Keywords Ramadan fasting - type 2 diabetes - insulin regimen - basal-bolus - premixed insulin
Introduction
Many individuals with type 2 diabetes (T2D) on insulin therapy fast irrespective of
their risk level and their physicians' advice. Physicians are required to assess the
individual's intention to fast and provide guidance for a safe fasting experience.[1 ] The IDF-DAR (International Diabetes Federation and Diabetes and Ramadan International
Alliance) Practical Guidelines 2021 recommend the application of a risk calculator
that considers 14 different risk elements, each with a separate scoring system. The
cumulative score indicates the individualized risk category for fasting.[2 ]
With regards to glucose-lowering therapies, individuals treated with multiple-dose
insulin therapy, either with premixed insulin or basal-bolus insulin regimen, are
identified to have the highest risk scores for this specific risk element, highlighting
the need for special precautions and careful consideration for this particular cohort
of patients who are potentially at risk of glycemic-related complications during Ramadan
fasting (RF).[3 ]
Although insulin use during fasting increases the risk of hypoglycemia, especially
with complex regimens, glycemic control during Ramadan also requires careful management
and should not be compromised.[4 ]
Maintaining blood sugar control reduces the risk of T2D complications, especially
vascular issues. However, complex insulin regimens can hinder adherence due to fear
of hypoglycemia and dosing challenges.[5 ] Intensive insulin therapy with multiple daily injections lowers HbA1c and improves
long-term outcomes, however, increases the risk of severe hypoglycemia.[6 ]
Few studies have evaluated insulin regimens during Ramadan; large randomized controlled
trials (RCTs) are still lacking.[2 ] The DAR global surveys of 2020 and 2022 gathered demographic, clinical, and fasting
data from 10,788 individuals with T2D. It serves as a platform to analyze insulin
regimens across different regions.[6 ]
[7 ] The objective of the sub-analysis is to compare the effects of basal-bolus and premixed
insulin regimens on glycemic control, hypoglycemia, and hyperglycemia incidence during
RF among individuals with T2D surveyed in 2020 and 2022.
Patients and Methods
Design and Settings
A cross-sectional survey (2020 and 2022) evaluated Muslim individuals with T2D on
insulin who chose to fast during Ramadan. Many Muslim majority countries, including
Bahrain, Bangladesh, Brunei, Egypt, Indonesia, Iraq, Iran, Jordan, Libya, Saudi Arabia,
Malaysia, Singapore, Pakistan, Türkiye, the United Kingdom, and the United Arab Emirates,
participated in the survey. For methodological consistency, the same survey questions
were used across 2020 and 2022.
Study Population
Muslim individuals with diabetes were invited to participate in the study during clinic
consultations within the 10-week post-Ramadan period. To ensure a diverse representation
of diabetes care across different countries, the study included health care professionals
from various specialties, including endocrinologists, general practitioners, and internal
medicine physicians.
Data Synthesis
Muslim individuals who regularly attended outpatient diabetes care, provided informed
consent, had a confirmed diagnosis of T2D, and were on either a premixed insulin or
basal-bolus regimen met the inclusion criteria. Individuals with type 1 diabetes,
pregnancy, and those who did not fast were excluded from this subgroup analysis. A
subset of patients classified as “high risk”—those who required emergency room visits
or hospitalization due to hypo- or hyperglycemia or experienced frequent hypoglycemia
(more than eight episodes per Ramadan)—underwent additional analysis. Compliance with
medications, pre-Ramadan hypoglycemia data, dietary intake pattern, physical activity,
and sleep habits were not evaluated.
Statistical Analysis
Descriptive statistics were used to describe the clinical aspects and the baseline
demographics. A continuous variable's mean and standard deviation were used to describe
it. In contrast, each event's frequency (%) and percentage were used to characterize
categorical variables based on the provided information. The total number of values
changes depending on the data provided for each measurement. A combined description
was given for the 2020 and 2022 DAR global survey data, and the study did not consider
missing values. The primary outcomes data were categorized solely on treatment regimen,
with those on a basal/bolus treatment plan pitted against those on mixed insulin therapy.
Pearson's chi-square test was employed to investigate the disparity between the two
groups. A p -value of less than 0.05 was considered statistically significant for the two-sided
statistical tests. The data were analyzed using IBM SPSS Statistics version 26 (Armonk,
New York, United States).
Results
Characteristics of Patients
A total of 10,788 individuals with T2D participated in the surveys, of whom 1,527
(14.1%) were on a basal-bolus regimen and 1,355 (12.6%) on premixed insulin therapy
([Table 1 ]). [Fig. 1 ] illustrates the geographical distribution of the individuals with T2D on both insulin
regimens in this study.
Fig. 1 The geographical distribution of individuals with T2D. T2D, type 2 diabetes.
Correlates of Insulin Use and Doses
The mean age was not significantly different between cohorts (56.0 ± 12.1 vs. 55.1 ± 11.3
years, NS) in the basal-bolus and premixed insulin cohorts, respectively. Insulin
use was marginally more among women in both groups (55.5% in basal-bolus vs. 53% in
premixed insulin). However, the basal-bolus group had a significantly longer diabetes
duration (14.1 ± 8.4 vs. 12.5 ± 7.5 years, p = 0.03). Other metabolic parameters, including HbA1c, body mass index (BMI), blood
pressure, and low-density lipoprotein levels, showed no significant differences ([Table 1 ]).
Complications, Monitoring, and Education
Diabetes-related complications and comorbidities were significantly higher in the
basal-bolus cohort, as shown in [Fig. 2 ]. [Table 2 ] depicts the fasting patterns, self-monitoring of blood glucose (SMBG), and Ramadan-specific
diabetes education in the basal-bolus and premixed insulin cohorts. Although no statistical
significance was found with all segments of fasting duration falling at p >0.05, more patients in the premixed insulin group fasted during Ramadan (88.5% vs.
80.1%, p = 0.5). The post-RF (Shawal) rates were similar (23% vs. 24.3%, p = 0.7) with no statistical significance. The SMBG and Ramadan-specific diabetes education
were comparable between the groups, with no significant difference (p = 0.9).
Fig. 2 Prevalence of diabetes-related complications and comorbidities in basal-bolus and
premixed insulin cohorts.
Table 1
Baseline characteristics and metabolic parameters of individuals with T2D on basal-bolus
and premixed insulin regimens
Parameters
Basal bolus insulin,
N = 1,527
Premixed insulin,
N = 1,355
p -Value
Age
(y)
<40
9.5%
7.7%
0.3
40–49
16.8%
23.2%
0.06
50–59
30.9%
31%
0.98
≥60
42.8%
38.1%
0.5
Mean (SD)
56 ± 12.1
55.1 ± 11.3
0.9
Diabetes
duration
(y)
<10
30.9%
38.3%
0.4
10–19
41.5%
41.6%
0.98
≥20
27.6%
20.1%
0.06
Mean (SD)
14.1 ± 8.36
12.5 ± 7.5
0.03
Sex
Female
55.5%
53%
0.5
Male
44.5%
47%
HbA1c (%)
<7.5
20.9%
24.1%
0.4
7.5–9.0
33.4%
37.4%
0.5
>9
45.7%
38.5%
0.3
Mean (SD)
9.2 ± 2
8.85 ± 1.8
0.8
BMI (kg/m2 )
Mean (SD)
28.2 ± 7.3
27.2 ± 6.55
0.8
SBP (mmHg)
Mean (SD)
133.4 ± 24.4
131.6 ± 25.6
0.9
DBP (mmHg)
Mean (SD)
76.8 ± 14.2
76.6 ± 15
0.9
LDL-C (mg/dL)
Mean (SD)
113.5 ± 49.9
106 ± 45.2
0.6
Medication 1:
non-insulin
Metformin
56.6%
69.1%
0.03
DPP4 inhibitors
23.4%
28%
0.3
Thiazolidinedione
1.8%
11%
<0.0001
SGLT2i
17.2%
21.4%
0.2
GLP1-RA
5.2%
1.2%
<0.0001
AGI
0.5%
1%
0.17
Medication 2:
insulins
Intermediate-acting
39%
0
–
Long-acting
61%
0
–
Short-acting
100%
0
–
Combination
0
100%
–
Abbreviations: AGI, alpha-glucosidase inhibitor; BMI body mass index; DBP, diastolic
blood pressure; DPPIV, dipeptidyl peptidase 4 inhibitors; GLP1 RA, glucagon like peptide
receptor agonists; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol;
SBP systolic blood pressure; SD, standard deviation; SGLT2i, sodium-glucose transporter
2 inhibitor.
Table 2
Fasting patterns, self-monitoring of blood glucose (SMBG), and Ramadan-specific diabetes
education in basal-bolus and premixed insulin cohorts
Parameters
Basal bolus insulin,
N = 1,527
Premixed insulin,
N = 1,355
p -Value
Fasted the month of Ramadan
Yes
80.1%
88.5%
0.5
Duration of Ramadan fasting
(days)
1–7
3.5%
2.8%
0.4
22–29
34.7%
28.6%
0.2
30
50%
59.1%
0.3
Mean ± SD
26.6 ± 6.3
27.2 ± 5.8
0.7
Intention for Shawal (post) Ramadan fasting
Yes
23%
24.3%
0.7
Did you do SMBG during Ramadan?
Yes, more frequent than before Ramadan
13.8%
12.4%
0.6
Yes, less frequent than before Ramadan
14%
15.7%
0.5
Yes, at the same frequency as before Ramadan
53%
47.5%
0.5
No
19.2%
24.2%
0.2
Received education
Yes
58%
57.4%
0.9
Method of education
In the clinic, during my routine consultation
74.9%
72.6%
0.8
Duration of sessions
0–15 min
79.5%
75.8%
0.7
Abbreviation: SD, standard deviation; SMBG, self-monitoring of blood glucose.
Frequency of Complications
[Fig. 3 ] illustrates the incidence of diabetes-related complications in individuals with
T2D who fasted for different durations in Ramadan while on insulin therapy in both
cohorts. Hypoglycemia was more frequent in the basal-bolus cohort (23.9% vs. 17.7%)
for the premixed insulin group. The emergency department visits or hospitalizations
for hypoglycemia occurred at a similar rate (6.5% in both groups).
Fig. 3 Frequency of emergency room (ER) attendance and hospitalization for hypoglycemia
and hyperglycemia in basal-bolus and mixed insulin cohorts during Ramadan.
Hospitalizations
However, hyperglycemia-related emergency visits and hospitalizations were significantly
higher in the basal-bolus group (9.0% vs. 3.7%, p < 0.001), given the fact that they encountered more frequent hypo- and hyperglycemia
episodes (≥8 per Ramadan) when using the basal-bolus insulin regimen. Among patients
requiring hospitalization or frequent emergency visits, those in the basal-bolus group
had significantly higher rates of retinopathy, microalbuminuria, nephropathy, and
hyperlipidemia compared with the premixed insulin cohort ([Fig. 4 ]).
Fig. 4 Potential contributors to hyperglycemia and hospitalizations in insulin-treated individuals
with T2D during Ramadan. T2D, type 2 diabetes. DM, diabete mellitus; HbA1c: glycosylated
hemoglobin; BMI: body mass index.
Discussion
Due to the progressive nature of pancreatic β cell loss during T2D, many patients
will eventually require insulin therapy.[8 ] In insulin-naive individuals with T2D, insulin therapy is usually initiated with
simple, single-daily injection regimens, such as once-daily basal or premixed insulin.
With a longer duration of diabetes and failure of optimal glycemic control while on
a combination of oral glucose-lowering therapies and single-dose insulin regimens,
intensification to multiple-dose insulin regimens, such as a basal-bolus insulin regimen
or two or three doses of premixed insulin, is then necessary.
Insulin therapy has several established negative associations, such as increased risk
of hypoglycemia (particularly during Ramadan and with the use of human insulin), nonadherence
to injections, inappropriate timing of insulin injections, incorrect insulin injection
techniques, suboptimal insulin dose adjustment and titration, inadequate self-blood
glucose monitoring, and being a sign of a worsening disease condition, among other
reasons.[9 ]
RF entails a significant shift in lifestyle practices and behaviors beyond simply
abstaining from food. Addressing these lifestyle modifications is crucial and challenging
for individuals with T2D. The DAR global survey, a post-Ramadan population-based study
conducted across more than 20 countries (the majority of which had predominantly Muslim
populations) in 2020 and 2022, found that 85.4% of individuals with T2D observed RF.
Among those on insulin therapy, 79% chose to observe the fast.
While insulin therapy can typically be titrated to achieve regulated fasting plasma
glucose levels, many patients will eventually require more intensive insulin replacement
by adding prandial insulin to basal insulin.[10 ]
Limited data are available regarding the optimal insulin type or regimen for patients
with T2D during Ramadan.[5 ] The current body of evidence does not support one insulin treatment regimen over
another; however, this analysis of the DAR global survey provides real-world data
on a large number of individuals with T2D (over 2,800) who received intensive insulin
therapy during Ramadan. More frequent cardiovascular complications occurred with basal-bolus
insulin treatment ([Table 2 ]). Surprisingly, more complication-free patients were in the premixed insulin cohort
(12.2% vs. 7%). More patients fasted during Ramadan in the premixed insulin cohort
(88.5% vs. 80%). Among them, significantly more patients completed the entire month
of fasting (59.1% vs. 50%) in the premixed insulin and basal-bolus insulin cohorts,
respectively. This observation may be due to the premixed insulin regimen being more
straightforward to adjust and modify to the particular nature of RF. Premixed insulins
tend to be better suited for individuals with predictable meal patterns.[11 ]
The CREED study demonstrated hypoglycemia as the most common risk associated with
insulin therapy, but did not elaborate on the effect of a specific type of insulin
regimen on hypoglycemia incidence.[12 ] Our real-world data suggest that both hypo- and hyperglycemia were of significantly
higher incidence in the basal-bolus insulin regimen versus the premixed insulin regimen
([Fig. 3 ]), a result at odds with a previous study that found no significant differences for
glycemic control, hypoglycemia rate, or BMI between the basal-bolus and premixed insulin
groups.[13 ] This discrepancy can be attributed to the considerable regional variations in the
use of each regimen ([Fig. 1 ]). A previous study found that insulin regimens differ substantially between European
countries, reflecting variations in regulations, reimbursement systems, national diabetes
care systems, and patient characteristics and expectations.[13 ]
[14 ]
During Ramadan, it is customary to experience dysregulation of regular eating patterns,
with higher caloric and carbohydrate consumption in the evening meal that breaks the
fast. This would explain the high rate of hyperglycemia experienced by both cohorts
(32 and 23.7%). Still, the significantly higher rate of hospitalization in the basal-bolus
cohort, at 9% versus 3.7% in the premixed insulin cohort (p = 0.0002), may be attributed to several baseline characteristics, such as older age,
longer diabetes duration, and a higher proportion with poor glycemic control in that
cohort, as demonstrated in [Fig. 4 ].
Following a pre-Ramadan medical assessment and application of the RF risk calculator,
individuals with T2D on an intensive insulin regimen would be assessed to have a higher
risk score compared with other treatment options and are expected to receive Ramadan-focused
patient education and to be advised to practice frequent SMBG. However, our data suggest
otherwise. Only a minority of patients (13.8% in basal-bolus insulin and 12.4% in
mixed insulin) performed SMBG more frequently than before Ramadan, and over two-fifths
of them (some 42%) did not receive any specific patient education ([Table 2 ]). This serves only to emphasize the importance of a strong push toward providing
comprehensive, Ramadan-focused, structured diabetes education to this group of insulin-treated
individuals with T2D.[15 ] Lack of Ramadan-specific education and infrequent blood glucose monitoring significantly
increase the risk of both hypoglycemia and hyperglycemia in people with diabetes who
fast. Without proper guidance, patients may mismanage medications, make poor dietary
choices, and fail to recognize when to break the fast. Infrequent self-monitoring
delays the detection of glucose abnormalities, raising the risk of complications like
diabetic ketoacidosis or hospitalization.[2 ] Structured education and regular monitoring are essential to ensure safe fasting
and reduce adverse outcomes.
Worse outcomes in patients on basal-bolus insulin during Ramadan are more likely due
to underlying disease severity rather than the insulin regimen itself. These patients
are usually on intensive insulin therapy because they have more advanced diabetes,
with longer disease duration, multiple comorbidities, or poor baseline glycemic control.
While basal-bolus regimens carry a higher risk of hypoglycemia if not adjusted properly
during fasting, with adequate education and dose modification, they can be managed
safely. Therefore, the poor outcomes seen in this group likely reflect the complexity
of their condition, not just the type of insulin regimen.
This study has notable limitations. Since it was survey-based, it is not possible
to infer a causal relationship from the data. Moreover, hypo- and hyperglycemia were
not clinically verified and are subject to recall bias after the Ramadan period. Hypoglycemia
and hyperglycemia were self-reported without validation using continuous glucose monitoring.
Additionally, residual confounders—such as regional prescribing norms and varying
levels of patient education, as well as baseline disparities in diabetes severity
and duration—may have influenced the outcomes. Post-Ramadan HbA1c and BMI data were
also unavailable. Nevertheless, the large, multinational dataset offers valuable real-world
insights.
Conclusion
This study presents the first large-scale, real-world analysis of T2D patients who
fast during Ramadan, examining the impact of insulin regimens on diabetes-related
risks. Findings suggest that premixed insulin may be more suitable for reducing hyperglycemia
and hospitalizations during RF; however, RCTs are needed for confirmation. Prioritizing
Ramadan-focused education, including glycemic control, insulin self-titration, hypoglycemia
prevention, and frequent SMBG, is essential for safe fasting and improved outcomes
in insulin-treated T2D patients.
