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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
Article views: 3
Download by: [New York University] Date: 28 February 2016, At: 21:40
Publisher: Taylor & Francis
DOI: 10.1586/17512433.2016.1159512
Review
Corresponding author:
Awadhesh Kumar Singh
Consultant Endocrinologist,
G.D Hospital & Diabetes Institute, Kolkata, West Bengal (India).
Downloaded by [New York University] at 21:40 28 February 2016
E mail: drawadheshkumarsingh@gmail.com
Abstract:
Introduction:
Nevertheless, since 1960 several SUs become available for clinical use.1
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.
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
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
Review method:
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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
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
Expert commentary:
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:
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
** Of considerable importance
11. WHO. 19th Expert Committee on the Selection and Use of Essential
Medicines. World Health Organization; 2013, Available at:
http://www.who.int/selection_medicines/
committees/expert/19/reviews/Glibenclamide_Rev2. pdf?ua=1 [08–
st
12.04.13]. Last accessed on Dec 31 2015.
12. Hosker JP, Rudenski AS, Burnett MA, Matthews DR, Turner RC. Similar
reduction of first- and second-phase B-cell responses at three different
glucose levels in type II diabetes and the effect of gliclazide therapy.
Metabolism 1989;38:767–72.
18. Pantalone KM, Kattan MW, Yu C, et al. The risk of overall mortality in
patients with type 2 diabetes receiving glipizide, glyburide, or glimepiride
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21. Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular
risk associated with different insulin secretagogues compared with
metformin in type 2 diabetes, with or without a previous myocardial
infarction: a nationwide study. Eur Heart J 2011; 32: 1900–1908.
(** This landmark observational study found significantly better outcome
with gliclazide compared to other SUs)
25. Abdelmoneim AS, Eurich DT, Gamble JM, et al. Risk of acute coronary
events associated with glyburide compared with gliclazide use in patients
with type 2 diabetes: a nested case-control study. Diabetes Obes Metab.
2014;16(1):22-9.
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26. Lee YH, Lee CJ, Lee HS, et al. Comparing kidney outcomes in type 2
diabetes treated with different sulphonylureas in real-life clinical practice.
Diabetes Metab. 2015;41(3):208-15.
(* This study found no difference between glimepiride and gliclazide,
however gliclazide arm showed better outcome in doubling of serum
creatinine and progression to end stage renal disease especially in older
patient)
27. Simpson SH, Lee J, Choi S, et al. Mortality risk among sulfonylureas:
a systematic review and network meta-analysis. Lancet Diabetes
Endocrinol. 2015;3(1):43-51
(**This network meta-analysis gliclazide having best mortality outcome
compared to other SUs)
30. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update.
Am J Kidney Dis 2012;60: 850–886.
32. Shaw KM, Wheeley MS, Campbell DB, Ward JD. Home blood glucose
monitoring in NIDDM: the effect of gliclazide on blood glucose and weight
control, a multicentre trial. Diabetic Med. 1985:2:484-490.
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(* This systematic review found highest hypoglycemia with glibenclamide)
47. Collier A, Watson HH, Patrick AW, et al. Effect of glycaemic control,
metformin and gliclazide on platelet density and aggregability in recently
diagnosed type 2 (non-insulin-dependent) diabetic patients. Diabete
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52. Furlong NJ, Hulme SA, O’Brien SV, Hardy KJ. Comparison of
repaglinide vs. gliclazide in combination with bedtime NPH insulin in
patients with Type 2 diabetes inadequately controlled with oral
hypoglycaemic agents. Diabet Med 2003;20: 935–941.
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effects of pioglitazone and metformin compared with gliclazide on
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Diabetes Care 2004;27: 41–46.
61. Landman GWD, de Bock GH, van Hateren KJJ, et al. Safety and
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62. Schopman JE, Simon ACR, Hoefnagel SJM, et al. The incidence of mild
and severe hypoglycaemia in patients with type 2 diabetes mellitus
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Diabetes Metab Res Rev 2014; 30: 11–22.
(** This meta-analysis found least hypoglycemia with gliclazide)
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78. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality
associated with the use of metformin compared with sulfonylurea
monotherapy in type 2 diabetes. Diabetes Care 2002;25(12):2244-8.
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patients with Type 2 diabetes receiving different combinations of
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with initial sulphonylurea treatment of patients with type 2 diabetes: a
matched case-control study. Diabetes Res Clin Pract 2008;82(3):391-5.
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generation sulfonylureas on survival in patients with diabetes mellitus
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86. Juurlink DN, Gomes T, Shah BR, Mamdani MM. Adverse cardiovascular
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high-risk population. Diabet Med. 2012;29(12):1524-8.
87. Nagendran J, Oudit GY, Bakal JA, et al. Are users of sulphonylureas at
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91. https://clinicaltrials.gov/ct2/show/NCT01794143?term=GRADE+study
&rank=2 (last accessed on Jan 10, 2016)
92. Rosenstock J, Marx N, Kahn SE, Zinman B, Cardiovascular outcome
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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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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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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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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