail and nondiabetic, and Group 4 -non-frail and non-diabetic.Comparisons among these 4 groups were assessed using Chi-square tests or Fisher's exact tests for categorical variables, and ANOVA test for continuous variables.Two-tailed P values < 0.05 were deemed statistically signi cant.

Results
A total of 384 participants were included in our study.They had a mean age of 81.11 (SD 6.373), and 57% were female.A diagnosis of diabetes was recorded in 45.1% of the participants (173/384).compared to 81.95 ± 6.18, respectively, p = 0.004).Age distribution of the participants is presented in Fig. 1.
The distribution of the Clinical Frailty Scale score in participants with and without diabetes is present in Fig. 2. Using the cut-off point of 4, the prevalence of frailty was 75.3% in all participants, 81.3% in those with diabetes and 70.5% in those without diabetes (p = 0.015).

The burden of comorbidities among 384 participants
The mean Charlson Comorbidity Index was 5.97 ± 2.05 in all participants.Compared to participants without diabetes, participants with diabetes had a higher Charlson Comorbidity Index (6.82 ± 2.02 versus 5.28 ± 1.80, p < 0.001).
Among 384 participants with strokes, 139 (36%) were classi ed into Group 1 -frail and diabetic, 32 (8%) were classi ed into Group 2 -non-frail and diabetic, 148 (39%) were classi ed into Group 3 -frail and non-diabetic, and 62 (16%) were classi ed into Group 4 -non-frail and non-diabetic.When comparing the four groups of frailty-diabetes, participants with diabetes and frailty had the highest comorbidity burden, as shown with the highest Charlson Comorbidity Index mean score in Fig. 3.The mean CCI was for the frail and diabetic group was 6.97 ± 1.97, followed by non-frail and diabetic, 6.00 ± 2.02, frail and non-diabetic, 5.49 ± 1.79, and non-frail and non-diabetic, 4.74 ± 1.68.
The cardiovascular risk factors and disease burden across the four groups of frailty-diabetes are presented in Fig. 4. Across the four groups, hypertension was the most prevalent.Frail participants (with or without diabetes) had a higher prevalence of previous stroke/TIA, while ischemic heart disease was most prevalent in the non-frail and diabetic groups.

Discussion
In this study in 384 older Malaysian admitted to hospital due to strokes, we found a high prevalence of diabetes (45.1%) among patients with strokes.Patients with diabetes had a higher burden of frailty, higher Charlson Comorbidity Index score, cardiovascular risk factors such as hypertension and CKD, and disease burden such as IHD and heart failure, and were at a younger age at the time of stroke.More than one-third (36%) of the patients had both diabetes and frailty.
The prevalence of diabetes in stroke inpatients in our study was higher compared to other countries in the Southeast Asian region.The mean age of our study participants is 81 years of age.9][30][31][32] Analysis from the National Neurology Registry for Acute Stroke in Malaysia showed estimates of diabetes prevalence ranged from 24.9-53.3% depending on rst or recurrent stroke across ischemic and haemorrhagic stroke. 33Studies in neighbouring countries such as Thailand, Indonesia and Singapore have reported prevalence ranging from 17.1-38.5%. 4,28,291][32] In a study of 208 stroke patients in a hospital in the city of Yogyakarta, Indonesia, the prevalence of diabetes was found to be 34.1% with common comorbidities including hypertension, dyslipidaemia and cardiac diseases like atrial brillation. 4In another analysis of 9766 patients across 3 hospitals in Singapore, the prevalence of diabetes in stroke inpatients was found to be 38.5%. 28With diabetes in uencing stroke prevalence and outcomes, countries like Malaysia, Indonesia and Singapore face similar challenges in managing the growing impact of non-communicable diseases like diabetes.
Older people in Malaysia were more than 10 times more likely to have diabetes compared to younger people. 18There is growing evidence of the association of diabetes with frailty in the older population. 34n a study among community-dwelling older adults in Malaysia, the prevalence of frailty was found to be 18.3% and the top 2 comorbidities associated were diabetes and hypertension. 35With the growing population of older people in Malaysia, there is a need to have routine frailty assessments when providing care for older persons with diabetes.Evidence-based interventions can be tailored to the different frailty groups.
Research on the role of frailty in stroke outcomes is still growing.In a study of 433 individuals with ischaemic stroke, the 28-day mortality was noted to be higher in frail participants compared to non-frail participants. 36A separate study also reported higher one-year mortality in frail participants. 22In another study of 530 patients in China, it was found that frailty was an independent risk factor for one-year allcause mortality among older stroke patients. 37A systematic review and meta-analysis described how the prevalence of frailty in acute stroke ranged from 2.2-54%, with outcomes inconsistently reported. 38udies that met inclusion criteria appeared to be mainly from higher-income countries although the methodology was designed to be inclusive and global. 38Age being an irreversible risk factor for stroke highlights the need for studies in the older population, especially in low to middle-income countries such as Malaysia.
In patients with diabetes, frailty was found to be associated with an increased risk of all-cause mortality, cardiovascular-related mortality, major adverse cardiovascular events and hypoglycaemia. 39It does highlight the need for frailty assessment and management to be incorporated into routine diabetes care.
The results of our analysis demonstrate a signi cant association between diabetes and increased frailty among older people with stroke.This aligns with previous studies that have further described the link between diabetes and frailty. 40The presence of diabetes appears to in uence frailty potentially due to metabolic and in ammatory interactions which may exacerbate age-related decline in physiological reserves.The accelerated pace of muscle wastage, decreased physical function and heightened vulnerability to stressors in individuals with diabetes could contribute to the increased likelihood of a stroke attack.
Our ndings highlight the compounded cardiovascular disease burden in older stroke survivors with diabetes and frailty.This is also similar to another study in an Egyptian population. 41The synergistic relationship between diabetes and cardiovascular disease burden has been extensively documented with diabetes serving as a signi cant risk factor for the development and progression of cardiovascular complications.In the context of stroke survivors, diabetes may also exacerbate underlying vascular damage, leading to greater impairment in vascular integrity and contributing to recurrent cardiovascular events.The increased prevalence of comorbidities such as hypertension, IHD, CCF, PVD, dyslipidaemia, cerebrovascular disease (including TIA) and chronic kidney disease observed in individuals with diabetes could further contribute to the ampli ed cardiovascular disease burden observed in our study population.
Clinical implications of our ndings underscore the need for tailored interventions and management strategies for older stroke survivors with diabetes.Furthermore, goals of treatment differ in people with varying levels of frailty, with many not tolerating the usual targets of treatment at the higher frailty levels.The integration of multidisciplinary approaches, encompassing medical management, lifestyle modi cations and rehabilitative interventions becomes imperative in addressing the intertwined challenges of frailty and cardiovascular disease burden.Optimizing appropriate glycaemic control and managing cardiovascular risk factors through appropriate pharmacological and lifestyle interventions could help reduce the adverse outcomes associated with diabetes in this population.This is more relevant as control rates for diabetes in the older population in Malaysia were reported to be low (21.8%) 42in comparison with neighbouring countries like Thailand reporting higher rates (26.4%). 43reover, the ndings emphasize the importance of early identi cation and screening for diabetes and frailty in the older population.Timely diagnosis and management of diabetes could potentially mitigate the progression of frailty and help reduce the impact of stroke.Routine comprehensive geriatric assessment that incorporates frailty assessment and cardiovascular risk assessment should be further encouraged even in non-routine settings.This can aid in identifying high-risk individuals who may bene t from early targeted interventions.

Strengths and limitations
Our study ndings provide insights into the complex interplay between diabetes, frailty, and comorbidities, particularly cardiovascular health, and further shed light on the multifaceted challenges in this vulnerable population.It also highlights the critical need for diabetes management particularly with the high prevalence of diabetes reported in Malaysia.Our study was conducted in a very old population in Malaysia and contributed to the evidence on the epidemiology of stroke, diabetes and comorbidities in low-and middle-income countries.
However, our study was a single-site study and results may not be generalisable to other health settings.The cross-sectional design prevents any establishment of a causal relationship between diabetes, frailty and cardiovascular disease burden.Future prospective studies with larger sample sizes and longitudinal follow-up can help to elucidate the temporal relationships and mechanisms underlying the observed associations.Although our study did not explore the in uence of diabetes on the likelihood of stroke, it does describe the higher prevalence of frailty and cardiovascular comorbidities burden in those with diabetes.The results of our analysis do provide an opportunity for this area to be further explored and its in uence on the management of post-stroke outcomes.

Conclusion
There was a very high prevalence of diabetes in older patients with stroke in this study.This study provides further evidence of the intricate interplay between diabetes, frailty and comorbidity burden in older individuals with stroke.Besides the management of diabetes, frailty and cardiovascular risk factors are potential target areas that healthcare providers can strive to address to enhance the overall wellbeing and quality of life for older stroke survivors with diabetes.Cardiovascular risk factors and disease burden across the four frailty-diabetes groups (*p-value<0.05)

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Figure 4

Table 1
Compared to participants without diabetes, those with diabetes were younger (mean age 80.09 ± 6.47