Mini review 475

Pharmacogenetics and individual responses to treatment of

hyperglycemia in type 2 diabetes
Line Engelbrechtsena, Ehm Anderssona, Soeren Roepstorffb,
Torben Hansena and Henrik Vestergaarda
The aim of this study was to summarize current knowledge
and provide perspectives on the relationships between
human genetic variants, type 2 diabetes, antidiabetic
treatment, and disease progression. Type 2 diabetes is a
complex disease with clear-cut diagnostic criteria and
treatment guidelines. Yet, the interindividual response to
therapy and slope of disease progression varies markedly
among patients with type 2 diabetes. Genegene,
geneenvironment, and genetreatment interactions may
explain some of the variation in disease progression.
Several genetic variants have been suggested to be
associated with response to antidiabetic drugs. Some are
present in drug receptors or drug metabolizers (OCT genes,
KCNJ11, ABCC8, and CYP2C9). Numerous type 2 diabetes
risk variants have been identified, but genetic risk score
models applying these variants have failed to identify
disease progressors among patients with diabetes.
Although genetic risk scores are based on a few known loci
and only explain a fraction of the heritability of type 2
diabetes, it seems that the genes responsible for the

Introduction
Type 2 diabetes (T2D) is an increasingly prevalent,
complex disease associated with a high risk of morbidity
and mortality because of microvascular and macrovascular
complications [13].
Diabetes mellitus is defined by the American Diabetes
Association (ADA) as elevated HbA1c level of at least
48 mmol/mol (6.5%) and/or elevated fasting plasma
glucose (FPG) concentrations of at least 7 mmol/l and/or
2 h-plasma glucose (h-PG) more than 11.1 mmol/l
[2 h-PG after a 75 g oral glucose tolerance test (OGTT)]
[4,5]. Repeated measurement of glucose levels should
be performed in case of absence of unequivocal
hyperglycemia.
Although T2D is a straightforward diagnosis, patients
vary markedly with respect to clinical characteristics, time
of diagnosis, treatment requirements, rate of disease
progression, and their susceptibility to diabetic
complications.
It is well established that hyperglycemia increases the
risk of diabetic complications [3,6]. Yet, improving glycemic control in patients with T2D is a challenging task.
Lifestyle changes, such as diet restriction, increase in
physical activity, and weight loss, as well as initiation of
1744-6872 Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

development of diabetes may not be the same driving

disease progression after the diagnosis has been made.
Pharmacogenetic interactions explain some of the
interindividual variation in responses to antidiabetic
treatment and may provide the foundation for future
genotype-based treatment standards. Pharmacogenetics
and Genomics 25:475484 Copyright 2015
Wolters Kluwer Health, Inc. All rights reserved.
Pharmacogenetics and Genomics 2015, 25:475484
Keywords: antidiabetic treatment, diabetes type 2, disease progression,
genotype, pharmacogenetics
a
Section of Metabolic Genetics, Novo Nordisk Research Foundation Center for
Basic Metabolic Research and bDigestive Disease Center, Bispebjerg Hospital,
University of Copenhagen, Copenhagen, Denmark

Correspondence to Line Engelbrechtsen, MD, Section of Metabolic Genetics,

Novo Nordisk Research Foundation Center for Basic Metabolic Research,
Universitetsparken 1, DIKU Building 1 Floor, DK-2100 Copenhagen, Denmark
Tel: + 45 353 33639; e-mail: line@sund.ku.dk
Received 30 January 2015 Accepted 10 June 2015

oral antidiabetic treatment are the first initiatives to

reduce HbA1c. When evaluating disease progression,
HbA1c levels and change of antidiabetic treatment type
or dose must be taken into account and the clinician
should perform thorough screening and detection for
diabetic complications. Failure to achieve normoglycemic
levels despite lifestyle interventions and antidiabetic
treatment among some patients with T2D has been
reported in various studies [711]. Identifying which
patients with T2D will respond well to a certain treatment of hyperglycemia or which patients are likely to
have rapid glycemic deterioration despite intervention
would be very useful in terms of identifying and reducing
long-term complications. For patients with T2D, genetic
as well as environmental factors can affect the rate of
disease progression and might contribute toward the
understanding of the diversity among patients with
T2D with respect to treatment and outcome [1216].
Identification of the genetic factors is very important as it
will contribute toward an understanding of the diversity
among T2D patients with respect to disease progression
and will form a basis for the introduction of individualized treatment.
A proof of concept for how specific genetic variants affect
treatment outcome (pharmacogenetics) can be found in
DOI: 10.1097/FPC.0000000000000160

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pharmacogenetics and Genomics 2015, Vol 25 No 10

monogenic forms of diabetes. For a subset of these

patients, the identification of mutations causing monogenic forms of diabetes has altered their treatment and
made it possible to achieve improved glycemic levels
[17]. For MODY (mature onset of diabetes of the young)
caused by HNF1A mutations, sulfonylurea treatment has
been shown to improve glycemic control compared with
conventional treatment with metformin [18]. Several
other monogenic forms of MODY and neonatal diabetes
have been identified and have resulted in targeted
treatment with better glycemic outcomes [19,20].
The purpose of this review is to summarize current
knowledge of pharmacogenetics in T2D and provide a
perspective on the relationships between human genetic
variants, antidiabetic treatment, and disease progression.
This topic is of utmost importance as an improved
understanding of genetreatment interactions may provide a basis for development of future individualized
therapies and treatment guidelines.

Definition of disease progression

Disease progression in T2D is a challenging issue to
address and there is no strict definition because of the
complexity of the disease. However, disease progression
is most simply described as a worsening of diabetes status
and a possible measure of deterioration is change in
glycemic indexes including FPG, HbA1c and postprandial glucose levels, add-on of antidiabetic drugs, and
occurrence of microvascular or macrovascular complications.
In the Baltimore Longitudinal study, the natural course
of progression from normal glucose tolerance to impaired
glucose tolerance and T2D was described. Over a 10-year
period, 43% of normoglycemic individuals progressed to
abnormal FPG levels and 43% progressed to abnormal
2 h-PG levels. Among those, 22% with impaired FPG and
17% with impaired 2 h-PG progressed to T2D over a
10-year period; the rest did not progress in diabetes status
[21]. These data imply that the natural course from normoglycemia to T2D is not an easy or a straightforward
path to understand, and that different progression patterns might reflect different phenotypes.
The assessment or identification of individuals with
progressive diabetes is difficult. Hence, disease progression has been measured in various ways in previous
studies. Common methods used have been: time from
diabetes diagnosis to add-on of second or third oral
antidiabetic drug; time from diagnosis to start of insulin
treatment; relapse of hyperglycemia HbA1c more than
53 mmol/mol (7%) despite intervention; as well as time
from diagnosis to development of diabetic complications
[13,22,23].
The progressive nature of T2D is not fully understood,
although a continuous decrease in -cell function is
believed to play a key role. The UK Prospective

Diabetes Study (UKPDS) reported that the decline in cell function starts as early as 12 years before manifestation of diabetes, and continues to decline despite intervention and treatment (see Fig. 1) [9,28,29]. Because of
the progressive decline in -cell function, HbA1c levels
increase on most antidiabetic treatments, and are estimated to increase approximately 11 mmol/mol (1%) every
2 years on sulfonylurea treatment [30].
In addition to the deterioration in -cell function, Festa
et al. [24] reported that insulin sensitivity declines over a
period of 5 years in normal glucose-tolerant, impaired
glucose-tolerant, and individuals with diabetes. Acute
insulin response to intravenous glucose was the main
determinant of glucose tolerance status at 5 years of
follow-up and individuals who remained euglycemic
showed a compensatory increase in insulin secretion to
maintain normoglycemic levels [24].

Pharmacotherapy in type 2 diabetes

Pharmacotherapy in progressed treatment of hyperglycemia in T2D is based on reduction of hepatic glucose
production, enhancement of -cell function, and/or
increasing the sensitivity of peripheral cells to insulin [31].
Strict glycemic control in patients with diabetes is to
reduce diabetes-related complications. A significant
association between hyperglycemia and development of
diabetes complications was reported in UKPDS 35. A
reduction in mean HbA1c of 11 mmol/mol (1%) was
associated with a decrease in progressed risk of microvascular complications and a 21% decrease of any end
point related to diabetes including death (P < 0.0001) [6].
According to current international guidelines, HbA1c is
considered the best measure for monitoring and management of diabetes treatment [5]. ADA and the
European Association for the Study of Diabetes (EASD)
Fig. 1
Deterioration of -cell function
Rates/levels

476

Years (020)
-Cell function (%)

HbA1C = 53 mmol/mol

HbA1C (mmol/mol)

-Cell function over time in relation to HbA1c in type 2 diabetic patients

[2427].

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pharmacogenetics in progression of T2D Engelbrechtsen et al. 477

recommend that HbA1c is measured every 3 months

until HbA1c is less than 53 mmol/mol (7%) and then at
least every 6 months, with a HbA1c more than 53 mmol/
mol (7%) indicating that adjustment of treatment may be
needed [5,25]. However, there seems to be a delay from
identifying an increasing HbA1c to prescribing a second
or a third antidiabetic drug among clinicians. Fu et al. [32]
reported an overall median time to intensification of
treatment among those who fail metformin monotherapy
of 14 months. For patients with diabetes with HbA1c
between 53 and 64 mmol/mol (78%), the median time to
intensification of treatment was 19 months, although for
higher levels of HbA1c, time to intensification of treatment decreased [32]. In patients with metformin failure,
early add-on of a second oral antidiabetic drug is associated with better achievement of glycemic goal attainment and subsequently a shorter period with
hyperglycemic blood levels [33].
Treatment of T2D is initiated with lifestyle changes and
prescription of metformin (Fig. 2) [5]. However, there is
considerable variation in response to metformin, with
some patients experiencing a decrease in HbA1c by up to
20 mmol/mol following initiation of treatment, whereas
others can experience no change or even an increase in
HbA1c [37]. Up to 47% of patients fail to achieve normoglycemic levels on metformin monotherapy and
require add-on of a second/third oral antidiabetic drug
and/or injections with either glucagon-like peptide 1
(GLP-1) analogs or insulin [9,26,27,3840]. Large differences in response to metformin over time have also
been reported, and even though glycemic control is
achieved initially, it is well known that the effectiveness
of treatment decreases over time, possibly because of a
continuous loss of -cell mass and function [31,41].
Subsequently, low -cell function (measured as either
add-on of a secondary oral antidiabetic drug or progression to insulin treatment) is also associated with glycemic
deterioration [13,28,39,4245]. Approximately 42% of
T2D patients on monotherapy experience secondary
failure of metformin, defined as HbA1c at least 58 mmol/
mol (7.5%) after an initial achievement of HbA1c less
than 53 mmol/mol (7%), with a mean failure rate of 17%
per year [46].
As for metformin, secondary failure of treatment can be a
problem in sulfonylurea-treated patients. Wallace and
Matthews [30] reported that chlorpropamide-treated
patients had a mean coefficient of failure of 0.34
HbA1c%/year and glibenclamide-treated patients of 0.50
HbA1c%/year. Similar results were reported by Matthews
et al. [28] in the UKPDS 26 study. Patients were randomized to treatment with either chlorpropamide or glibenclamide. At the 6-year follow-up, 44% of the patients
required additional antidiabetic therapy. Nonobese
patients (BMI < 30) were more likely to have additional
therapy than obese patients within the first 3 years of the
study period. Higher failure rates were associated with

phenotypical traits such as high glucose concentration,

younger age, and low -cell reserve among those treated
with glibenclamide compared with chlorpropamide [28].
These data suggest that secondary failure of sulfonylurea
depends on both phenotype as well as the type of drug.

Characteristics of disease progression

The current understanding on the natural course and
development of T2D is based on large cohort studies
with data on baseline FPG, HbA1c levels, or OGTT with
a follow-up period of 227 years [4751].
Phenotypical traits associated with the development of
T2D have many similarities to characteristics associated
with disease progression, which makes it difficult to
identify individuals who are more susceptible to a rapid
slope of glycemic deterioration. The clinical characteristics associated with disease progression are described in
Table 1.
BMI has been identified as a clinical determinant of
disease progression in a study of 5250 T2D patients.
Zhou et al. [13] used time to insulin event as a determinant of disease progression and reported that individuals
with a BMI between 24 and 26 kg/m2 had the least risk of
disease progression and patients with either a BMI less
than 24 kg/m2 or BMI more than 26 kg/m2 were more
likely to progress in their diabetes status. The relation
between BMI and progression of diabetes is possibly a
U-shaped curve, with low BMI and high BMI reflecting
two extreme phenotypes, namely, that lean individuals
are more likely to be -cell deficient and obese individuals are more likely to be insulin resistant [13].
BMI, weight, body fat percentage, and waist circumference are frequently used clinical measures to
assess the degree of obesity and have all been tested for
association with disease progression [13,15,22]. Pani et al.
[12] reported that in patients with diabetes, each 1 lb
(453 g) gain in weight was associated with a 2% increase
in odds of progression measured as worsening of glycemic
control or initiation of antidiabetic treatment. In addition,
waist circumference, as an individual factor, has been
associated with hyperglycemic relapse in patients with
T2D and metabolic syndrome [52]. However, weight loss
is associated with improved insulin sensitivity and
decreased need for treatment [53].
Biochemical parameters associated with disease progression are increased plasma levels of triacylglycerides, low
high-density lipoprotein-cholesterol, increased FPG,
increased HbA1c, and positive glutamic acid decarboxylase antibody concentrations [43]. In a meta-analysis of
59 randomized-controlled studies, the association
between baseline HbA1c and absolute change in HbA1c
following initiation of 10 different glucose-lowering
agents was tested. The authors reported a weighted R2
of 0.35; however, a subanalysis of metformin studies
showed a stronger association with a weighted R2 of 0.67.

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

478

Pharmacogenetics and Genomics 2015, Vol 25 No 10

Fig. 2

Initial drug
monotherapy

Metformin

Efficacy
Hypoglycemia
Weight
Side-effects

Metformin +
sulfonylurea

Two-drug
combinations

Metformin +
thiazolidinedione

Metformin +
DPP-4 inhibitor

Metformin +
GLP-1 receptor
agonist

Metformin +
insulin (basal)

Efficacy
Hypoglycemia
Weight
Side-effects

Three-drug
combinations

Metformin +
sulfonylurea +

Metformin +
thiazolidinedione +

Metformin +
DPP-4 +

Metformin +
GLP-1 RA +

Metformin +
insulin basal +

either
TZD or
DPP-4-1 or
GLP-1 RA or
basal insulin

either
SU or
DPP-4-1 or
GLP-1 RA or
basal insulin

either
SU or
TZD or
GLP-1 RA or
basal insulin

either
SU or
TZD or
DPP-4-1 or
basal insulin

either
SU or
TZD or
DPP-4-1 or
GLP-1 RA

Insulin
strategies

Insulin in
multiple daily doses

Treatment guidelines for antihyperglycemic therapy in type 2 diabetes patients on the basis of guidelines from American Diabetes Association and
European Association for the Study of Diabetes [30]. Thiazolidinediones are of limited use in the treatment of type 2 diabetes because of withdrawal
of troglitazone and rosiglitazone. Troglitazone was withdrawn because of the risk of hepatitis, and more recently, rosiglitazone was withdrawn because
of the risk of heart failure [34,35]. Pioglitazone is still in use, but may be possibly associated with increased risk of bladder cancer [36]. DPP-4,
dipeptidyl peptidase-4; GLP-1, glucagon-like peptide 1; SU, sulfonylurea; TZD, thiazolidinedione.

Clinical and biochemical characteristics associated with

disease progression in type 2 diabetics

Table 1

Clinical variables

Biochemical variables

Young age at diagnosis

Low BMI
High BMI
High body fat percentage
Low -cell functiona
Increase in weight
Increase in waist circumference
Hypertension

High triacylglyceride levels

Low HDL
High HbA1c [ > 53 mmol/mol (7%)]
High fasting plasma glucose
Positive GAD antibodies

This table is based on data from large cohort studies [18,20,32,43].

GAD, glutamic acid decarboxylase; HDL, high-density lipoprotein.
a
Low -cell function: measured as either add-on of a secondary oral antidiabetic
drug or progression to insulin treatment.

These data suggest that 67% of the reduction of HbA1c

after initiation of metformin is dependent on baseline
HbA1c [54].

Pharmacogenetics in disease progression

Over the recent years, more than 90 susceptibility genes
have been identified by genome-wide association studies
(GWAS) [5558]. However, the knowledge of the
potential interactions between T2D predisposing genetic
variants and the efficacy of treatment of T2D is sparse.
Identification of genetreatment interactions is challenging and requires large sample sizes and sophisticated
analytical methods. Furthermore, detailed information on
lifestyle and compliance to treatment as well as a long
follow-up period are necessary for analysis of pharmacogenomics in T2D.
Genetic susceptibility to disease progression was tested
recently in a population of American Indians, and a high
heritability (h2 = 0.65) was reported. Disease progression
was measured as worsening of glycemic levels, which led

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pharmacogenetics in progression of T2D Engelbrechtsen et al. 479

to diagnosis of T2D from normoglycemic levels. Three

genetic variants (WFS1, TSPAN8, THADA) were associated with disease progression after adjustment analyses
[15]. The role of these genetic variants in disease progression of T2D has not been clarified as yet.
Genetic risk score models based on known diabetes
susceptibility variants have failed to show association
with disease progression [13,22]. These results were
unexpected as diabetes developers share much of the
same phenotypical traits as disease progressors. Zhou
et al. [13] found a significant association between a high
genetic risk score (derived from 61 known diabetes risk
variants) with younger age of diagnosis and younger age
of starting insulin, but was not associated with progression rate from diagnosis to start of insulin treatment.
These findings were supported recently by Hornbak
et al. [22] and suggest that the genetic factors that cause a
rapid progression in glycemic deterioration might be
different from the genetic factors that predispose toward
development of diabetes.
Diabetes progression is a multifactorial process; however,
pharmacogenetics seems to play an important role in
understanding the different phenotypes and progression
rates among diabetic patients. Genetic variants associated
with decreased effect of a certain drug might explain why
some individuals are more likely to experience glycemic
deterioration on a given treatment. In the following
sections, different genetic variants and their impact on
treatment efficacy and outcome will be addressed.
Metformin

Metformin is the first drug of choice when initiating

treatment for T2D. Metformin increases insulin sensitivity and uptake of glucose in peripheral tissues, and
decreases gluconeogenesis in the liver. Metformin relies
on drug transporters for intestinal uptake and distribution, and for renal excretion [59]. Thus, drug transporters
have been the main focus in pharmacogenetic studies of
metformin efficacy.
Recent trends in pharmacogenetic studies have been the
use of GWAS on large population cohorts, enabling the
detection of multiple common genetic variants with a
small effect on disease progression. The first GWAS on
metformin response was published in 2011 and identified
the minor allele (C-allele) of rs11212617 near ATM, the
ataxia telangiectasia mutated gene, to be associated with
a better response to metformin with an odds ratio of 1.64
in the discovery cohort (n = 1024). After replication in two
cohorts, the authors reported a combined odds ratio of
1.35, 95% confidence interval (CI) 1.221.49, among
3920 individuals [60]. A subgroup of the patients
(n = 284), who were homozygotes for the minor C-allele
at rs11212617, had a 3.3-fold greater likelihood of
achieving an HbA1c 7% or less on metformin monotherapy. The association between rs11212617 and

metformin response was confirmed in a European cohort

[61]; however, different results have also been reported.
Florez et al. [62] tested the effect of the C-allele at the
rs11212617 on metformin response in a cohort of 2994
participants and could not replicate the findings of the
GWAS. Furthermore, two other groups reported that the
glucose-lowering effect of metformin in mice does not
require AMPK (AMP-activated protein kinase, a target
downstream of ATM and of metformin action), suggesting
that ATM may not be the causal gene behind glycemic
response to metformin [63,64].
The variation in steady-state metformin plasma concentration is high and reported to be nearly 80-fold
(544133 ng/ml), which reflects an interindividual variation in bioavailability, distribution, and elimination from
the kidneys. The only clinical determinant of response to
metformin, besides baseline HbA1c as described previously, is renal clearance. Decreased renal clearance is
associated with a higher plasma concentration of metformin and subsequently a risk of metformin-induced
lactate acidosis in patients with renal insufficiency [65].
Although metformin is one of the most widely used
drugs, the underlying mechanisms of its glucose-lowering
effect have not been completely clarified. Metformin has
been described thoroughly in vitro as a substrate of the
organic cation transporters (OCTs), including the liverspecific OCT1 and OCT2, which is expressed in the
kidneys [66]. Genetic variations in OCT1 and OCT2
[encoded by Solute Carrier Family (SLC) SLC22A1 and
SLC22A2], as well as the multidrug and toxin extrusion
proteins MATE1 and MATE2 (encoded by SLC47A1
and SLC47A2) are associated with altered pharmacokinetic and pharmacodynamic response to metformin [66
71]. OCT1 is a major determinant of the glucoselowering effect of metformin. Shu et al. [71] reported
that elimination of functional OCT1 from in-vitro cultures of mice hepatocytes reduced the response to metformin. In addition, in-vivo studies in mice showed that
OCT1 is crucial for metformin response as OCT1-deficient mice have abolished the glucose-lowering effects of
metformin. In humans, the OCT1 polymorphisms have
been shown to modulate cellular and clinical response to
metformin [71].
Christensen et al. [72] reported that the mean steadystate metformin plasma concentration and absolute
decrease in HbA1c following initiation of treatment with
metformin were correlated to the number of reduced
function alleles in OCT1 in a large cohort of patients with
T2D. Steady-state metformin plasma concentration was
significantly decreased in patients heterozygous for the
minor allele rs72552763 in OCT1. Furthermore, alleles in
OCT1, rs12208357, rs34130495, rs72552763, and
rs34059508 showed an additive decrease in the steadystate plasma concentration. In the Diabetes Prevention
Program, a significant interaction of a missense SNP,

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

480

Pharmacogenetics and Genomics 2015, Vol 25 No 10

rs683369 in OCT1, with metformin was reported, with the

major allele protecting from diabetes in individuals with a
high risk of developing diabetes treated with metformin
[hazard ratio (HR) 0.69, 95% CI 0.530.89], but not in the
placebo group. The major allele was associated with a
31% risk reduction in the incidence of diabetes in highrisk individuals treated with metformin [73].
No correlation was found between genetic variants in
OCT2 and reduction in HbA1c on metformin treatment in
a Danish randomized-controlled trial, although genegene
interactions between polymorphisms in the OCT2 and
MATE1 genes were found to influence the renal clearance
of metformin [67].
Variants in MATE1 (g.66TC, rs2252281) and MATE2
(g.130GA, rs12943590) are associated with altered
post-metformin glucose tolerance in healthy individuals.
Post-metformin glucose tolerance, measured as glucose
AUC and HbA1c, were changed in individuals homozygous for the MATE1 C-allele, which had significantly
lower HbA1c levels and glucose levels after OGTT.
Consistent with these results, patients with diabetes
carrying the MATE1 variant show enhanced metformin
response [68]. The rs2289669 is also associated with a
reduction in HbA1c levels [70]. In the Diabetes
Prevention Program, an interaction with rs8065082 in
MATE1 and metformin was reported, with the minor
allele associated with a lower incidence of diabetes in a
group of individuals with a high risk of developing diabetes treated with metformin (HR 0.78, 95% CI
0.640.96), but not in the placebo group (HR 1.15, 95%
CI 0.971.37). At this locus, major allele homozygotes did
not benefit from metformin treatment in terms of diabetes prevention, whereas minor allele carriers did benefit from metformin [73].
A recent genome-wide complex trait analysis suggested
that the heritability of response to metformin is based on
several genetic variants scattered across the genome and
not on single variants with large effects on response. The
heritability of response to metformin was 34% for an
absolute reduction in HbA1c after adjustment for baseline HbA1c [74].
Sulfonylureas

Sulfonylureas increase the secretion of insulin from the cells in the pancreas. Sulfonylureas are typically prescribed as a second-line drug as an add-on to metformin
treatment. Side effects such as weight gain and episodes
of hypoglycemia are common in patients on sulfonylurea
treatment [38].
Sulfonylureas bind to the K-ATP channel proteins, and
induce channel closure and subsequently release of
presynthesized insulin from the -cells in the pancreas.
Sulfonylureas are metabolized in the liver by the cytochrome P450 isoenzyme 2C9 (encoded by CYP2C9). In a
previous GoDARTS study of 1073 sulfonylurea-treated

patients, 6% of the study participants were carriers of two

loss-of-function CYP2C9 variants. The carriers of these
loss-of-function alleles had a 0.5% greater reduction in
HbA1c and were 3.4 times more likely to achieve an
HbA1c less than 53 mmol/mol (7%) [75].
Genetic variants in ABCC8 and KCNJ11 are associated
with response to sulfonylurea in patients with diabetes.
ABCC8 and KCNJ11 encode K-ATP channel proteins
SUR1 and Kir6.2, which play important roles in glucosestimulated insulin secretion. Rare mutations in SUR1 and
Kir6.2 can cause transient and permanent neonatal diabetes, and sulfonylurea treatment is effective in these
patients, making it possible to replace insulin injection
treatment [76]. Common variants, E23K in KCNJ11 and
S1369A in ABCC8, which are in strong linkage disequilibrium, predispose to development of T2D and for
these common variants response to sulfonylurea is
increased [7581]. Hamming et al. [82] reported that the
ABCC8 S1369A variant alters the properties of the K-ATP
channel, which contributes toward the increased risk for
T2D associated with the K23/A1369 risk haplotype.
Carriers of the K23/A1369 variant K-ATP had a 3.5 times
increased sensitivity to gliclazide compared with glibenclamide [82].
Carriers of transcription factor 7-like 2 (TCF7L2) T2D
risk variants are more likely to show failure of sulfonylurea treatment. Pearson et al. [83] reported that carriers of
the rs12255372 T-allele and the rs7903146 T-allele were
less likely to respond to sulfonylurea treatment, with an
odds ratio for failure of 1.94 for the rs12255372 T/T
genotype. There was no significant effect of genotype on
metformin response in the same cohort. Similarly,
Javorsky et al. [84] reported a genotype-specific effect on
sulfonylurea efficacy among 101 patients with diabetes.
Fifty-one patients were homozygous for the rs7903146
wild-type C-allele (CC-genotype), 41 patients were heterozygous (CT-genotype), and nine patients were
homozygous for the T2D-associated T-allele (TT-genotype) of TCF7L2. Homozygous CC-allele carriers showed
an 80% greater reduction in HbA1c than T-allele carriers
after 6 months on gliclazide treatment. No significant
difference in genotype-specific effect was observed in
patients treated with glimepiride, glibenclamide, or glipizide [84]. The study, however, had limited power
because of the number of individuals included.
Genetic variants in the IRS-1 gene have also been associated with response to sulfonylurea treatment. Carriers
of the Arg972 polymorphism in the IRS-1 gene are more
likely to have secondary failure of sulfonylurea treatment
[85]. Prudente et al. [23] confirmed this association and
reported that carriers of IRS-1 G792R had a 30%
increased risk of secondary failure of sulfonylurea.
For sulfonylurea treatment, several of the known T2D
risk alleles have been shown to influence the response to
treatment, as it is seen for ABCC8, KCNJ11, TCF7L2, and

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pharmacogenetics in progression of T2D Engelbrechtsen et al. 481

IRS-1. These important findings may enable future studies to identify sulfonylurea response patterns among
patients with T2D, which may enable identification of
specific sites of action of the genetic variants and subsequently tailor antidiabetic drugs according to genotype.
The knowledge gained so far on genotype-response
patterns to sulfonylurea treatment may facilitate implementation of pharmacogenetic testing before initiation of
treatment. For homozygotic carriers of the K23/A1369
variant K-ATP, initiation of gliclazide treatment could be
an example of tailored pharmacotherapy in the future.
Thiazolidinediones

Thiazolidinediones, also known as glitazones, are agonists of the peroxisome proliferator-activated receptor
(PPARG-) that increase glucose uptake in skeletal
muscle, enhance lipolysis, and inhibit hepatic glucose
production. Currently, thiazolidinediones are of limited
use in the treatment of T2D because of withdrawal of
troglitazone and rosiglitazone from the marked.
Troglitazone was withdrawn because of the risk of
hepatitis, and more recently, rosiglitazone was withdrawn
because of the risk of heart failure [34,35]. Pioglitazone is
still in use, but may be associated with increased risk of
bladder malignancy [36].
The use of pioglitazone is associated with a high rate of
nonresponse among patients with T2D who are prescribed pioglitazone treatment. The nonresponder rate to
treatment with pioglitazone is reported to be up to nearly
20% [86]. A genetic variant, the S447X in the lipoprotein
lipase gene, is associated significantly with increased
response to pioglitazone treatment measured as a
reduction in FPG following 10 weeks of treatment [86].
Identification of other variants associated response to
pioglitazone could enable pharmacogenetic testing
before initiation of pioglitazone and prevent useless
intake among nonresponders.

glycemic efficacy and can induce a reduction in HbA1c of

821 mmol/mol (0.71.9%) after 2430 weeks of combination treatment with either metformin or
metformin + sulfonylurea/glitazones [9195].
Zimdahl et al. [96] recently reported that response to
DPP-4 inhibitors was affected in carriers of TCF7L2 risk
alleles. Among 941 patients with T2D, linagliptin treatment showed a significant reduction in HbA1c according
to genotype. In the nonrisk carriers with an rs7903146
CC-genotype, HbA1c was reduced by 9 mmol/mol
(0.82%), in CT-genotype carriers, HbA1c was reduced by
8.5 mmol/mol (0.77%), and in the high-risk homozygotes TT-genotype carriers, HbA1c was only reduced
by 7 mmol/mol (0.57%). The response to treatment was
significant on comparing the CC with the TT genotype
[96]. Similarly, for the TCF7L2 variants, rs7903146 and
rs12255372, GLP-1 infusion combined with a hyperglycemic clamp showed a reduction in GLP-1-induced
insulin secretion in carriers [97]. For response to GLP-1,
the T2D risk variant, rs10010131 in WFS1, is associated
with reduced insulin secretion during an OGTT independent of insulin sensitivity in nondiabetic participants [98].
These findings highlight that individuals carrying the
above-mentioned variants may be at increased risk of
developing T2D, likely because of decreased insulin
secretion from -cell following GLP-1 stimulation.
Individuals carrying these variants may be susceptible to
a kind of incretin resistance because of the decreased
insulin secretion following GLP-1 infusion. For these
individuals, GLP-1 agonists may not be the appropriate
therapy if they develop T2D.
GLP-1 receptor agonists and DPP-4 inhibitors are relatively new drugs, and limited information on long-term
efficacy of treatment is available. Therefore, the role of
these drugs in disease progression is not fully elucidated.

Incretin-based therapies

Perspectives and concluding remarks

Incretin mimetics include the relatively new drugs

GLP-1 receptor agonists and dipeptidyl peptidase-4
(DPP-4) inhibitors. GLP-1 receptor agonists induce
secretion of insulin, inhibit glucagon release and gastric
emptying, and reduce appetite. GLP-1 is produced in the
human intestinal L-cells and has a half-life of approximately a couple of minutes [87]. Synthetically produced
GLP-1 receptor agonists have properties similar to those
of human GLP-1, but are optimized with a longer halflife. DPP-4 inhibitors inhibit degradation of endogenous
GLP-1 and therefore mimic the actions of GLP-1
receptor agonists [87].

Disease progression in T2D is a continuous process,

largely because of decline in -cell function and failure of
antidiabetic drugs. Phenotypes related to the development of T2D are similar to phenotypes associated with
disease progression, although the common susceptibility
variants for the development of diabetes do not seem to
be responsible for disease progression. Genetic risk score
models including known T2D risk variants have failed to
identify disease progressors among patients with T2D.
However, genetic risk scores are based on known loci and
can only explain a fraction of T2D heritability. Despite
the missing heritability, number of genes included, and
limited statistical power, these risk score models indicate
that the genes responsible for development of diabetes
are not mainly driving disease progression.

The glycemic efficacy in patients with diabetes has been

tested for both drugs. DPP-4 inhibitors can reduce
HbA1c by 714 mmol/mol (0.61.3%) in patients treated
with vildagliptin, saxagliptin, or linagliptin monotherapy
[8890]. GLP-1 receptor agonists have slightly better

T2D patients treated according to international guidelines and standards show a variable response to

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

482 Pharmacogenetics and Genomics 2015, Vol 25 No 10

glucose-lowering drugs, and it seems from previous studies that the response is partly heritable. Most pharmacogenetic studies are, however, of limited statistical
power because of the number of participants ranging
from 50 to 1100 individuals. Furthermore, studies are
difficult to compare as they differ in data on baseline
treatment, type of drug, dosage, comorbidity, concomitant treatment, and how they measure disease progression. Compliance and adherence to therapy is
another major issue among patients with T2D, as previous studies report an adherence to treatment of 3693%
[99,100]. Many studies have reported data on prescription
dosage, but not on compliance and actual consumption
dosage. Furthermore, as was shown for metformin, the
interindividual variation in bioavailability, distribution,
and elimination is high among patients receiving the
same drug dosage. Although it is difficult to assess
adherence to therapy, consumption data, and bioavailability, it must be considered a likely contributor toward
disease progression [100].
To date, a number of genetic variants have been identified to be associated with response to antidiabetic
drugs. Of these, some variants are present in either drug
receptors or drug metabolizers as for OCT genes, KCNJ11,
ABCC8, and CYP2C9. Other variants are known T2D
susceptibility variants such as TCF7L2. To identify variants of importance for antiglycemic drug response,
GWAS in large cohorts of patients with diabetes with
detailed measures of pharmacotherapy are lacking. The
pharmacologic management of patients with diabetes
often involves drug classes other than antidiabetics.
Pharmacogenetic studies on statin and antihypertensive
treatment have reported several genetic variants associated with treatment response and adverse drug reactions [101,102]. It therefore seems natural to conclude
that the future perspectives in pharmacogenetics is to
conduct genetic studies in large cohorts with wellphenotyped individuals, thorough data collection on
baseline treatment, concomitant treatment, adherence to
therapy as well as data collection on comorbidity and
additional disease diagnoses. These types of pharmacogenetic studies may provide unique opportunities for
future genotype-based treatment standards and may help
in delaying or changing the slope of disease progression
among patients with T2D.

Acknowledgements
This work was supported by research grants from the
Danish Diabetes Academy and the Novo Nordisk
Foundation.

Conflicts of interest

There are no conflicts of interest.

References
1 Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of
type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a
population-based study of 13,000 men and women with 20 years of followup. Arch Intern Med 2004; 164:14221426.
2 Pyram R, Kansara A, Banerji MA, Loney-Hutchinson L. Chronic kidney
disease and diabetes. Maturitas 2012; 71:94103.
3 De Vegt F, Dekker JM, Ruh HG, Stehouwer CD, Nijpels G, Bouter LM,
Heine RJ. Hyperglycaemia is associated with all-cause and cardiovascular
mortality in the Hoorn population: the Hoorn Study. Diabetologia 1999;
42:926931.
4 Gillett MJ. International Expert Committee report on the role of the A1c
assay in the diagnosis of diabetes. Diabetes Care 2009; 32:13271334.
5 American Diabetes Association. Standards of medical care in diabetes
2014. Diabetes Care 2014; 37 (Suppl 1):S14S80.
6 Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al.
Association of glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective
observational study. BMJ 2000; 321:405412.
7 Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet,
sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus:
progressive requirement for multiple therapies (UKPDS 49). UK
Prospective Diabetes Study (UKPDS) Group. JAMA 1999;
281:20052012.
8 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose
control with sulphonylureas or insulin compared with conventional treatment
and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet 1998; 352:837853.
9 U.K. Prospective Diabetes Study Group. U.K. prospective diabetes study
16. Overview of 6 years therapy of type II diabetes: a progressive disease.
Diabetes 1995; 44:12491258.
10 United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative
efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in
patients with newly diagnosed non-insulin dependent diabetes followed for
three years. BMJ 1995; 310:8388.
11 United Kingdom Prospective Diabetes Study Group. United Kingdom
Prospective Diabetes Study 24: a 6-year, randomized, controlled trial
comparing sulfonylurea, insulin, and metformin therapy in patients with
newly diagnosed type 2 diabetes that could not be controlled with diet
therapy. Ann Intern Med 1998; 128:165175.
12 Pani LN, Nathan DM, Grant RW. Clinical predictors of disease progression
and medication initiation in untreated patients with type 2 diabetes and A1C
less than 7%. Diabetes Care 2008; 31:386390.
13 Zhou K, Donnelly LA, Morris AD, Franks PW, Jennison C, Palmer CN,
Pearson ER. Clinical and genetic determinants of progression of type 2
diabetes: a DIRECT study. Diabetes Care 2014; 37:718724.
14 Fonseca VA. Defining and characterizing the progression of type 2
diabetes. Diabetes Care 2009; 32 (Suppl 2):S151S156.
15 Franceschini N, Haack K, Gring HH, Voruganti VS, Laston S, Almasy L,
et al. Epidemiology and genetic determinants of progressive deterioration of
glycaemia in American Indians: the Strong Heart Family Study. Diabetologia
2013; 56:21942202.
16 Franks PW, Pearson E, Florez JC. Gene-environment and gene-treatment
interactions in type 2 diabetes: progress, pitfalls, and prospects. Diabetes
Care 2013; 36:14131421.
17 Pearson E. RD Lawrence lecture 2013. Stratified approaches to the
management of diabetes. Diabet Med 2014; 31:393398.
18 Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT.
Genetic cause of hyperglycaemia and response to treatment in diabetes.
Lancet 2003; 362:12751281.
19 Rubio-Cabezas O, Hattersley AT, Njlstad PR, Mlynarski W, Ellard S,
White N, et al. The diagnosis and management of monogenic diabetes in
children and adolescents. Pediatr Diabetes 2014; 15 (Suppl 20):4764.
20 McDonald TJ, Ellard S. Maturity onset diabetes of the young: identification
and diagnosis. Ann Clin Biochem 2013; 50 (Pt 5):403415.
21 Meigs JB, Muller DC, Nathan DM, Blake DR, Andres R. Baltimore
Longitudinal Study of Aging. The natural history of progression from normal
glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study
of Aging. Diabetes 2003; 52:14751484.
22 Hornbak M, Allin KH, Jensen ML, Lau CJ, Witte D, Jrgensen ME, et al. A
combined analysis of 48 type 2 diabetes genetic risk variants shows no
discriminative value to predict time to first prescription of a glucose lowering
drug in Danish patients with screen detected type 2 diabetes. PLoS One
2014; 9:e104837.
23 Prudente S, Morini E, Lucchesi D, Lamacchia O, Bailetti D, Mercuri L, et al.
IRS1 G972R missense polymorphism is associated with failure to oral

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pharmacogenetics in progression of T2D Engelbrechtsen et al. 483

24

25

26
27

28

29

30

31

32

33

34

35

36

37

38
39

40

41

42
43

44

45

46

antidiabetes drugs in white patients with type 2 diabetes from Italy.

Diabetes 2014; 63:31353140.
Festa A, Williams K, DAgostino R Jr, Wagenknecht LE, Haffner SM. The
natural course of beta-cell function in nondiabetic and diabetic individuals:
the Insulin Resistance Atherosclerosis Study. Diabetes 2006;
55:11141120.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M,
et al. Management of hyperglycemia in type 2 diabetes: a patient-centered
approach: position statement of the American Diabetes Association (ADA)
and the European Association for the Study of Diabetes (EASD). Diabetes
Care 2012; 35:13641379.
Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:574579.
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al.
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
N Engl J Med 2006; 355:24272443.
Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26:
sulphonylurea failure in non-insulin-dependent diabetic patients over six
years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med 1998;
15:297303.
Heine RJ, Diamant M, Mbanya JC, Nathan DM. Management of
hyperglycaemia in type 2 diabetes: the end of recurrent failure? BMJ 2006;
333:12001204.
Wallace TM, Matthews DR. Coefficient of failure: a methodology for
examining longitudinal beta-cell function in Type 2 diabetes. Diabet Med
2002; 19:465469.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R,
et al. Medical management of hyperglycemia in type 2 diabetes: a
consensus algorithm for the initiation and adjustment of therapy. A
consensus statement of the American Diabetes Association and the
European Association for the Study of Diabetes. Diabetes Care 2009;
32:193203.
Fu AZ, Qiu Y, Davies MJ, Radican L, Engel SS. Treatment intensification in
patients with type 2 diabetes who failed metformin monotherapy. Diabetes
Obes Metab 2011; 13:765769.
Rajpathak SN, Rajgopalan S, Engel SS. Impact of time to treatment
intensification on glycemic goal attainment among patients with type 2
diabetes failing metformin monotherapy. J Diabetes Complications 2014;
28:831835.
Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM. Two cases of severe
clinical and histologic hepatotoxicity associated with troglitazone. Ann
Intern Med 1998; 129:3638.
Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of
thiazolidinediones and risk of heart failure in people with type 2 diabetes: a
retrospective cohort study. Diabetes Care 2003; 26:29832989.
Turner RM, Kwok CS, Chen-Turner C, Maduakor CA, Singh S, Loke YK.
Thiazolidinediones and associated risk of bladder cancer: a systematic
review and meta-analysis. Br J Clin Pharmacol 2014; 78:258273.
Rena G, Pearson ER, Sakamoto K. Molecular action and pharmacogenetics
of metformin: current understanding of an old drug. Diabetes Manag 2012;
2:439452.
Hermann LS. Biguanides and sulfonylureas as combination therapy
in NIDDM. Diabetes Care 1990; 13 (Suppl 3):3741.
Cook MN, Girman CJ, Stein PP, Alexander CM, Holman RR. Glycemic
control continues to deteriorate after sulfonylureas are added to metformin
among patients with type 2 diabetes. Diabetes Care 2005; 28:9951000.
Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The
prevalence of meeting A1C, blood pressure, and LDL goals among people
with diabetes, 19882010. Diabetes Care 2013; 36:22712279.
Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR. Beta-cell
deterioration determines the onset and rate of progression of secondary
dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the
Belfast Diet Study. Diabet Med 1998; 15:290296.
Bagust A, Beale S. Deteriorating beta-cell function in type 2 diabetes: a
long-term model. QJM 2003; 96:281288.
Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, et al.
UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid
decarboxylase for prediction of insulin requirement in type 2 diabetes. UK
Prospective Diabetes Study Group. Lancet 1997; 350:12881293.
Donnan PT, MacDonald TM, Morris AD. Adherence to prescribed oral
hypoglycaemic medication in a population of patients with type 2 diabetes:
a retrospective cohort study. Diabet Med 2002; 19:279284.
Ringborg A, Lindgren P, Yin DD, Martinell M, Stlhammar J. Time to insulin
treatment and factors associated with insulin prescription in Swedish
patients with type 2 diabetes. Diabetes Metab 2010; 36:198203.
Brown JB, Conner C, Nichols GA. Secondary failure of metformin
monotherapy in clinical practice. Diabetes Care 2010; 33:501506.

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63
64
65
66

Droumaguet C, Balkau B, Simon D, Caces E, Tichet J, Charles MA,

Eschwege E. DESIR Study Group. Use of HbA1c in predicting progression
to diabetes in French men and women: data from an Epidemiological Study
on the Insulin Resistance Syndrome (DESIR). Diabetes Care 2006;
29:16191625.
Schiel R, Franke S, Appel T, Voigt U, Ross IS, Kientsch-Engel R, et al.
Improvement of the quality of diabetes control and decrease in the
concentrations of AGE-products in patients with type 1 and insulin-treated
type 2 diabetes mellitus: results from a 10 year-prospective, populationbased survey on the quality of diabetes care in Germany (JEVIN). Eur J Med
Res 2004; 9:391399.
Charles MA, Fontbonne A, Thibult N, Warnet JM, Rosselin GE,
Eschwege E. Risk factors for NIDDM in white population. Paris
prospective study. Diabetes 1991; 40:796799.
De Vegt F, Dekker JM, Jager A, Hienkens E, Kostense PJ, Stehouwer CD,
et al. Relation of impaired fasting and postload glucose with incident type 2
diabetes in a Dutch population: The Hoorn Study. JAMA 2001;
285:21092113.
Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL,
Dowse GK, et al. Predictors of progression from impaired glucose
tolerance to NIDDM: an analysis of six prospective studies. Diabetes 1997;
46:701710.
Blaha MJ, Gebretsadik T, Shintani A, Elasy TA. Waist circumference, not the
metabolic syndrome, predicts glucose deterioration in type 2 diabetes.
Obesity (Silver Spring) 2008; 16:869874.
Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R.
Reversal of type 2 diabetes: normalisation of beta cell function in
association with decreased pancreas and liver triacylglycerol. Diabetologia
2011; 54:25062514.
DeFronzo RA, Stonehouse AH, Han J, Wintle ME. Relationship of baseline
HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis
of randomized clinical trials. Diabet Med 2010; 27:309317.
Morris AP, Voight BF, Teslovich TM, Ferreira T, Segr AV, Steinthorsdottir V,
et al. Large-scale association analysis provides insights into the genetic
architecture and pathophysiology of type 2 diabetes. Nat Genet 2012;
44:981990.
Grarup N, Sandholt CH, Hansen T, Pedersen O. Genetic susceptibility to
type 2 diabetes and obesity: from genome-wide association studies to rare
variants and beyond. Diabetologia 2014; 57:15281541.
Sun X, Yu W, Hu C. Genetics of type 2 diabetes: insights into the
pathogenesis and its clinical application. Biomed Res Int 2014;
2014:926713.
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM)
Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes
(AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D)
Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type
2 Diabetes Genetic Exploration by Nex-generation sequencing in multiEthnic Samples (T2D-GENES) Consortium, Mahajan A, et al. Genomewide trans-ancestry meta-analysis provides insight into the genetic
architecture of type 2 diabetes susceptibility. Nat Genet 2014;
46:234244.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al.
Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;
50:8198.
Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, Tavendale R,
et al. GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group;
Wellcome Trust Case Control Consortium 2; MAGIC investigators.
Common variants near ATM are associated with glycemic response to
metformin in type 2 diabetes. Nat Genet 2011; 43:117120.
Van Leeuwen N, Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BH,
et al. A gene variant near ATM is significantly associated with metformin
treatment response in type 2 diabetes: a replication and meta-analysis of
five cohorts. Diabetologia 2012; 55:19711977.
Florez JC, Jablonski KA, Taylor A, Mather K, Horton E, White NH, et al. The
C allele of ATM rs11212617 does not associate with metformin response in
the Diabetes Prevention Program. Diabetes Care 2012; 35:18641867.
Yee SW, Chen L, Giacomini KM. The role of ATM in response to metformin
treatment and activation of AMPK. Nat Genet 2012; 44:359360.
Woods A, Leiper JM, Carling D. The role of ATM in response to metformin
treatment and activation of AMPK. Nat Genet 2012; 44:360361.
Harrower AD. Pharmacokinetics of oral antihyperglycaemic agents in
patients with renal insufficiency. Clin Pharmacokinet 1996; 31:111119.
Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y.
Involvement of organic cation transporter 1 in hepatic and intestinal
distribution of metformin. J Pharmacol Exp Ther 2002; 302:510515.

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

484

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

Pharmacogenetics and Genomics 2015, Vol 25 No 10

Christensen MM, Pedersen RS, Stage TB, Brasch-Andersen C, Nielsen F,

Damkier P, et al. A gene-gene interaction between polymorphisms in the
OCT2 and MATE1 genes influences the renal clearance of metformin.
Pharmacogenet Genomics 2013; 23:526534.
Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A, et al. The
effect of novel promoter variants in MATE1 and MATE2 on the
pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol
Ther 2013; 93:186194.
Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, et al. A
common 5-UTR variant in MATE2-K is associated with poor response to
metformin. Clin Pharmacol Ther 2011; 90:674684.
Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG,
Stricker BH. Genetic variation in the multidrug and toxin extrusion 1
transporter protein influences the glucose-lowering effect of metformin in
patients with diabetes: a preliminary study. Diabetes 2009; 58:745749.
Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al.
Effect of genetic variation in the organic cation transporter 1 (OCT1) on
metformin action. J Clin Invest 2007; 117:14221431.
Christensen MM, Brasch-Andersen C, Green H, Nielsen F, Damkier P,
Beck-Nielsen H, Brosen K. The pharmacogenetics of metformin and its
impact on plasma metformin steady-state levels and glycosylated
hemoglobin A1c. Pharmacogenet Genomics 2011; 21:837850.
Jablonski KA, McAteer JB, de Bakker PI, Franks PW, Pollin TI, Hanson RL,
et al. Diabetes Prevention Program Research Group. Common variants in
40 genes assessed for diabetes incidence and response to metformin and
lifestyle intervention in the diabetes prevention program. Diabetes 2010;
59:26722681.
Zhou K, Donnelly L, Yang J, Li M, Deshmukh H, Van Zuydam N, et al.
Heritability of variation in glycaemic response to metformin: a genome-wide
complex trait analysis. Lancet Diabetes Endocrinol 2014; 2:481487.
Zhou K, Donnelly L, Burch L, Tavendale R, Doney AS, Leese G, et al. Lossof-function CYP2C9 variants improve therapeutic response to sulfonylureas
in type 2 diabetes: a Go-DARTS study. Clin Pharmacol Ther 2010;
87:5256.
Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT.
Neonatal Diabetes International Collaborative Group. Effective treatment
with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor
1 (SUR1) mutations. Diabetes Care 2008; 31:204209.
Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glmer C,
et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum
insulin response and increased risk of type 2 diabetes. Diabetes 2003;
52:573577.
Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, et al.
Large-scale association studies of variants in genes encoding the
pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1
(ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2
diabetes. Diabetes 2003; 52:568572.
Feng Y, Mao G, Ren X, Xing H, Tang G, Li Q, et al. Ser1369Ala variant in
sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy
of gliclazide in Chinese type 2 diabetic patients. Diabetes Care 2008;
31:19391944.
Hansen T, Echwald SM, Hansen L, Mller AM, Almind K, Clausen JO, et al.
Decreased tolbutamide-stimulated insulin secretion in healthy subjects with
sequence variants in the high-affinity sulfonylurea receptor gene. Diabetes
1998; 47:598605.
Sesti G, Laratta E, Cardellini M, Andreozzi F, Del Guerra S, Irace C, et al.
The E23K variant of KCNJ11 encoding the pancreatic beta-cell adenosine
5-triphosphate-sensitive potassium channel subunit Kir6.2 is associated
with an increased risk of secondary failure to sulfonylurea in patients with
type 2 diabetes. J Clin Endocrinol Metab 2006; 91:23342339.
Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL,
Light PE. Coexpression of the type 2 diabetes susceptibility gene variants
KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea
sensitivities of the ATP-sensitive K(+ ) channel. Diabetes 2009;
58:24192424.
Pearson ER, Donnelly LA, Kimber C, Whitley A, Doney AS, McCarthy MI,
et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas:
a GoDARTs study. Diabetes 2007; 56:21782182.

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100
101

102

Javorsky M, Babjakova E, Klimcakova L, Schroner Z, Zidzik J, Stolfova M,

et al. Association between TCF7L2 Genotype and Glycemic Control in
Diabetic Patients Treated with Gliclazide. Int J Endocrinol 2013;
2013:374858.
Sesti G, Marini MA, Cardellini M, Sciacqua A, Frontoni S, Andreozzi F, et al.
The Arg972 variant in insulin receptor substrate-1 is associated with an
increased risk of secondary failure to sulfonylurea in patients with type 2
diabetes. Diabetes Care 2004; 27:13941398.
Wang G, Wang X, Zhang Q, Ma Z. Response to pioglitazone treatment is
associated with the lipoprotein lipase S447X variant in subjects with type 2
diabetes mellitus. Int J Clin Pract 2007; 61:552557.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1
receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Lancet 2006; 368:16961705.
Lajara R, Aguilar R, Hehnke U, Woerle H-J, von Eynatten M. Efficacy and
safety of linagliptin in subjects with long-standing type 2 diabetes mellitus
(>10 years): evidence from pooled data of randomized, double-blind,
placebo-controlled, phase iii trials. Clin Ther 2014; 36:15951605.
Zeng Z, Choi DS, Mohan V, Emser A, Siddiqui K, Gong Y, et al. Efficacy and
safety of linagliptin as monotherapy or add-on treatment in Asian patients
with suboptimal glycemic control: a pooled analysis. Curr Med Res Opin
2015; 31:99106.
Li CJ, Liu XJ, Bai L, Yu Q, Zhang QM, Yu P, Yu DM. Efficacy and safety of
vildagliptin, Saxagliptin or Sitagliptin as add-on therapy in Chinese patients
with type 2 diabetes inadequately controlled with dual combination of
traditional oral hypoglycemic agents. Diabetol Metab Syndr 2014; 6:69.
Madsbad S. Exenatide and liraglutide: different approaches to develop
GLP-1 receptor agonists (incretin mimetics) preclinical and clinical
results. Best Pract Res Clin Endocrinol Metab 2009; 23:463477.
Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H,
Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in
type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P).
Diabetes Obes Metab 2013; 15:10001007.
Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D,
Porter L. DURATION-1 Study Group. Exenatide once weekly versus twice
daily for the treatment of type 2 diabetes: a randomised, open-label, noninferiority study. Lancet 2008; 372:12401250.
Pratley RE, Nauck MA, Barnett AH, Feinglos MN, Ovalle F, HarmanBoehm I, et al. Once-weekly albiglutide versus once-daily liraglutide in
patients with type 2 diabetes inadequately controlled on oral drugs
(HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase
3 study. Lancet Diabetes Endocrinol 2014; 2:289297.
Deacon CF, Mannucci E, Ahrn B. Glycaemic efficacy of glucagon-like
peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on
therapy to metformin in subjects with type 2 diabetes a review and meta
analysis. Diabetes Obes Metab 2012; 14:762767.
Zimdahl H, Ittrich C, Graefe-Mody U, Boehm BO, Mark M, Woerle HJ,
Dugi KA. Influence of TCF7L2 gene variants on the therapeutic response to
the dipeptidylpeptidase-4 inhibitor linagliptin. Diabetologia 2014;
57:18691875.
Schfer SA, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B, et al.
Impaired glucagon-like peptide-1-induced insulin secretion in carriers of
transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia
2007; 50:24432450.
Schfer SA, Mssig K, Staiger H, Machicao F, Stefan N, Gallwitz B, et al. A
common genetic variant in WFS1 determines impaired glucagon-like
peptide-1-induced insulin secretion. Diabetologia 2009; 52:10751082.
Ho PM, Rumsfeld JS, Masoudi FA, McClure DL, Plomondon ME, Steiner JF,
Magid DJ. Effect of medication nonadherence on hospitalization and
mortality among patients with diabetes mellitus. Arch Intern Med 2006;
166:18361841.
Cramer JA. A systematic review of adherence with medications for
diabetes. Diabetes Care 2004; 27:12181224.
SEARCH Collaborative Group, Link E, Parish S, Armitage J, Bowman L,
Heath S, et al. SLCO1B1 variants and statin-induced myopathy a
genomewide study. N Engl J Med 2008; 359:789799.
Turner RM, Pirmohamed M. Cardiovascular pharmacogenomics:
expectations and practical benefits. Clin Pharmacol Ther 2014;
95:281293.

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.