Diabetologia (2017) 60:1561–1565

DOI 10.1007/s00125-017-4343-y

EDITORIAL

60 years of metformin use: a glance at the past and a look

to the future
Sally M. Marshall 1

Published online: 3 August 2017

# Springer-Verlag GmbH Germany 2017

Abbreviations diabetes want medication that is effective at reducing blood

DPP Diabetes Prevention Program glucose levels, easy to take, preferably has once-daily dosing,
DPPOS Diabetes Prevention Program Outcomes Study has no short- or long-term side effects, carries no risk of
eGFR Estimated GFR hypoglycaemia, does not cause weight gain and is affordable
GLP-1 Glucagon-like peptide-1 worldwide. In addition, the ideal drug would address the un-
PCOS Polycystic ovary syndrome derlying pathophysiology of type 2 diabetes and have added
SGLT2 Sodium–glucose cotransporter 2 value in terms of reducing non-glycaemic risk factors for, and
UKPDS UK Prospective Diabetes Study the incidence of, micro- and macrovascular complications of
diabetes. How does metformin match up to these demands?
The medication is certainly an effective glucose-lowering
agent, generally reducing HbA 1 c by approximately
This year marks the 60th anniversary of the first clinical use of
10–15 mmol/mol (1.0–1.5%) in type 2 diabetes [4].
metformin for diabetes. From small beginnings (and despite a
However, we are beginning to realise that not everyone re-
somewhat chequered history), metformin is currently recom-
sponds to the drug equally and that genetic variation may
mended as the first-line oral glucose-lowering agent in most, if
influence individual response [5]. Further, many people with
not all, clinical guidelines on the management of type 2 dia-
diabetes would argue that it is not easy to take, finding the
betes. Perhaps as a reflection of this, metformin was pre-
large tablet size off-putting and the need for more than once-
scribed for 83.6% of individuals with type 2 diabetes in the
daily consumption inconvenient. With 60 years of clinical use,
UK in 2013 [1]. Meanwhile, in the USA, metformin was the
we have a good understanding of metformin’s short- and long-
eighth most commonly prescribed drug consistently from
term side effects. The common gastrointestinal side effects
2008 to 2012 [2], the number of prescriptions rising from
can be minimised by titrating the dose up slowly, taking the
51.6 million in 2008 to 61.6 million in 2012. Metformin and
medication with/after food and, if necessary, switching to the
gliclazide are the only two oral glucose-lowering agents on the
extended-release preparation. With long-term use, fear of
WHO Model List of Essential Medications [3]. How did this
metformin-associated lactic acidosis initially blighted the use
drug reach such a commanding position and is such wide-
of metformin in some countries. However, a recent systematic
spread use justified?
review of prospective comparator trials and observational co-
If pharmacological therapy is really needed in addition to
horts suggests that lactic acidosis is extremely rare, with a
lifestyle measures, diabetes specialists and people with type 2
similar incidence in people with diabetes taking metformin
or other glucose-lowering agents [6]. Indeed, many people
* Sally M. Marshall have suggested that the contraindication of metformin use in
sally.marshall@newcastle.ac.uk chronic kidney disease stage 3 and beyond (estimated GFR
[eGFR] <60 ml min−1 [1.73 m]−2) is too restrictive. A further
1
Diabetes Research Group, Institute of Cellular Medicine, Faculty of meta-analysis, however, supports the cautious use of metfor-
Clinical Medical Sciences, Newcastle University, 4th Floor William
Leech Building, Framlington Place, Newcastle upon Tyne NE2 4HH,
min in individuals with chronic kidney disease with an eGFR
UK as low as 30 ml min−1 [1.73 m]−2, with appropriate dose
1562 Diabetologia (2017) 60:1561–1565

reductions and meticulous ongoing measurement of renal recognition that the risk of some cancers is increased in type
function [7]. However, there is a very small but real risk of 2 diabetes, attention has turned to the effects of glucose-
lactic acidosis particularly in individuals taking metformin lowering agents on cancer. Observational studies have sug-
who develop acute kidney injury [8]. Thus, individuals taking gested that cancer-related mortality was lower in individuals
metformin and their healthcare providers must remember to prescribed metformin compared with those taking insulin or
omit metformin temporarily during illnesses that may increase sulfonylureas [17]. Despite several meta-analyses suggesting
the risk of acute kidney injury. the contrary (that metformin does not lower cancer risk or
What about metformin and body weight? Clinicians often mortality [18, 19]), much effort is currently being devoted to
emphasise the weight-loss effects of metformin, but a system- in vitro and in vivo studies exploring potential mechanisms of
atic review and meta-analysis of placebo-controlled action and biological effects of this drug on cancer prevention
randomised trials suggests that the mean weight loss with and treatment. Metformin is also increasingly being promoted
metformin is 1.1 kg [9]. Metformin has a clear advantage over as an anti-ageing drug [20]. How much substance is in this
sulfonylureas, which lead to a weight gain of 2–3 kg. hype?
However, compared with the glucose-lowering and weight- To mark this 60th anniversary of the first clinical use of
reducing effects of glucagon-like peptide-1 (GLP-1) ana- metformin in diabetes, Diabetologia has commissioned a se-
logues and sodium−glucose cotransporter 2 (SGLT2) inhibi- ries of articles on many of these controversial and evolving
tors, metformin appears not to provide any additional weight aspects of metformin. In addition to providing a critical review
benefit [10]. of the current evidence, our authors were asked to look to the
So, overall, in metformin we have a tried and trusted med- future and to speculate where the metformin journey might
ication that meets some of our criteria for a good medication take us.
for diabetes, at least modestly. This is particularly so in com- Our series begins with an introduction to the drug by
parison with the other class of well-established glucose-low- Clifford Bailey [21], who outlines its herbal history, tracing
ering agents, the sulfonylureas. However, will the newer clas- it to Galega officinalis, which was first indicated to treat
ses of glucose-lowering agents succeed in knocking metfor- diabetes-associated symptoms in 1772. Bailey describes how
min from its lofty pedestal? Currently, these drugs are much it was not until 1957 that a physician named Jean Sterne re-
more expensive than metformin and their long-term safety is awakened interest in metformin. He had noted the fact that
not yet clear, so they are generally recommended as second- or flumamine (metformin hydrochloride) was able to lower
third-line agents for the management of type 2 diabetes. There blood glucose in influenza patients (in whom this drug was
is a possibility, however, that as data and clinical experience being used as an anti-influenza agent). Setting out to investi-
accrue, they will displace metformin and become first-line gate the pharmacodynamics of guanidine-based compounds,
therapy, at least for some individuals with type 2 diabetes. Sterne ‘translated the blood-glucose-lowering potential of
The central role of metformin in managing type 2 diabetes metformin into a therapeutic reality’. Motivated by these find-
is all the more remarkable as, even after 60 years, we still do ings, research between 1960 and 1980 verified the efficacy of
not fully understand its mechanism of action. That it inhibits this drug for lowering blood glucose, with little evidence for
hepatic gluconeogenesis is probably beyond doubt, but exact- serious safety implications, resulting in this drug eventually
ly how it does so is unclear. Whether other actions on the being labelled the ‘optimal’ therapy in type 2 diabetes.
gastrointestinal tract and perhaps even a gut–brain–liver axis Despite metformin taking the top spot in the hierarchy of
are more important is hotly debated [11]. Furthermore, evi- glucose-lowering agents, many questions remain regarding
dence that metformin actually alters the underlying diabetes the mechanisms of metformin action. Metformin’s effects on
disease process is lacking. Mainly on the basis of the UK the liver are widely reported, reducing hepatic gluconeogene-
Prospective Diabetes Study (UKPDS) randomised trial and sis and improving insulin sensitivity. In their review, Rena and
open follow-up results, we believe that metformin reduces colleagues [22] discuss the impact of metformin on mitochon-
the incidence of macrovascular disease at least in obese indi- drial function and AMPK activity in the liver, as well as
viduals [12, 13], but are uncertain whether this is purely a AMPK-independent effects. Further, the authors highlight a
glucose-lowering effect or whether metformin has other pleo- more recently established critical role for the intestine in
morphic effects. For the GLP-1 analogues and SGLT2 inhib- metformin’s actions, with metformin altering glucose metab-
itors, there is preliminary evidence of cardiovascular benefit olism in the gut, suppressing hepatic glucose production via
for individual agents in each class [14–16]. More data from liver–gut–brain crosstalk, and altering the gut microbiome.
other agents in both classes are awaited. Sanchez-Rangel and Inzucchi [23] address the hierarchical
Metformin is no exception to the current vogue for the place of metformin in clinical therapy. They present data in-
repurposing of old drugs for new applications. It is widely dicating the efficacy of metformin for lowering glucose levels
used in the management of polycystic ovary syndrome in type 2 diabetes, both as monotherapy and in combination
(PCOS), but is this use justified? Further, following the with other agents. In this cohort, the drug also does not appear
Diabetologia (2017) 60:1561–1565 1563

to increase hypoglycaemia risk and is weight-neutral, whilst findings suggested that metformin reduces risk of all-cause
having potential cardiovascular benefits. The authors do not mortality by up to 16%, but that it may also increase risk of
ignore the adverse effects related to this drug, discussing clin- stroke by up to 48%. However, the authors point out that
ical approaches taken to avoid side effects. Finally, they ac- several important limitations (including study bias and small
knowledge that, although many drug trials have been carried sample size) should be acknowledged when interpreting these
out on a background of metformin therapy, some novel ther- findings and that well-designed randomised studies of metfor-
apies have not been tested head-to-head against metformin. min therapy are needed to enable comparison with newer
Therefore, they question how this biguanide will fare against glucose-lowering drugs (e.g. empagliflozin and liraglutide),
new upcoming glucose-lowering agents in the treatment of for which rigorous cardiovascular endpoint data are available.
type 2 diabetes. For some conditions, metformin stands as a relatively new
In type 1 diabetes, insulin is the first-line therapy. However, therapeutic approach. In their review, Sam and Ehrmann [27]
despite advances in insulin formulations and modes of deliv- discuss the use of metformin for PCOS. In addition to its
ery, insulin use is associated with increased risk of reproductive manifestations, PCOS also has metabolic conse-
hypoglycaemia and weight gain, the latter leading to insulin quences, including insulin resistance, impaired glucose toler-
resistance and an escalating insulin dose requirement, higher ance and type 2 diabetes. Metformin was first shown to ame-
BP and increased LDL-cholesterol. Therefore, diabetologists liorate hyperandrogenism in women with PCOS in the 1990s
and people with type 1 diabetes seek an adjunct to insulin and, although the precise mechanism of action is not fully
therapy that might improve glycaemic control in type 1 dia- understood, its use in PCOS is common. Sam and Ehrmann
betes, without weight gain and its adverse consequences. use the small pool of available evidence to outline how met-
Could metformin be such a therapy? In their review, formin acts on PCOS-relevant tissues to reduce hepatic glu-
Livingstone et al [24] outline evidence of metformin use in cose output, increase muscle glucose uptake and regulate an-
type 1 diabetes. Overall, studies suggest that metformin use drogen production by the ovary. These metformin-induced
does not lead to sustained improvements in glycaemic control effects mainly prevent the metabolic consequences of the dis-
but reduces insulin dose requirement, weight and, potentially, ease, whilst having only limited effects on reproductive com-
LDL-cholesterol. The authors also present novel data from the plications. To establish the true potential of metformin in
Reducing with Metformin Vascular Adverse Lesions PCOS, however, the authors express the need for large well-
(REMOVAL) study, showing that atherosclerosis progression designed prospective trials.
may also be reduced with metformin use, whilst only transient Important insight into metformin use in pregnancy has been
reductions in HbA1c were observed. Hence, there appears to gained from studies of its use in PCOS. Metformin has been
be potential for this drug to have glucose-independent effects used in pregnancy for over 40 years. The drug crosses the
that may be beneficial for those with type 1 diabetes. placental barrier, and the proposed increased lactic acidosis risk
Alongside disease management, one of the major goals of and relatively hypoxic fetal environment have raised concerns
therapy is to prevent disease onset. The Diabetes Prevention about its use in pregnancy. However, studies in PCOS
Program (DPP) is the largest and longest clinical trial of met- suggested that metformin does not increase congenital
formin for the prevention of diabetes and, in this review series, malformations or miscarriage. In their review, Lindsay and
Aroda et al [25] present the main metformin-associated findings Loeken [28] discuss the use of metformin in gestational
from the DPP and its follow-on study, the DPP Outcomes diabetes, presenting evidence that metformin has a good
Study (DPPOS). Most notably, metformin reduced diabetes safety profile and is effective at reducing rates of severe
incidence by 31% vs placebo after 2.8 years follow-up, with hypoglycaemia and weight gain in pregnant women. In con-
the reduction in risk (18%) still being observed over 10 and trast, however, in pregestational type 2 diabetes the evidence
15 years post-randomisation. Moreover, favourable effects of base for metformin use is not strong, but observational evidence
metformin on several cardiovascular risk factors were observed. suggests increased risk of preeclampsia and perinatal mortality.
Hence, the findings from the DPP/DPPOS show promise for Evidence of long-term effects of metformin use in the offspring
metformin use for the prevention of type 2 diabetes, with addi- of mothers with gestational diabetes is equivocal for changes in
tional benefits extending to its cardiovascular complications. body composition, whilst no differences in BP, and motor, so-
Griffin et al [26] delve deeper into the association between cial and linguistic development have been observed. Thus, al-
metformin and cardiovascular disease risk. These authors con- though there is potential for metformin to act as a suitable
ducted a meta-analysis of randomised trials reporting cardio- therapy in gestational diabetes (but not pregestational diabetes),
vascular outcomes in which the effect of metformin was ‘iso- there is concern with its use because of a paucity of robust data.
lated’ through comparison with diet, lifestyle or placebo. Risk Studies have also shown that metformin can reduce diabe-
of all-cause mortality, cardiovascular death, myocardial in- tes risk in those aged 60 years or over, and also that ageing
farction, stroke and peripheral vascular disease was analysed outcomes, such as frailty and impaired physical and cognitive
and all outcomes, except for stroke, favoured metformin; function, are improved with its use. In their review, Valencia
1564 Diabetologia (2017) 60:1561–1565

et al [29] outline potential mechanisms by which metformin Regardless of the condition it is being used to treat, the
interferes with the ageing process, independent of blood glu- response to metformin therapy varies from person to person.
cose regulation. For example, the effects of metformin on In his review, Jose Florez [32] discusses why heterogeneity in
inflammation and reactive oxygen species are thought to re- response occurs and how we can predict it. In doing so, the
duce DNA damage, whilst its effects on ceramides (which hope is that a personalised approach to metformin therapy
contribute to reduced myoblast numbers in the elderly) may may be possible. However, our lack of knowledge of
also help to improve tissue health and function. Furthermore, metformin’s precise molecular target and mechanism of action
cardio- and neuroprotective roles of metformin, and the im- make patient stratification difficult. Nonetheless, Florez pro-
pact of metformin on psychological health and cognitive func- vides a potential solution: the genetic approach. Candidate
tion may also promote healthy ageing and increase lifespan. gene studies have revealed that mutations in the gene
Valencia et al conclude by outlining several upcoming clinical encoding the organic cation transporter 1 (OCT1) are most
trials of metformin in ageing that offer an exciting opportunity likely to impact metformin response, compared with other
to discover the true potential of metformin in the ageing pop- metformin transporter proteins. Findings from genome-wide
ulation, with or without diabetes. association studies point towards a role for mutations in ATM
In his review, Michael Pollak [30] also discusses the non- and SLC2A2 (the latter encoding GLUT2) in glycaemic re-
glycaemic effects of metformin. He suggests that metformin’s sponse to metformin. However, a personalised approach to
function may be partly explained by its effect on the human metformin therapy is not on the cards just yet, with a need
microbiota (e.g. decreased Intestinibacter levels, increased for much more evidence from genetic studies before this hope
Caenorhabditis elegans lifespan) and gut metabolome (e.g. becomes a reality.
increased butyrate synthesis), although the precise mecha- In summary, this review series demonstrates how a drug
nisms for these changes are yet to be determined. For exam- that could easily have been lost and forgotten following a
ple, specific microbiota profiles are associated with glucose turbulent start, has not only come to play a leading role in
intolerance, whilst gut-derived metabolites can alter insulin the treatment of type 2 diabetes but also shows promise for
resistance and glycaemic control. Alternatively, metformin the treatment of type 1 diabetes, diabetes in pregnancy, PCOS,
may alter gastroenteric mechanisms that influence systemic ageing and cancer. However, a common theme throughout this
carbohydrate metabolism, for example, by changing bile acid series is that robust evidence is lacking for metformin use in
physiology, GLP-1 levels and duodenal AMPK signalling. many of these conditions, threatening the chance of this drug
Metformin also has immunomodulatory effects via its impact remaining in the top spot, whilst other newer glucose-
on energy metabolism in immune cells, which may alter im- lowering therapies are quickly being introduced to the market.
mune function. This is thought to result in anti-tumour activ- Nonetheless, at present, metformin remains as one of ‘the
ities or a reduction in inflammation. These effects of metfor- most efficacious, safe and cost-effective medicines for priority
min may be relevant in conditions other than diabetes, includ- conditions’ [3] and, there is a fine chance that in another
ing cancer. 60 years’ time solid evidence will support its use in diseases
In line with this, evidence for the association between met- other than diabetes.
formin and reduced cancer incidence and mortality has been I hope you will agree that our authors have risen to the
provided by epidemiological studies. In this review series, challenge we presented to them, and that you find this series
Heckman-Stoddard et al [31] discuss the potential use of met- informative, stimulating and thought-provoking from both the
formin for cancer prevention and treatment. Two main routes clinical and scientific perspectives.
are proposed to contribute to metformin’s anti-neoplastic
activity: (1) an indirect route via a reduction in insulin,
which may slow tumour proliferation in individuals with References
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