Predictors of Metformin Side Effects in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

Abstract

Introduction Metformin has become the first-line agent for the treatment of type 2 diabetes mellitus (T2DM) in several international guidelines. Up to 25% of patients suffer from gastrointestinal side-effects, with approximately 5% unable to tolerate metformin at all.
Objective We aimed to study the effect of variables that may influence the development of metformin side effects and/or intolerance.
Method A prospective study was conducted from April 1, 2021 to March 30, 2022. One-hundred and forty-eight patients newly diagnosed with T2DM were enrolled in the study, and divided into two groups—those who were escalate to the maximum dose of metformin over 2 weeks (n = 43) and the other group over 4 weeks (n = 105). We studied the variables that may affect the development of side effects including age, gender, body mass index (BMI), lipid profile, glycemic level, and the use of other antidiabetic medications besides the duration of dose escalation.
Results Total number of patients who developed side effects was 59 (39.9%). Twenty-four (55.8%) and 35 (33.3%) patients were put in the rapid and slow escalation groups, respectively. Twenty-six (17.6%) patients developed diarrhea that was the most common side effect. Two (2.7%) men and ten women (13.5%) had stopped metformin due to severe side effects developed after initiation (p = 0.016). The mean BMI for the patients who discontinued metformin was 34.7 ± 4.1 kg/m2 in the rapid escalation arm and 31.6 ± 3.3 kg/m2 in the slow escalation arm (p = 0.003). The mean of fasting blood glucose for the patients who discontinued metformin in the rapid and slow escalation arms was 200.6 ± 25.6 and 173.4 ± 36.5 mg/dL, respectively (p = 0.022).
Conclusion The severity of metformin side effects is higher in women than in men, making more women to discontinue the drug. Besides, a higher fasting blood sugar and BMI are associated with a higher rate of discontinuation. A rapid dose escalation is associated with a higher frequency of side effects. Diarrhea is the commonest side effect encountered.

Full text

Predictors of Metformin Side Effects in Patients
with Newly Diagnosed Type 2 Diabetes Mellitus
Nassar Taha Yaseen Alibrahim1Mohammed Ghazi Chasib1Saad Shaheen Hamadi2
Abbas Ali Mansour1
1Faiha Specialized Diabetes, Endocrine and Metabolism Center,
University of Basrah, Basrah, Iraq
2College of Medicine, University of Basrah, Basrah, Iraq
Ibnosina J Med Biomed Sci
Address for correspondence Nassar Taha Yaseen Alibrahim, CABM,
Faiha Specialized Diabetes, Endocrine and Metabolism Center,
University of Basrah, Basrah, Iraq 61013
(e-mail: nassar.yaseen@fdemc.iq).
Keywords
►diabetes mellitus
►metformin
►side effects
►intolerance
►dose escalation
Abstract Introduction Metformin has become the first-line agent for the treatment of type 2
diabetes mellitus (T2DM) in several international guidelines. Up to 25% of patients suffer
from gastrointestinal side-effects, with approximately 5% unable to tolerate metformin at all.
Objective We aimed to study the effect of variables that may influence the develop-
ment of metformin side effects and/or intolerance.
Method A prospective study was conducted from April 1, 2021 to March 30, 2022.
One-hundred and forty-eight patients newly diagnosed with T2DM were enrolled in the
study, and divided into two groups—those who were escalate to the maximum dose of
metformin over 2 weeks (n¼43) and the other group over 4 weeks (n¼105). We
studied the variables that may affect the development of side effects including age,
gender, body mass index (BMI), lipid profile, glycemic level, and the use of other
antidiabetic medications besides the duration of dose escalation.
Results Total number of patients who developed side effects was 59 (39.9%). Twenty-
four (55.8%) and 35 (33.3%) patients were put in the rapid and slow escalation groups,
respectively. Twenty-six (17.6%) patients developed diarrhea that was the most
common side effect. Two (2.7%) men and ten women (13.5%) had stopped metformin
due to severe side effects developed after initiation (p¼0.016). The mean BMI for the
patients who discontinued metformin was 34.7 4.1 kg/m
2
in the rapid escalation arm
and 31.6 3.3 kg/m
2
in the slow escalation arm (p¼0.003). The mean of fasting blood
glucose for the patients who discontinued metformin in the rapid and slow escalation
arms was 200.6 25.6 and 173.4 36.5 mg/dL, respectively (p¼0.022).
Conclusion The severity of metformin side effects is higher inwomen than in men, making
more women to discontinue the drug. Besides, a higher fasting blood sugar and BMI are
associated with a higher rate of discontinuation. A rapid dose escalation is associated with a
higher frequency of side effects. Diarrhea is the commonest side effect encountered.
DOI https://doi.org/
10.1055/s-0043-1761215.
ISSN 1947-489X.
© 2023. The Libyan Biotechnology Research Center. All rights
reserved.
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Research Paper
Article published online: 2023-04-01

Introduction
According to the World Health Organization, diabetes melli-
tus (DM) is a chronic, progressive disease characterized by
high levels of glucose in the blood. Type 2 diabetes mellitus
(T2DM) accounts for 90% of all cases of diabetes, a condition
caused by either decline in pancreatic B cell function or
peripheral insulin resistance.1Diabetes risk factors include
(genetic, metabolic, and environment that interact with each
other leading to its prevalence. T2DM risk factors are divided
into nonmodifiable r isk factors (ethnicity and family history/
genetic predisposition) and modifiable risk factors (obesity,
low physical activity, and an unhealthy diet).2,3 The preva-
lence of T2DM in 2019 in the Middle East was 12.2% and is
estimated to increase to 15.7% by 2045. In Iraq, the preva-
lence of T2DM in 2018 was ranging from 8.5 to 13.9%.4T2DM
can be managed with different strategies (lifestyle modifica-
tion, the use of insulin, or the antidiabetic medications
administration) together with monitoring of blood glucose.5
Metformin—dimethylbiguanide—is an oral glucose-lower-
ing medication. Its origin was based on a plant extract com-
monly named as goat’s rue or French lilac, the Galega
officinalis.6Since its discovery early in the last century, it
became well known for its blood glucose lowering effects, in
animals initially, when Jean Sterne extensively studied it and
later developed the glucophage in the fifties of last century.7Its
good reputation, regarding both the efficacy and safety pro-
files, placed it at the top of most T2DM management guidelines
recommendations.8Although one can recall some past bumps
through its history, when, at some point, it was shadowed by
phenformin, which had contributed to serios lactic acidosis
until the 1970s when it was withdrawn.9Several large ran-
domized control trials had proven that metformin improves
glycemic control and has a good safety profile and is not
associated with hypoglycemia besides its low cost.10 Metfor-
min, like any medications, has side effects, and up to 25% of
patients may suffer from side effects mostly gastrointestinal
with approximately 5% could not tolerate metformin.11
The most noticeable metformin side effects include nau-
sea, vomiting, bloating, dyspepsia, metallic taste, abdominal
pain, abdominal cramps, and/or changes in intestinal motili-
ty, leading to loose stools and overt diarrhea that becomes,
sometimes, intractable. The etiology behind metformin in-
tolerance is still unclear.12
The aim of this article was to study the effect of variables
that may influence the development of metformin side
effects and/or intolerance and the frequency of each side
effect.
Method
Patients and Setting
A prospective study was conducted in Faiha Specialized
Diabetes, Endocrine and Metabolism Center in Basrah city
from April 1, 2021 to March 30, 2022. Data were collected
from the patients attending the center and from patients
referred from private specialized endocrinology clinics (as
mentioned in the acknowledgment) using the same inclu-
sion and exclusion criteria. One hundred and forty-eight
patients with newly diagnosed T2DM on any one of the
following criteria: (non-fasting blood glucose more than
200 mg/dL (>11.1 mmol/L), fasting (8 hours or longer) blood
glucose more than or equal to 126 mg/dL (7.0 mmol/L), or
glycated hemoglobin (HbA1c) more than or equal to 6.5%13,
in patients who had symptoms suggestive of DM (polyuria,
polydipsia and weight loss), their age 35 years old and above.
Patients with abnormal renal function (raised serum creati-
nine level 1.5 mg/dL i n m en, a nd m ore th an 1.4 mg/ dL i n
women), pregnancy, liver cirrhosis, peptic ulcer disease,
congestive heart failure, inflammatory bowel disease, and
patients with gastrointestinal surgery were excluded. In this
study, we divided the patients into two groups, those who
escalated their metformin dose to the maxi mum (200 0 mg/
day) over 2 weeks (500 mg twice daily [bid] in the first week
and 1000 mg bid in the second week), while the other group
escalated over 4 weeks (500 mg on ce daily in the first week
and increase the dose by 500 mg weekly). Anthr opometric
data were collected from th e patients through careful histor y
and clinical examination; patients were sent for HbA1c,
fasting, and/or random blood glucose and lipid profile; a
questionnaire involving all the required data was filled by
physicians who volunteered to help. Verbal consents were
taken from all patients prior to enrollment. We studied the
effect of the above variables on the development of the side
effects including the use of other antidiabetic medications.
Statistical Analysis
We used the statistical package for the social sciences (SPSS
v23); for the comparison of the continuous variables, Stu-
dent’st-test was used, and for the categorical variables
Pearson’s chi-squared or Fisher’s exact test was used when
appropriate. Receiver operator characteristics (ROC) curve
statistics were used to extract a cutoff value of some contin-
uous variables. A p-value of less than 0.05 was considered as
a level of significance.
Results
►Table 1 shows the general characteristics of the patients at
the beginning of our study. Of the 148 enrolled patients, 72
(48.6%) were men and 74 (51.4%) women. Forty-three (29%)
patients were in the rapid escalation arm and 105 (71%) in
the slow escalation arm.
Out of all the enrolled patients, 59 (39.9%) developed one
or more of the metformin side effects (gastrointestinal tract
[GIT] and non-GIT), and the frequency of each side effect can
be seen in ►Fig. 1. While diarrhea was the most frequently
observed side effect seen in 26(17.6%) patients, myalgia was
observed in the least 2 patients (1.4%). The effect of escala-
tion methods on the frequency of side effects can be seen
in ►Table 2. Higher frequencies of side effects occurred in the
rapid escalation arm in comparison to the slow escalation
arm, with the exception of chest discomfort (although sta-
tistically not significant).
Some of the features of the 59 patients who developed
side effects can be seen in ►Table 3. A lthough no single factor
Ibnosina Journal of Medicine and Biomedical Sciences © 2023. The Libyan Biotechnology Research Center. All rights reserved.
Predictors of Metformin Side Effects in T2DM Alibrahim et al.

was significantly associated with the development of the
metformin side effects between both arms, generally they
tend to occur more in women. In 12(8.1%) patients, the side
effects were rather more severe that obligated them to
discontinue metformin; some features of these patients
are illustrated in ►Table 4. Ten women (13.5%) versus two
men (8.1%) had discontinued metformin due to the develop-
ment of severe side effects (p¼0.016). Patients who discon-
tinued metform in had a higher BMI (mean ¼34.7 0 
4.05 kg/m
2
) than t hose who did not (m ean ¼31.64 3.29
kg/m
2
)(p¼0.003) and were having a higher basal fasting
blood sugar (200 .60 25.57 vs. 173.36 36.48; p¼0.022).
From the area under the curve retrieved from the ROC
curve drown for the BMI against the development of metfor-
min discontinuation (►Fig. 2), we can see that patients with
BMI 32.2 kg/m
2
and above were more likely to be intolerant
to metformin (s ensitivity ¼75%, specificity ¼72%; odds ratio
[OR] ¼6.930 with 95% confiden ce interval ¼1.462–32.844;,
p¼0.004).
While data from the area under the curve retrieved
from the ROC curve (►Fig. 3)drownfortheFBGagainst
discontinuation of metformin, we can see that patients
with FBG of 180 mg/dL and below were less likely to be
intolerant to metformin (sensitivity ¼90%, specificity
¼74%; OR ¼22.629 with 95% confidence interval ¼2.763–
185.304, p¼0.001).
Discussion
Oral hypoglycemic drugs were reported as a common cause
of side effects especially gastrointestinal14 the mechanism
behind these side effects was still in a controversy and the
studies’results were conflicting.15–17 Moreover, these symp-
toms were very common in diabetic patients and normal
people in the community making the relationship difficult to
prove. And even in patients with diabetes, the frequency and
severity were subjected to a significant interindividual vari-
ation that may hinder a genetic predisposition.11
To our knowledge, this was the first study ever looking for
the effect of escalation time on the development of metformin
Table 1 General characteristics of the patients at the
beginning of the study,
a
n¼148
Rapid
escalation
n¼43
Slow
escalation
n¼105
p-Value
Age (yea rs) 50.4 8.1 48.5 5.8 0.103
Male gender 22(51.2) 52(49.5) 0.856
Female gender 21(48.2%) 53(50.5%)
BMI (kg/m
2
)32.15.1 31.8 2.5 0.685
FBS (mg/dL) 184.7 41.2 172.2 34.3 0.083
RBG (mg/dL) 262.1 103.2 225.3 100.2 0.387
TG (mg/dL) 208.2 81.1 210.8 36.4 0.838
Tot a l
cholesterol
(mg/dL)
205.1 52.6 213.9 36.1 0.465
HbA1c % 9.7 2.1 9.5 1.1 0.575
SU 13(30.2) 38(36.2) 0.622
DPP4i 12(27.9) 22(21.0) 0.361
TZD 6(14.0) 7(6.7) 0.303
Insulin 10(23.3%) 8(7.6%) 0.008
Abbreviations: BMI, body mass index; FBG, fasting blood glucose; RBG,
random blood glucose; TG, triglycerides; HbA1c, glycated hemoglobin;
SD, standard deviation; SGLT2i, sodium/glucose cotransporter-2 inhib-
itors; SU, sulphonylureas; DPP4i, dipeptidyl peptidase type 4 inhibitors;
TZD, thiazolidinedione.
Data were ex pressed either as m ean SD or n(%).
a
Four patient were on SGLT2i in the rapid escalation arm, while no one in
the slow arm.
Fig. 1 Percentages of metformin side effects.
Ibnosina Journal of Medicine and Biomedical Sciences © 2023. The Libyan Biotechnology Research Center. All rights reserved.
Predictors of Metformin Side Effects in T2DM Alibrahim et al.

side effects; any previous advice about gradual escalation was
delivered from clinical observations and was advised for
escalation of the dose over a period of 4 weeks.18 Though, in
our clinical practice, we were frequently facing patients who
escalated their metformin rapidly on their own without com-
plaining from serious side effects, which made us thinking
about including the study of this factor and its effect on the
development of metformin side effects.
The frequency of metformin side effects differs between
the studies and as more than one third of our patients
Table 2 Frequency of metformin side effects in the whole studied patients
a
Total Rapid escalation Slow escalation p-Value
Any side effect 59(39.9%) 24(55.8%) 35(33.3%) 0.011
GIT related
Epigastric pain 11(7.4%) 4(9.3%) 7(6.7%) 0.402
b
Diarrhea 26(17.6%) 15 (34.9%) 11(10.5%) <0.001
Bloating 15(10.1%) 9(20.9%) 6(5.7%) 0.005
Nausea 25(16.9%) 12(27.9%) 13(12.4%) 0.22
Vomiting 16(10.8%) 8(18.6%) 8(7.6%) 0.051
Abd pain 8(5.4%) 3(7.0%) 5(4.8%) 0.424
b
Heart burn 17(11.5%) 9(20.9%) 8(7.6%) 0.021
Non-GIT
Chest discomfort 3(2.0%) 0(0.0%) 3(2.9%) 0.354
b
Palpitation 9(6.1%) 7(16.3%) 2(1.9%) 0.003
b
Headache 5(3.4%) 4(9.3%) 1(1%) 0.025
b
Myalgia 2(1.4%) 1(2.3%) 1(1.0%) 0.498
b
Abbreviation: GIT, gastrointestinal tract.
a
No patients in our study had complained of dyspepsia, constipation, flushing, or distension.
b
F-test.
Table 3 Factors associated with the development of metformin side effects, n¼59
Rapid escalation
n¼24
Slow escalation
n¼35
p-Value
Age (years) 51.29 7.81 48.17 8.305 0.152
Male gender 10/22(45.5%) 11/52(21.2%) 0.420
a
Female gender 14/21(66.7%) 24/53(45.3%)
BMI (kg/m
2
) 32.05 5.77314 32.38 3.35 0.780
FBG (mg/dL) 188.53 44.98 174.55 54.111 0.356
RBG (mg/dL) 253.89 106.107 231.86 120.763 0.704
TG (mg/dL) 202.2055.966 200.47 69.745 0.948
Cholesterol (mg/dL) 219.27 36.266 202.65 41.553 0.288
HbA1c % 9.44 1.86 9.19 1.52 0.569
SU 12(50.0%) 10(28.6%) 0.095
DDP4 5(20.8%) 8(22.9%) 0.854
TZD 4(16.7%) 3(8.6%) 0.293
b
SGLT2 2(8.3%) 0(0.0%) 0.161
b,c
Insulin 4(16.7%) 4(11.4%) 0.418
b
Abbreviations: BMI, body mass index; DPP4i, dipeptidyl peptidase type 4 inhibitors; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; RBG,
random blood glucose; SD, standard deviation; SGLT2i, sodium/glucose cotranspor ter-2 inhibitors; SU, sulphonylureas; TG, triglycerides; TZD,
thiazolidinedione.
Data were ex pressed either as m ean SD or n(%).
a
Percentages were calculated by dividing the number of patients who did develop side effects by the number of those who did not in each field.
b
F-test.
c
Already there are no patient on SGLT2i in the slow arm.
Ibnosina Journal of Medicine and Biomedical Sciences © 2023. The Libyan Biotechnology Research Center. All rights reserved.
Predictors of Metformin Side Effects in T2DM Alibrahim et al.

Table 4 Factors associated with discontinuation of metformin
Yes No p-Value
Number 12(8.1%) 136(91.9%) NA
Age (yea rs) 49.17 5.54 49.02 6.71 0.942
Male gender 2(2.7%) 72(97.3%) 0.016
Female gender 10(13.5%) 64(86.5%)
BMI (kg/m
2
)34.704.05 31.64 3.29 0.003
FBG (mg/dL) 200.60 25.57 173.36 36.48 0.022
RBS (mg/dL) 207.33 19.35 252.82 107.22 0.479
TG (mg/dL) 205.50 108.45 210.38 47.60 0.852
Cholesterol (mg/dL) 207.20 26.03 210.38 45.40 0.879
HbA1c % 9.79 1.07 9.54 1.49 0.562
SU yes 6(11.8%) 45(88.2%) 0.237
No 6(6.2%) 91(93.8%)
DDP4 yes 2(5.9%) 32(94.1%) 0.450
a
No 10(8.8%) 104(91.2%)
TZD yes 2(15.4%) 11(84.6%) 0.284
a
No 10(7.4%) 125(92.6%)
SGLT2 yes 0(0.0%) 4(100.0%) 0.710
a
No 12(8.3%) 132(91.7%)
Insulin yes 2(11.1%) 16(88.9%) 0.641
No 10(7.7%) 120(923%)
Abbreviations: BMI, body mass index; DPP4i, dipeptidyl peptidase type 4 inhibitors; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; RBG,
random blood glucose; SGLT2i, sodium-glucose cotransporter type 2 inhibitor; SU, sulphonylureas; TG, triglycerides; TZD, thiazolidinediones.
a
F-test.
Fig. 2 Receiver operator characteristics (ROC) curve for the effect of
body mass index on metformin discontinuation rate.
Fig. 3 Receiver operator characteristics (ROC) curve for the effect of
fasting blood glucose on metformin discontinuation rate.
Ibnosina Journal of Medicine and Biomedical Sciences © 2023. The Libyan Biotechnology Research Center. All rights reserved.
Predictors of Metformin Side Effects in T2DM Alibrahim et al.

developed one or more side effects, other studies found it to
be as high as 53.3%.19
Diarrhea continues to be the most frequently encoun tered
side effect in about sixth of the patients followed by nausea
with comparable frequencies of diarrhea in other stud-
ies,20,21 but much less than the observation of Florez et al
who found it to be reaching to the half.22
Heartburn, vomiting, and bloating were seen in around
tenth of the patients, a percentage quite smaller than what
was seen by other studies: 52, 25, and 35%, respectively.22–24
Epigastric and abdominal pain were seen in less than 10%
of the patients, and in contrast to other side effects, epigas-
tric pain was higher than what was noticed previously.21
Patients also reported some nongastrointestinal side effects
of metformin, such as palpitation, headache, chest discomfort,
and myalgias, but none of these have reached 10% in prevalence,
similar to the findings of previous investigators.24,25
Most of the patients who developed side effects were
around the age of 50 years, Flory et al found that patients
aged between 50 and 65 years were 8% less likely to have side
effects than patients more than 65 years old, although their
results were not statically significant.26
Obesity was evident in the patients who developed met-
formin side effects, although this was in contrast to the
finding of Guo et al who found that the proportion of patients
who reported more than one side effect did not differ
significantly between BMI groups.27
As a common finding, women reported side effects more than
men did, although statistically not significant in our study.28
Some of these side effects were severe enough to obligate
the patients to discontinue metformin, at a rate slightly
higher than the finding of Bouchoucha et al.29 Most of
them were females as in the observations of previous inves-
tigators who found, besides, women were prescribed lower
doses of metformin to avoid discontinuation.28,30–32 One
explanation for this gender difference could be attributed
to fact that women may be more eager to read about drug
information including side effects than men did, which may
cause reporting biase.33 Or it can be attributed to pharma-
cokinetics differences between genders that may result from
differences in body fat percentage and its effect on the drug
distrbution.34 Likely wise, this could be the explanation
behind the higher BMI of the patients who discontinued
metformin in our study.
We failed to find studies investigating the effect of glyce-
mia or lipid profile on the development of the metformin
adverse effects to compare it with our results regarding both
the frequency of side effects and the rate of discontinuation
of metformin, which will merit the need for further inves-
tigations and studies in the future. And apart from hypogly-
cemia which accompanies sulfonylureas and insulin, the
coadministration of other anti-diabetic medications had no
effect on the patterns of side effects.
Surprisingly, other gastrointestinal symptoms like consti-
pation, flushing, dyspepsia, abnormal taste, and distension
were not reported by any patients in our cohort.
Whether the side effects mentioned by the patients were
due to undiagnosed gastrointestinal diseases or due to
metformin itself was hardly to be confirmed, making it
one of the limitations of the study. Another limitation of
the study was that we have only studied (from medication-
wise) the effect of antidiabetic medications and have not
included other medications that may contribute to these
symptoms. But as we have asked the patients to report only
new symptoms they felt after metformin use, we proposed
that these symptoms were due to metformin use.
Conclusion
Metformin side effects (gastroi ntestinal and to a lesser extent
nongastrointestinal) were common in our population. Diar-
rhea was the most frequently noticed side effect. Women
exhibit side effects to metformin more than men did, and
were more likely to discontinue the drug due to higher
severity of the side effects. Patients who titrated their
medication in a short period were more prone for the
development of side effects in comparison with those who
titrated it over a longer period. Female gender, higher BMI,
and higher FBG were associated with more metformin dis-
continuation events.
Authors’Contributions
Data collection was performed by MG Chasib. Results and
statistical analyses were done by NTY Alibrahim. The
study was designed by SS Hamadi and AA Mansour was
responsible for literature review and discussion.
Compliance with Ethical Principles
The research was approved by the ethical committee at
Faiha Specialized Diabetes, Endocrine and Metabolism
Center in Basrah.
Funding and Sponsorship
None.
Conflict of Interest
None declared.
Acknowledgments
We would like to express our sincere gratitude to Dr.
Haider Ayad Alidrisi, Dr. Safaa Adulmonim, and Haider
Abd-Oan for their help in patients referral and advice.
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Predictors of Metformin Side Effects in T2DM Alibrahim et al.