Metformin
Improves Glycemic Variability in Adults with Type 1 Diabetes
Mellitus:
an open-label randomized control trial
Short title: Metformin improves glycemic variability in type 1 diabetes
Xiuzhen Zhang, Dan Xu, Ping Xu,
Shufen Yang, Qingmei Zhang, Yan Wu, Fengyi Yuan
Department
of Endocrinology and Metabolism, Shenzhen People’s hospital ,The Second
Clinical Medical College,Jinan University,1017 Dongmen North Road,
Shenzhen, Guangdong, China
518020
Corresponding author: Fengyi Yuan, M.D. Department of Endocrinology and
Metabolism, Shenzhen People’s hospital ,The Second Clinical Medical
College,Jinan University,1017 Dongmen North Road, Shenzhen, Guangdong,
China, 518020, Tel:86-25533018, Email:janexz521@outlook.com
Conflict of interest: none declared.
Acknowledgements
We thank all of the patients participated in this study. We also thank
the colleagues that devoted their efforts to this study, including
dietician, diabetic educator, nurses, and technicians.
What’ new?
Glycemic variability (GV) is increasingly becoming recognized as a
contributing risk factor of cardiovascular disease in type 1 diabetes
mellitus (T1DM). And GV metrics in patients with T1DM with intensive
insulin therapy is far from satisfactory. We found that 3 months of
metformin therapy improved GV in patients with T1DM when compared with
control participants. In addition, T1DM patients with a higher BMI may
benefit more in aspects of GV from additional metformin therapy than
those with lower BMI.
Metformin Improves Glycemic Variability in Adults with Type 1 Diabetes
Mellitus: an open-label randomized control trial
Abstract
Introduction: Metformin has been demonstrated to enhance
cardioprotective benefits in type 1 diabetes(T1DM). Although glycemic
variability (GV) is associated with increased risk of CVD in diabetes,
there is a scarcity of research evaluating the effect of metformin on GV
in T1DM.
Objectives: In the present study, the effects of adjuvant metformin
therapy on GV and metabolic control in T1DM were explored.
Patients and methods: A total of 65 adults with T1DM were enrolled and
subjected to physical examination, fasting laboratory tests and
continuous glucose monitoring, and subsequently randomized 1:1 to 3
months of 1000- 2000 mg metformin daily add-on insulin (MET+INS, n=34)
or insulin (INS, n=31). After, baseline measurements were repeated.
Results: The mean amplitude of glycemic excursions was substantially
reduced in the MET+INS group, compared with the INS group (-1.47±3.39
mmol/L versus 1.05±4.24 mmol/L, P =0.012). In parallel, the
largest amplitude of glycemic excursions (-2.28±4.71 mmol/L versus
1.77±5.71 mmol/L, P =0.003), the standard deviation of blood
glucose (-0.62±1.15 mmol/L versus 0.08±1.23 mmol/L,P =0.023),
and the coefficient of variation (-6.08±12.31 % versus 2.29±11.57 %,P =0.008) all demonstrated improvement in the MET+INS group,
compared with the INS group. Significant reduction in the insulin dose,
body mass index and body weight were observed in patients with MET+INS,
not those with INS.
Conclusion: Additional metformin therapy improved GV in adults with
T1DM, as well as improving body composition and reducing insulin
requirement. Hence, metformin as adjunctive therapy has potential
prospects in reducing the CVD risk in patients with T1DM in the long
term.
Keywords :Continuous Glucose Monitoring; Glycemic variability;
Metformin; Type 1 diabetes mellitus;
Introduction
Amongst the background of the rising incidence of Type 1 diabetes
mellitus (T1DM) across the globe, public concern has reached a new high
[1]. Despite progress in diabetes care, as the leading cause of
mortality in T1DM[2], cardiovascular disease (CVD), contributes to a
two- to four-times higher death rate in patients with T1DM, compared
with the general population [3, 4]. Diabetes Control and
Complications Trials (DCCT) have exhibited that intensive insulin
therapy attenuated atherosclerosis in T1DM patients, which was primarily
ascribed to the reduction in hemoglobin A1c (HbA1c) level [5]. As
the standard metric of glycemic control, the HbA1c level is ideally
maintained as close to normal as possible for the purpose of reducing
the incidence rate of long-term diabetic complications [6]. However,
the titration of increased insulin dosage is usually accompanied with
weight gain and glycemic variability (GV). Further, with the increasing
prevalence of obesity and overweight in patients with T1DM [7, 8],
insulin resistance (IR) considered to increase the CVD risk has become
prominent in these individuals [9, 10]. Moreover, a culmination of
evidence proposes that GV is integral in predicting adverse clinical
outcomes in patients with diabetes, including hypoglycemia, diabetic
complications as well as mortality[11], emerging as one of the core
treatment targets of potential therapeutic strategies . High GV is an
independent risk factor of CVD and could lead to further complications
than constant hyperglycemia [12]. For this reason, novel approaches
to flattening glucose fluctuations that will reduce the risk of CVD in
T1DM are in dire need.
For over five decades, metformin is an oral antihyperglycemic drug that
has been used extensively in the treatment of type 2 diabetes (T2DM).
Prior research has reported that metformin achieved glycemic control by
lowering hepatic glucose output, increasing the glucose uptake in
muscle, and decreasing the intestinal carbohydrates absorption rate, as
well as improving insulin sensitivity [13, 14]. The UK Prospective
Diabetes Study (UKPDS) revealed that metformin reduced the CVD risk in
patients with T2DM[15]. Metformin is not recommended by most
guidelines, and the role thereof in adjuvant therapy for T1DM has drawn
increasing concern in recent years. Aside from reduction in the daily
insulin dose and body weight, direct improvements in insulin sensitivity
and carotid intima-media thickness (cIMT) were also detected in T1DM
patients after additional metformin therapy, indicating that this
therapeutic strategy can form potential CVD risk protection [16-18].
On the basis of present knowledge, whether metformin as adjuvant therapy
could help reduce GV in patients with T1DM has not yet been illustrated.
Therefore, the present 3-month randomized-control trial was conducted in
accordance with the following objectives: to evaluate the effect of
additional metformin in insulin treatment on the primary outcome of GV
and HbA1c, in addition to other parameters of glycemic control and
anthropometric indexes.
Methods and Patients
The present trial was a 3-month open-label, randomized, controlled
clinical trial. Subjects with T1DM were consecutively recruited between
July 2017 and July 2019 at the outpatient clinic of the Department of
Endocrinology and Metabolism of the
Shenzhen
People’s hospital (The Second Clinical Medical College,Jinan
University). This trial was registered at clinicaltrials.gov
(NCT03590262) and conducted in accordance with the Declaration of
Helsinki and the International Conference of Harmonization-Good Clinical
Practice. The study protocol was approved by the Ethics Committee of the
hospital and written informed consent was obtained from each
participant. The inclusion criteria included: age range of 18 to 75
years, T1DM (positive for ≥1 diabetes mellitus–associated
autoantibody), and treated with continuous subcutaneous insulin infusion
or multiple daily injections at a stable regimen, with self-monitoring
of blood glucose (SMBG) at least three times per day for at least 1
month being required prior to participation in the study. The exclusion
criteria consisted of: resting blood pressure (BP) >140/90
mm Hg, smoking, medications affecting insulin sensitivity (steroids,
immunosuppressants, noninsulin antidiabetic agents), history of CVD,
hypertension, renal failure defined as glomerular filtration rate
< 45 mL/min/1.73 m2, diabetic ketoacidosis or severe illness
within 30 days, inability to tolerate ≥500 mg metformin twice per day
and pregnancy. The same diet and physical activity instructions were
given by the same dietician and diabetic educator to all patients before
randomization, and compliance was reinforced at each follow-up.
Study Design
After preliminary screening, 65 eligible participants were recruited and
randomized by a ratio of 1:1 into a group receiving 1000- 2000 mg
metformin daily add-on insulin therapy (MET+INS, n=34) or a group
receiving insulin treatment only (INS, n=31), with the trail lasting 3
months. The mean metformin dose was 1500 mg/d (range, 1000–2000 mg/d),
which was adjusted pursuant to the patient’s drug tolerance, while the
insulin dosage was adjusted predicated on SMBG. All participants were
subjected to a comprehensive evaluation at baseline and a 3-month
follow-up visit, including physical examination (BP, weight, height),
data concerning lifestyle (physical activity and eating habit),
frequency of hypoglycemia and the daily insulin regimen.
Laboratory Measurements
Blood analyses that included serum glucose, total
cholesterol
(TC), triglyceride (TG), high- density lipoprotein- cholesterol (HDL-C),
low-density lipoprotein- cholesterol (LDL-C) were performed at the
central laboratory of the hospital by using a biochemical analyzer
(Modular Analytics, Roche, Mannheim, Germany).These parameters were
investigated in all participants at fasting during the first visit, and
subsequently repeated after completion of the 3-month follow-up.
CGM Measurements and Parameter Calculation
Glucose levels were continuously monitored in all participants by
professional retrospective CGM (iPro™2, Medtronic Minimed Inc.,
Northridge, CA, USA) for 72 hours at baseline and at the end of the
3-month intervention. All participants were required to do pre-prandial
SMBG four times a day (before breakfast, lunch, dinner and before
bedtime) with a glucometer (Accu-Chek Mobile, Roche Diagnostics,
Mannheim, Germany) for calibrating the CGM. The accuracy of the
glucometer was calibrated by fasting blood glucose levels tested in the
central laboratory, and the deviation was less than 15%. Consecutive
72-hour calibrated glucose profiles of each participant at baseline and
after the 3-month intervention were recorded for further statistical
analysis. CGM data from iPro™2 sensor was downloaded via Carelink iPro
for analysis.
Parameters of GV were calculated, such as the standard deviation of
blood glucose (SDBG), mean amplitude of glucose excursions (MAGE),
largest amplitude of glycemic excursions (LAGE), coefficient of
variation (CV), and mean of daily differences (MODD). The time in range
(TIR, glucose range of 3.9-10.0 mmol/L during a 24-hour period) and mean
sensor glucose (MSG) were also calculated from the CGM data.
Outcomes
The primary outcomes were changes in MAGE and HbA1c from baseline to 3
months, while the secondary outcomes were changes in SD, LAGE, CV, MODD,
TIR, BMI, BP, lipid profiles and the daily insulin dose at the 3-month
follow-up, compared with baseline. Safety data includes the incidence of
all symptomatic or biochemically proven hypoglycemic episodes
(<2.8 mmol/L) and medication adverse events.
Power Calculations and Statistical Analyses
Owing to being a pilot study, the sample size was estimated pursuant to
the feasibility of conducting the study, with a convenience sample size
of 70 ultimately being adopted. Descriptive statistics were employed to
summarize baseline characteristics as mean ± SD for normally distributed
data and as median (interquartile range [IQR]) for non-normally
distributed data. Variables were checked for the distributional
assumption of normality with normal plots, in addition to
Kolmogorov-Smirnov and Shapiro-Wilks tests, and categorical variables
were expressed as percentages. In the univariate comparisons between the
MET+INS group and the INS group, categorical variables were compared by
chi-squared tests, while continuous variables were compared by t-tests
or Wilcoxon-Mann-Whitney tests as appropriate. A p-value of <
0.05 (two-tailed) was considered statistically significant. All
statistical analyses were conducted by utilizing the Statistical Package
for the Social Sciences (version 23.0; SPSS Inc., Chicago, IL, USA).
Results
A total of 70 patients participated, with 5 of them being ineligible or
lost to follow up. Among the 65 eligible randomized participants, 3
participants (2 in the MET+INS group, and 1 in the INS group) did not
complete the study protocol. Figure 1 exhibits the diagram depicting the
randomization and follow-up visit sample sizes, while baseline clinical
characteristics of the 65 patients with T1DM are summarized in Table 1.
The mean age of participants was 31±10 years old, and the median
duration of diabetes was 8 years (interquartile range, 2–15years). The
mean daily insulin dose was 0.63±0.09 U/ kg of body weight and BMI was
23.0± 1.8kg/m2. The baseline characteristics of patients with T1DM
randomized into two groups that finished the study are presented in
Table 2. There were no major differences in sex, age, duration of
diabetes, BMI, or parameters of metabolic control (HbA1c value, lipid
profiles) between the two groups at baseline. Further, no substantial
differences in the CGM parameters, such as MAGE, LAGE, SDBG, MODD, CV,
TIR or MSG were found between the two groups at baseline.
Effect of Metformin on Glycemic End Points
The results of the 3-month treatments with MET+INS and INS for the
investigated variables are revealed in Table 3. The primary outcome of
MAGE demonstrated significant improvement in the MET+INS group, as
against the INS group (-1.47±3.39 mmol/L versus 1.05±4.24 mmol/L,P =0.012, Figure 2A). Additionally, SDBG (-0.62±1.15 mmol/L versus
0.08±1.23 mmol/L , P =0.023, Figure 2B), LAGE(-2.28±4.71 mmol/L
versus 1.77±5.71 mmol/L , P =0.003, Figure 2C),and CV(-6.08±12.31
% versus 2.29±11.57%, p =0.008, Figure 2D) all exhibited improvement
in the MET+INS group, compared with the INS group. MSG was reduced
(-0.13±0.58mmol/l versus 0.23±0.75 mmol/l, P =0.038) with
additional metformin. Reduction in HbA1c (-0.05±0.22 % versus
0.03±0.28%, P =0.217) was discovered in the MET+INS group
compared with the INS group, but did not reach statistical significance.
In parallel, changes in TIR displayed no major difference between the
two groups.
Subgroup Analysis of Glycemic Variability and Glycemic Control in the
MET+INS group
The patients in the MET+INS group were further divided into two
subgroups on the basis of the median of baseline BMI (23.2 kg/m2), FPG
(8.6 mmol/L) and HbA1c (8.2%), respectively (Table 4). The patients
with a higher BMI presented greater reduction in MAGE (-2.76±3.12 mmol/L
versus 0.19±3.08 mmol/L, P =0.012) and CV (-9.96 ±11.49 % versus
-1.10±11.88%, P =0.041) as against those with a lower BMI. Yet,
the changes in SDBG, LAGE, MODD, TIR, MSG and HbA1c were not especially
different between the two subgroups. No significant difference in the
changes of GV and glycemic control was found between patients with
different levels of FPG or HbA1c at baseline.
Effect of Metformin on Insulin Requirement and Markers of Body
Composition
Significant reduction in daily insulin dose per body weight
(-0.02±0.01U/kg of body weight versus 0.00±0.02 U/kg of body weight,P <0.001; Figure 3A and Table 5) was identified in the MET+INS
group as against the INS group. Both body weight (-0.4±0.6kg versus
0.2±0.5 kg , P <0.001; Figure 3B and Table 5) and BMI (-0.2±0.2
kg/m2 versus 0.1±0.2 kg/m2, P <0.001; Figure 3C and Table 5) were
substantially reduced in the MET+INS group compared with the INS group
after the 3-month intervention.
Effect of Metformin on Other Traditional CVD Risk Factors
The adjuvant metformin therapy resulted in no notable change of lipids
profile (TG, TC, HDL-c and LDL-c), systolic BP and diastolic BP between
the two groups (Table 5).
Safety Data
Among the 65 randomized participants, only 3 participants (4.6%) failed
to complete the study protocol. There were no severe adverse events,
with only minor gastrointestinal side effects (nausea, flatulence,
reduced appetite, diarrhea) being reported in 8 participants in the
MET+INS group (23.5%). This led to de-escalation in the metformin dose
in 4 participants (11.8%), while for the other 4 patients, these
symptoms spontaneously resolved within 7 days. Hence, all participants
tolerated at least 1000 mg metformin per day. Hypoglycemia events were
recorded in 4 subjects with MET+INS and 3 subjects with INS, and no
sever hypoglycemia events were identified during the whole study. No
major changes in serum creatinine, alanine aminotransferase, aspartate
aminotransferase were observed between the two groups (data not shown).
Discussion
In the present randomized, open-label, controlled trial, a slight
decline in the HbA1c level in the MET+INS group was observed, in
contrast to the rising trend in the INS group. However, there was no
significant difference of these changes between the two groups.
In recent years, a profusion of attempts have been made to assist T1DM
patients in achieving near-normal glycemic control, including
advancement in diabetes management through the development of insulin
analogs, insulin infusion devices, as well as glucose monitoring
systems. Despite these attempts, the current situation is far from
satisfactory [19-21]. Previous clinical studies and meta-analyses
have reported that metformin, as an adjuvant therapy to T1DM, has
minimal benefits for glycemic control [7, 16, 18, 22, 23].
Conversely, new evidence has revealed modest improvements in the HbA1c
level of T1DM patients with adjuvant metformin therapy. One
meta-analysis highlighted that metformin reduced the HbA1c level by
0.26% in T1DM [24]. These discrepancies may be attributed to
different study durations with a 3-month cutoff point, implying that the
reduction in the HbA1c level caused by metformin could not sustain over
time[24]. Moreover, a study of T1DM patients under real-world
conditions reported that the HbA1c level decreased after a 1-year
follow-up owing to scheduled follow-up visits rather than additional
metformin treatment [25].
For further evaluation, TIR, which generally describes the percent of
time spent within the target glucose range (3.9-10mmol/L), was also
calculated from the CGM data. Yet, no notable difference was observed in
TIR before and after the 3-month treatment between the two groups.
Emerging as one of the central metrics of glycemic control, TIR has
close association with vascular complications of diabetes [26, 27].
Although a goal of >70% TIR was recommended by recent
consensus statements for people with diabetes [28], baseline TIR of
T1DM patients in the present study was considerably below target and was
seemingly not improved by the adjuvant metformin therapy.
Tough robust data has suggested HbA1c and TIR are important predictors
of the CVD risk in patients with diabetes [6, 26-29], but these
metrics can only reflect the average glucose levels over a period of
time. Further metrics are required to understand glycemic control in the
entirety thereof, particularly those reflecting glucose fluctuations,
such as hypoglycemia. Notably, hypoglycemia is a crucial barrier for
patients with T1DM to achieve near-normal glycemic control [19, 21].
Reports have indicated that T1DM patients with HbA1c levels of
<7.0% or >7.5% suffered more frequent severe
hypoglycemia than those with HbA1c levels of 7.0% to 7.5% [21].
GV, meanwhile, reflects the glucose homoeostasis over a given interval
of time and has become prominent as another vital metric for assessing
glycemic control in clinical practice. Further, GV supposedly
contributes more to the onset of diabetic cardiovascular complications
than persistent hyperglycemia. Prior research has demonstrated that
acute glycemic fluctuations could lead to CVD through oxidative stress
and nuclear factor-κB activation [30, 31]. Moreover, a positive
association between intermittent high blood glucose exposure,
endothelial dysfunction and damage has already been illustrated
[32], while flattening GV has been reported to mitigate IR and
reduce cIMT, a surrogate of CVD, in patients with T2DM [33]. As
against T2DM, GV notably has more robust impact on diabetes
complications in T1DM, most likely being attributed to the marked islet
cell secretory dysfunction in the latter group[12].
As previously mentioned, the effect of metformin on HbA1c levels has
been fully explored in patients with T1DM, while studies focusing on the
aspect of GV are scarce. The other primary finding of the present study
was that, in patients with T1DM, adjuvant metformin therapy reduced
MAGE, together with other metrics of GV (SDBG, LAGE and CV). Similar
reductions in MAGE and SD were also detected by Fei Gao et al. in
patients with T2DM by employing metformin add-on insulin
therapy[34]. Various metrics have been introduced to describe GV
over the years, yet no consensus has been reached on the most
appropriate characterization thereof. Introduced by Service et al.as the
“gold standard” for the evaluation of the intra-day GV, MAGE centers
on major glycemic excursions rather than minor ones [35]. Dasari P S
et al. reported that MAGE was closely linked with oxidative stress
markers [36]. Further, a meta-analysis conducted by Pu Z et al.
revealed that a higher MAGE was associated with a higher risk of major
adverse cardiovascular events (MACEs) in individuals, whether with or
without diabetes [37]. However, no significant changes in MODD,
which estimates between-day GV[38], were identified between the two
groups in the present study. Since only 72 hours of CGM data were
collected for quantification of GV in the present study, a longer CGM
time might be required for the further evaluation of this metric.
Thus, the hypothesis in the present study is that metformin add-on
insulin therapy could reduce glycemic fluctuation in T1DM to some
extent, which may serve as one of the mechanisms of alleviating
endothelium damage and enhance cardioprotective benefits. This
hypothesis needs to be verified by prospective studies.
The final finding of the present study was that additional metformin
decreased BMI and body weight by 0.2 kg/m2 and 0.4kg respectively.
Bjornstad P et al. reported similar results in youth with T1DM [16],
and even further reduction in BMI was detected by Agnieszka Z et al. in
adults with T1DM, in addition to excess body fat[17]. Moreover,
adjuvant metformin therapy also reduced the insulin requirement in the
present study. Lund et al. correspondingly identified a sustained
reduction in weight and insulin dosage in T1DM patients over a one-year
treatment with metformin [39]. All of the aforementioned research
has indicated that additional metformin improved metabolic control while
reducing IR in patients with T1DM. Be that as it may, in the present
study, no improvement was observed in other cardiovascular risk factors,
such as lipid profiles and blood pressure, in the MET+INS group. These
results align well with previous research on youth with T1DM [16].
In contrast, conflicting conclusions were reported by Liu Y S et al.,
who found improvement in partial lipid profiles and diastolic blood
pressure in T1DM patients with additional metformin[24].
According to the previous literature, metformin supposedly increases the
risk of gastrointestinal adverse effects and may induce more
hypoglycemia events in patients with T1DM [24, 40]. In the present
study, no severe adverse events were observed and only 4 participants
(11.8%) in the metformin group had the insulin dose thereof down
escalated due to gastrointestinal side effects. Further, all patients
tolerated at least 1000mg metformin per day during the whole study, and
metformin did not increase the incidence of hypoglycemia.
There are several significant strengths and limitations of the present
study. First, this carefully designed, well-conducted clinical study is
the first study to explore the effects of additional metformin on the GV
in adults with T1DM. Second, both normal-weight and overweight/obese
patients with T1DM were included, allowing further subgroup analysis in
patients with different BMI levels. Third, the patients in both groups
demonstrated relatively well adherence to CGM and had high visit
attendance. The limitations in our study include the fact that the
open-label design thereof may lead to a degree of bias. Moreover, CGM
data were collected for 72 hours, while a recommendation of 2-4 weeks of
data collection has been proposed by current guidelines in clinical
practice [28, 41]. This is because prolonging the duration of CGM
could minimize the statistical bias of GV and TIR on the individual
level. Additionally, the effect of individual diet and exercise
deviations on GV could not be wholly excluded. The bias was minimized by
reinforcing the guidance for diet and physical activity at each visit
and urging the patients to maintain the same diet and physical activity
during the CGM period.
Conclusions
Additional metformin therapy for 3 months reduced blood glucose
fluctuation in adults with T1DM, particularly in those with higher BMI.
Further, metformin improved the body composition and reduced the insulin
requirement, indicating the reduction in insulin resistance in patients
with T1DM. No severe adverse events or hypoglycemia were induced by
additional metformin. To conclude, metformin as adjunctive therapy has
potential prospects in the management of CVD risk in T1DM in the long
term, which needs to be further elucidated in outcome trials.
Contribution
statement
XZ conceived the study and wrote the paper. XZ and FY contributed to the
design of the research. All authors were involved in data collection.
DX, PX and SY analyzed the data. QZ and WY revised the manuscript. XZ
and FY are the guarantors of this work. All authors edited and approved
the final version of the manuscript.
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