Diabetes distress, the mediator of the poor glycemic control and depression: A meta-analysis

Abstract

BACKGROUND

Diabetes-related distress (DRD) is a common psychological disorder specifically associated with diabetes, its cross-talk with depression, and glycated hemoglobin (HbA1c) was discussed controversially. Interventions addressing DRD were shown to improve HbA1c. However, the primary concern is to investigate the association of DRD with glycemic control. No meta-analyses have compared the effects of depression and diabetes distress on HbA1c.

AIM

To assess the relationship between DRD, depression, and glycemic control.

METHODS

We systematically searched PubMed MEDLINE, Google Scholar, and Cochrane Library from inception up to May 2024. The keywords diabetes distress, depression, psychopathology, glycemic control, HbA1c, glycated hemoglobin, fasting, and postprandial blood glucose were used. A datasheet was used to extract the author’s name year and country of publication, diabetes distress, depression, and HbA1c among patients with DRD, depression, and control subjects.

RESULTS

Out of the 2046 studies retrieved, 55 full texts were screened and 22 studies were included in the final meta-analysis. Diabetes distress was associated with poor glycemic control, odd ratio = 0.42, 95% confidence interval (CI): 0.17-0.67, and P value < 0.001, and odd ratio = 0.52, 95%CI: 0.38-0.72, and P value < 0.001 respectively. No significant difference was observed between depression and DRD regarding the impact on HbA1c, odd ratio = 0.13, 95%CI: 0.15-0.41, P value = 0.37, I² for heterogeneity = 76%. However, when heterogeneity was eliminated, diabetes distress influenced the HbA1c more compared to depression, odd ratio = 0.29, 95%CI: 0.17-0.41, and P value < 0.001.

CONCLUSION

DRD negatively influenced the HbA1c and glycemic control more than depression. Further studies using more specific measures (ecological momentary assessment) to assess DRD are recommended.

Key Words: Diabetes-related distress; Depression; Glycemic control; Glycated hemoglobin; Diabetes

Core Tip: Literature on the effects of diabetes distress is scarce, the available meta-analyses focused on interventions to tackle diabetes (to improve glycemic control) distress instead of investigating the direct influence of diabetes distress on the same. However, the association of depression with glycemic control was touched before. However, this is the first meta-analysis to compare the effects of diabetes distress and depression on glycated hemoglobin (HbA1c). We found an association between diabetes distress, depression, and HbA1c with a higher impact of distress arm compared to depression. Due to the overlap between the symptoms of diabetes distress and depression, diabetes distress could mediate the association between depression and HbA1c. Although the reverse could be true, diabetes distress is commoner than depression. The current findings challenged the scientific community and recommended screening for both diabetes distress and depression among patients with diabetes mellitus and poor glycemic control. In addition, we suggested future studies using continuous glucose monitoring and ecological momentary assessment to evaluate the association of diabetes distress, depression, and glycemic control.

INTRODUCTION

Diabetes mellitus is a chronic disabling disease with lethal complications; the disease is approaching an epidemic and is rapidly spreading with 463 million people suffering from it in the year 2017, this number is projected to be 700 million by 2045. Diabetes management is complex, time-consuming, and distressful to the patients[1,2]. Because of this, nearly 40% of patients with type 2 diabetes experience psychological problems including diabetes distress, anxiety, and depression[3]. Diabetes-related distress (DRD) is a psychological reaction (negative) among people living with diabetes and is special to diabetes rather than other psychological diseases[4]. DRD is common and nearly half of patients with diabetes are affected with negative influence on the patient’s emotion and quality of life. Importantly, DRD is usually undiagnosed despite its high prevalence and negative effects on diabetes management[5]. The association between diabetes distress, glycemic control, and microvascular complications was discussed controversially, some studies found an association, while others found no relationship[6,7]. However, DRD’s negative effects on diabetes self-care, medication adherence, diabetes severity, and burden were documented. Non-compliance to diabetes medications and diabetes distress were indirectly correlated and might influence diabetes self-management[8,9]. The debate observed in the relationship between diabetes distress and diabetes outcomes could be explained in part by the overlap between diabetes distress and depression, both conditions are highly prevalent among patients with diabetes[10].

Depression affects one in five patients with diabetes and is associated with poor glycemic control, depression is closely related to diabetes distress and could mediate the poor glycemic control observed among distressed patients with diabetes, but the cross-talk between diabetes distress and depression is controversial and literature on this important medical issue scarce[11].

Importantly, diabetes distress might initiate a vicious cycle of increasing diabetes severity, more complex diabetes therapy, polypharmacy, depression, and hence more diabetes distress[12,13]. Surprisingly, most of the recent reviews focused on interventions to mitigate DRD to improve glycemic control[14,15], while the logical first step is to assess the rationale behind the intervention which is the effect of diabetes distress on glycated hemoglobin (HbA1c). To the best of our knowledge, few studies have assessed the effects of DRD on glycemic control and no meta-analysis has compared diabetes distress and depression effects on the HbA1c. Thus, we aimed to assess the effects of DRD on glycemic control and to compare its influence on HbA1c with that of depression.

MATERIALS AND METHODS

Eligibility criteria according to population, intervention, comparison, outcomes and study

We conducted this systematic review with great adherence to the PRISMA guidelines during March and April 2024 to assess and compare the effects of DRD on glycemic control among patients with diabetes.

Inclusion and exclusion criteria

Studies were included if they were retrospective studies, prospective cohorts, cross-sectional studies, and case-control studies. Case series, editorials, opinions, protocols with no results, and editorials were excluded. The effect of depression on glycemic control was extensively touched before[16-19]; therefore, studies assessing the same were not included in the present meta-analysis.

Outcome measures

To assess diabetes distress and depression effects on glycemic control, and HbA1c. To compare the effects of diabetes distress and depression on glycemic control, no tests were specified for the diagnosis of depression and diabetes distress.

Literature search and data extraction

A systematic literature search was conducted in PubMed MEDLINE, Cochrane Library, and Google Scholar from the date of the first inception up to April 2024. The reviewer searched the databases for relevant articles. The keywords diabetes distress, depression, psychopathology, glycemic control, HbA1c, glycated hemoglobin, fasting blood glucose, and postprandial blood glucose were used. In addition, the references of the included studies were screened for relevant articles. We identified 2046 studies, and 1838 stands after the removal of duplication, from them, 55 full texts were screened, and only 22 studies were included in the final meta-analysis. A datasheet was used to extract the author’s name year and country of publication, diabetes distress, depression, HbA1c, age, body mass index, and duration of diabetes (Table 1, Table 2, Table 3, Figure 1, Figure 2, Figure 3A-C and Figure 4).

Figure 1  Studies on the effects of diabetes distress and depression on glycemic control and glycated hemoglobin.

Figure 2 The glycated hemoglobin among patients with and without diabetes distress (Forest and Funnel plots). CI: Confidence interval.

Figure 3 Forest plots. A: The glycated hemoglobin among patients with and without diabetes distress after sensitivity analysis; B: Glycemic control among patients with and without diabetes distress (results in numbers of glycemic control); C: Glycemic control among patients with and without diabetes distress (results in numbers of glycemic control after addressing the heterogeneity); D: The glycated hemoglobin among patients with diabetes distress and depression after addressing the heterogeneity. CI: Confidence interval.

Figure 4  The glycated hemoglobin among patients with diabetes distress and depression (Forest and Funnel plots).

Table 1 Glycated hemoglobin among patients with diabetes distress and control subjects, mean ± SD.

Ref.	Country	Study type	Diabetes distress HbA1c	Total number	Controls HbA1c	Total number	Results
Al-Ozairi et al[21]	Kuwait	Cross-sectional	9.2 ± 3.5	69	8.4 ± 2.49	396	Sig.
Alzughbi et al[22]	Saudi Arabia	Cross-sectional	9.4 ± 1.7	67	8.7 ± 1.7	233	Sig.
Ascher-Svanum et al[23]	Five European countries	Prospective	9.91 ± 2.09	289	9.39 ± 1.97	677	Sig.
Asuzu et al[24]	United States	Cross-sectional	7.9 ± 1.8	615	8.66 ± 1.8	615	Not sig.
Chen et al[25]	Taiwan	Cross-sectional	10.98 + 7.56	255	10.39 + 2.09	255	Not sig.
Cummings et al[26]	United States	Prospective	9.4 ± 0.3	45	8.8 ± 0.2	84	Sig.
Davis et al[27]	Australia	Prospective	6.87 ± 0.7	435	7.6 ± 0.8	93	Sig.
Guo et al[28]	Singapore	Cross-sectional	9.7 ± 1.4	62	9.4 ± 1.5	294	Not sig.
Hayashino et al[29]	Japan	Retrospective	7.9 ± 1.4	371	7.5 ± 1.1	2747	Not sig.
Ismail et al[30]	United Kingdom	Prospective	7.20 ± 1.61	111	6.98 ± 1.40	1540	Sig.
Khan and Choudhary[31]	United Kingdom	Cross-sectional	8.7 ± 1.8	24	7.7 ± 0.9	59	Sig.
Matsuba et al[32]	Three Asian countries	Cross-sectional	8.68 ± 1.63	671	7.77 ± 1.63	671	Sig.
Nguyen et al[33]	Vietnam	Cross-sectional	7.7 ± 1.4	14	7.1 ± 1.5	98	Sig.
Pandit et al[12]	United States	Prospective	9.3 ± 2.0	94	7.8 ± 1.7	391	Sig.
Park et al[34]	Korea	Retrospective	7.27 ± 0.7	589	6.97 ± 0.6	1293	Sig.
Schmitt et al[35]	Germany	Cross-sectional	8.8 ± 1.5	42	8.6 ± 1.7	221	Not sig.
Sidhu and Tang[36]	Canada	Cross-sectional	7.0 ± 0.9	20	7.0 ± 1.1	19	Not sig.
Totesora et al[37]	Philippines	Cross-sectional	9.0 ± 2.5	40	7.7 ± 1.7	47	Sig.

HbA1c: Glycated hemoglobin; Sig.: Significant.

Table 2 Diabetes distress effects on glycemic control.

Ref.	Country	Study type	Diabetes distress glycemic control	Total number	Controls, glycemic control	Total number	Results
Bhaskara et al[38]	Indonesia	Cross-sectional	53	75	19	49	Sig.
Huynh et al[39]	Vietnam	Cross-sectional	118	152	236	365	Sig.
Lim et al[40]	Singapore	Cross-sectional	58	146	91	379	Sig.
Sasi et al[41]	India	Cross-sectional	144	270	126	270	Sig.
Totesora et al[37]	Philippines	Cross-sectional	28	40	27	47	Sig.

Sig.: Significant.

Table 3 Diabetes distress and depression effects on glycemic control, mean ± SD.

Ref.	Country	Study type	Diabetes distress HbA1c	Total number	Depression HbA1c	Total number	Results
Al-Ozairi et al[21]	Kuwait	Cross-sectional	9.2 ± 3.5	69	8.7 ± 2	44	Sig.
Ascher-Svanum et al[23]	United States	Prospective	9.91 ± 2.09	289	9.62 ± 2.02	485	Not sig.
Davis et al[27]	Australia	Prospective	6.87 ± 0.7	435	7.5 ± 1.28	50	Sig.
Hayashino et al[29]	Japan	Retrospective	7.9 ± 1.4	371	7.6 ± 1.2	862	Sig.
Ismail et al[30]	United Kingdom	Prospective	7.20 ± 1.61	111	7.11 ± 1.37	232	Not sig.
Nanayakkara et al[13]	Australia	Retrospective	9.3 ± 2.1	177	8.85 ± 2.0	698	Sig.
Sidhu and Tang[36]	Canada	Cross-sectional	7.0 ± 0.9	21	7.0 ± 0.9	6	Not sig.

HbA1c: Glycated hemoglobin; Sig.: Significant.

Risk of bias assessment

The Newcastle Ottawa scale[20] was used to assess the quality of the included studies. All the included studies are of good quality (Table 4).

Table 4 The risk of bias assessment and questionnaires used to assess diabetes distress and depression among patients with diabetes.

Ref.	Questionnaires used	Selection bias	Comparability bias	Outcome	Total score
Al-Ozairi et al[21]	The PAID, patient health questionnaire-9	5	1	2	8
Alzughbi et al[22]	The 17-item diabetes distress scale and the patient health questionnaire-9	5	1	2	8
Ascher-Svanum et al[23]	Severity of depressed/anxious mood (EuroQol-5D item) and diabetes-related distress (psychological distress domain of the diabetes health profile-18)	4	2	3	9
Asuzu et al[24]	The 17-item diabetes distress scale, and patient health questionnaire	5	2	2	9
Chen et al[25]	The short-form problem areas in diabetes scale, psychological factors questionnaire	4	1	2	7
Cummings et al[26]	The 17-item diabetes distress scale	4	2	3	9
Davis et al[27]	The PAID, patient health questionnaire-9	4	2	3	9
Guo et al[28]	The PAID, patient health questionnaire-9	4	1	3	8
Hayashino et al[29]	The PAID questionnaire, center for epidemiological studies-depression	4	2	3	9
Ismail et al[30]	The patient health questionnaire-9 and PAID scores	4	2	3	9
Khan and Choudhary[31]	Diabetes distress scale-2	5	1	2	8
Matsuba et al[32]	Diabetes distress scale-25-item	5	1	2	8
Nguyen et al[33]	The 17-item diabetes distress scale	5	1	1	8
Pandit et al[12]	The 17-item diabetes distress scale	5	2	2	9
Park et al[34]	The problem areas in diabetes scale	5	1	2	8
Schmitt et al[35]	Center for epidemiologic studies depression scale, diabetes distress scale	5	1	2	8
Sidhu and Tang[36]	Diabetes distress scale, patient health questionnaire-9	5	1	2	8
Totesora et al[37]	PAID-20	5	1	2	8
Bhaskara et al[38]	Diabetes distress scale	5	1	2	8
Huynh et al[39]	Diabetes distress scale	5	1	2	8
Lim et al[40]	The problem area in diabetes
Sasi et al[41]	Diabetes distress scale	5	1	2	8

PAID: Problem areas in diabetes.

Glycemic control definition

The HbA1c was used to measure glycemic control; some studies provide the number of patients with good glycemic control and do not provide the details of HbA1c and blood glucose levels.

Diabetes distress and depression evaluation

The problem areas in diabetes, diabetes distress scale were used for the diagnosis of diabetes distress, while the patient health questionnaire-9, center for epidemiologic studies depression scale, psychological factors questionnaire, and severity of depressed/anxious mood [EuroQol (EQ)-5D item] were used for the diagnosis of depression (Table 4).

Diabetes distress was assessed by different-items problem areas in diabetes scale in references, while the different-items diabetes distress scale was used in references, and depression was evaluated by the patient health questionnaire-9, severity of depressed/anxious mood [EuroQol (EQ)-5D item] questionnaire, psychological factors questionnaire, and center for epidemiological studies-depression questionnaire.

Statistical analysis

The data were analyzed by the most recent version of the RevMan system (5.4.1 United Kingdom). We pooled 30 cohorts to assess the effects of diabetes distress on glycemic control and HbA1c, of them 18 studies assessed the effects on HbA1c, five assessed glycemic control, and seven compared depression and diabetes distress regarding glycemic control. The dichotomous and continuous date data were entered manually and the fixed effect was used in the sub-analyses in Figure 3A, Figure 3C and D to address heterogeneity, while the random effect was applied when the heterogeneity was significant, Figure 2, Figure 3B, and Figure 4. A P value of < 0.05 was considered significant.

RESULTS

Characteristics of the included studies

Out of the twenty-two studies included[12,21-41], five were prospective, two were retrospective studies, and fifteen were cross-sectional, fourteen studies were conducted in Asia, four from Europe, three from the United States, and one from Canada.

In the present meta-analysis, twenty-two studies were included (13519 patients with diabetes). The HbA1c was lower among patients without diabetes distress, odd ratio = 0.42, 95% confidence interval (CI): 0.17-0.67, χ² = 269.31, and P value = 0.001. Substantial heterogeneity was observed, I² for heterogeneity = 95%, P value for heterogeneity < 0.001 (Figure 2).

The negative effect of diabetes distress was maintained after the most possible elimination of heterogeneity, odd ratio = 0.39, 95%CI: 0.28-0.50, χ² = 17.18, and P value < 0.001, I² for heterogeneity = 30%, P value for heterogeneity = 0.14 (Figure 3A).

Five studies[37-41] assessed glycemic control collectively (only numbers were provided) and found poor glycemic control among patients with diabetes distress, odd ratio = 0.52, 95%CI: 0.38-0.72, χ² = 8.25, and P value < 0.001. No significant heterogeneity was observed, I² for heterogeneity = 52%, P value for heterogeneity = 0.08, and SD = 4 (Figure 3B). A sub-analysis to address heterogeneity was conducted, odd ratio = 0.46, 95%CI: 0.35-0.60, χ² = 2.72, and P value < 0.001. No significant heterogeneity was observed, I² for heterogeneity = 0%, P value for heterogeneity = 0.44, and SD = 4 (Figure 3C).

The relationship between diabetes distress, depression, and HbA1c showed contradicting results; seven studies[21,23,25,27,29,30,37] compared the effects of depression and diabetes distress (3850 patients with diabetes) and indicated no difference regarding their influence of the HbA1c, odd ratio = 0.13, 95%CI: 0.15-0.41, χ² = 25.09, and P value = 0.37. A significant heterogeneity was observed, I² for heterogeneity = 76%, P value for heterogeneity = 0.0003 (Figure 4). However, the results differ when heterogeneity was eliminated (6 studies remained with 3365 patients), diabetes distress negatively impacted the HbA1c substantially compared to depression, odd ratio = 0.29, 95%CI: 0.17-0.41, χ² = 2.77, and P value < 0.001 (Figure 3D).

DISCUSSION

In the current meta-analysis, DRD was associated with higher HbA1c and poor glycemic control, odd ratio = 0.46, 95%CI: 0.26-0.66, and odd ratio = 0.52, 95%CI: 0.38-0.72 respectively. When comparing the effects of DRD and depression on the HbA1c; no significant statistical difference was found, odd ratio = 0.13, 95%CI: 0.15-0.41, the significant heterogeneity (I² for heterogeneity = 76%), limited the above findings. Interestingly diabetes distress showed more negative effects on HbA1c compared to depression following a sub-analysis to eliminate the heterogeneity, odd ratio = 0.29, 95%CI: 0.17-0.41.

The above results imply that diabetes distress screening is vital for better glycemic control and lower rates of diabetes microvascular disease. On the other hand, diabetes distress is linked to fear of hypoglycemia. In addition, patients with diabetes distress and depression were more likely to have severe hypoglycemia than patients with diabetes distress alone[42-44]. Therefore, DRD is associated with fluctuating blood glucose with deleterious consequences. There is a piece of evidence suggesting the association between within-day and between-days glucose variability, oxidative stress, and diabetes complication[45], and Chen et al[46] found an association between glucose variability and mortality among acute coronary syndrome patients. Surprisingly, physicians usually ignore diabetes distress and do not frequently discuss it with the patients[47].

An interesting study found that people with persistently poor glycemic control had lower DRD than their counterparts with good glycemic status[48]. Therefore, psychological problems in interaction with blood glucose among patients with diabetes are complex and multidirectional. Some patients with diabetes might keep their blood glucose high to avoid hypoglycemia, thus, less attention is paid to diabetes care and they develop less DRD. Further explanations could be in the fact that hypoglycemia is not considered as a continuum of blood glucose and glycemic control is not interpreted in the light of clinical scenario[49,50].

Ehrmann and colleagues in their secondary analysis of the HypoDE Study found that contiguous glucose monitoring was an effective measure to improve glycemic control with no significant effect on diabetes distress[51]. A plausible explanation for the above findings might be living with a chronic disease seems to be more important than glycemic status at least in some. More explanation might be the reliance on HbA1c to assess the glycemic control because HbA1c retrospectively assesses mean serum glucose during the past 8-12 weeks. In contrast, continuous glucose monitoring provides more details including hypoglycemia and time in the range[52-54].

Depression, which is common among patients with diabetes, could play an important role in the effects of diabetes distress and glycemic control. Previous evidence suggested that diabetes distress mediated the poor glycemic control observed among patients with depression[55]; further studies showed that patients with diabetes distress and diabetes complications had higher rates of depression than their counterparts with distress or diabetes complications alone. However, the conclusion depends on observational studies[56,57]. This meta-analysis could potentially be the first to compare the effects of depression and diabetes distress on glycemic control and confirm the above observation. We found a greater influence on DRD compared to depression. Because DRD is commoner than depression, physicians might need to screen patients with diabetes and target diabetes distress to avoid microvascular complications. Our findings may improve the quality of diabetes care by shedding light on the significance of screening patients with diabetes for distress and depression. The current conclusion calls for collaboration with psychiatrists and psychologists for better outcomes in the face of the diabetes surge.

The strength of this meta-analysis is that it is the first to compare the effects of diabetes distress and depression on glycemic control. In addition, an updated view of diabetes distress’s influence on glycemic control was provided. However, the high heterogeneity observed limited this study. In addition, DRD and depression diagnoses were based on questionnaires that were more prone to subjectivity.

The use of a questionnaire for the diagnosis of depression and diabetes distress

The use of questionnaires as measures of diabetes distress and depression inappropriately reflects the current situation and context. Questionnaires are prone to bias and give retrospective information irrespective of the frequency and duration of psychological distress[58,59]. Traditional questionnaires are shortcomings and cannot mirror the day-to-day variation of diabetes distress; ecological momentary assessment via smartphone can overcome the limitations of traditional questionnaires and reflect the extent and severity of diabetes distress[60]. The ecological momentary assessment reflects the varying degrees of DRD and diabetes burden contextually in contrast to the stable (trait-like) questionnaire evaluation. Therefore, combining ecological momentary assessment and continuous glucose monitoring reflects the real world of the psychological status of patients living with diabetes, and allows for an individualized approach[61,62]. Selecting which aspect of glycemic status (hyperglycemia, hypoglycemia, and glucose variability) is associated with diabetes distress is vital.

CONCLUSION

Diabetes distress was associated with poor glycemic control and higher HbA1c. Diabetes distress had a higher impact on glycemic control compared to depression. Physicians might need to screen for both depression and diabetes distress among patients with poor glycemic control. Further studies applying continuous glucose monitoring and ecological momentary assessment are needed to evaluate the association of diabetes distress, depression, and glycemic control. Future studies could also assess the overlap between depression symptoms and those of diabetes distress.

ACKNOWLEDGEMENTS

We would like to acknowledge Dr. Farah I, Biostatistician, Faculty of Science, Tabuk, Saudi Arabia for data analysis.