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Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Is gliclazide a sulfonylurea with difference? A


review in 2016

Awadhesh Kumar Singh & Ritu Singh

To cite this article: Awadhesh Kumar Singh & Ritu Singh (2016): Is gliclazide a sulfonylurea
with difference? A review in 2016, Expert Review of Clinical Pharmacology, DOI:
10.1586/17512433.2016.1159512

To link to this article: http://dx.doi.org/10.1586/17512433.2016.1159512

Accepted author version posted online: 27


Feb 2016.

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Publisher: Taylor & Francis

Journal: Expert Review of Clinical Pharmacology

DOI: 10.1586/17512433.2016.1159512
Review

Is gliclazide a sulfonylurea with difference? A review in 2016

Corresponding author:
Awadhesh Kumar Singh
Consultant Endocrinologist,
G.D Hospital & Diabetes Institute, Kolkata, West Bengal (India).
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E mail: drawadheshkumarsingh@gmail.com

Name and designation of second author:


Ritu Singh
Consultant Gynecologist,
G.D Hospital & Diabetes Institute, Kolkata, West Bengal (India).
E mail: drritusingh73@gmail.com

Abstract:

Sulfonylureas (SUs) remain the most commonly prescribed drug after


metformin in the treatment of type 2 diabetes (T2DM), despite the
availability of several newer agents. The primary reason of SUs being
most popular is their quick glycemic response, time-tested experience and
least cost. Although SUs are one amongst the several other second line
agents after metformin in all major guidelines, the new Dutch type 2
guidelines specifically advise gliclazide as the preferred second line drug
instead of SUs as a class. The World Health Organization (WHO) has also
included gliclazide in their Model List of Essential Medicines 2013
motivated by its safety data in elderly patients. Specifically advising
gliclazide may have been based on emerging evidence suggesting
cardiovascular neutrality of gliclazide over other SUs. This prompted us to
do a literature review of gliclazide efficacy and safety data compared to
other SUs as well as oral anti-diabetic drugs.
Key words:

Sulfonylureas, gliclazide, hypoglycemia, Ramadan, cardiovascular


mortality

Introduction:

The initial sulfonylureas (SUs) introduced several decades ago were


derivatives of the antibacterial sulfonamides. Carbutamide (1-butyl-3-
sulfonylurea) was the first SU to be used to treat diabetes. However, it
was withdrawn, due to the bone marrow related adverse effects.
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Nevertheless, since 1960 several SUs become available for clinical use.1

SUs are basically substituted aryl-sulfonyl-ureas. While the aryl portions


of aryl-sulfonyl-urea provide lipophilic characteristics, the urea moiety
renders them hydrophilic. Although, the structural difference amongst
SUs lies in the types of substitutions at both the aryl and urea moiety
ends of the molecule, only the lipophilic aryl component account for the
individual differences in its potency (SU receptor binding), metabolism,
duration, and routes of elimination. SUs have traditionally been classified
as first-generation, that includes tolbutamide, acetohexamide, tolazamide
and chlorpropamide; second-generation such as glibenclamide, glipizide,
gliquidone and gliclazide; and third-generation that includes glimepiride,
gliclazide-MR (Modified Release), glipizide GITS (Gastrointestinal
Therapeutic System) preparation. Interestingly, although the SUs are
classified as first-, second-, and third-generations, there is no structural
or functional basis for this traditional classification.1,2 Prokes et al
proposed that SUs should be classified instead as sulfonylurea-receptor-1
(SUR1)-specific or non-SUR1-specific, depending upon the affinity to SUs
types of receptor bindings.3

Notably, the first-generation SUs are not used currently, owing to their
unacceptable side effects. Moreover, second- and third-generation SUs
are more potent, can be administered in lower doses and glimepiride,
gliclazide-MR and glipizide-GITS preparation can be used as once daily
basis. It should be noted however, that gliclazide is not available in USA.

Regarding the mechanism of action (MOA), SUs increase plasma insulin


concentration by β-cell stimulation and also by delaying the hepatic
clearance of insulin. The later mechanism perhaps works only when
stimulation of insulin secretion has already taken place.2 In basal
physiological state, the rate of insulin secretion from β-cells is minimal
and the plasma membrane of the β-cell is hyperpolarized. When the
glucose enters to β-cell via GLUT2 transporters present at the plasma
membrane of β cell, it is metabolised to generate intracellular ATP, which
in turn inhibit plasma membrane bound K+/ATP channel (an octamer
composed of Kir6.2 and SUR1 subunits). Inhibition of K+/ATP channel
decrease K+ influx resulting in depolarization of membrane, which in turn
activates voltage-gated Ca++ channels and thus cause exocytosis of
insulin-containing secretory vesicle leading to insulin secretion. While
glucose-generated ATP binds to and inhibits Kir6.2 part of octamer, SUs
bind to and inhibits SUR1 subunits, independent to glucose and thus
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cause stimulation of insulin secretion.3

While stimulation of pancreatic β-cell mediated insulin secretion is main


MOA of SUs, other mechanism may also contribute to glucose reduction to
a certain extent. While, SUs stimulate somatostatin secretion from δ-cell
through a similar mechanism, it reduces glucagon level due to the indirect
inhibition, owing to enhanced release of both somatostatin and insulin.
Moreover, SUs increases peripheral glucose utilisation by stimulating
hepatic gluconeogenesis and perhaps by augmenting insulin receptors and
sensitivity at the target tissues. Although several other extra-pancreatic
actions have also been cited in literature, these actions require a supra-
therapeutic concentration of SUs over and above the one to achieve
glycemic control and therefore, may not carry much clinical
significance.2,3

Although, the SUs have traditionally been categorised as a drug “class”, it


appears now that there could be a numerous differences among SUs in
terms of pharmacological properties. This includes differences in SUR
subtypes specificity and affinity, hypoglycaemic risk, and ability to abolish
ischemic preconditioning. Individual SUs express a different selectivity for
pancreatic β-cell (SUR1), myocardial SU receptors (SUR2A) and vascular
smooth muscle receptors (SUR2B). While gliclazide and glipizide are
specific for the pancreatic SUR1 receptors which principally stimulates
insulin secretion from β-cell; glimepiride and glibenclamide are non-
specific. The latter drugs stimulate both the pancreatic SUR1 and SUR2
receptors of both cardiac myocytes and vascular smooth muscle cells.
Thus glimepiride and glibenclamide carry the potential to mediate affects
both at the level of heart and smooth muscles.3 While both glimepiride
and glibenclamide are agonist to SUR2 receptors, only glibenclamide
possess the characteristics to abolish ischemic preconditioning (IP, a
cardio-protective phenomenon limiting ischemic injury or infarct size after
repeated episodes of ischemia and thereby protecting the heart) as
observed in experimental studies as well as in humans.4 The difference
between glimepiride and glibenclamide on SUR2 receptors could lie in
their potential difference on sarcolemmal versus mitochondrial K+/ATP
channel. While glibenclamide inhibits both sarcolemmal and mitochondrial
channels, glimepiride has minimal effect on mitochondrial channels. Since
mitochondrial K+/ATP channels have been primarily linked to IP rather
than sarcolemmal, glimepiride does not appear to interfere with IP.5
Intriguingly, although the inhibition of K+/ATP channels interferes with IP,
in the atria it increases the duration of action during ischemia–reperfusion
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injury, and thus carry the potential of reduction in the occurrence of atrial
fibrillation. Interestingly, both pre-clinical and clinical studies found that
prolonged closure of cardiac K+/ATP channels by glibenclamide to
decrease the effects of pro-arrhythmic substrates and reduce the risk of
re-entry arrhythmias including atrial fibrillation.6 Nonetheless, gliclazide
seems to possess most selectivity with respect to SUR1 of β-cell.7

Consequently, it is increasingly apparent that significant and substantial


pharmacological differences may exist between the different SUs.
However, whether these differences can lead to significant difference on
any hard end-points such as cardiovascular (CV) outcome or all-cause
mortality or both is far from clear till date. Pooled data from the
observational studies have also been unable to give clear answers in this
context. The reasons for this unclarity perhaps could be multi-factorial.
Lack of proper comparative analyses taking into account the design of
study, the population studied and several other confounding variables
may be some of the reasons for these conflicting results. Besides, SUs
being inexpensive, the probability of a future comparative prospective
randomised trial to assess any differences in outcomes also appear bleak.
Therefore, in the absence of such available evidence, data gathered thus
far from the observational studies and their meta-analysis, are the only
source of information at this point of time and has to be relied upon, until
further evidence is available.

Very few randomised trial studied SUs. Historically in 1960, The University
Group Diabetes Program (UGDP) reported an increased risk of all-cause
and cardiovascular (CV) mortality with tolbutamide; despite the fact that,
the UGDP was neither designed nor powered to test for CV safety of SU
over placebo. Nevertheless, as a consequence, every SU approved for use
in the US carries its product labels which mention that SUs could be
associated with increased CV mortality. It is unclear whether this finding
of the UGDP conducted during pre-statin era is currently applicable to
other second or third-generation SUs, commonly used in clinical practice.
Moreover, modern diabetes management requires a multi-factorial
approach which was not typically observed in UGDP. However, this finding
largely prompted the initiation of the UK Prospective Diabetes Study
(UKPDS), which did not find increased risk of CV death with
chlorpropamide and glibenclamide. Nonetheless, SUs have been
controversial ever since, as several subsequently reported retrospective
studies suggested an increased risk of adverse CV outcomes, mortality, or
both, specifically when compared with metformin.
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While SUs are one amongst the several other second line drugs after
metformin as recommended by latest American Diabetes Association and
European Association for the Study of Diabetes (ADA-EASD) position
statement; they are the preferred second line agents in current UK-NICE
(National Institute of Clinical Excellence) guidelines.8,9 Interestingly, the
new Dutch type 2 diabetes management guideline specifically advise
gliclazide as the preferred second line drug, instead of SUs as a class.10
Moreover, The World Health Organization (WHO) also included gliclazide
in their Model List of Essential Medicines 2013 along with metformin and
insulin, motivated by the safety data of gliclazide in elderly patients over
60 years of age.11

Specifically advising gliclazide may have been based on favourable


emerging evidence. Low risk of hypoglycemia and cardiovascular (CV)
neutrality of gliclazide over other SUs appears to be the main reason. The
low risk of hypoglycemic events could be attributed to the pattern of
insulin-secretion with gliclazide. The restoration of the early insulin peak
in response to glucose stimulation and higher reversibility of binding of
gliclazide to the SUR1 receptor of β-cell in comparison to glimepiride and
glibenclamide could be responsible for lesser pancreatic overstimulation
and thereby causing less hypoglycemia.12,13 The CV neutrality of gliclazide
also appears to be of distinct advantage over other SUs.14-27 Interestingly,
one study found additional anti-oxidant, hemo-rheological and fibrinolytic
properties of gliclazide.28 Moreover, Sliwinska et al reported that gliclazide
can diminish oxidative stress-related cell damage and death as it
decreases ROS (reactive-oxygen species) production, elevates
mitochondrial membrane potential and diminishes intracellular calcium in
human normal and cancer cells.29 This may have the potential to protect
oxidative stress-related diabetic complications and possibly malignancy.
Lower incidence of hypoglycemic events and less weight gain, compared
to other SUs while using gliclazide are also proposed as an explanation for
a possible favourable CV safety profile. From the renal perspective too, no
dose adjustment appear necessary in case of impaired renal function with
gliclazide, which could one important advantage.30

This article is a systematic review of efficacy and safety data of gliclazide


compared to other SUs as well as other oral anti-diabetic drugs.

Review method:
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An electronic search was conducted in PubMed, The Cochrane Library, and


Clinicaltrial.gov applying MeSH word “gliclazide”. All articles evaluating
gliclazide in type 2 diabetes and published in English literature till
December 31, 2015 were retrieved. Paper presented at international
conference as abstract was also included. All relevant articles pertaining
to the present topic were reviewed by the authors and systematically
collated in chronological order.

Efficacy and safety data of gliclazide:

a. gliclazide versus other SUs:

In 1983 a multi-centric, double blind, randomized study (n=289) was


conducted in Japan, when Baba et al evaluated the efficacy and safety of
gliclazide and compared to glibenclamide. Study found lower incidence of
hypoglycemia in gliclazide group versus glibenclamide group (7% versus
15% respectively, p<0.10), despite no significant differences in efficacy.
Moreover, funduscopic aggravations of retinopathy (using Scott’s
classification) and improvement in lipid profile was also superior with
gliclazide, compared to glibenclamide.31

A multi-centric, randomised, 3-month study (n=224) conducted by Shaw


et al in 1985 found that gliclazide was able to achieve adequate blood
glucose control (PPBG <8 mmol/l) in 65% of the patients. Moreover,
gliclazide also improved glucose control in 49% of patients who had failed
to other SUs (chorpropamide, tolbutamide, gliquidone and glipizide),
however, glycemic efficacy was similar to glibenclamide. Furthermore,
there was a significant mean weight loss (-0.62 kg, p<0.05) in all patients
shifted to gliclazide.32

Harrower in 1985, compared glycemic efficacy of five SUs (n=112)


chlorpropamide, glibenclamide, glipizide, gliquidone and gliclazide over a
follow-up period of 1 year. This study found that gliclazide was
significantly superior in HbA1c lowering compared to glipizide (p<0.01)
and chlorpropamide (p=0.01). 80% of patients achieved normal HbA1c in
gliclazide arm, compared to glibenclamide (74%), glipizide (40%) and
chlorpropamide (17%). Only glibenclamide group had significant (p<0.05)
weight gain (~2.0 kg) compared to other four SUs. This study concluded
that individual SUs could be different. However, this study was limited by
smaller sample size, un-equipoise of baseline HbA1c and higher pre-
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treatment HbA1c in gliclazide and gliquidone arm.33

A prospective double-blind controlled study by Jerums et al compared


gliclazide versus placebo in insulin-treated (n=32) and gliclazide versus
glibenclamide in non-insulin-treated (n=17) diabetic subjects. This study
found no significant difference in glycemic control in gliclazide arm over
others, in a 2 year period of follow-up.34

Jennings et al in a retrospective chart review (n=203) evaluated the


prevalence of hypoglycemia in older (age 40-65 years) patients receiving
oral hypoglycemic agents. This study found significantly higher prevalence
of hypoglycemic symptoms in patients treated with glibenclamide
compared to gliclazide (P <0.01) or chlorpropamide (P <0.05), despite
similar HbA1c.35

A randomized, three-cohort, 5-year follow-up study (n=248), found


lowest rate of secondary failure with gliclazide (7%) compared to glipizide
(25.6%) and glibenclamide (17.9%). While, the failure rate was
significantly less with gliclazide compared to glipizide (p <0.05), no
statistical difference was observed between gliclazide and glibenclamide
(p <0.1). However, the incidence of hypoglycemia was significantly higher
with glibenclamide versus gliclazide (p <0.05) and the author proposed
gliclazide to be the first choice of therapy in T2DM who failed on diet and
exercise.36,37 Similarly, in a retrospective analysis Satoh et al found that
patients treated with gliclazide required exogenous insulin support
significantly less frequently (p <0.001) than those treated with
glibenclamide.38 Moreover, the association of glibenclamide with increased
beta-cell apoptosis in human islets has also been demonstrated in vitro by
Meadler et al.39 These observations tempts to suggest that gliclazide but
not glibenclamide has the potential to protect beta-cells and thereby could
delay the development of a secondary failure.

Tessier et al in a 6 month follow-up of a randomized, double-blind


hyperglycaemic clamp study (n=22), compared glibenclamide to gliclazide
in elderly patients. This study suggested that although the glycemic
control were equivalent in both drugs, incidence of hypoglycaemia were
significantly higher in glibenclamide arm compared to gliclazide arm (17
versus 4 episode, p <0.01). Authors pointed to a significant increase in
insulin sensitivity index (p<0.05) with glibenclamide compared to
gliclazide that could be accountable to increased hypoglycemia with
former drug.40
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In a retrospective, cohort study (n=33,243), Van Staa et al evaluated the


hypoglycemia in patients treated with SUs and found higher rate of
hypoglycemia for glibenclamide compared to other SUs including
gliclazide.41

The European GUIDE (GlUcose control in type 2 diabetes: Diamicron MR


vs. glimepiride) study (n=845) was the first double-blind, 27-week,
parallel-group large-scale, head-to-head study, that compared once-daily
gliclazide modified-release (MR) (maximum dose up to 120 mg) to once
daily glimepiride (maximum dose up to 6 mg) either as monotherapy or in
combination with existing treatment (metformin or acarbose). While
HbA1c found to be similarly decreased in both groups, hypoglycemia
occurred significantly less in frequency with gliclazide MR, compared to
glimepiride (3.7% versus 8·9% respectively, p=0·003). This study
suggested significantly better safety of gliclazide MR, owing to ~50%
fewer confirmed hypoglycaemic episodes when compared to glimepiride.42

In DIACOM (effect of DosIng frequency of oral Antidiabetic agents on the


COMpliance and biochemical control of type 2 diabetes) study (n=105) by
Kardas, compared gliclazide MR (maximum dose up to 90 mg) to
glibenclamide (maximum dose up to 15 mg). This study suggested that
patients in the gliclazide MR group did achieve significantly better fasting
blood glucose (-19 vs -3.0 mg/dl, p<0.0001) and HbA1c control (-0.5 vs
+0.4 %, p<0.0001) compared to glibenclamide. In addition, compliance
to treatment with once-daily gliclazide MR was significantly better (94 vs
87%, p<0.05) than twice-daily glibenclamide.43
In a 6-month, randomized, controlled trial conducted in 172 Japanese
type 2 diabetic patients, Inukai et al found no difference in glycemic
control (HbA1C and fasting plasma glucose) when patients were switched
to glimepiride from gliclazide and glibenclamide. However, HbA1c
reduction was significantly better in glimepiride switched, obese (BMI ≥
25) subjects (OR 1.33, 95% CI 1.00 to 1.27; p=0.038). Moreover, the
homeostasis assessment model of insulin resistance (HOMA-IR) was
significantly reduced by 10% (p =0.015) in all glimepiride switched
arms.44 Table 1 depicts the result of gliclazide studies compared to other
SUs.

In a systematic review to determine comparative tolerability of SUs,


Harrower AD found increased relative risk of recorded hypoglycemia for
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glibenclamide-treated patients compared to other SUs (adjusted RR vs.


glibenclamide are 0.74, 0.75, 0.60 for gliclazide, tolbutamide and glipizide
respectively).45 In other systematic review of 21 randomized, controlled
trials, Gangji et al found glibenclamide group having 83% greater risk of
experiencing at least one episode of hypoglycemia compared to other SUs
(RR 1.83, 95% CI 1.35 to 2.49).46

b. gliclazide versus other oral drugs:

Some studies compared gliclazide to metformin. Collier et al, compared


gliclazide to metformin (n=36) in newly diagnosed T2DM and found both
agents to be similar in glycemic control, as well as in improving index of
platelet aggregability markers.47 Noury et al compared gliclazide and
metformin over a 3-month follow-up (n=60) and found both agents to be
equally effective in reducing HbA1c, although significant weight loss
(p<0.05) and reduction in fasting serum insulin (p<0.001) was observed
in metformin group only.48 In another comparative study, Tessier et al
(n=36) found similar reduction in glucose and lipid peroxidation markers
with gliclazide compared to metformin.49

Studies comparing gliclazide with alpha-glucosidase inhibitors yielded


interesting observations. A 6 month follow-up of a randomized, double-
blind study (n=40) by Guvener et al, found similar glycemic control with
gliclazide compared to acarbose as an add-on to insulin, although
acarbose arm had some distinct advantage. While there was no change in
total insulin dose at the end of study in acarbose arm, gliclazide arm had
higher mean insulin requirement (∆ +6 U/day, p=0.016) and higher
weight gain (∆ mean BMI +1 Kg/m2, p=0.003). Moreover, acarbose
reduced LDL cholesterol significantly.50 In another 26 week follow-up
study (n=72), Salman et al found a similar glycemic change with
gliclazide and acarbose, although gliclazide arm had better reduction in
mean fasting plasma glucose (-0.84 mmol/l, p=0.04), while acarbose arm
had better triglyceride lowering (∆ -13.3 mmol/l, p<0.005) and weight
loss (∆ -1.1 Kg, p=0.001).51

Gliclazide was also found to be comparable to glinides. In a 13-week


open-label study (n=80), Furlong et al found similar HbA1c reduction,
weight gain and hypoglycemia, when gliclazide was compared to
repaglinide as an add-on to NPH insulin therapy.52 Ristic et al in a 24-
week randomized, double-blind, double-dummy, parallel group, multi-
centric study compared gliclazide to nateglinide (n=262) as an add-on to
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metformin, and found similar efficacy and hypoglycemia with both agents,
although post-prandial glucose were better (∆ -0.61 mmol/l, p=0.037) in
nateglinide arm.53 A Chinese study also find comparable efficacy of
gliclazide and repaglinide.54

Study comparing gliclazide to pioglitazone also yielded equivalent efficacy


result. Lawrence et al compared gliclazide, pioglitazone and metformin in
60 overweight T2DM subjects and found comparable efficacy of all three
drugs, although only pioglitazone and metformin improved lipid fractions
with similar glycemic control.55 Charbonnel et al in a randomized, double-
dummy, double-blind, parallel, 52-week study of 1270 treatment naive
T2DM patients compared gliclazide to pioglitazone and found equivalent
HbA1c reduction, although fasting glucose was slightly better lowered (∆ -
0.4 mmol/l, p =0.002) with pioglitazone. While hypoglycemia was more
frequently observed with gliclazide (10.1%) in comparison to pioglitazone
(3.5%), oedema was more commonly observed in pioglitazone arm
(8.7%) compared to gliclazide arm (4.5%). Increase in the body weight
was observed in both pioglitazone (2.8 Kg) and gliclazide (1.9 Kg) arms.
Interestingly, increment in high-density cholesterol (HDL-C) and total
cholesterol/HDL-C ratio was significantly higher (p<0.001) with
pioglitazone compared to gliclazide.56 In another 52-weeks randomized
double-blind study (n=630) Matthew et al reported that despite having
similar glucose lowering (both HbA1c and FPG) ability, pioglitazone
significantly improved triglyceride and HDL-C (p<0.001), while gliclazide
lowered LDL-cholesterol significantly (p<0.001) in the background
metformin therapy. Moreover, a significant decrease in mean urinary
albumin/creatinine ratio was also observed in pioglitazone arm (10 vs 6%
with gliclazide, p=0.027). Notably hypoglycemia was more frequently
observed in gliclazide arm (11.25 vs 1.3% with pioglitazone), while
oedema was more often seen in pioglitazone arm (6.3% vs 2.2% with
gliclazide). Interestingly, increase in body weight was similar in both arms
(1.5 Kg in pioglitazone vs 1.4 Kg in gliclazide).57 In a randomized double-
blind multi-centric, 1-year follow-up study conducted in 283 T2DM
subjects, Perreillo et al found similar HbA1c and FPG reduction with
gliclazide and pioglitazone, although decrease in insulin resistance, slope
of fall of FPG and decrease in systematic glucose production (measured
by clamp techniques) was significantly better with pioglitazone (p=0.002,
p=0.004 and p=0.042, respectively) compared to gliclazide.58

Two studies directly compared gliclazide with vildagliptin. Foley et al in a


randomized, double-blind multi-centric study compared gliclazide to
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vildagliptin in treatment naive T2DM subjects (n=1092) over 2 years.


Interestingly, this study could not establish non-inferiority of vildagliptin
to gliclazide. Although, the mean reduction of HbA1c from baseline was
similar in both groups (-0.5 % in vildagliptin vs. -0.6 % in gliclazide; ∆
0.13 %, 95% CI -0.06 to 0.33 %), yet the non-inferiority margin based
on an upper limit of the CI of 0.3 % was not met. Moreover, the FPG was
significantly lower in gliclazide arm (∆ -0.5 mmol/l, p <0.025) as
compared to vildagliptin. However, weight increase was significantly less
with vildagliptin compared to gliclazide (0.8 vs. 1.6 kg, p <0.01) and
fewer minor hypoglycemic episodes observed in vildagliptin arm in
comparison to gliclazide (0.7 vs. 1.7%). Notably, no severe hypoglycemic
episode observed in either groups.59 In other multi-centric, randomised,
double-blind, active-controlled 52-week study (n=1007), Filozoff et al
compared vildagliptin to gliclazide in a background metformin therapy.
This study showed a similar reduction of HbA1c (∆ -0.03, 95% CI -0.11 to
0.20) in both arms and therefore the main objective of non-inferiority
margin of 0.4% of vildagliptin was met. Similar reduction in FPG was also
noted in both arms (1.31 vs. 1.52 mmol⁄l, p=0.257). Although, the
hypoglycemic events (6 vs. 11 events in gliclazide) and gain in body
weight gain (+0.08 vs. +1.36 in gliclazide, p<0.001) was lower in the
vildagliptin group; higher number of patients discontinued therapy in
vildagliptin group (22 vs. 13 in gliclazide) due to unsatisfactory glycemic
effects.60

It should be noted however, that none of these studies compared the


mortality outcomes between these agents. Table 2 depicts the safety and
efficacy result of studies comparing gliclazide with other oral glucose
lowering drugs.
Few meta-analyses have also evaluated gliclazide to other anti-diabetic
agents. In a meta-analysis of 19 trials comparing gliclazide to other oral
glucose lowering agents, Landman et al found gliclazide to be slightly
more effective over others (∆ -0.13%; 95% CI -0.25 to -0.02) excluding
metformin, although significantly high range of heterogeneity (I2 up to
55%) existed across the trials, included in this analysis.61 Another meta-
analysis of 22 trials of SUs versus incretin-based therapies, further re-
affirms lowest risk of hypoglycemia with gliclazide among all SUs.
Schopman et al found that hypoglycaemic events (confirmed glucose
≤3.1 mmol/L) and severe hypoglycaemia (requiring third party
assistance) was experienced by 10.1% and 0.8% of patients respectively
with any SUs treatment, while these rates were 1.4% and 0.1%
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respectively with gliclazide. Moreover, severe hypoglycaemia were


observed in only lower proportion of patients on gliclazide (0.1%),
compared to glimepiride (0.9%) and glipizide (2.1%). Furthermore, mild
hypoglycaemic event were lower in those patients taking gliclazide (1.4%)
compared to glimepiride (15.5%).62

c. Gliclazide during Ramadan:

Several observation and randomised studies have been conducted to


evaluate safety of SUs during Ramadan. In the UK retrospective audit
(n=52), Devendra et al found significantly fewer hypoglycaemic events
(defined as blood glucose < 3.5 mmol/L with or without symptoms) in
vildagliptin group, compared to gliclazide (7.7% vs. 61.5%; ∆ -53.8%,
95% CI -74.9 to -26.3; p < 0.001). Severe hypoglycaemia was observed
in only one patient (3.8%) in gliclazide group, compared to none in
vildagliptin group.63 However, in another observational study conducted
during Ramadan, Zargar et al (n=136), found no increase in
hypoglycemia with gliclazide-MR switched to evening (during Ramadan)
time from the pre-breakfast time (during pre-Ramadan), despite similar
glucose control.64

In a multi-centric, observational study (n=1378) conducted during


Ramadan, Aravind et al studied the hypoglycemic potential of different
SUs with or without background metformin therapy. Study reported least
hypoglycemia (at least one or more episodes) with gliclazide (14% vs.
17% vs. 26% with gliclazide, glimepiride and glibenclamide, respectively).
Moreover, the severe hypoglycemic episodes requiring third-party
assistance was also least in gliclazide group (1.6 vs. 2.3 vs. 6.5% with
gliclazide, glimepiride and glibenclamide respectively) compared to other
SUs. Notably, hypoglycemia was defined on the basis of symptoms and or
blood glucose <3.9 mmol/L.65

In the VECTOR (Vildagliptin Experience Compared To gliclazide Observed


during Ramadan) Study, Hassanein et al compared vildagliptin to
gliclazide in 72 diabetic patients undergoing Ramadan. Notably,
hypoglycemic events (at least one episodes) were significantly less in the
vildagliptin arm compared to (∆ -41.7%, 95% CI -57.8 to -25.6%,
p=0.0002) gliclazide. Moreover, significantly less number of patients
missed vildagliptin dose (∆ -7.4, p=0.0204). However, this study is
limited by very less sample size and lack of dietary/ exercise data.66

In another large, multi-centric, observational, VIRTUE (VildagliptIn


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expeRience compared wiTh sulphonylUreas observed) study (n=1333),


conducted during Ramadan, Al-Arouj et al found vildagliptin group had
significantly less hypoglycemic events (5.4 vs. 19.8%, p<0.001)
compared to those having SUs. Moreover, descriptive analysis of
individual SUs found a lower frequency of hypoglycemia seen with
glimepiride (18%) and gliclazide (19%), compared to glibenclamide
(32%). Hypoglycemia was defined on the basis of symptoms and or
plasma glucose <3.9 mmol/L in this study.67

Three randomised studies were also conducted during Ramadan assessing


the safety of SUs/gliclazide versus DPP-4 (di-peptidyl peptidase-4)
inhibitors. Al Sifri et al compared the safety of SUs to sitagliptin (n=1066)
with or without background metformin therapy in a multi-centric,
randomised, open-label study. This study reported a significantly fewer
symptomatic hypoglycemic events in sitagliptin arm compared to SUs
(6.7% vs. 13.2%, relative risk ratio 0.51, 95% CI 0.34 to 0.75;
p<0.001). However, no reports of severe hypoglycemic episodes
(requiring third-party assistance) were observed in either arm. Moreover,
comparative analysis in terms of hypoglycemia amongst SUs revealed
least hypoglycemic episodes in gliclazide arm compared to glimepiride
and glibenclamide (6.4% vs. 12.4% vs. 19.7 % in gliclazide, glimepiride
and glibenclamide arm, respectively). However, authors recognised the
limitations of hypoglycemia detection which was based on symptoms and
not through the confirmed blood glucose measurement that perhaps could
have overestimated the results.68
Similarly, Aravind et al in a randomised, open-label, multi-centric study
(n=870) compared sitagliptin to SUs and reported a significantly few
symptomatic hypoglycemia in sitagliptin arm compared to SUs (3.8 vs.
7.3%, risk ratio 0.52, 95% CI 0.29 to 0.94, p=0.028). No episode of
severe hypoglycemia (requiring medical assistance) was observed in
either arm. Among the patients randomised to SUs, “at least one or more
symptomatic hypoglycemic episode” was lower in gliclazide compared to
other SUs (1.8% vs. 5.2% vs. 9.1% in gliclazide, glibenclamide and
glimepiride respectively). Although, study was not adequately powered to
compare hypoglycemic episodes of each SU with sitagliptin, authors
concluded similar hypoglycemic events between sitagliptin and gliclazide.
One limitation as seen in almost all studies includes diagnosing
hypoglycemia based primarily on symptoms, which would generally
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overestimate the findings or may underestimate due to hypoglycemic


unawareness.69

Hassanein et al in a randomised, double-blind, multi-centric (n=557),


STudy Evaluating vildAgliptin compareD to gliclazide in patients with type
2 diabetes FASTing during Ramadan (STEADFAST), found significant less
confirmed hypoglycemia (blood glucose <3.9 mol/L) in vildagliptin arm
compared to gliclazide (3 vs. 7%, p=0.039), despite similar glucose
control. It is worthwhile to note that frequency of hypoglycemic episodes
were much lesser with gliclazide in this study, compared to other
observational study such as VIRTUE.70

In a meta-analysis of randomised trial Mbanya et al found gliclazide


carries similar risk of hypoglycemia compared to DPP-4 inhibitors (5.6 vs.
7.2%, risk ratio 1.12, 95% CI 0.73 to 1.73; p=0.61).71 Table 3 depicts
the results of hypoglycemic events seen with gliclazide compared to DPP-
4 inhibitors in randomised clinical trial conducted during Ramadan.

Cardiovascular and mortality data of gliclazide versus other SUs:

Cardiovascular safety of SUs is mired with controversy and is far from


being settled. Several recent observational studies have re-ignited the CV
safety of SUs, erstwhile reported in UGDP study several decades ago.
UGDP study conducted during pre-statin era found increase in all-cause
and CV-mortality with tolbutamide and phenformin, compared to insulin;
although study was neither designed, nor powered to detect these
finding.72 Moreover, both tolbutamide and phenformin are not in use
currently, therefore, UGDP findings perhaps may not be that important in
current clinical perspective. Subsequently, UKPDS did not find any
increase in mortality with SUs (chorpropamide, glibenclamide and
glipizide) and metformin monotherapy, although combination of
metformin to SUs did find a significant increase in mortality.73 Few other
subsequent observational studies also found increase mortality with SUs
and metformin combination, even after adjusting for potential
confounders.74-77 However, several other studies have refuted those
findings.78-81 In a meta-analysis of 9 observational studies, Rao et al
reported no significant increase in all-cause and CV mortality with SUs
and metformin combination, although composite end points of CV
hospitalisation and mortality was significantly higher with combination
therapies.82

Nevertheless, some studies also evaluated the comparative outcomes


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with different SUs. In a case-control, hospital discharge registry from


Denmark, Johnsen et al found a significantly increased risk of myocardial
infarction associated with glibenclamide and glipizide (by 2-fold), while it
was non-significantly increased with glimepiride and gliclazide (by 1.4-
fold). Although, this study was limited by differences in baseline risk
factors amongst different arms and also by including study cohort without
type 2 diabetes.83 In a retrospective matched case-control, multi-centric,
Indian study (n=228), Sadikot et al reported a differential risk of
developing coronary artery disease (CAD) with different SUs. While the
hazard of developing CAD with the initial treatment was unchanged with
metformin, it increased significantly with glibenclamide (2.4-fold, 95% CI
1.3 to 4.3; p = 0.004) and glipizide (2-fold, 95% CI 0.9 to 4.6; p =
0.099). Conversely, the hazard decreased insignificantly with glimepiride
(0.3-fold, 95% CI 0.7 to 1.7; p = 0.385) and gliclazide (0.4-fold, 95% CI
0.7 to 1.3; p = 0.192).84

Besides, several studies evaluated the most important outcome of CV, all-
cause, as well as cancer mortality with different SUs and found a notable
differences. In a 3-year follow-up of an observational study (n=2002),
Monami et al reported a significantly higher annual mortality with
combination therapy of metformin plus glibenclamide (8.7%), compared
to metformin plus gliclazide (2.1%, p=0.001), and metformin plus
glimepiride (0.4%, p<0.0001). Moreover, this finding persisted even after
adjusting for potential confounders.14

In a 5-year follow-up of a retrospective observational cohort study


(n=568), Monami et al reported a significantly higher annual mortality
rate with glibenclamide compared to gliclazide (4.3% vs. 2.2%, p<0.05).
All-cause mortality was also significantly higher with glibenclamide
compared to gliclazide, even after adjustment for potential confounders
(OR 2.1, 95% CI 1.2 to 2.7, p<0.05). Moreover, higher cardiac events
were noted in glibenclamide group compared to gliclazide, in those
patients having a background coronary disease.15

In a Danish nationwide population-based follow-up study (n=3930),


Horsdal et al reported 35.3% annual mortality among SUs users admitted
with MI. Although, there was no substantial differences in annual
mortality among different SUs users, gliclazide monotherapy showed a
trend towards lower mortality (adjusted HR 0.70, 95% CI 0.48 to 1.00).16

From a population-based registry in Ukraine (n=64188), Khalangot et al


reported lower total mortality with gliclazide (HR 0.33, 95% CI 0.26 to
0.41) and glimepiride (HR 0.605, 95% CI 0.41 to 0.88) versus
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glibenclamide monotherapy. CV mortality was also lower with gliclazide


(HR 0.29, 95% CI 0.21 to 0.38) versus glibenclamide.17

Pentalone et al from a diabetes registry (n=11141) of Cleveland Clinic,


USA did not find any significant difference in overall mortality among
individual SUs monotherapy that includes glipizide, glibenclamide and
glimepiride. Although this study did not examine gliclazide, as the latter
SU is not available for clinical use in US. However, trend of increased
mortality risk was noted with both glibenclamide and glipizide group
compared to glimepiride in patients having a background CAD
(glibenclamide HR 1.36, 95% CI 0.96 to 1.91; glipizide HR 1.39, 95% CI
0.99 to1.96 vs. glimepiride).18

Zeller et al in a nationwide French registry of patients (n=1310), reported


lower in-hospital mortality in patients hospitalized for acute MI and
receiving gliclazide or glimepiride, (OR 0.15, 95% CI 0.04 to 0.56)
compared to glibenclamide.19

Jorgensen et al in a 2.2 year follow-up of retrospective Danish national


registry (n=9876) found increased CV mortality in all SUs monotherapy
users except gliclazide, compared to metformin (glibenclamide HR 1.31,
95% CI 1.17 to 1.46; glimepiride HR 1.19, 95% CI 1.06 to 1.32; glipizide
HR 1.25, 95% CI 1.11 to 1.42; gliclazide HR 1.03, 95% CI 0.88 to 1.22)
especially in those admitted with MI and not treated with emergent PCI
(percutaneous coronary intervention).20

In a median 3.3 year follow-up from the Danish registry (n=107806),


Schramm et al evaluated several mortality end-points with different
insulin secretagogue compared to metformin in patients with or without
previous history of myocardial infarction (MI). The all-cause mortality was
significantly higher with all SUs except gliclazide. While all-cause mortality
was significantly higher with glimepiride (HR 1.32, 95% CI 1.24 to 1.40),
glibenclamide (HR 1.19, 95% CI 1.11 to 1.28) and glipizide (HR 1.27,
95% CI 1.17 to 1.38) compared to metformin; it was not increased with
gliclazide (HR 1.05, 95% CI 0.94 to 1.16), especially in patients without
history of previous MI. Similar significant increase in all-cause mortality
was observed with all SUs except gliclazide in those with a previous
history of MI.21

Andersson et al from a Danish registry (n=3477) found no difference


among SUs, in those patients hospitalized with heart failure and remained
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alive 1 month post-discharge. The risk of mortality was similar with


glimepiride (HR 1.10, 95% CI 0.92 to 1.33), glibenclamide (HR 1.12, 95%
CI 0.93 to 1.34) and glipizide (HR 1.14, 95% CI 0.93 to 1.38), compared
to gliclazide.22

Pentalone et al, in a retrospective cohort study using electronic health


record (n=23915) reported a significant increase in overall mortality with
different SUs monotherapy compared to metformin (glipizide HR 1.64,
95% CI 1.39 to 1.94; glibenclamide HR 1.59, 95% CI 1.35 to 1.88;
glimepiride HR 1.68, 95% CI 1.37 to 2.06 versus metformin).
Interestingly, no increase in mortality was observed in glimepiride
monotherapy among patients having documented coronary disease, while
significant increase observed with glipizide (HR 1.41, 95% CI 1.07 to
1.87) and glibenclamide (HR 1.38, 95% CI 1.04 to 1.83) compared to
metformin.23 Gliclazide was not evaluated in this study as it is not
available in US.

In a retrospective study (n=1277) Bo et al evaluated the all-cause and


cause-specific mortality with different SUs and found that the gliclazide
and tolbutamide users had a significantly lower cancer mortality
compared to glibenclamide users (HR 0.30; 95% CI 0.16–0.55, and HR
0.48; 95% CI 0.29–0.79, respectively).24

Abdelmoneim et al from Canadian nested case-control study (n=21,325)


found 14% increased odds of acute coronary syndrome related
hospitalization and or death with glibenclamide in elderly subjects in a
~5.4 year median follow-up, compared to gliclazide.25 Lee et al in a
Korean retrospective cohort study (n=2854) compared glimepiride to
gliclazide and found no difference in renal outcome after 4.7 years of
median follow-up, although an increased risk of progression to doubling of
creatinine and end stage renal disease for patients aged 62 years or older
were observed with glimepiride compared to gliclazide.26

A network meta-analysis conducted by Simpson et al from 18 studies


suggested gliclazide seemed to possess the lowest risk of mortality (RR
0.65, 95% CI 0.53 to 0.79) followed by glimepiride (RR 0.83, 95% CI
0.68 to 1.00) and glipizide (RR 0.98, 95% CI 0.80 to 1.19), compared to
glibenclamide. This study thereby suggests that while glipizide use had
similar risk, gliclazide and glimepiride use may have significantly lower
risk of mortality compared to glibenclamide. Similarly, network meta-
analysis from 13 studies also found that gliclazide use was associated with
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a significantly lower risk of cardiovascular-related mortality (RR 0.60,


95% CI 0.45-0.84) when compared to glibenclamide, although, no
difference was observed with other SUs including glimepiride. Neither any
difference in MI was observed amongst SUs in this network meta-
analysis. These findings must be interpreted in the light of limitations
which is inherent to any meta-analysis of observation studies. It should
be noted however, that these limitations are primarily related to the
observational design of the studies rather than fault of meta-analysis.27
Table 4 depicts the mortality outcome with different SUs.

Notably, some studies found no difference in mortality among SUs.


Arruda-Olson et al in a population based study (n=2189) evaluated the
adverse effects of second-generation SUs on survival, among patients
who had MI and found no deleterious effect with any SUs. Interestingly,
SUs arm had lower risk of death than those receiving insulin (HR 0.41,
95% CI 0.21 to 0.80, p=0.009).85 Juurlink et al in a small follow-up (<1
year) of a Canadian population-based retrospective study (n=2674) did
not find any difference in composite outcome of death or hospitalisation,
for either acute MI or heart failure with glibenclamide compared to
gliclazide.86 Nagendran et al from a administrative database link
(n=21023) did not find increased risk of heart failure or death with any
SUs following 30 days of acute coronary syndrome.87 Huang et al in a
Canadian retrospective cohort study (n=6283) did not find any difference
in the risk of composite outcome of all-cause mortality or any individual
CV outcome (atrial fibrillation, stroke, MI) between gliclazide and
glibenclamide in a 30-days follow-up after hospitalization for ischemic
heart disease.88
In prospective randomised clinical trial ADVANCE (Action in Diabetes and
Vascular disease: PreterAx and Diamicron MR Controlled Evaluation),
there was significant reduction (14%, P=0.015) in micro-vascular
outcome in gliclazide-treated-intensive arm, compared to non-gliclazide-
treated-conventional arm.89 Moreover, weight gain was only 0.7 kg in
gliclazide-treated-intensive arm, which appears trivial, compared to the
weight gain observed in the intensive arm of other studies such as
UKPDS, DCCT (Diabetes Control and Complication Trial), ACCORD (Action
to Control Cardiovascular Risk in Diabetes) and VADT (Veterans Affairs
Diabetes Trial). Moreover, in another analysis of ADVANCE examining the
combined effect of blood pressure (perindopril-indapamide arm) and
intensive glucose lowering (gliclazide MR-based intensive arm), suggested
a significant reduction in new onset microalbuminuria by 26% (95% CI 17
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to 34%), new onset macroalbuminuria by 54% (95% CI, 35 to 68%; p <


0.0001), new or worsening nephropathy by 33% (95% CI 12 to 50%; p =
0.005), and all-cause death by 18% (95% CI 1 to 32%; p = 0.04).90
Nevertheless, these benefits cannot be ascribed to gliclazide alone, as
intensive glucose and blood pressure control either alone or conjointly
(irrespective of drug used) could be responsible for the improved micro-
vascular and all-cause mortality.

Expert commentary:

This article systemically reviewed the safety and efficacy of gliclazide


compared to other SUs and oral agents including metformin, pioglitazone,
glinides and DPP-4 inhibitors. In addition, safety of gliclazide during long
fasting such as Ramadan has also been reviewed. Furthermore, mortality
data with gliclazide compared to other SUs has been systematically
analysed to have a clearer perspective.

Any interpretation of this systematic review must be appreciated in the


background limitations of observational design, selection bias, inadequate
statistical power and significant heterogeneity across the studies.
Nevertheless, from the available data gathered over the decades it
appears that gliclazide (especially gliclazide MR) carries least potential
while glibenclamide possess highest potential of hypoglycemia, despite
similar glycemic control. To this end, all recent large outcome trial
including ACCORD, ADVANCE and VADT have demonstrated severe
hypoglycemia related to the poor CV outcome, and thus lesser episodes of
severe hypoglycemia (requiring third party assistance) observed with
gliclazide does appear encouraging. Studies comparing gliclazide to other
oral agents also suggest, equivalent glucose lowering, although weight
loss with metformin and improvement in HDL-C with pioglitazone is
clearly notable when compared to gliclazide. Head-to-head studies of
gliclazide with vildagliptin found lower hypoglycemia in vildagliptin arm;
however, this could have been attributed to the larger dose (320 mg) of
gliclazide used in these two comparative studies. Studies conducted
during Ramadan found higher hypoglycemic episodes with SUs compared
to DPP-4 inhibitors, however, sub-group analysis found gliclazide having
least hypoglycemic episodes amongst all SUs, almost similar to DPP-4
inhibitors.

In terms of mortality data, amongst SUs gliclazide appears to carry least


potential to increase all-cause, CV and cancer mortality which could be
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assumed to be attributed to additional anti-oxidant, hemo-rheological and


fibrinolytic properties of gliclazide coupled with lesser incidence of
hypoglycemia and also possibly due to the less weight gain. Nonetheless,
this needs to be conclusively proved through a dedicated trial.

Five year view:

Although the jury is still out regarding whether or not SUs are associated
with adverse CV and mortality outcome, gliclazide appears to carry
comparatively safer data in terms of adverse CV or mortality outcome.
Nevertheless, this needs to be substantiated through a prospective CV
outcome trial. Although no such trials are currently being planned, few
ongoing trials may throw some further light in this regard. Glycemia
Reduction Approaches in Diabetes (GRADE), a comparative effectiveness
study (time frame of 4-7 year), is currently evaluating metabolic outcome
(primary failure defined as HbA1c ≥7%) of glimepiride, sitagliptin,
liraglutide and insulin glargine in ~5000 diabetes subjects with expected
completion in August 2020.91 Cardiovascular Outcome Study of Linagliptin
versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) is being
evaluated in ~6000 diabetic subject on MACE and unstable angina
hospitalisation.92 Although, neither GRADE nor CAROLINA studies are
evaluating gliclazide, one interesting study to watch out for is a 48-month
Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents
Intervention Trial (TOSCA IT), comparing pioglitazone with different SUs
(glibenclamide, glimepiride, gliclazide) in a background metformin
therapy. This study is evaluating ~3371 subjects on composite endpoints
that include all-cause mortality, non-fatal myocardial infarction (MI), non-
fatal stroke, and unplanned coronary revascularization. And, about to be
completed by December 2018.93
Key points:

• Sulfonylureas differ from each other on several pharmacological


properties including their affinity to SU receptors on different
tissues. Binding to SU receptors other than pancreas (SUR1) such
as myocardium (SUR2A) and blood vessels (SUR2B) can potentially
produce undesirable extra-pancreatic effect. Gliclazide acts
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exclusively on pancreatic SUR1, while glibenclamide and glimepiride


are non-specific and bind to SUR2A/SUR2B. While glibenclamide has
been found to be associated in abolishing myocardial ischemic
preconditioning, glimepiride does not appear to interfere with this.

• Despite similar glycemic control, glibenclamide has been maximally


associated with hypoglycemia, while gliclazide appears to cause
least (especially with the gliclazide MR preparation). This could
perhaps be due to the quick binding and reversal of gliclazide to the
β-cell receptor.

• Although studies conducted during Ramadan found higher


hypoglycemia with SUs as a class, compared to DPP-4 inhibitors;
among SUs, gliclazide appeared to carry similar hypoglycemic
potential as DPP-4 inhibitors.

• Majority of the studies suggest gliclazide to exhibit least or no


increase in all-cause, cardiovascular and cancer mortality, although
few studies have found no difference among SUs.

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in the
manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
References:

*Of importance
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76. Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality
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77. Tzoulaki I, Nolokhia M, Curcin V et al. Risk of cardiovascular disease


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78. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality
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79. Gulliford M, Latinovic R. Mortality in type 2 diabetic subjects


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81. Pantalone KM, Kattan MW, Yu C, et al. The risk of overall mortality in
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(** This meta-analysis found no increased risk of mortality with SUs and
metformin combination therapy)

83. Johnsen SP, Monster TB, Olsen ML, et al. Risk and short-term
prognosis of myocardial infarction among users of antidiabetic drugs. Am
J Ther 2006;13(2):134-40.

84. Sadikot SM, Mogensen CE. Risk of coronary artery disease associated
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85. Arruda-Olson AM, Patch RK, Leibson CL, et al. Effect of second-
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(*This study found no difference among SUs on mortality outcome those


admitted with myocardial infacrtion)

86. Juurlink DN, Gomes T, Shah BR, Mamdani MM. Adverse cardiovascular
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87. Nagendran J, Oudit GY, Bakal JA, et al. Are users of sulphonylureas at
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90. Zoungas S, de Galan BE, Ninomiya T, et al. Combined effects of


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Table 1: Efficacy and safety of gliclazide compared to other sulfonylureas -

Author, year Study arm N D MBL EOT HbA1c ∆ HbA1c vs. gliclazide Hypo’s Ref.
(max. dose) (Wk) HbA1c (%), p value (95% CI)
(%)
Baba Gliclazide 160 mg 146 24 FBS 18%! No difference in efficacy 7% 31
et al, 1983 Glibenclamide 10 mg 131 >130mg/dl 17%! 15%
P<0.10
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Harrower Gliclazide 320 mg 20 52 13 -3.7, p<0.01 nr 33


et al, 1985 Glibenclamide 30 mg 19 11 -2.8, p<0.02 -0.97 (-1.53, -0.41); p=ns
Glipizide 20 mg 20 10 +0.6, p=ns -4.3; p<0.01
Jerums Gliclazide 240 mg 9 104 9.6 +0.5, p=nr nr 34
et al, 1987 Glibenclamide 15 mg 8 -0.6, p=nr 1.10 (-0.57, 2.77), p=ns
Jennings Gliclazide 80 52 11.1 nr nr 13.8 35
et al, 1989 Glibenclamide 74 11.1 31.5
P<0.01
Tessier Gliclazide 320 mg 11 26 8.6 -0.4, p=nr 4 episodes 40
et al, 1994 Glibenclamide 20 mg 11 -1.5, p=0.07 1.10 (0.06, 2.14), p=ns 17 episodes
p<0.01
Schernthaner# Gliclazide MR 120 mg 388 27 8.3 -1.1, p<0.001 3.7% 42
et al, 2004 Glimepiride 6 mg 427 -1.0, p<0.001 -0.10 (-0.25, 0.05), p=ns 8.9%
p=0.003
Kardas* Gliclazide MR 90 49 16 7.2 -0.5, p=0.0006 nr 43
et al, 2005 Glibenclamide 15 mg 50 +0.4, p=0.0001 -0.90 (-1.40, -0.40), p<0.0001
#
add-on to metformin/acarbose, * add-on to metformin in 28% of patients, ! % of patients achieved excellent control (fasting blood glucose
~109 and 2-h blood glucose ~139 mg/dl), FBS-fasting blood glucose, max.– maximum, D– duration, Wk– weeks, hypo’s– hypoglycemia,
MBL- mean base line, EOT- end of treatment, ref. – reference, ns- not significant, nr- not reported

A prospective double-blind controlled study was performed over 2 years, comparing


Table 2: Efficacy and safety of gliclazide compared to other oral drugs -

Author, Study arm N D MBL EOT ∆ HbA1c vs. Gliclazide Other Ref.
year (max dose) (Wk) HbA1c HbA1c (95% CI) parameters
(%) (%)
Collier Gliclazide 240 mg 12 24 11.9 -4.7 0.00 (-2.96, 2.96), p=ns No difference in platelet 47
et al, 1989 Metformin 3000 mg 12 -4.7 aggregability in two arms
Noury Gliclazide 240 mg 27 13 9.7 -0.77 0.52 (-0.68, 1.72), p=ns Significant weight loss with 48
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et al, 1991 Metformin 1700 mg 30 -1.29 metformin (p<0.05)


Tessier Gliclazide 320 mg 18 24 7.5 -1.0 0.00 (-1.32, 1.32), p=ns Both agents reduced lipid 49
et al, 1999 Metformin 1700 mg 18 -1.0 peroxidation markers
Guvener# Gliclazide 320 mg 18 26 8.5 -1.12 0.07 (-1.04, 1.18), p=ns Increase in TDD of insulin in 50
et al, 1999 Acarbose 600 mg 20 -1.19 gliclazide but not in acarbose
Salman Gliclazide 320 mg 30 24 8.8 -2.2 -0.40 (-1.90, 1.10), p=ns 10% in gliclazide group 51
et al, 2001 Acarbose 600 mg 27 -1.8 reported at least one mild HE
Furlong# Gliclazide 240 mg 39 13 9.3 -1.0 -0.10 (-0.91, 0.71), p=ns Similar glycemic control, hypo 52
et al, 2003 Repaglinide 12 mg 41 -0.9 and weight change
Ristic* Gliclazide 240 mg 133 24 7.6 -0.57 -0.16 (-0.38, 0.06), p=ns Nateglinide shown better PP 53
et al, 2006 Nateglinide 180 mg 129 -0.41 glucose control (p=0.037)
NCT01022762* Gliclazide 240 mg 218 16 7.2 -0.87 -0.01 (-0.19, 0.17), p=ns Treatment emergent HE was 54
2010 Repaglinide 12 mg 217 -0.86 numerically lower in gliclazide
Lawrence@ Gliclazide 320 mg 20 24 7.7 -1.21 -0.40 (-0.85, 0.05), p=ns Favourable change in HDL 55
et al, 2004 Pioglitazone 45 mg 20 -0.81 and LDL subfractions with pio
Charbonnel Gliclazide 320 mg 1270 52 8.7 -1.4 0.08 (-0.18, 0.02)!, p=ns Better HDL increase and FPG 56
et al, 2005 Pioglitazone 45 mg (T) -1.4 lowering with pio
Matthews* Gliclazide 320 mg 313 52 8.6 -1.01 -0.02 (-0.15, 0.19), p=ns Pio had marked improvement 57
et al, 2005 Pioglitazone 45 mg 317 -0.99 of microalbuminuria and HDL
%
Pierriello Gliclazide 320 mg 140 52 8.8 -0.79 0.00 (-0.57, 0.57), p=ns Better durability of FPG 58
et al, 2006 Pioglitazone 45 mg 135 -0.79 control with pio
Foley Gliclazide 320 mg 546 104 8.6 -0.6 -0.13 (-0.06, 0.33), p=ns HE lower with vildagliptin 59
et al, 2006 Vildagliptin 100 mg 546 -0.5
Filozof* Gliclazide 320 mg 494 52 8.5 -0.85 -0.03 (-0.11, 0.20), p=ns HE lower with vildagliptin 60
et al, 2009 Vildagliptin 100 mg 513 -0.81
#
add-on to insulin, * add-on to metformin, @ add-on to low dose oral agents (66%), % add-on to diet or one oral agents, !90% CI, HE-
hypoglycemic events, T- total number, Pio- pioglitazone, FPG- fasting plasma glucose, PP- post prandial, Hypo- hypoglycemia, HDL- high density
lipoprotein, LDL- low density lipoprotein, MBL- mean base line, EOT- end of treatment, D- duration, N- number, Max.- maximum, Wk - weeks
Table 3: Hypoglycemia with gliclazide versus DPP-4 inhibitors in randomized clinical trial during Ramadan

Study (Year) N Mean baseline Hypo’s events (%) Hypo’s events (%) Hypo’s events (%) Ref
HbA1c (%) with SUs with DPP-4Is with different SUs
Al Sifri et al, 2011 SUs - 514 SUs - 7.6 13.2 Sita - 6.7 Gliben - 19.7 68
Sita - 507 Sita - 7.5 Glime - 12.4
Glicla - 6.4
Aravind et al, 2012 SUs - 427 SUs - 7.9 7.3 Sita - 3.8 Gliben - 5.2 69
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Sita - 421 Sita - 8.0 Glime - 9.1


Glicla - 1.8
Hassanein et al, Glicla - 278 Glicla - 6.9 Glicla - 8.7 Vilda - 6.0 - 70
2014 Vilda - 279 Vilda - 7.0
Mbanya et al, 2015 Glicla - 489 - - DPP-4Is - 5.6 Glicla - 7.2 71
(Meta-analysis) DPP-4Is - 1207
SUs- sulfonylureas, DPP-4Is- DPP-4 inhibitors, Sita- sitagliptin, Vilda- vildagliptin, Glicla- gliclazide, Glime- glimepiride, Gliben-
glibenclamide, Hypo’s- hypoglycemia

Table 4: Mortality outcome with gliclazide versus other SUs

Study, year N Study FU ACM/ Arms Results [95%CI], p value Ref.


types (Yr) CVM/
R/CM
Monami 2002 RO 3 ACM Gliben + Met 8.7% (vs. Glicla, p=0.001; vs. Glime, p<0.0001) 14
et al, 2006 Glicla + Met 2.1%
Glime + Met 0.4%
Monami 568 RO 5 ACM Glibenclamide 4.3% (vs. Glicla OR 2.1 [1.2-2.7]; p<0.05) 15
et al, 2007 Gliclazide 2.2%
Horsdal 3930 PB 1 ACM All SUs 35.3% 16
et al, 2009 Gliclazide Glicla aHR 0.70 [0.48-1.00] vs. tolbutamide
Khalangot 64,188 RO - ACM Glicla vs. Giben HR 0.33 [0.26 to 0.41], p<0.001 17
et al, 2009 Glime vs. Gliben HR 0.60 [0.41 to 0.88], p<0.01
CVM Glicla vs. Gliben HR 0.29 [0.21 to 0.38], p<0.001
Pentalone 11,141 RO 2.4 ACM Gliben vs. Glime HR 1.00 [0.89 to 1.14], HR 1.36 [0.96 to 1.91]# 18
et al, 2010 Glipi vs. Glime HR 1.05 [0.92 to 1.19], HR 1.39 [0.99 to 1.96]#
Glipi vs. Gliben HR 1.04 [0.94 to 1.15], HR 1.03 [0.80 to 1.31]#
Zeller 1310 RO - ACM Glicla/Glime 2.7% {OR 0.15 [0.04 to 0.56] vs. gliben, p=0.019} 19
et al, 2010 Gliben 7.5%
Jorgensen 9879 RO 2.2 CVM Gliben vs. Met HR 1.31, [1.17 to 1.46] 20
et al, 2010 Glipi vs. Met HR 1.25, [1.11 to 1.42]
Glime vs. Met HR 1.19, [1.06 to 1.32]
Glicla vs. Met HR 1.03, [0.88 to 1.22]
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Schramm 107,806 RO 3.3 ACM Gliben vs. Met HR 1.19 [1.11 to 1.28]; HR 1.47 [1.22 to 1.76]# 21
et al, 2011 Glipiz vs. Met HR 1.27 [1.17 to 1.38]; HR 1.53 [1.23 to 1.89]#
Glime vs. Met HR 1.32 [1.24 to 1.40]; HR 1.30 [1.11 to 1.44]#
Glicla vs. Met HR 1.05 [0.94 to 1.16]; HR 0.90 [0.68 to 1.20]#
Andersson 3477 RO - ACM Giben vs. Glicla HR 1.12 [0.93 to 1.34] 22
et al, 2011 Glime vs. Glicla HR 1.10 [0.92 to 1.33]
Glipi vs. Glicla HR 1.14 [0.93 to 1.38]
Pentalone 23915 RO 2.2 ACM Gliben vs. Met HR 1.59 [1.35 to 1.88]; HR 1.38 [1.04 to 1.83]# 23
et al, 2012 Glipi vs. Met HR 1.64 [1.39 to 1.94]; HR 1.41 [1.07 to1.87]#
Glime vs. Met HR 1.68 [1.37 to 2.06]; HR 1.00 [0.69 to 1.44]#
Bo 1277 RO 14 CM Glicla vs. Gliben HR 0.30 [0.16 to 0.55] 24
et al, 2013
Abdelmoeim 21,325 NCC 5.5 CVM Gliben vs. Glicla OR 1.14 [1.06 to 1.23] 25
et al, 2014
Lee 2854 RO 4.7 Renal Glicla vs. Glime HR 0.21 [0.04 to 0.99] vs. glime in patients aged 62 26
et al, 2015 outcome years or older
Simpson 18 Meta - ACM Glipi vs. Gliben RR 0.98 [0.80 to 1.19] 27
et al, 2015 studies Glime vs. Gliben RR 0.83 [0.68 to 1.00]
Glicla vs. Gliben RR 0.65 [0.53 to 0.79]
13 Meta - CVM Glicla vs. Gliben RR 0.60 [0.45 to 0.84]
studies
#
In patients with background coronary artery disease, FU- follow-up, Yr- year, RO- retrospective observational, PB- population based,
NCC- nested case control, Meta- meta-analysis, ACM- all-cause mortality, CVM- cardio-vascular mortality, CM- cancer mortality, R- renal
outcome (doubling of creatinine and progression to end-stage renal disease), Gliben- glibenclamide, Glipi- glipizide, Glime- glimepiride,
Met- metformin, HR- hazard ratio, OR- odds ratio