AM McBain

Anders Svare

C Schnack

CA Naranjo

D Kirpichnikov

HM Mather

I Alon

JR Weisinger

O Gorelik

SA Ewis

English

PubMed

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A patient presenting with symptomatic hypomagnesemia caused by metformin-induced diarrhoea: a case report

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BioMed CentralCases Journal
ssOpen AcceCase Report
A patient presenting with symptomatic hypomagnesemia caused by 
metformin-induced diarrhoea: a case report
Anders Svare1,2
Address: 1Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 
Trondheim, Norway and 2Department of Medicine, Namsos Hospital, N-7800 Namsos, Norway
Email: Anders Svare - anders.svare@hnt.no
Abstract
Introduction: Metformin is licensed for treatment of diabetes mellitus type 2. This report
describes a patient on metformin who developed diarrhoea and symptomatic hypomagnesemia. To
the author's knowledge, this is the first report on metformin-induced symptomatic
hypomagnesemia.
Case presentation: The patient was a 57-year old Caucasian male with diabetes mellitus type 2.
He had been on metformin for nine years and presented with chronic diarrhoea, spasms,
paresthesias, pain, and malaise. Blood tests revealed hypomagnesemia, hypocalcemia, and
hypokalemia.
Conclusion: Drugs associated with diarrhoea may induce malabsorption. If malabsorption is
substantial it may result in further symptoms of clinical importance. In some cases potentially life-
threatening conditions may occur.
Introduction
Metformin is a drug licensed for treatment of diabetes
mellitus type 2 [1]. The use of metformin is associated
with dose dependent side effects related especially to the
gastrointestinal tract [1]. Diarrhoea is very common. Dia-
betes mellitus and diarrhoea are both common causes of
hypomagnesemia [2]. Although some animal studies
have shown a potential beneficial effect of metformin on
magnesium status [3-5], there have been small clinical
studies which have found biguanides (the drug group to
which metformin belongs) to be associated with magne-
sium depletion [6,7].
Case presentation
The patient was a 57-year-old Caucasian male. He was an
ex-smoker and reported normal alcohol consumption.
His medical history included coronary artery disease,
hypertension and gastrointestinal reflux. He had been
diagnosed with type 2 diabetes mellitus back in 1996. At
the time he got the diabetes diagnosis, he reported that his
stools for many years had tended to be a little loose. How-
ever, he described it as a minor problem, the main annoy-
ance being the passing of loose stools once every morning.
Initially he was treated with glipizide (a SU drug). Met-
formin was added in 1999. The dose had been gradually
increased, and since 2004 he had been taking 1 g with
breakfast and 0.5-1 g with supper. He had no known com-
plications to his diabetes.
He was admitted to the Medical Ambulatory in March
2008 because of carpal and calf spasms, pain (especially
in the legs), paresthesias of the lips, hands and feet, and
malaise. His GP had diagnosed hypomagnesemia, hypoc-
alcemia and hypokalemia. When seen in the Medical
Published: 16 October 2009
Cases Journal 2009, 2:156 doi:10.1186/1757-1626-2-156
Received: 24 September 2009
Accepted: 16 October 2009
This article is available from: http://www.casesjournal.com/content/2/1/156
© 2009 Svare; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
Cases Journal 2009, 2:156 http://www.casesjournal.com/content/2/1/156Ambulatory, he reported a substantial diarrhoea problem
which had lasted a long time. He did not recall exactly
when the diarrhoea had become a problem, but at least he
remembered that it was after the introduction of met-
formin in 1999. When asked about any relation between
the diarrhoea and the introduction of metformin or
increase of metformin dose, he had not noticed any such
relation. The last months before his admission in March
2008 his diarrhoea had worsened even more. These
months he had been passing loose stools on average four
times a day. Sometimes he had observed some mucilage
in the stools. His additional medication included
glimepirid (a SU drug), metoprolol, isosorbide mononi-
trate, ramipril, atorvastatin, clopidogrel, aspirin, and lan-
soprazol.
On examination his blood pressure was 192/100 mmHg.
Sodium was 143 mmol/l (reference range 137-145),
potassium 3.4 mmol/l (3.6-4.6), calcium 1.97 mmol/l
(2.15-2.51), magnesium 0.33 mmol/l (0.71-0.94), albu-
min 45 g/l (36-45), creatinine 80 μmol/l (62-133), glu-
cose 9.9 mmol/l (4.0-6.0), HbA1c 7.1% (4.0-6.0),
Vitamin B12 272 pmol/l (113-603), free thyroxin 17.2
nmol/l (9.0- 19.0), TSH 2.32 mU/l (0.20- 4.5), PTH 2.3
pmol/l (1.3-7.6), 25-OH-Vitamin D 67 nmol/l (20-100),
1.25-(OH)2-Vitamin D 113 pmol/l (48-160), and anti-
tissue transglutaminase antibodies IgA was negative.
Thus, the blood tests showed hypomagnesemia, hypocal-
caemia and hypokalemia.
It was concluded that he suffered from severe hypomag-
nesemia, most likely due to diarrhoea caused by met-
formin. Therefore, metformin was discontinued and daily
intake of magnesium and potassium was instituted. He
reported that the consistency of his stools improved mark-
edly in the course of a few days after the discontinuation
of metformin.
At a follow-up consultation three weeks later, magnesium
was 0.80 mmol/l, calcium 2.49 mmol/l, albumin 43 g/l
and potassium 4.4 mmol/l. However, his blood glucose
was found to be unacceptably high. The glimepiride dose
was increased, and he also started to take sitagliptin. In
addition, he was suggested to try a reduced metformin
dose, 0.5-1.0 g daily. When seen again in August 2008, he
was still not feeling well. Because of diarrhoea he had
stopped taking metformin a few days after the reinstitu-
tion of the drug, and again the stools' consistency had
improved rapidly. His plasma glucose was 10-20 mmol/l.
Therefore, the oral antidiabetic drugs were discontinued
and a two-dose NPH insulin regime was instituted. At a
follow-up consultation in December 2008 his diabetes
was well regulated, serum electrolyte levels were within
the normal range and loose stools now was a minor prob-
lem. About two months before this consultation the
patient, without consulting any physician, had discontin-
ued the magnesium and potassium tablets.
When seen last time in September 2009, he still was in
good shape and with only minor bowel problems. His
blood tests were all within the normal range: magnesium
0.99 mmol/l, sodium 142 mmol/l, potassium 4.1 mmol/
l, calcium 2.40 mmol/l, creatinine 102 mmol/l, and albu-
min 45 g/l.
Discussion
The electrolyte deficiencies described in this case are
assessed to be the result of metformin-induced chronic
diarrhoea. The Naranjo algorithm is a questionnaire used
to assess whether symptoms or findings are actually
adverse effects of specific drugs, or caused by other fac-
tors[8]. Scores range from -3 to +12. A score of 5-8 classi-
fies the symptoms or findings as probable adverse drug
effects, whereas a score ≥ 9 describes a definite adverse
drug effect. When the Naranjo algorithm is applied to this
patient, using the combination of hypomagnesemia and
severe diarrhoea as the adverse effect, the following scores
are obtained: These adverse effects have been reported
before (+1). The adverse effects appeared after metformin
was given (+2). The diarrhoea and hypomagnesemia
improved after metformin was discontinued (+1). The
diarrhoea (and presumably the hypomagnesemia) reap-
peared when metformin was tried again later (+2). The
electrolyte deficits were objectively verified (+1). At last,
there is the question whether the symptoms and findings
were definitely caused by the drug, or if there are alterna-
tive explanations. Diabetes may cause hypomag-
nesemia[2]. Besides, even before he got the diabetes
diagnosis, he reported his stools to be loose, and diar-
rhoea unrelated to metformin could also be causal [2]. At
last, there are many other theoretical causes, including his
other drugs [2]. However, based on the HbA1c, his diabe-
tes was well regulated at the time of his admission. His
diabetes treatment was changed during the months after
the metformin discontinuation. Glimepiride was
increased, sitagliptin was tried for a few months, and from
August the patient was put on NPH insulin in mono-
therapy. A small study from 1988 showed a beneficial
effect of glipizide on serum magnesium in poorly regu-
lated type 2 diabetics [7]. However, the patient had been
on SU drugs for a long time at his admission, and it is very
unlikely that the dose increment caused the serum magne-
sium improvement. In a study from 1992, neither insulin
nor SU drugs improved hypomagnesemia in diabetes
mellitus type 2 patients [9]. This should also rule out insu-
lin treatment as the probable cause of improvement. No
reports on the effect of sitagliptin or related drugs on mag-
nesium status exist, and the short spell it was used, makes
an effect highly unlikely. His stools were still a little loose
after the discontinuation of metformin, but the electro-Page 2 of 4
(page number not for citation purposes)
Cases Journal 2009, 2:156 http://www.casesjournal.com/content/2/1/156lytes remained inside the reference range. Diarrhoea not
caused by metformin is then also an unprobable cause. As
no other interventions than a change in diabetes treat-
ment and temporary treatment with magnesium and
potassium were done, potential side-effects of his other
drugs can be ruled out. At last, even if all other theoretical
causes have not been investigated, the substantial
improvement after the metformin discontinuation makes
other explanations highly unlikely. The refusal of alterna-
tive explanations gives a Naranjo algorithm score of +2,
and a total score of +9. This then, according to the Naranjo
algorithm, definitely defines metformin as the cause of
the diarrhoea and electrolyte deficits.
The patient's symptoms were caused by the electrolyte
deficits, of which hypomagnesemia was the most impor-
tant. Hypomagnesemia is a common cause of hypocal-
cemia.
After discontinuation of metformin his blood glucose and
HbA1c increased to unacceptable levels. This occurred
despite the use of other oral antidiabetic agents. There-
fore, insulin had to be instituted. The author presumes
that metformin, apart from the antidiabetic effect per se,
also may have caused some malabsorption of carbohy-
drate, since HbA1c was 7.1% when the patient was ini-
tially seen.
Metformin has been known since the 1950s, and its use
has increased over the last 20 years. Today it is a drug of
choice for the treatment of diabetes mellitus type 2. In the
USA, it is one of the most prescribed drugs, with over 34
million prescriptions for generic metformin alone in 2006
[10]. Metformin is commonly associated with gastrointes-
tinal side effects, such as diarrhoea, flatulence and
abdominal discomfort [1]. Approximately 5% of patients
who start taking metformin do not tolerate these side
effects. Due to malabsorption about one in five patients
develops vitamin B12 deficiency. However, the vitamin
deficiency is usually not of clinical significance. Apart
from this deficiency, reports on nutritional deficits caused
by metformin are rare. One reason may be that studies
just report deficits associated with diarrhoea in general,
without emphasizing the cause of the diarrhoea.
Diabetes mellitus is a risk factor for magnesium depletion
[2]. Studies in animals suggest a beneficial effect of met-
formin per se on magnesium status. In diabetic rats, met-
formin was shown to improve the concentration of liver
magnesium, but no effect on serum magnesium was
described [3,4]. In diabetic patients on metformin, intrac-
ellular magnesium levels measured in peripheral mono-
cytes were found to be substantially higher than in
patients not receiving metformin [5]. However, in a study
using cultured human peripheral blood monocytes, expo-
sure to metformin was not associated with high intracel-
lular content of magnesium [11]. In a study on 34 poorly
regulated diabetes mellitus type 2 patients with hypomag-
nesemia from 1988, treatment with glipizid improved the
serum magnesium status, whereas metformin treatment
had no effect [7]. However, this study only reported on-
treatment data, while reporting intention-to-treat data is
generally considered the correct method today. A study
from 1979 measured serum magnesium in a mixture of
582 type 1 and type 2 diabetics [6]. Multiple regression
analyses showed treatment with biguanides to be associ-
ated with lower serum magnesium than sulphonylurea-
based therapy. However, only 36 patients were treated
with biguanides, and the biguanide most frequently used
was not metformin but phenformin. To sum up, the rela-
tion between metformin and magnesium has previously
been very infrequently studied, and no definite conclu-
sions can be drawn. Further research should aim at eluci-
dating this topic.
Conclusion
This report presents a patient where the use of metformin
caused chronic diarrhoea which subsequently led to
severe hypomagnesemia. To the author's knowledge, this
is the first report of symptomatic hypomagnesemia
caused by metformin-induced diarrhoea. Several medica-
tions are associated with gastrointestinal side effects such
as diarrhoea. Usually the side effects do not induce clini-
cally relevant deficits. However, the physician should bear
in mind that diarrhoea may cause severe and potentially
life-threatening malabsorption.
Abbreviations
GP: general practitioner; PCI: percutaneous coronary
intervention; PTH: parathyroid hormone; NPH: neutral
protamine Hagedorn; SU: sulphonylurea; TSH: thyroid
stimulating hormone.
Competing interests
The author declares that he has no competing interests.
Authors' contributions
AS was responsible for the treatment of the patient and
wrote the manuscript.
Consent
Written informed consent was obtained from the patient
for publication of this case report. A copy of the written
consent is available for review by the Editor-in-Chief of
this journal.
Acknowledgements
I want to thank the patient this case presentation is based on for his coop-
eration in preparing this manuscript. I also thank professor Valdemar Grill, 
Norwegian University of Science and Technology, Trondheim, and assistant Page 3 of 4
(page number not for citation purposes)
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A patient presenting with symptomatic hypomagnesemia caused by metformin-induced diarrhoea: a case report

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