M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 65 ( 20 1 6 ) 2 0–29

Available online at www.sciencedirect.com

Metabolism
www.metabolismjournal.com

Metformin-associated lactic acidosis: Current

perspectives on causes and risk

Ralph DeFronzo a , G. Alexander Fleming b , Kim Chen c , Thomas A. Bicsak c,⁎

a
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
b
Kinexum LLC, Harpers Ferry, WV, USA
c
Elcelyx Therapeutics, Inc., San Diego, CA, USA

A R T I C LE I N FO AB S T R A C T

Article history: Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus,
Received 24 June 2015 some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other
Accepted 5 October 2015 drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent
manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma
metformin concentrations (as occur in individuals with renal impairment) and a secondary event
Keywords: or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or
Metformin hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As
Drug mechanism these secondary events may be unpredictable and the mortality rate for MALA approaches 50%,
Lactic acidosis metformin has been contraindicated in moderate and severe renal impairment since its FDA
MALA approval in patients with normal renal function or mild renal insufficiency to minimize the
Renal impairment potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis
in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups
have suggested that current renal function cutoffs for metformin are too conservative, thus
depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin
therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a
direct consequence of conservative labeling, the absence of which could have led to excess patient
risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An
investigational delayed-release metformin currently under development could potentially
provide a treatment option for patients with renal impairment pending the results of future
studies. This literature-based review provides an update on the impact of renal function and other
conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.
© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction first line therapy for newly diagnosed type 2 diabetes by many
professional diabetes organizations [1]. With approximately
Metformin is the most commonly prescribed oral 50 years of accumulated real-world global clinical experience,
antihyperglycemic medication in the world and is considered metformin is generally regarded as safe with the most

Abbreviations: AUC, Area under the concentration–time curve; DR, Delayed release; eGFR, Estimated glomerular filtration rate; FDA,
Food and Drug Administration; GLP-1, Glucagon-like peptide 1; MALA, Metformin-associated lactic acidosis; NDA, New Drug Application;
XR, Extended release.
⁎ Corresponding author at: 11975 El Camino Real, Suite 305, San Diego, CA 92130, USA. Tel.: + 1 858 876 1814; fax: + 1 858 509 4165.
E-mail address: [email protected] (T.A. Bicsak).
http://dx.doi.org/10.1016/j.metabol.2015.10.014
0026-0495/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 5 ( 20 1 6 ) 2 0–2 9 21

frequent adverse effects being gastrointestinal in nature: (duodenum and proximal jejunum) and only ~ 10% is
diarrhea, nausea, and to a lesser extent, vomiting [2–4]. In absorbed in the ileum and colon. Unabsorbed drug accumu-
particular, metformin is less well tolerated in patients with lates in the mucosa of the bowel [18] and is ultimately
preexisting gastrointestinal conditions [5]. eliminated in the feces [19]. Current metformin formulations
Metformin is contraindicated in patients with renal or have a bioavailability of ~ 50%–60%; metformin circulates in
hepatic insufficiency, in very elderly patients, and in patients the plasma unbound and is eliminated unchanged by the
with conditions of circulatory dysfunction such as congestive kidneys [3,19]. When metformin accumulates in the plasma to
heart failure, due to increased risk of lactic acidosis [6]. Though concentrations > 5 mg/L, elimination may be prolonged [20].
metformin-associated lactic acidosis (MALA) is an extremely
rare condition (most estimates are ≤ 10 events per 100,000
patient-years of exposure), cases continue to be reported and 4. Risk Factors for MALA
are associated with mortality rates of 30 to 50% [6–12].
At the time of initial US approval, the safety review and Owing to the multiple and often nonspecific signs and
risk management of the New Drug Application (NDA) for symptoms of MALA, as well as the potential impact of other
metformin (Glucophage®) focused on the fact that MALA can conditions and medications that can predispose a patient to
be precipitated by drug accumulation, most notably in lactic acidosis, MALA can be difficult to predict or diagnose
patients with chronic or newly acquired renal insufficiency [21–23]. This is true especially in the absence of knowing the
or failure, complicated by lactate overproduction (from circulating metformin concentration in a patient presenting
hypoxic tissues in respiratory and circulatory failure) and/or with symptoms [24]. However, it is known that MALA occurs
impaired lactate removal (in liver damage, which inhibits when there is an imbalance between increased lactate
gluconeogenesis). Current metformin product labeling there- production and impaired metabolism/reduced clearance.
fore includes warnings regarding lactic acidosis [6]. Metformin plasma levels > 5 μg/mL are generally found
when metformin is implicated as the cause of lactic acidosis
[6]. Such sustained very high elevations in plasma metformin
2. Biguanides and Lactic Acidosis concentrations (therapeutic range < 2 μg/mL [19]) usually are
observed in individuals with poor renal function (i.e., reduced
The biguanides, metformin, phenformin, and buformin, com- metformin clearance), impaired hepatic metabolism (i.e.,
prise a class of glucose-lowering drugs developed in the 1950s reduced lactate clearance) [25,26], and/or in the presence of
for the treatment of type 2 diabetes, although only metformin is increased production (i.e., sepsis, CHF, reduced tissue perfu-
approved for use today in most countries. Phenformin was sion, or anoxia). Although not contraindicated for metformin
approved in the US and Europe in the 1950s, while metformin use in either the US or other countries, other conditions that
and buformin were only approved in Europe at that time. By the may increase the risk of lactic acidosis include severe
end of the 1970s, evidence of an increased risk of lactic acidosis dehydration, shock, alcohol use, hypoxic states, sepsis, and
with phenformin use led to its withdrawal in most countries [3]. advanced age (because of age-related decline in renal function
Although less widely used, buformin has largely been with- and increased risk for acute renal failure and other cata-
drawn from the market for the same reason. strophic medical conditions) [6,8,27–29]. However, MALA can
The strong association of lactic acidosis with phenformin occur in patients with even mild renal dysfunction [30] and
use resulted in a reluctance on the part of pharmaceutical patient outcome seems to be correlated with severity of the
companies to pursue regulatory approval for metformin in underlying disease, highlighting the need for judicious use of
the US until the Glucophage NDA submission to the Food and metformin even in otherwise lower-risk patients.
Drug Administration (FDA) by Lipha Pharmaceuticals culmi- MALA is more likely to occur in patients who acutely
nated in approval of the drug in 1995. Glucophage was develop renal impairment from dehydration, vomiting or
subsequently marketed by Bristol-Myers Squibb [13]. diarrhea, surgery, etc., especially in elderly subjects who have
In contrast to phenformin, which exhibits a well-defined a reduced glomerular filtration rate [31–38]. Dehydration can
hyperlactatemic effect, therapeutic doses of metformin used cause acute renal failure and reduce metformin clearance,
according to the current label cause little (usually less than resulting in increased plasma metformin levels, especially if
1–2 mmol/L) to no increase in basal and postprandial blood metformin administration is continued [27]. The effect of
lactate levels [3,14,15]. The incidence of lactic acidosis with metformin on plasma lactate concentrations in bariatric
metformin is estimated to be 20 times less than with surgery patients has not been examined, but these individ-
phenformin [16]. Preclinical studies also indicate that increased uals may be at higher risk for MALA due to increased
plasma lactate concentrations and lactic acidosis are related to metformin absorption and bioavailability [39].
biguanide dose and plasma levels, with phenformin being the Metformin plasma concentrations are approximately 2–4
most potent, followed by buformin, and metformin [7,17]. fold higher in patients with type 2 diabetes and moderate to
severe renal impairment (i.e., eGFR of 30 to < 60 mL/min/
1.73 m2 or < 30 mL/min/1.73 m2, respectively) compared to
3. Metformin Pharmacokinetics and Metabolism healthy subjects [6,29]. Patients with type 2 diabetes are also
at greater risk for hyperlactatemia, which is attributed to
When metformin is administered orally, approximately 40% alterations in the redox potential [40]. As a consequence,
of the dose is absorbed in the upper small intestine patients with diabetes, especially those treated with
22 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 65 ( 20 1 6 ) 2 0–29

metformin, have a reduced threshold for the development of decided that any degree of renal insufficiency as reflected by
lactic acidosis in response to a secondary event [19,25,26,41]. the very rough proxy of serum creatinine should be contra-
This scenario is consistent with individual patient case indicated. The commonly listed upper limits of normal serum
reports [42,43]. While some publications report a lack of creatinine levels for men and women were used to define the
association between plasma metformin concentrations and contraindication with the understanding that these creati-
prognosis in MALA [44–46] and metformin levels in patients nine levels in some patients could reflect more than border-
with MALA [45], these findings likely reflect the multiple line renal dysfunction.
different clinical conditions associated with lactic acidosis The contraindication thresholds limit metformin use to
and varying degree of certainty in the timing of collection of patients who could be treated without having metformin
key data such as plasma lactate and metformin concentra- plasma concentrations significantly exceed the ‘typical’
tions proximal to the event [47]. therapeutic range of <2 μg/mL [19] and never reach or exceed
Renal dialysis to remove metformin (and correct metabolic 5 μg/mL, a concentration that has been associated with
acidosis) has been recommended to treat MALA [34,35,48,49], MALA. The FDA also encouraged the sponsor of the
arguing in favor of a relationship between elevated plasma Glucophage NDA to continue to evaluate the effect of renal
metformin and increased plasma lactate levels. Although insufficiency and age on metformin clearance [53]. This led to
individuals can develop lactic acidosis for other reasons, in subsequent efforts by FDA to identify other conditions
the case of MALA, metformin exposure appears to be the associated with increased MALA risk such as congestive
main risk factor. This is consistent with the observation in heart failure [9,54]. Labeling also includes recommendations
several publications [46,50,51] that patients with lactic acido- that patients temporarily discontinue metformin before
sis who are taking metformin often have better outcomes receiving radiocontrast medium, which can cause acute
than those who are not, suggesting that less severe secondary renal failure [6,55]. Additionally, patients with type 2 diabetes
events may be sufficient to result in lactic acidosis in the who have microvascular complications, especially diabetic
presence of metformin. One possibility is that metformin nephropathy, are at increased risk for acute renal failure
limits a patient’s capacity to accommodate further increases following administration of radiocontrast medium [4].
in lactate induced by such secondary intercurrent events that
ultimately trigger an event of MALA. 4.2. Metformin Use in Contraindicated Populations

4.1. History of Metformin Labeling Regarding Patients Many individuals with diabetes continue to receive metfor-
with Impaired Renal Function min, despite having conditions that place them at risk for
lactic acidosis [56,57]. According to some estimates, approx-
The specific criteria put forth in metformin labeling (serum imately 25% of patients taking metformin have one or more
creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or contraindications [58,59].
abnormal creatinine clearance) to contraindicate metformin For example, despite the contraindication for metformin use
use correspond roughly to an estimated glomerular filtration in diabetic patients with moderate to severe renal impairment
rate (eGFR) of < 60 mL/min/1.73 m2 [6]. A creatinine clearance (eGFR <60 mL/min/1.73 m2), metformin is often used off-label
of 60 mL/min/1.73 m2 is at the threshold of meeting the in patients with moderate renal impairment [60].
National Kidney Foundation’s definition of chronic kidney Some health authorities, e.g., the National Institute for
disease, stated as “either kidney damage or GFR < 60 mL/min/ Health and Clinical Excellence (NICE) recommend initiation of
1.73 m2 for 3 months.” This level falls between Stage 2 (kidney metformin in patients with eGFR 45 to < 60 mL/min/1.73 m2
damage with mild decreased GFR) and Stage 3 (moderate and continuation with additional caution and dose reduction
decreased GFR). The specified serum creatinine levels in the if the eGFR decreases to 30 to < 45 mL/min/1.73 m2) [61].
metformin label reflect a then practical but imprecise estimate Similar treatment guidelines are endorsed by the Canadian
of GFR because calculation of GFR from serum creatinine Diabetes Association and the Australian Diabetes Society [62]
levels by the Cockcroft–Gault, MDRD equation and similar and the results of numerous studies support this measured
approaches is highly dependent on age, sex, and body weight approach to the use of metformin in patients with moderate
[52]. As an illustration from the National Kidney Foundation renal impairment [63,64]. At the same time, recent safety
(Frequently Asked Questions about GFR Estimates), a serum alerts by some health authorities continue to highlight a more
creatinine of 1.2 mg/dL in a 22-year-old Black man, a 58-year- restricted use of metformin to minimize the risk of MALA
old white man, and an 80-year-old white woman result in [65,66]. Similarly, recent publications [67–69] continue to
calculated GFRs of 98, 66, and 46 mL/min/1.73 m2, respective- highlight the increased risk of MALA with metformin use in
ly. These values correspond to renal function categories of renally-impaired patients. While it has been suggested that
Stage 1, 2, and 3, respectively for those individuals. using lower doses of metformin (eg, 500 to 1000 mg/day) could
Although not documented in detail in the FDA’s Summary be safe even in patients with severe renal impairment [70], it
Basis of Approval for Glucophage, the appropriateness of is questionable whether such doses would provide meaning-
these criteria was the subject of considerable discussion by ful glycemic control [71]. Recently, the US FDA has been in
both internal Agency staff and outside subject matter experts. receipt of Citizen Petitions to ease the contraindication to
Because of the concern about potential for MALA and the allow use in patients with moderate renal impairment,
dependence on renal function for drug elimination, reviewers similar to the clinical treatment guidelines in place in the
concluded that a conservative approach was warranted for United Kingdom. However, in the absence of controlled
metformin use in patients with renal insufficiency. Reviewers clinical trial data to support such a change it is unclear how
 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 5 ( 20 1 6 ) 2 0–2 9 23

it could be justified, especially in light of continuing concern Plasma Glucose

in the medical and health authority communities.

Glucose Glycogen
NAD +
5. Incidence of MALA Cori Cycle
(Liver, kidney) NADH NADH NAD +

MALA is an extremely rare event with an estimated incidence 3 Pyruvate Lactate

of 0.03 to 0.06 per 1000 patient-years [3,11]. However, the 2
Cytosol 1
precise incidence of lactic acidosis in metformin users is not
Mitochondria O2 present
known, as event rates are very low and are based on
spontaneous case reports. Decades of clinical experience Acetyl CoA
have provided insight to clinicians and regulators about the TCA Cycle
optimal use of metformin to insure safety. Two years after (ATP production)

metformin was introduced into the US market, the incidence CO2+ H2O
of MALA was estimated at 5 cases per 100,000 patient-years
based on 47 reported cases among an estimated 1 million
users [9]. Similarly, MALA has been reported at a rate of 9 per Fig. 1 – Biochemistry of lactate production. Pyruvate, the only
100,000 patient-years in Canada [72]. Other reports indicate a precursor to lactate, is produced in the cytoplasm from
comparably low incidence of MALA, but all are consistent in metabolism of glucose via glycolysis. (1) When oxygen is
that most cases occurred in patients with pre-disposing available, pyruvate enters the mitochondria and is oxidized
conditions or intercurrent precipitating events that predis- to CO2 and H2O in the TCA cycle. (2) Under anaerobic
pose to lactic acidosis [3,8,9,27,28,72]. Cases of lactic acidosis conditions, pyruvate is unable to enter the mitochondria to
with “normal” metformin levels have been reported in be oxidized and is reduced to lactate. (3) In the liver and
patients with [33,49,73–83] and without a history of diabetes kidney, pyruvate also can be converted to glucose. The Cori
[73,80,81,84–86]. cycle describes a process by which lactate is produced by one
A comparative outcomes study that examined patients tissue (muscle) and converted back to glucose in another
with type 2 diabetes treated with metformin vs. patients tissue (liver). Lactate accumulates under anaerobic condi-
treated with non-metformin antihyperglycemic therapies for tions. Adapted from Fall & Szerlip, 2005 [91].
1 year reported no cases of lactic acidosis [87]. Analyses of two
large clinical studies with metformin showed similar results
[88,89]. A systematic review from the Cochrane library that
included 347 comparative trials and cohort studies found no 6. Mechanism of MALA
cases of fatal or non-fatal lactic acidosis and no difference in
plasma lactate levels between metformin-treated and non- Irrespective of its underlying etiology, lactic acidosis is a life
metformin-treated groups [88]. Another case–control analysis threatening condition characterized by low blood pH (< 7.35)
[89], which compared the incidence of lactic acidosis between and elevated arterial lactate (>5.0 mmol/L) levels [91]. Lactate
metformin and sulfonylurea users in 50,048 patients, found is produced by the gut, liver, and peripheral tissues
no difference in the incidence of lactic acidosis between during glycolysis and can accumulate during hypoxic condi-
metformin and sulfonylurea (3.3 and 4.8 per 100,000 patient- tions (Fig. 1) [91]. The liver, kidney, heart, and skeletal muscle
years, respectively). All reports of lactic acidosis in this study are the primary lactate metabolizers, while the liver and
occurred in patients with preexisting comorbidities. Some kidney account for ~60% and ~ 30%, respectively, of lactate
investigators have attributed the association between met- clearance [92,93], although lactate clearance by the kidney
formin and lactic acidosis to the fact that type 2 diabetes is does not correlate with renal function [94]. Lactate can either
itself a risk factor for lactic acidosis [44,88], although this be oxidized to carbon dioxide and water by mitochondria to
likely reflects the accompanying deterioration in other organ generate energy or converted back to glucose (gluconeogen-
systems (e.g., hepatic and renal) that in turn predisposes esis) in the liver and kidney [17]. Lactic acidosis occurs during
patients to a higher risk of MALA. conditions of excessive lactate production and/or impaired
Estimates of the incidence of MALA are confounded by hepatic lactate removal [91,92]. Hepatic lactate clearance can
multiple factors. Data obtained from published trials, which reach 320 mmol/h, which far exceeds the normal rate of
typically exclude patients with risk factors for lactic acidosis lactate production [91]. Therefore, increased peripheral lac-
and which are designed to provide standard of care, likely do tate production alone is rarely responsible for lactic acidosis.
not reflect actual rates in clinical practice [56,90]. Case- However, increased lactate production in the presence of
controlled studies reflect use of metformin as indicated on impaired hepatic metabolism, such as occurs with cirrhosis,
the label, thus excluding, in most cases, patients at higher risk sepsis, or hypoperfusion, can result in sustained lactate
of MALA. Furthermore, information on plasma metformin accumulation and clinically significant lactic acidosis.
concentrations, serum creatinine levels, arterial lactate levels, Lactic acidosis has been divided into two categories. Type
and history of concurrent pathologies is inconsistently A lactic acidosis results from the accumulation of lactate via
reported, complicating characterization of MALA vs. lactic glycolysis in the absence of oxygen. Type B lactic acidosis,
acidosis of other etiologies [31]. exemplified by MALA, occurs during conditions when lactate
24 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 65 ( 20 1 6 ) 2 0–29

8 Intravenous isolated hepatocytes, metformin inhibits complex 1 of the

Loge Blood Lactate mitochondrial respiratory chain in a concentration-
AUC(mmol/L*min) 7 dependent manner and impairs gluconeogenesis [17,26,107].
The increase in plasma lactate concentration observed with
6
metformin exposure in vivo correlates with the inhibition of
mitochondrial oxidative phosphorylation in vitro [17].
5
R = 0.83
p = 0.0007 6.1. Evidence from Metformin Overdose Cases
4
05 0 100 150

8 Intragastric Reported cases of metformin overdose provide insight about

the mechanisms linking metformin accumulation, increased
Loge BloodL actate
AUC(mmol/L*min)

7 plasma lactate levels, and the development of lactic acidosis. A

retrospective analysis of metformin overdose cases [50] dem-
6 onstrated a strong correlation between increased circulating
metformin concentrations (as would be expected to occur in
5
R = 0.75
subjects with renal impairment receiving effective doses of
p = 0.0003 current metformin formulations) and decreased arterial pH.
4 High plasma lactate concentrations and pH were both predic-
01 02 03 0
tors of fatal outcomes; patients who died had 100% higher
8 Intra-Ileum
circulating plasma metformin levels, 30% higher plasma lactate
Loge Blood Lactate

concentrations, and lower arterial pH compared to those who

AUC(mmol/L*min)

7
survived. In addition, individual overdose case studies indicate
that metformin alone, in the absence of an intercurrent
6
precipitating event, can cause MALA in instances of a major
5 overdose, even in healthy individuals [108].
R = 0.17
p = 0.6452
4
01 02 03 04 05 0
Plasma Metformin (µg/mL) 7. Relationship Between Metformin and
Increased Lactate: Results of Novel Studies
Fig. 2 – Relationship between blood lactic acid exposure (AUC)
and plasma metformin concentration in normoglycemic rats. We performed both nonclinical and clinical studies to better
Rats received vehicle or metformin doses via the stomach, understand the relationship between systemic metformin
via the ileum and via a peripheral vein in randomized exposure and increased plasma lactate concentrations.
sequence. Blood glucose and lactic acid concentrations were
determined before metformin administration (0 min) and at 7.1. Results of Preclinical Studies
time points up to 4 h after administration. Plasma metformin
concentration was measured at the 4-h time point. In a nonclinical study [109], normoglycemic rats were
administered vehicle or metformin by infusion through
chronic indwelling catheters implanted into the stomach
(intragastric), into the ileum (intra-ileum), or into a peripheral
production is increased at a time when clearance of lactic acid vein (intravenous) (Fig. 2).
by oxidation or gluconeogenesis is reduced [91]. The remain- Plasma metformin concentrations following intra-ileum
der of this review will focus on MALA rather than the general administration were very low (≤ 10 μg/mL) compared to
topic of lactic acidosis. intravenous administration, which resulted in plasma levels
In animals [95] and humans [96,97], biguanide administra- that were up to 10 times higher. The increase in plasma
tion is associated with an increase in blood lactate levels. The metformin levels with intragastric administration was inter-
increase in plasma lactate concentration with therapeutic mediate between intra-ileum and intravenous metformin
doses of metformin is small, usually <2 mmol/L [3,14,15,98,99], administration. The increase in blood lactate concentration
although higher levels may occur [100]. Metformin also elevates following metformin administration varied as a function of (i)
plasma lactate levels during exercise [101,102]. The small metformin dose, (ii) circulating metformin concentration, and
magnitude of increase in plasma lactate with metformin (iii) route of administration. While the lowest metformin dose
under typical conditions most likely explains why elevated tested (300 mg/kg) did not produce a significant increase in
plasma lactate levels have not been observed in some studies lactate AUC for the intragastric and intra-ileum routes of
[13,103]. administration, it did result in a significant increase following
One mechanism via which metformin increases plasma intravenous administration.
lactate levels relates to the inhibition of mitochondrial Intravenous and intragastric administration of metformin
respiration in tissues (i.e., liver and muscle) responsible for produced statistically significant increases in lactate AUC at
lactate removal [17,26,104–107]. This results in both acceler- the higher metformin doses tested (500 and 750 mg/kg), but
ated lactate production and reduced lactate metabolism. In intra-ileum administration did not produce an increase in
 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 5 ( 20 1 6 ) 2 0–2 9 25

4000
lactate AUC relative to vehicle at either dose. Importantly,

Plasma Metformin (ng/mL)

while it has previously been shown that metformin increases
lactate concentration in the intestine [18], administration of 3000
metformin directly into the ileum did not produce an increase
in blood lactate concentration even at very high doses. In 2000
contrast, with both intravenous and intragastric administra- Metformin DR
tion, the blood lactate concentration increased significantly Metformin XR
1000
and the rise was strongly correlated with the increase in
plasma metformin concentration. There was no relationship
between the plasma metformin concentration and blood 0
0 6 10 18 24 36 48 72
lactate level following ileum infusion, most likely because
Time (h)
that route of administration produced very low plasma
0
metformin concentrations.

Reduction in Relative
Bioavailability
7.2. Results of Clinical Studies -20

We examined the relationship between metformin exposure -40 - 48% - 45%

and lactate production across the spectrum of renal function
ranging from normal to severely impaired in patients with type 2
-60
diabetes [110]. In this study, we used an investigational delayed-
release metformin formulation (Metformin DR) designed to
** **
-80
release metformin in the distal small intestine, thereby
AUC0-t Cmax
restricting metformin exposure to the distal bowel where it
activates L cells resulting in the release of hormones such as
glucagon-like peptide-1 (GLP-1) and peptide YY [111]. This Fig. 3 – Plasma metformin concentrations following a single
formulation differs from currently available IR and XR metfor- dose of metformin DR and metformin XR in patients with type
min products that are absorbed mainly in the proximal small 2 diabetes and severe renal impairment. Patients with severe
intestine, resulting in high plasma metformin levels (Table 1). renal impairment (eGFR < 30 mL/min per 1.73 m2) were
We have demonstrated that Metformin DR retains the full administered single doses of 1000 mg Metformin DR,
glucose lowering capacity of currently available metformin 1000 mg Metformin XR, and Placebo in a cross-over study
preparations [112]. design. Top panel: Time-course plasma metformin concen-
Results from this study showed that, although plasma tration after a single administration of Metformin DR or
metformin concentrations increased with decreasing renal Metformin XR. Bottom panel: Reduction in metformin
function, the metformin plasma AUC was significantly re- bioavailability (Cmax and AUC) with Metformin DR relative to
duced (by ~ 25%-50%) after administration of a single 1000 mg the same dose of Metformin XR.
dose of Metformin DR compared to a 1000 mg dose of
Metformin XR (Fig. 3). In addition, Metformin XR, administered
as a single 1000 mg dose, resulted in a significant relationship
between the plasma metformin concentration and the change consistent with the low dose used and the lack of opportunity
in placebo-corrected plasma lactate concentration from base- for metformin accumulation due to the single dose adminis-
line (p < 0.0001) (Fig. 4). No relationship between plasma tration. However, based on the observed relationship between
metformin and plasma lactate levels was observed when plasma metformin and lactate concentrations, repeated
metformin was administered to the distal small intestine with Metformin XR dosing in patients with renal impairment
Metformin DR (p = 0.94), most likely because metformin could result in metformin concentrations that cause a
plasma concentrations were not high enough. clinically significant increase in circulating plasma lactate
It should be noted that the change in plasma lactate levels. The results of this study are consistent with those in
concentration with Metformin XR was relatively small, rats discussed earlier.

Table 1 – Characteristics of the Metformin Delayed-Release (Metformin DR) formulation.

Status Investigational new drug in development
Delivery Target Lower Bowel (Ileum)
Systemic Exposure ~50% lower than metformin immediate- or extended-release at equivalent doses
Glucose Lowering Effect Using ~50% lower dose, appears to be comparable to metformin immediate- or extended-release based on
Phase 2 clinical trials. Needs to be confirmed in Phase 3 trials.
Gastrointestinal Tolerability To be determined
Utility in Treating Patients with To be determined
Renal Impairment
26 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 65 ( 20 1 6 ) 2 0–29

Metformin DR
Placebo-Adjusted Changein
0.6
dictated caution in prescribing practices, judicious use of
Plasma Lactate (mmol/L) Metformin XR metformin in moderate renal impairment is common and is
0.4
sanctioned by several health authorities, including those in
0.2 the United Kingdom, Canada, and Australia. However, the
success of metformin as the first-line diabetes therapy may
0.0 be a direct consequence of conservative labeling, the absence
of which could have led to excess patient risk and
-0.2 withdrawal from the market as was done with earlier
biguanide therapies. Given that excessive plasma metfor-
-0.4
0 4 8 12 18 24 min accumulation is a necessary predisposing condition for
MALA, alternative methods of delivering metformin to
Time (hours)
high-risk diabetic patients that minimize systemic expo-
4 Metformin DR, R=0.003, p=0.94
Placebo-Adjusted Change in

sure while maintaining glycemic efficacy are desirable.

Plasma Lactate (mmol/L)

Metformin XR, R=0.26, p<0.0001 Limiting exposure by simply administering lower doses is
2 likely not to provide optimal glycemic control. However,
investigational formulations of metformin that target the
0 lower bowel [112] potentially could impact the ability to
treat currently contraindicated (e.g., renally impaired) or
otherwise metformin-intolerant patients who could benefit
-2
from this biguanide.

-4
0 1000 2000 3000 4000
Metformin (ng/mL)
Contributions of Authors

All authors contributed equally to the conception and writing

Fig. 4 – Plasma lactate concentration during a single-dose
of the manuscript.
metformin administration in patients with type 2 diabetes.
Patients with normal or impaired renal function were admin-
istered single doses of 1000 mg Metformin DR, 1000 mg
Metformin XR, and Placebo in a cross-over study design. Top Funding
panel: Placebo-adjusted change in plasma lactate concentra-
tion after a single-dose administration of Metformin DR or This work was funded by Elcelyx Therapeutics, Inc.
Metformin XR. Time 0 to 24 h post-dose. Study medication
administered at t = 0 h; meals administered at t = -0.33, 5.5,
8.5, 12.5, and 15.5 h. Bottom panel: Placebo-adjusted change Acknowledgments
in plasma lactate and metformin concentrations after a single-
dose of Metformin DR or Metformin XR. Evaluable population. The authors thank Drs. Clifford Bailey, Alain Baron, and Mark
Time 0 to 24 h post-dose. Fineman for insightful discussions and reviewing the manu-
script, and Dr. Sonja K. Billes (August Scientific) for assistance
with writing and preparing the manuscript.

7.3. Strengths and Weaknesses of Metformin DR Studies

and Translational Potential Conflicts of Interest

The premise that Metformin DR acts substantially through T.A.B. and K.C. hold stock or stock options in Elcelyx
activation of the L cell in the lower bowel is supported by the Therapeutics, Inc. R.D. is a member of Elcelyx Therapeutics,
rodent data and early clinical data. The precise efficacy and Inc.’s Clinical Advisory Board. The authors declare no other
safety profile of Metformin DR relative to existing metformin conflicts of interest.
formulations remain to be confirmed with further clinical
studies, as does the important potential use in patients with
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