Does SU remain acceptable as the first of choice

in T2DM Treatment in Asia Patient?

Laksmi Sasiarini

Kongres Nasional PERKENI XI

PADANG 2018
Number of people with
diabetes worldwide and
per region in 2017 and
2045 (20-79 years)

Amongst the 425 million people affected with diabetes in 2017,

over 200 million come from Asia.
 Clinical Features in Asian Populations with
Diabetes (Asian phenotypes)

• Asian is relatively lean subjects, but more insulin resistant than non-
Asians
• Insulin secretory impairment might be induced by insufficient -cell
mass, functional defects of -cells, or both.
Juliana CNChan et al. Diabetes Voice March2014
 Pathogenic Mechanisms
of Diabetes Mellitus

Genetic and environmental risk

factors impact inflammation,
autoimmunity, and metabolic stress

Environmental Influences
Dietary factors, endocrine disruptors and
other environmental
polluters, and gut microbiome
composition

Jay S. Skyler,1 George L. Bakris,2 Ezio Bonifacio,3 Tamara Darsow,4 Robert H. Eckel,5
Leif Groop,6 Per-Henrik Groop,7,8,9 et al. Differentiation of Diabetes by Pathophysiology, Natural History,
and Prognosis Diabetes 2017;66:241–255 | DOI: 10.2337/db16-0806
 Beta cells mass in people with type 2 diabetes
-cell mass is determined as the sum of replication, neogenesis and hypertrophy minus the rate
of apoptosis.

Cho JH et al. J Diabetes Invest 2011; 2: 6-17

 Natural History of Type 2 Diabetes
Altered
Glucose Diagnosis Progression
Normal Metabolism IGT* of T2D of T2D Insulin
Resistance

Post-meal
glucose

Fasting
glucose

Insulin
concentration

-Cell
Dysfunction
Microvascular disease
Macrovascular disease

*IGT=impaired glucose tolerance

Ramlo-Halsted & Edelman. Clinical Diabetes,2000;18:80–85

 Poor glycaemic control is a global problem

Patients
achieving
targets (%)
60 HbA1c<7%
<7%
50
53
40
51 <7%
<6.5%
30
36
20 31
10

0
USA Canada EUROPE Emerging countries*
(NHANES)1 (DICE)2 (CODE-2)3 (IDPMS)4
*Asia, Eastern Europe, Latin America and the Middle East and Africa

• In the real world, 50% of patients do not achieve their glycaemic goals1
1. Casagrande S, et al. Diabetes Care 2013;36:2271-9; 2. Harris SB, et al. Diabetes Res Clin Pract 2005;70:90-7;
3. Liebl A, et al. Diabetologia 2002;45:S23-8; 4. Chan JC, et al. Diabetes Care 2009;32:227-33.
 Depicted are patient and disease factors used to determine
optimal A1C targets (ADA, 2018)

ADA. Diabetes Care 2018;41(Suppl. 1):S55–S64 | DOI: 10.2337/dc18-S006

 Glycemic Target
Individualizing A1c target

Canadian Diabetes Association, 2013

Profile of oral antihyperglycemic
AGENT  HbA1c
Sulfonilurea 1,0 – 2,0%
Glinid 0.5 – 1.5%
Metformin 1,0 – 1.4%
Alfa-Glucosidase Inhibitor 0,5 – 0,8%
Thiazolidinedion 0,5 – 1,4%
DPP-4 inhibitor 0,5 – 0,8%
SGLT-2 inhibitor 0,8 – 1,0%

1Indonesia Endocrine Society (Perkeni) Consensus 2015

2Fonseca V. Current Medical Res Opin 2003; 19: 635–641
 Treatment algorithm for people with
type 2 diabetes

IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes, 2012. www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-
Diabetes.pdf
 Algorithm of type 2 diabetes management in
Indonesia
Healthy Life Style Modification

HbA1C <7.5% HbA1C ≥7.5%

HbA1C >9.0%
In 3 months, + Monotherapy in 3
HbA1C > 7% months, HbA1C > 7%
Clinical features (-) Clinical features (+)

Monotherapy* with one of Combination 2 drugs* with Combination 2 drugs

below different mechanism
Insulin ± other drugs
- Metformin - GLP1 R-agonist Combination 3 drugs Combination 3 drugs
- GLP1 R-agonist - DPP4-I
- GLP1 R-agonist
- DPP4-I - Thiazolidindione
Metformin or other first line drug

- DPP4-I
- AGI - SGLT2-I *
- Thiazolidindione
Metformin or other first line drug

- SGLT2-I * - Basal Insulin

- SGLT2-I *
- Thiazolidindione - SU / Glinide
- Basal insulin
2 second line drugs

- Sulfonylurea - Cholesevelam**
- SU / Glinide
- Bromocriptin QR** Starts or intensification insulin
- Glinide - Cholesevelam**
- AGI
therapy
- Bromocriptin QR**
If HbA1C is not - AGI
achieved in 3 months, If HbA1C is not
Notes:
added second drug achieved in 3 months,
(combination 2 drugs) added third drug If HbA1C is not * Registered drugs, it selection and usage is considered
(combination 3 drugs) achieved in 3 months, based on benefit, adverse, and availability
started or intensified ** Cholesevelam is not yet available in Indonesia, and
insulin therapy Bromocriptin QR is generally used in pituitary tumor

Indonesian Endocrine Society (Perkeni) Consensus 2015

History of diabetes medications

White JR. Diabetes Spectrum Volume 27, Number 2, 2014

 Sulfonylureas

• First Generation - rarely used today: Tolbutamide, Chlorpropamide

• Second Generation: Glibenclamide, Glipizide, Gliclazide, Gliquidone
• Third Generation: Glimepiride
Cheng and Fantus. CMAJ 2005; 172: 213-226
 Issue with SU treatment
• Beta cells apoptosis
– Gliclazide is less likely to induce B-cells failure as compared to
conventional SUs
• Beta cells de-differentiation
– Account for reduced B-cell mass and insulin secretion
– Glimeperide enhanced B-cell secretory capacity
• Weight gain
– Glimeperide, ER glipizide, Gliclazide MR: ≈netral; Glibenclamide:
increased body weight
• Hypoglycemia
– Glimeperide < Glibenclamide
• Cardiovascular safety
– Modern SUs (Gliclazide MR, glimeperide) < risk of all cause CV-related
mortality compared to conventional SUs

Adopted from Kalra S et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A
consensus Statement. Indian J Endocrinol Metab 2015; 20: 577-596
 Safety: Hypoglycemia
Significantly lower incidence of severe hypoglycemic events with
Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)
# Episodes/1000 person-years

6
Prospective, population-
based, 4-year study to
compare frequency of
4 severe hypoglycemia in
5.6 patients with T2DM
treated with Glimepiride
2 (estimated n=1768) versus
glibenclamide (estimated
n=1721)
0.86
0
Glimepiride Glibenclamide

*Defined as requiring IV glucose or glucagon

Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73

Safety: Weight
Treatment with Glimepiride resulted in significant and stable weight loss
Open, uncontrolled, observational study. 1770 T2DM patients were enrolled and
284 were followed-up for 1.5 years.
Patients received 0.5 to > 4 mg glimepiride once daily.

Mean intra-individual weight change relative to baseline

Months of treatment
4 12 18
0
Mean weight change (kg)

-1

-2
-1.9 kg
(p<0.0001*)
-3 -2.9 kg -3.0 kg
(p<0.05*) (p<0.005*)

*vs. baseline
Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19 17
Safety: Cardiovascular
Unlike glibenclamide, Glimepiride does not block the beneficial cardioprotective
effect of ischemic preconditioning
Double-blind, randomized, placebo-controlled trial in 45 patients with stable coronary artery
disease. Mean ST segment shift (mV) after repetitive balloon dilatation was measured to compare
the effects of Glimepiride, glibenclamide and placebo on ischemic preconditioning.

Mean ST segment depression during

balloon occlusion according to treatment

p = 0.049 p = 0.01 p = NS
% change in mean ST shift

100

50

0
Placebo Glimepiride Glibenclamide
(n=15) (n=15) (n=15)

Baseline After drug administration

18
Klepzig et al. Eur Heart J 1999;20:439-446
 Meta-analysis of SU CV safety trials (≥ 6 months)
found no consistent association with MACE risk
MH-OR (95% CI)
First author (year) Total # patients* Total # events*
Birkeland 1996 36 1
Chou 2008 452 3
Perriello 2006 283 9
Gerstein 2010 672 55
UKPDS 33 1998 3041 610
Hanefeld 2007 587 4
Seino 2010 400 4
Charbonnel 2005 630 14
Matthews 2005 1250 15
Rubin 2008 1805 46
Home 2009 2222 312
Arechavaleta 2011 1035 4
va der Laar 2004 96 2
Mazzone 2006 458 4
Riddle 1998 145 2
Giles 2010 300 26
Tolman 2009 2097 61
Kahn 2006 4351 72
Goke 2010 858 13
Garber 2009 495 13
Nissen 2008 543 24
Ristic 2007 262 5
Ferrannini 2009 2789 34
Bakris 2006 374 11
Gallwitz 2012 1551 38
Jain 2006 502 11
Johnston 1998 272 4
Nauck 2011 801 3
Seck 2010 1172 4
Overall 29,783 1495
0.01 0.1 1 10 100
Favours SUs Favours comparators

Overall MACE risk estimate for SU vs comparators was not

increased: MH-OR 1.08 (95% CI: 0.86–1.36); p = 0.52

*SU + comparator groups combined.

Monami et al. Diabetes Obes Metab 2013;15:938–53.
Dose Adjustment for insulin Compounds and oral medicines for
Diabetes in CKD

National Kidney Foundation. Am J

Kidney Dis. 2012; 60(5): 850-886
 Possible effects of glimepiride beyond glycemic control in
patients with type 2 diabetes: a preliminary report

34 patients with type 2 diabetes received glimepiride for 24 weeks.

Significant decreases in the levels of glyceraldehyde-derived
advanced glycation end products, (glycer-AGE: toxic AGE),
eotaxin and fibroblast growth factor (FGF)-2 were recognized
after the administration of glimepiride. Moreover, there were
trends for there to be increases in the levels of granulocyte-colony
stimulating factor (G-CSF) and granulocyte macrophage-colony
stimulating factor (GM-CSF), and decreases in the levels of fractalkine,
soluble CD40 ligand (sCD40L), macrophage inflammatory protein (MIP)-
β , vascular endothelial growth factor (VEGF) and soluble receptor for
AGE (sRAGE).

Conclusions: Glimepiride may have potent anti-oxidative, anti-inflammatory and angiogenic

properties and it may potentially repair tissue damage by decreasing the levels of toxic AGE and
increasing colony-stimulating factors.
Nakamura I et al. Cardiovascular Diabetology 2014; 13: 15-22
 349 Korean patients
Mean age : 50.9 years
Mean HbA1c : 7.8%,
Mean BMI : 25.6 kg/m2
The blood glucose lowering effect was not significantly
different among the three drugs, and a sufficient glucose-
lowering effect was observed at half-maximal dose.

a Significant differences between HbA1c at 0 week and 48 weeks (Pvalue<0.001)

 J Diabetes Invest2014; 5: 701–708

A randomized, open label, parallel group, multicenter study, 209 Korean type 2
diabetic patients (HbA1c 7.0–10.0%, on metformin 500–1,000 mg/day) received
glimepiride/metformin fixed-dose combination (G/M FDC) or metformin
uptitration treatment (Met UP)
Efficacy: Glimepiride + Metformin Combination
Combination therapy was more efficient in reducing HbA1cthan metformin or
Glimepiride alone
Mean (+SEM) change in HbA1c
at week 20 according to treatment

Baseline HbA1c * p < 0.001 vs. Met

# p < 0.001 vs. glimepiride
6.79% 6.52% 6.42%
0.3
0.2 +0.07 +0.27
0.1 ±0.14 ±0.09
Δ in HbA1c (%)

0
-0.1
-0.2
-0.3 -0.74*#
±0.08
-0.4
-0.5
-0.6
-0.7

Metformin Glimepiride Metformin + Glimepiride

n = 75 n = 150 n = 147

Prospective, multicenter, randomized, double-blind, double-dummy parallel

group study of 372 T2DM patients inadequately controlled by metformin 850 mg
tid. Patients received metformin, glimepiride or both for 20 weeks.
Charpentier G et al. Diabet Med. 2001;18:828-34 25
Achieve better adherence to therapy with
fixed-dose combination

*p < 0.001

Patients receiving combination therapy who are switched to fixed

dose combination therapy exhibit significantly greater adherence
after the switch
Melikian C, et al. Clin Ther 2002; 24 (3): 460-467.
ADVANTAGES of Fixed Dose Combination (FDC) Pill :

 Improves patient compliance compared with taking multiple

pills
 Minimizes the side-effects caused by high-dose monotherapy
 Minimizes the medication burden to the patient
 Improves glycemic control showing better efficacy
 Reduces medical expenditures due to hospitalization
 Decreases the frequency of drug administration in patients
with T2DM
 Prevents polypharmacy
DISADVANTAGES of Fixed Dose Combination (FDC) Pill :

 Dose titration will be difficult.

 A patient who is satisfied taking separate medications may not
switch to FDCs.
 The combination may affect the bioavailability of agents.
Take home messages…
 Diabetes is a chronic -progressive disease with a complex etio-
pathogenesis.
 No medication used to treat diabetes is free of side effects.
 Choosing the most appropriate patients to use the
medications is something that the practicing clinician needs to
do.
 Sulfonylurea is the most commonly used primary drug or
secondary add-on drug when glycemic goal is not achieved,
especially in Asian countries.
 It seems advisable to use combination therapy with a
complementary mechanism rather than increasing to the
maximal dose in type 2 diabetes patients inadequately
controlled by monotherapy.
Take home messages…

• Glimepiride as an oral antidiabetic, can be chosen as an initial

monotherapy or combination with oral antidiabetics/
insulin/GLP-1 agonist in treating patients with newly
diagnosed T2DM :
- Efficacy : Effective in lowering AIC
- Safety : cardiovascular protection and with minimal
hypoglycemic side effect
• Fixed dose combination concept can improved the adherence
rate of a patient.
 Cardiovascular Safety: Antiaggregatory Effects
Glimepiride has the most potent antithrombotic effect among
sulfonylureas in vitro
Inhibition of ADP-induced platelet aggregation in vitro
as a function of concentration of sulfonylurea derivatives

60

50 Glimepiride

Gliclazide
40
Inhibition (%)

Glibornuride
30

20
Glibenclamide
10
Chlorpropamide
0
0 100 200 300 400 500 C (µmol/L)
In vitro anti-aggregatory testing was used
to assess the effects of 13 sulfonylureas
following induction of platelet aggregation
using 10 µmol/L ADP
Siluk D et al. Diabetologia. 2002;45:1034-7