7.

Systematic Review

Efficacy of eHealth Interventions for

Adults with Diabetes: A Systematic
Review and Meta-Analysis

Giulia Bassi, Elisa Mancinelli, Gaia Dell’Arciprete, Silvia Rizzi, Silvia Gabrielli and Silvia Salcuni

https://doi.org/10.3390/ijerph18178982
 International Journal of
Environmental Research
and Public Health

Systematic Review
Efficacy of eHealth Interventions for Adults with Diabetes: A
Systematic Review and Meta-Analysis
Giulia Bassi 1,2 , Elisa Mancinelli 1, * , Gaia Dell’Arciprete 1 , Silvia Rizzi 2 , Silvia Gabrielli 2
and Silvia Salcuni 1

1 Department of Developmental and Socialization Psychology, University of Padova, Via Venezia 8,

35131 Padova, Italy; [email protected] (G.B.); [email protected] (G.D.);
[email protected] (S.S.)
2 Digital Health Lab, Centre for Digital Health and Wellbeing, Fondazione Bruno Kessler, Trento,
Via Sommarive 18, 38123 Povo, Italy; [email protected] (S.R.); [email protected] (S.G.)
* Correspondence: [email protected]

Abstract: The aim is to provide meta-analytical evidence on eHealth interventions’ efficacy in support-
ing the psychosocial and physical well-being of adults with type 1 or type 2 Diabetes Mellitus (DM),
and to investigate differences in interventions primarily targeted at providing glycemic control vs.
psychosocial support. A PRISMA-guided systematic search was conducted. Randomized Controlled
Trials (RCTs) regarding eHealth interventions for adults (18–65 years) with DM were included. Data
were pooled using Standard Mean Difference (SMD); sub-group analysis and meta-regressions were
performed when appropriate. Outcomes were Hemoglobin A1c (HbA1c), diabetes distress, quality
of life, anxiety, stress, and depression. Intervention acceptability was assessed performing the Odds





 Ratio (OR) of drop-out rates. Thirteen RCTs comprising 1315 participants were included (52.09% fe-
males; Mage = 46.18, SD = 9.98). Analyses showed intervention efficacy on HbA1c (SMD = −0.40;
Citation: Bassi, G.; Mancinelli, E.;
Dell’Arciprete, G.; Rizzi, S.; Gabrielli,
95% CI = −0.70, −0.12; k = 13) and depressive symptoms (SMD = −0.18; 95% CI = −0.33, −0.02;
S.; Salcuni, S. Efficacy of eHealth k = 6) at RCTs endpoint and were well accepted (OR = 1.43; 95% CI = 0.72, 2.81; k = 10). However,
Interventions for Adults with efficacy on HbA1c was not maintained at follow-up (SMD = −0.13; 95% CI = −0.31, 0.05; k = 6).
Diabetes: A Systematic Review and eHealth interventions providing medical support were acceptable and effective in fostering glycemic
Meta-Analysis. Int. J. Environ. Res. control and decreasing depressive symptoms in the short-term only. Digital solutions should be
Public Health 2021, 18, 8982. https:// developed on multiple levels to fully support the psychophysical well-being of people with DM.
doi.org/10.3390/ijerph18178982

Keywords: diabetes mellitus; eHealth; psychosocial factors; HbA1c; meta-analysis

Academic Editor: Paul B. Tchounwou

Received: 22 July 2021

Accepted: 25 August 2021
1. Introduction
Published: 26 August 2021
Diabetes Mellitus (DM) is a chronic metabolic disease, which has a significant impact
Publisher’s Note: MDPI stays neutral
on issues related to clinical, social, and economic factors, as well as on people’s quality
with regard to jurisdictional claims in
of life, thereby leading to increased morbidity and mortality [1,2]. In particular, Type 1
published maps and institutional affil- DM (T1DM), once referred to as juvenile diabetes or insulin-dependent diabetes mellitus,
iations. is a chronic autoimmune condition in which the pancreas is not able to produce enough
insulin due to the loss of beta cells [2]. On the other hand, the most common form is Type 2
DM (T2DM), once referred to as adult-onset diabetes or non-insulin-dependent diabetes
mellitus, which occurs when the body becomes resistant to insulin, namely when cells fail to
Copyright: © 2021 by the authors.
respond to insulin properly [2]. The World Health Organization (WHO) estimated that the
Licensee MDPI, Basel, Switzerland.
global prevalence of DM was at 8.5% among adults of 18 years and above, and 422 million
This article is an open access article
adults were living with DM, compared to 108 million in 1980 [3]. The WHO further reports
distributed under the terms and that deaths from diabetes increased by 70% worldwide between 2000 and 2019, with
conditions of the Creative Commons mortality rates being greater among males as compared to females, cross-culturally and
Attribution (CC BY) license (https:// independently of age [4].
creativecommons.org/licenses/by/ Most studies have found evidence that diabetes and its complications can be prevented
4.0/). by introducing healthier lifestyle changes [5]. Psychosocial factors have an impact on

Int. J. Environ. Res. Public Health 2021, 18, 8982. https://doi.org/10.3390/ijerph18178982 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2021, 18, 8982 2 of 17

quality of life and often influence chronic disease outcomes; for this reason, the healthy
coping construct was included, in line with the awareness that psychological distress affects
the general health of people with DM and, thus, affects their motivation to keep their
chronic disease under control. In this regard, clinical recommendations for effective self-
care behaviors are deemed particularly challenging to maintain, and the associated barriers
(i.e., non-adherence and treatment non-compliance) appear to be difficult to untangle.
Therefore, coping strategies turn out to be pivotal resources for people with DM to better
manage their disease. As such, motivation represents a core component to acquire these
coping skills. Diabetes educators play an important role in the identification of persons’
motivation to support their behavior change by helping them to set behavioral goals and
guiding them in confronting their barriers [6].
In this context, digital solutions can further support people with diabetes by en-
couraging and motivating them to better manage their health. In recent decades, the
high availability of digital solutions for DM, such as smartphone-based applications, has
been an important resource to provide highly accessible and low-cost personalized care;
consequently, it has improved the monitoring and communication of various biometric
information relevant to disease management, and fostered involvement of patients in their
self-care [7–10]. Most of the digital solutions developed have focused on the monitoring
of physical factors associated with Hemoglobin A1c (HbA1c), diet, physical activity, and
adherence to the prescribed medication. For instance, a systematic review of Random-
ized Controlled Trials (RCTs) investigated computerized educational programs’ efficacy
in enhancing the diet and metabolic measures of people with DM [11], while four recent
meta-analyses evaluated telemedicine interventions aimed at supporting specific aspects
of diabetes-management [12–15]. More specifically, one study has evaluated the efficacy of
telemedicine in improving glycemic control among adults, children, and adolescents with
T1DM [15]; another study has analyzed the efficacy of smartphone-based interventions for
people with T2DM, reporting beneficial effects on self-efficacy, self-care activities, health-
related quality of life and glycemic control [12]; the other two studies have both assessed
the efficacy of eHealth interventions on glycemic control [13,14], although Ferigerlovà
et al. [14] only focused on people with T1DM, while Bonoto et al. [13] considered both
types of DM and further evaluated health-related quality of life as a secondary outcome.
In this regard, studies have also found that high levels of anxiety, depression, and stress
are associated with reduced quality of life leading to poor disease outcomes [16–19]. For
instance, the literature suggests that people with DM are two to three times more likely to
develop depression [20]. Concurrently, co-morbid depression in older patients with T2DM
carries an increased risk of developing cognitive impairment, which can exacerbate the
vicious cycle of self-criticism with consequences on self-care [21]. Then, depression predicts,
together with diabetes distress, medication adherence, proper dieting and physical activ-
ity [17]. In light of this evidence, one can assume bidirectionality between psychological
and physical effects, meaning that they influence one another.
Although, as just mentioned, many studies have investigated the physical and medical
factors involved in diabetes management, there seems to be a lack of research on the impact
of psychosocial factors, such as healthy coping. Therefore, there is a need for evidence
regarding the efficacy of digital solutions concurrently supporting both the psychosocial,
physical and medical well-being of people with DM, to further guarantee the choice of ap-
propriate treatment, tailored to their needs. With this in mind, this is the first meta-analysis
aimed at providing evidence gathered from RCTs evaluating eHealth interventions for
adults with T1DM or T2DM that account for both medical and psychosocial variables.
Specifically, the primary aim was to assess the efficacy of eHealth interventions in reducing
diabetes distress and distress-related symptoms—including symptoms of depression, anxi-
ety, and stress—and improving patients’ quality of life and HbA1c levels, thereby fostering
both the psychosocial well-being and glycemic control of adults with DM. The secondary
aim was then to determine whether there are differences in the efficacy of eHealth inter-
Int. J. Environ. Res. Public Health 2021, 18, 8982 3 of 17

ventions primarily aimed at providing psychosocial support vs. those primarily aimed at
improving glycemic control.

2. Materials and Methods

The current meta-analysis was conducted following the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22] and following the
recommendations of the Cochrane handbook for systematic reviews [23]. The protocol for
this meta-analysis was approved and registered on PROSPERO in March 2021 (Registration
Number: CRD42021238090).

2.1. Eligibility Criteria

Studies that met any of the following criteria were included in the current meta-
analysis: (a) RCTs comparing any eHealth intervention with any control condition (e.g., no
intervention group, waiting list, treatment as usual (TAU), active conditions); (b) adults
aged between 18 and 65 years, diagnosed with T1DM or T2DM. Studies were excluded if
they involved women with gestational diabetes, adolescents, children, groups of adults
with other medical or psychological disorders different from or comorbid to T2DM or
T1DM, and adults at risk of DM or with prediabetes.

2.2. Primary and Secondary Outcomes

Primary outcomes were mean changes in both psychosocial (i.e., diabetes distress,
depression, anxiety, stress, and quality of life) and medical measurements (i.e., HbA1c
levels). Time points included in this meta-analysis are endpoints defined as the end of
the eHealth intervention and follow-up (when assessed). Secondary outcomes were the
results of two different sensitivity analyses: one designed to assess the efficacy of eHealth
interventions primarily aimed at providing psychosocial support, and one designed to
assess the efficacy of eHealth interventions primarily aimed at improving glycemic control.
Acceptability of the intervention was measured by analyzing drop-out rates.

2.3. Search Strategy

The literature was systematically searched via Web of Science, PubMed, and CEN-
TRAL, using the following search terms: diabetes mellitus, eHealth, Mobile Health, mHealth,
Telehealth, serious games, glyc*, glucose, HbA1c, anxiety, stress, distress, depression, quality of
life, adults, randomized controlled trial, experimental, clinical. A further manual search was
implemented to identify any other relevant articles not found through the mentioned
academic databases. The search was limited to articles written in English and published
in peer-reviewed scientific journals between 2000 and 2021. The resulting abstracts were
screened independently by two authors (GB and SR) through a double-blind process;
potentially eligible articles were then read in full text by two authors (GB and GD), using
again the double-blind process. Any disagreement concerning both abstract and full-text
articles was resolved by discussion or by consulting a third author (EM) until consensus
was achieved.

2.4. Data Extraction

Data extraction was carried out independently by two authors (GB and GD), gathering
the following data from the full texts of the included studies: first author’s name, year
of publication, geographical location of the study, population characteristics (i.e., N, age,
gender, type of diabetes and its duration), type and length of eHealth intervention (e.g.,
smartphone-based application, Internet-based system, mobile-health intervention), type
of control condition (i.e., waitlist/no treatment, TAU, active), type of analyses performed
in the studies (intention-to-treat (ITT) or per-protocol), drop-out rates, study’s primary
and secondary outcomes, mean and standard deviation of every outcome measurement at
baseline, endpoint and follow-up (when included) and, if reported, effect size with 95%
Confidence Intervals (CIs) for each outcome in both study arms.
Int. J. Environ. Res. Public Health 2021, 18, 8982 4 of 17

2.5. Quality Assessment

The Risk of Bias (RoB) of the included RCTs was independently assessed by two
authors (GB and EM), using Cochrane’s Risk of Bias tool version 2 (RoB 2.0). Individ-
ual studies were judged on the following domains: randomization process, deviations
from the intended interventions (effect of assignment to intervention; effect of adhering
to intervention), missing outcome data, measurement of outcome data and selection of
reported results. Each domain’s risk was rated as either “low”, “some concern” or “high”,
depending on whether or not the requirements were adequately fulfilled. Discrepancies
between evaluations were resolved by discussion or by consulting a third author (GD).
Every domain’s assessment merges in a comprehensive domain, named overall judgment,
included in the RoB 2.0 to provide a summary of the whole study’s quality assessment.

2.6. Data Analysis

Analyses were performed using Review Manager Version 5 [24] and Comprehensive
Meta-Analysis [25]. Outcomes at the endpoint and follow-up were meta-analyzed when
at least three studies provided the necessary data. SMD with 95% CI was calculated.
Heterogeneity was assessed using I2 , with values greater than 50% indicating heterogeneity.
As such, outcomes were assessed using a random effect model when I2 > 50%, while the
fixed effect model was used when studies showed I2 < 50%. Odds Ratio (OR) with 95% CI
was calculated to assess intervention acceptability based on drop-out rates. Drop-out rates
are usually considered as a measure of treatment acceptability [26,27].
Publication bias was assessed by visually inspecting the funnel plot and through the
Egger’s regression test [28,29]; when publication bias emerged, the trim and fill proce-
dures and the fail-safe number [30] were calculated, thereby evaluating whether results
remained unchanged when accounting for publication bias. Sub-group analyses were
performed based on T1DM vs. T2DM, control conditions (i.e., waiting list/no treatment,
TAU, active), eHealth intervention format (i.e., smartphone-based application, internet-
based telemedicine system, mobile-health intervention), and type of analysis (i.e., ITT
vs. per-protocol). Meta-regression was performed when at least ten studies provided
moderator data; moderators were samples’ age, gender, diabetes duration (assessed in
years), and intervention duration (assessed in weeks).

3. Results
3.1. Search Result
The search process is shown in Figure 1 and the PRISMA checklist is reported in the
Supplementary Material Reporting Checklist file (Figure S1). The initial search yielded
822 studies. After duplicates were removed, the titles and abstracts of 714 studies were
screened resulting in 77 studies considered for full-text screening. Following the exclusion
of 64 studies (see, Supplementary Material Table S1 for the full list of excluded studies and
reasons for exclusion), 12 studies reporting data on k = 13 RCTs were finally included and
meta-analyzed. In this regard, as shown in Table 1, among the included 12 studies, Trief
et al. [31,32] separately assessed the efficacy of two experimental interventions considering
different samples. As such, the study of Trief et al. [31,32] has been considered as two
separate RCTs, ultimately resulting in a total of k = 13 RCTs included.

3.2. Studies’ Characteristics

Included RCTs’ characteristics are reported in Table 1, which shows data collected
between 2006 and 2020 [31–43]. A total of N = 1315 adults were considered in the current
meta-analysis, of which N = 725 received the experimental intervention and N = 590 were
under the control condition. Overall, 52.09% of adults were females, although one RCT [38]
did not report its participants’ gender distribution (the percentage is evaluated on the
remaining 12). Adults’ mean age was 46.18 years (SD = 9.98), and their mean diabetes
duration was 13.60 years (SD = 8.28). Only one study [41] did not provide information
on the sample’s diabetes duration. Moreover, k = 6 RCTs considered participants with
Int. J. Environ. Res. Public Health 2021, 18, 8982 5 of 17

T1DM [33–35,38,40,41] and k = 7 with T2DM [31,32,36,37,39]. All studies provided data
on participants’ glycemic levels (i.e., HbA1c) assessed at the intervention endpoint, and
k = 6 RCTs also evaluated it at follow-up [31,33,36,40,41]. The psychosocial variables
relevant for the current meta-analysis and considered in the included RCTs were: quality
of life referred to the participants’ diabetes management (k = 7) [32–35,38,40,42], diabetes
distress (k = 4) [31,39,42] and depressive symptoms (k = 6) [31,32,36,37,42,43]. None of
the included studies provided data on participants’ quality of life, diabetes distress, or
depressive symptoms at follow-up. No data regarding anxiety nor stress symptoms were
evaluated in the identified studies.
Moreover, only in three of the included studies a preliminary pilot study was con-
ducted to assess the intervention feasibility and acceptability [31–34].

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA Statement) [22].
’
’
–

[38] did not report its participants’ gender distribution (the percentage is evaluated on the
Int. J. Environ. Res. Public Health 2021, 18, 8982 6 of 17

Table 1. Characteristics of the included studies.

Sample Size Intervention

Author, Mean Age Outcomes
Country Sample Treatment Control Treatment Control Time Points Data Type
Year (Years); (SD) Included
Endpoint HbA1c
57.35 Telephone-based
[31] USA T2DM 97 CC 78 Active Follow-up (16 and Diabetes distress ITT
(10.60) intervention
32 weeks) Depression
Endpoint HbA1c
56.25 Telephone-based
[32] USA T2DM 93 IC 78 Active Follow-up (16 and Diabetes distress ITT
(10.91) intervention
32 weeks) Depression
35.70 Mobile-based Endpoint HbA1c
[33] Italy T1DM 67 63 TAU ITT
(9.40) telemedicine system Follow-up (12 weeks) QoL
36.90 Mobile-based HbA1c
[34] Italy T1DM 63 64 TAU Endpoint ITT
(10.50) telemedicine system QoL
41.30 Mobile-phone HbA1c
[35] France T1DM 30 30 Waitlist Endpoint Per-protocol
(11.30) software QoL
Comprehensive
60.00 Endpoint HbA1c
[36] USA T2DM 25 25 telemedicine TAU ITT
(8.81) Follow-up (13 weeks) Depression
intervention
52.93 HbA1c
[37] Turkey T2DM 23 21 Tele-rehabilitation TAU Endpoint Per-protocol
(11.18) Depression
31.85 Internet-based HbA1c
[38] Spain T1DM 54 64 TAU Endpoint Per-protocol
(9.57) telemedicine system QoL
Interactive
51.50 web-based tablet, Diabetes distress
[39] USA T2DM 93 95 Active Endpoint Per-protocol
(9.01) computer-delivered HbA1c
tool
Int. J. Environ. Res. Public Health 2021, 18, 8982 7 of 17

Table 1. Cont.

Sample Size Intervention

Author, Mean Age Outcomes
Country Sample Treatment Control Treatment Control Time Points Data Type
Year (Years); (SD) Included
25.00 Telephone-based Endpoint HbA1c
[40] Spain T1DM 19 16 TAU ITT
(8.54) telecare Follow-up (26 weeks) QoL
35.20 Smartphone-based Endpoint HbA1c
[41] Australia T1DM 36 36 TAU ITT
(10.43) app Follow-up (12 weeks) QoL
HbA1c
54.09 Mobile Health Diabetes distress
[42] USA T2DM 62 35 Active Endpoint Per-protocol
(8.30) intervention Depression
QoL
Tailored HbA1c
61.30
[43] Australia T2DM 63 63 telemonitoring TAU Endpoint QoL Per-protocol
(11.10)
intervention Depression
Note. USA = United States; CC = Couple Calls; IC = Individual Calls; T1DM = Type 1 Diabetes Mellitus; T2DM = Type 2 Diabetes Mellitus; TAU = Treatment as usual; HbA1c = Hemoglobin A1c; QoL = Quality of
life; ITT = Intention-To-Treat.
Int. J. Environ. Res. Public Health 2021, 18, 8982 8 of 17

3.3. eHealth Interventions’ Characteristics

eHealth interventions’ characteristics are described in Table 2. All interventions were
behavioral and primarily aimed at improving glycemic control and self-management, with
only four RCTs that also considered and assessed the efficacy of social support [31,32,42]
and quality of life [33,34]. No study was primarily aimed at providing psychosocial support
to improve the considered psychosocial variables (i.e., quality of life, diabetes distress,
depressive symptoms). The delivery format of the eHealth interventions comprises Short
Message Service (SMS) (k = 1) [35], phone calls (k = 3) [31,32,36], video calls (k = 1) [37]
and web, smartphone or computer-based applications (k = 8) [31,34,38–43].

Table 2. eHealth Interventions’ characteristics.

Author, Treatment Length Type of Digital

Intervention Delivery Format Aim
Year (Weeks) Intervention
Improve glycaemic
Telephonic couples or
Telephone-based control, physical health,
[31] 16 individual behavioural Phone calls
intervention and psychological
diabetes intervention
outcomes.
Improve glycaemic
Telephonic couples or
Telephone-based control, physical health,
[32] 16 individual behavioural Phone calls
intervention and psychological
diabetes intervention
outcomes.
Mobile-based Improve metabolic control,
Diabetes Interactive Mobile phone
[33] 26 telemedicine quality of life and reduces
Diary (DID) software software
system the risk of hypoglycaemia.
Improve metabolic control
Mobile-based
Diabetes Interactive Mobile phone while avoiding weight
[34] 12 telemedicine
Diary (DID) software software gain and reducing time
system
devoted to education.
Mobile phone Short Message Improve metabolic control
[35] 26 GlucoNet system
software Service (SMS) through telemonitoring.
Foster telemedicine-based
Advanced
Comprehensive management of clinic
Comprehensive
[36] 26 telemedicine Phone calls refractory Persistent
Diabetes Care (ACDC)
intervention Poorly Diabetes Mellitus
program
(PPDM).
Improve glucose control,
Tele-rehabilitation (TR) exercise capacity, physical
[37] 6 Tele-rehabilitation Video calls
program fitness, muscle strength,
and psychosocial status.
Medical Guard Internet-based
Improve metabolic
[38] 26 Diabetes (MGD) telemedicine Web-based system
control.
system system
Web-based
personally tailored, Improve key diabetes
Tablet computer-
interactive outcomes by focusing on
[39] 12 iDecide program delivered
diabetes treatment barriers and
tool
medication diabetes management.
decision aid
Telephone-based Improve metabolic control
[40] 26 GlucoBeep device Telephone device
telecare and self-management.
Int. J. Environ. Res. Public Health 2021, 18, 8982 9 of 17

Table 2. Cont.

Author, Treatment Length Type of Digital

Intervention Delivery Format Aim
Year (Weeks) Intervention
Glucose Buddy app
combined with weekly
Diabetes Improve glycaemic control
text-message feedback Smartphone
[41] 26 self-management and other diabetes-related
from a Certified application
iPhone application outcomes.
Diabetes Educator
(CDE)
Community-based
diabetes
self-management
education (DSME) Mobile Health Foster changes in
[42] 26 Web application
plus mobile health intervention glycaemic control.
(mHealth)-enhanced
peer support
intervention
Townsville Broadband Tailored Improve glycaemic control
Tablet computer-
[43] 26 Diabetes Telehealth telemonitoring and reduce healthcare
software
(TBDT) trial intervention costs.

Control conditions were waiting list (k = 1) [35], TAU (k = 8) [33,34,36–38,40,41,43] and

active control condition (k = 4) [32,38,39,42]. Lastly, k = 7 RCTs considered all randomized
participants for analysis (ITT) [31–34,36,40,41], while k = 6 considered only the observed
case (per-protocol) [35,37–39,42,43]. Additionally, none of the included studies relied on
behavior change theories, to the exception of one study. This latter study is based on the
Social Learning Theory (comprising knowledge development, goal setting, self-monitoring,
and behavioral contracting) and on the Interdependence Theory only for the Couple Calls
intervention [31,32].

3.4. Quality Assessment of Included Studies

RoB assessment of included RCTs is reported in Figure 2 (a second Figure picturing
RoB results in an aggregated form per domain are reported in Supplementary Material
Figure S2). Overall, studies quality yielded a high RoB (k = 11) and only k = 2 RCTs showed
some concern. The primary sources of bias were the domain investigating deviation from
the intended intervention (84.62% high RoB, 15.38% some concern), and the selection of
reported results domain (100% some concern). For the latter, all studies were deemed as
holding some concern, as most of the studies did not provide a pre-specified protocol,
while those that did not provide information on the intended analyses to be performed.
Other sources of bias refer to the randomization process domain (15.38% high RoB, 53.85%
some concern).

3.5. Interventions’ Efficacy and Meta-Regression

3.5.1. Hemoglobin 1c (HbA1c)
A random-effect meta-analysis was performed to assess eHealth interventions’ efficacy
in improving participants’ HbA1c levels. Results showed a significant effect on HbA1c
(Figure 3a) at intervention endpoint (SMD = −0.40; 95% CI = −0.70, −0.12; I2 = 85%;
k = 13) [31–43], favoring participants in the intervention group, thereby showing more
balanced (i.e., within the optimal range of glycemic level) glycemic levels compared to the
higher glycemic levels reported by participants in the control group. Overall, interventions
were well-accepted (drop-out OR = 1.43; 95% CI = 0.72, 2.81; I2 = 74%; k = 10), but the
beneficial effect on HbA1c was not maintained at follow-up (Figure 3b; SMD = −0.13;
95% CI = −0.31, 0.05; I2 = 67%; k = 6) [31–33,36,40,41], as reported in Figure 3b.
Int. J. Environ. Res. Public Health 2021, 18, 8982 10 of 17

Figure 2. Risk of Bias color-coded.

erventions’

analysis was performed to assess eHealth interventions’ effi-

cacy in improving participants’ HbA1c levels. Results show
−0 −0 −0
–

−0
−0 –

(a)

(b)
Figure 3. (a). HbA1c at endpoint. (b). HbA1c at follow-up.

As displayed in Table 3, subgroup analysis was then performed, considering the type
of DM (i.e., T1DM vs. T2DM), control condition (i.e., waiting list/no treatment, TAU, active
Int. J. Environ. Res. Public Health 2021, 18, 8982 11 of 17

control group), intervention delivery format (i.e., SMS, phone calls, video calls, applications)
and the type of analysis (i.e., ITT vs. per-protocol). No significant difference in the effect
size was shown. In addition, as indicated in Table 3, meta-regression results showed no
significant moderator (i.e., age, gender, DM duration, and intervention duration).

Table 3. Sub-group and meta-regression analyses.

HbA1c
Sub-Group Analysis
k SMD 95% CI I2 p
Control condition
Waiting list 1 −0.25 −0.76, 0.26 -
TAU 8 −0.63 −1.08, −0.17 88% 0.10
Active control 4 −0.08 −0.28, 0.11 31%
Diabetes Type
T1DM 6 −0.54 −1.16, 0.07 91%
0.08
T2DM 7 −0.27 −0.51, −0.03 63%
Intervention delivery format
SMS 1 −0.25 −0.76, 0.26 -
Phone calls 3 −0.25 −0.45, −0.05 0%
0.28
Video calls 1 −0.88 −1.5, −0.26 -
Applications 8 −0.42 −0.88, 0.04 91%
Type of analyses
ITT 7 −0.58 −1.04, −0.11 89%
0.18
Per-protocol 6 −0.20 −0.50, 0.10 85%
Meta-Regression
k β SE z p
Age 13 0.02 0.02 0.97 0.33
Female gender 12 0.006 0.01 0.62 0.54
Diabetes duration 12 −0.02 0.04 −0.62 0.54
Intervention Duration 13 −0.007 0.03 −0.29 0.77
Note. HbA1c = Hemoglobin A1c; SMD = Standard Mean Difference; CI = Confidence Interval; I2 = Heterogeneity; TAU = Treatment as
usual; T1DM = Type 1 Diabetes Mellitus; T2DM = Type 2 Diabetes Mellitus; SMS = Short Message Service; ITT = Intention-To-Treat; p < 0.05.

3.5.2. Psychosocial Outcomes

eHealth interventions’ efficacy on psychosocial outcomes (i.e., depressive symptoms,
quality of life, diabetes distress) was also assessed; since no heterogeneity was found for
depressive symptoms, a fixed-effect meta-analysis was only performed for this outcome.
Results showed a significant effect on participants’ depressive symptoms at endpoint
(Figure 4; SMD = −0.18; 95% CI = −0.33, −0.02; I2 = 0%; k = 6) [31,32,36,37,42,43]. Data
on depressive symptoms at follow-up were only provided by one RCT [36], thus the
interventions’ efficacy at follow-up could not be assessed for this outcome.
A random-effect meta-analysis was instead performed to assess interventions’ efficacy
on participants’ quality of life (Figure 5; SMD = −0.20; 95% C I = −0.72, 0.32; I2 = 90%;
k = 7) [31,32,39,42] and diabetes distress (SMD = −0.04; 95% CI = −0.36, 0.27; I2 = 74%;
k = 4) [33–35,38,40,42,43] at interventions’ endpoint. As regards both quality of life and
diabetes distress, no significant effect was found among people with DM. No data was
reported to assess interventions’ efficacy at follow-up for either quality of life or diabetes
distress. The figures related to both outcomes are reported in the Supplementary Materials
Figures S3 and S4, respectively.
 ults showed a significant effect on participants’ depressive symptoms at endpoint (Fig-
−0 −0 −
Int. J. Environ. Res. Public Health 2021, 18, 8982 12 of 17

tions’ efficacy at follow

Egger’s regression test

to either HbA1c (β0 = −2 17), quality of life (β0 = 1.53;
(β0 = −3 .36). Egger’s regression test, instead, revealed the presence of significant
publication bias among RCTs assessing depressive symptoms (β0 = −8

−1 −1 −1
Figure 4. Depressive symptomsthatatthe
theinterventions’
endpoint. Note.effect
SD = on depressive
Standard symptoms
Deviation; wasDifference=
Std. Mean not influenced by the
Standard pr
Mean
Difference; CI = Confidence Interval; df = degrees of freedom.

(a) HbA1c analysis was instead performed to Distress

(b) Diabetes assess interventions’ effi-
cacy on participants’ quality of life (Figure 5; SMD = −0 −0
−0 −0
– ] at interventions’ endpoint. As regards both quality of life

assess interventions’ efficacy at follow

(c) Quality of Life (d) Depressive Symptoms

Figure 5. Publication bias Funnel Plots (observed and imputed). Note. Each dot represents a single RCT; Y-axis = the
standard error (RCTs with lower power are shown at the bottom, those with higher power at the top of the funnel);
X-axis = the SMD; an asymmetrical dots distribution suggest bias.

None of the sub-group analysis concerning the above-mentioned comparisons showed

significant differences in the effect size for any of the considered psychosocial outcomes.
Meta-regression could not be performed as less than 10 studies provided the necessary data.
Int. J. Environ. Res. Public Health 2021, 18, 8982 13 of 17

3.5.3. Publication Bias

Publication bias was assessed for all considered outcomes as shown in Figure 5. The
Egger’s regression test was also performed, and no publication bias was found, referring
to either HbA1c (β0 = −2.95; p = 0.17), quality of life (β0 = 1.53; p = 0.41) or diabetes
distress (β0 = −3.66; p = 0.36). Egger’s regression test, instead, revealed the presence
of significant publication bias among RCTs assessing depressive symptoms (β0 = −8.26;
p = 0.02). Hence, the trim and fill procedures were performed, trimming two studies to the
left (Point estimate = −1.31; 95% CI = −1.44, −1.18). The fail-safe N was equal to 54. These
results suggest that the interventions’ effect on depressive symptoms was not influenced
by the presence of publication bias.

4. Discussion
The present meta-analysis examined the efficacy of eHealth interventions in improv-
ing psychosocial outcomes and glycemic control in patients with DM, including data from
13 RCTs of 1315 adults with T1DM or T2DM. The current study further aims to determine
whether there were differences in the efficacy of eHealth interventions in fostering psy-
chosocial support (i.e., decreasing diabetes distress, stress, anxiety, depression symptoms,
and increasing quality of life) and improving HbA1c levels for adults with DM. Referring
specifically to the goal of investigating the efficacy of eHealth interventions aimed at pro-
viding psychosocial support, such intent could not be satisfied, as none of the included
studies was designed accordingly. On the other hand, all included studies were focused on
supporting glycemic control by favoring diabetes management.
Overall, the results demonstrated the efficacy of eHealth interventions among adults
with DM, highlighting acceptable support in controlling HbA1c levels and thereby con-
firming previous studies [12,13]. Indeed, the evaluated interventions are mainly delivered
using applications embedded in smartphones or tablets, designed to monitor and improve
individuals’ metabolic control, physical activity, diabetes self-management, and the risk
of hypoglycemia, as well as to reduce healthcare costs [31–43]. However, the beneficial
effects of eHealth interventions on the metabolic control of people with DM was not main-
tained at follow-up. Several reasons can justify this loss of efficacy, first and foremost
the lack of generalizability of the enhancements assigned to interventions, which could
entail recidivism [44]. Indeed, generalizability is fundamental for the long-term effect
of intervention since it assumes the transfer of behavioral change to other areas of an
individual’s functioning. In addition, the difference between efficacy and effectiveness is
also important to mention. Efficacy refers to the effect of intervention when assessed in a
controlled condition, thus the preferred design for efficacy studies is the RCT. Indeed, RCTs
carefully plan the conditions in which the intervention is tested and closely monitor and
control any possible confounding factor, and then aim to generalize the results to the whole
population [45]. Effectiveness, on the other hand, is tested in more ecological environments,
meaning that the intervention’s effects are assessed imitating everyday conditions (e.g.,
not using randomized designs and not systematically excluding confounding variables);
this allows for inter-contextual generalizability of the results [45].
As previously mentioned, the considered eHealth interventions were not developed
to provide psychosocial support to improve adults’ well-being, and, indeed, no significant
results concerning adults’ quality of life and diabetes distress have emerged, nor were
data referred to anxiety and stress symptoms evaluated by any of the included RCTs. This
is interesting considering that the American Association of Diabetes Educators (AADE)
has provided guidelines for effective diabetes management, and thus to provide healthy
behavioral strategies. More specifically, AADE refers to seven self-care behaviors [46]:
healthy eating, being physically active, monitoring blood glucose levels, adhering to
prescribed medications, adequate problem-solving skills, risk-reduction behaviors, and
healthy coping. The latter is a construct that encompasses several interrelated psychosocial
dimensions, namely diabetes distress, distress (subsuming depression, anxiety, and stress
symptoms referred to life at large) and mental well-being (encompassing quality of life,
Int. J. Environ. Res. Public Health 2021, 18, 8982 14 of 17

positive attitudes, and positive relationships) [6]. These findings give rise to reflections
on the importance of developing and delivering eHealth interventions suitable to provide
psychosocial support to people with DM, using an RCT design to test their effectiveness;
indeed, most research on eHealth interventions developed to provide psychosocial support
consists of pilot or proof-of-concept studies [47–49].
Notwithstanding these shortcomings, results from this meta-analysis yielded en-
couraging evidence on the efficacy of eHealth interventions in decreasing depressive
symptoms [31,32,36,37,42,43], albeit results show a small effect size. The literature suggests
several possible biological mechanisms to explain the onset of depressive symptoms, which
can then interfere with HbA1c levels. For instance, studies suggest that the effects of
insulin deficiency on the metabolism of neurotransmitters may be at the basis of both
depression and chronic high glycemic levels, which in turn have potentially hindering
effects on the hypothalamic–pituitary–adrenal axis (HPA) [50,51]. The results of the present
meta-analysis confirm and extend those previously emerged, suggesting a bidirectional
relationship between depression and metabolic control, whereby eHealth interventions
aimed at fostering glycemic control and improving HbA1c levels also lead to improve-
ments in depressive symptoms. This bidirectional association exposes adults with DM
to a group of various cardiovascular risk factors, comprising elevated blood pressure,
hyperglycemia, obesity, hypertriglyceridemia, and decreased high density lipoprotein
(HDL) cholesterol [52]. Indeed, the bidirectionality between psychosocial and medical
factors is a pivotal aspect that should be taken into account to extend intervention efficacy
to the whole functioning of an individual. A quite recent longitudinal study also suggested
a “dynamic interaction” [53] (p. 952) between depressive symptoms and HbA1c levels,
in which depressive symptoms may be risk factors for the increase of HbA1c levels and
vice versa [53,54]. Moreover, depression can involve feelings of hopelessness and help-
lessness [55], which can influence the individual’s motivation to adopt healthy behaviors,
namely following a healthy diet, doing regular physical activity, and taking oral medication
and/or insulin injections. Adherence to the recommended regimen continues to represent
a barrier for many people with DM: most of them, indeed, present difficulties in regularly
engaging with all the aforementioned healthy behaviors, and this influences their diabetes
management [56,57]. Therefore, not fully adhering to the prescribed medical regimens
constitutes a risk factor from both a medical and psychosocial standpoint, since it can
entail poor glycemic control in the short-term which, in turn, can have an impact on the
psychosocial functioning of an individual.
Notwithstanding the differences in possible complications and management of T1DM
and T2DM, it is noteworthy that the results of the studies included in the current meta-
analysis highlighted no significant differences in eHealth interventions’ efficacy when
compared considering the type of diabetes as moderator. These findings suggest that inter-
ventions might be focused on the broader concept of DM, concentrating on the similarities
among patient’s lifestyles and making the self-management of metabolic control their main
core. Indeed, only in one study was the intervention specifically focused on the risk of
hypoglycemia among people with T1DM [34], thereby supporting this hypothesis.
The main limitation of the present meta-analysis is that most interventions were
developed for monitoring and/or improving glycemic control in DM, except for four
studies, in which the authors also designed an interactive diary to motivate the person
to achieve a better quality of life [33,34] and to provide social support [31–33]. Therefore,
the current meta-analysis could not assess the differences between eHealth interventions
aimed at fostering psychosocial vs. medical support. Additionally, most studies currently
available in the literature that have integrated the psychosocial factors within the digital
health solutions are mostly pilot or proof-of-concept studies [47–49], thus not feasible for
rigorous systematic reviews and meta-analyses. Therefore, future studies should move
towards RCT designs to prove the effectiveness of eHealth interventions while also taking
into account the bidirectionality between psychosocial and medical factors. Noteworthy
is also the high risk of bias of the included evidence. Although the reduced RCTs quality
Int. J. Environ. Res. Public Health 2021, 18, 8982 15 of 17

was for the most caused by a lack in properly investigating adherence to intervention, all
studies properly assessed the outcomes of interest and satisfactorily dealt with missing
data. As such, the identified RCTs’ low quality mainly poses concern on the evaluation of
interventions’ tolerability, albeit not greatly undermining the reliability of the results.

5. Conclusions
This meta-analysis provides a contribution to the growing literature on eHealth
interventions for supporting and motivating people with DM in the adoption of healthy
goals within the management of their chronic disease. Indeed, results highlighted that
eHealth interventions aimed at monitoring individuals’ metabolic control and enhancing
depressive symptoms are effective and acceptable in the short-term; however, no evidence
on efficacy at follow-up was found. Future studies should design digital solutions following
standard guidelines, such as those identified by AADE [46], thereby including the healthy
coping construct within their intervention protocol. As such, future works should develop
eHealth interventions on multiple levels, including a broad range of psychosocial factors
to fully address the barriers of non-adherence as well as foster psychophysical well-being.
Lastly, studies should develop new approaches to support the long-term maintenance of
interventions’ efficacy related to glycemic levels as well as depressive symptoms.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/

10.3390/ijerph18178982/s1, Figure S1: PRISMA 2020 Checklist, Table S1: Excluded Studies with
reasons, Figure S2: Risk of Bias Plot, Figure S3: Quality of Life at the endpoint, Figure S4: Diabetes
Distress at the endpoint.
Author Contributions: Conceptualization, G.B., E.M. and S.S.; methodology, G.B. and E.M.; data
curation, G.B. and E.M.; writing—original draft preparation, G.B., E.M., G.D., S.R.; writing—review
and editing, G.B., E.M., G.D., S.R., S.G. and S.S.; supervision, S.G. and S.S. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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