2. Situational Assessment…
Sulfonylureas In Asia
• Oral antidiabetic drugs (OADs) still dominate the prescribing
pattern (56.4%) followed by insulin alone (43.6%).
• Sulfonylureas (SUs) alone or in combination with metformin
have been the most commonly prescribed OADs in some Afro-
Asian countries.
Kalra S, et al.Consensus recommendations on sulfonylurea and sulfonylurea combinations in the management of
Type 2 diabetes mellitus – International task force. Indian J Endocr Metab 2018;22:132-57
3. HEALTHY LIFESTYLE MODIFICATION
GOAL THERAPY: HbA1c <7% (Individualized)
Metformin
GLP-1 RA
DPP-4i
AG-i
SGLT-2i
TZD
SU/GN
MONOTHERAPY
If not at
goal in 3
months,
proceed
to DUAL
THERA
PY
GLP-1 RA
DPP-4i
TZD
SGLT-2i
Basal
Insulin
SU/GN
AG-i
If not at
goal in 3
months,
proceed
to
TRIPLE
THERA
PY
(combin
ation of
3 drugs)
Metformin
or
other
first
line
drug
DUAL THERAPY
(combination of 2
drugs with different
mechanism)
DUAL
THERAPY
TRIPLE
THERAPY
INSULIN
±
Other
Agents
OR
SYMPTOMS
ADD OR INTENSIFY
INSULIN
GLP-1 RA
DPP-4i
TZD
SGLT-2i
Basal Insulin
SU/GN
If not at
goal in 3
months,
proceed
to ADD
OR
INTENSI
FY
Insulin
Therapy
TRIPLE THERAPY
(combination of 3 drugs with
different mechanism)
Algorithm of type 2 diabetes management in Indonesia
Entry HbA1c
<7.5%
Entry HbA1c
>7.5%-9%
Entry HbA1c
>9%
NO YES
Metformin
or
other
first
line
drug
Second
line
drugs
AG-i
PB PERKENI. 2019.Pedoman Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia
4. Non-western countries with national guidelines
for type 2 diabetes
First-line Medication Therapy for Glucose-Lowering in Type 2 Diabetes
Metformin as the treatment of choice for first-line therapy. Specific recommendations for non-obese, weight-unspecified, or metformin-intolerant people were
available in guidelines from 26 (79%) countries. Seventy seven percent (77%) of countries recommend sulfonylurea as alternatives first line
Second- and Third-line Medications for Glucose-lowering in Type 2 Diabetes
Most recommendations were for a second oral agent rather than an injectable; usually (in 66% of guidelines) addition of a sulfonylurea to metformin.
Home P et al. Diabetes Ther. 2013;4:91-102
5. Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S111-S124
6. 1. Choose later generation SU to lower
risk of hypoglycemia, Glimepiride has
shown similar CV safety to DPP-4i
2. Consider country-and region-specific
cost of drugs. In some countries, TZD
relatively more expensive and DPP4i
relatively cheaper
3. If no specific comorbidities (i.e, no
established CVD, low risk of
hypoglycemia and lower priority to
avoid weight gain and no weight-
related comorbidities
In those WITHOUT indicators
of high risk or established
ASCVD, CKD, or HF
Use principles in Figure 1
To Avoid
Clinical inertia
Reassess and
Modify treatment
Regularly
(3-6 months)
First-line therapy is metformin and comprehensive lifestyle
(including weight management and physical activity)
If HbA1c above target
If HbA1c above target
SU1
SU1
TZD2
TZD
2
If HbA1c above target
• Insulin therapy: Basal insulin with lowest acquisition
cost
OR
• Consider other therapies based on cost
Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S111-S124
7. Sulfonylureas: An Established Treatment of DM
Srivastava, Manoj K, et al. Evolution of Sulfonylureas: Commentary on Developmental Process and Initial Trials. JAPI. 2019: 9-11
8. Mechanism of Action Sulfonylurea
Modern SUs do not
inhibit the
mitochondrial KATP
channel opening in
cardiac myocytes
and thereby
preserve myocardial
ischemic
preconditioning
Kalra S, et al. Indian J Endocrinol Metab. 2015;19(5):577–596.
9. 1Indonesia Endocrine Society (Perkeni)Consensus 2015
2Fonseca V. Current Medical Res Opin 2003; 19: 635–641
Profile of Oral Antihyperglycemic
10. Efficacy SUs as Monotherapy: Data from Meta-Analysis of RCTs
Hirst, et al. Diabetologia. 2013;56:973–984.
In a meta-analysis of
9 trials with a mean
duration of 16 weeks
(12–36 weeks), SU
monotherapy
reduced HbA1c by
1.51% as compared
to placebo.
SU VS Placebo
11. 11
Korytkowski M et al. Diabetes Care 2002; 25(9):1607-11.
Insulin Secretion of Glimepiride
Glimepiride : Treat fasting AND postprandial hyperglycemia
First Phase Second Phase
Insulin secretion
Before treatment After treatment
Incremental
plasma
insulin
(pmol/L)
0
50
100
p=0.04
First and second phase insulin secretion
before and after treatment with Glimepiride
p=0.02
Euglycemic and hyperglycemic
clamp studies in 11 obese
patients with T2DM
with good glycemic control
before and after 4 months
treatment with glimepiride to
assess effect of glimepirideon
insulin secretion
12. Müller G et al. Diabetes Res Clin Pract 1995;28 (suppl):S115-S137
Glimepiride®
5
0 10 15 20
Mean plasma insulin increase (µU/ml) PI
Mean blood glucose decrease (%) BG
Mean increase in plasma insulin (PI) and mean % decrease
in blood glucose (BG) over 6 hours after single dose
PI/BG ratio
Sulfonylurea
Glibenclamide
Gliclazide
Glipizide
0.03 (n=16)
0.16 (n=16)
0.07 (n=14)
0.11 (n=13)
Sulfonylureas
tested in fasted
male beagle
dogs to
determine
ratios of mean
plasma insulin
release/ blood
glucose
decrease
Glimepiride Controls Glycemia With Less Insulin Secretion
Than Other SUs
13. Extra-Pancreas Effect of Glimepiride
Tsunekawa T, Hayashi T, Suzuki Y, Matsui-Hirai H, et al. Diabetes Care. 2003;26:285–289
14. Cardio Vascular Safety
Unlike glibenclamide, Glimepiride does not block the beneficial cardioprotective effect of ischemic preconditioning
%
change
in
mean
ST
shift
Baseline After drug administration
Mean ST segment depression during
balloon occlusion according to treatment
Klepzig et al. Eur Heart J 1999;20:439-446.
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.
50
100
Placebo
(n=15)
Glimepiride®
(n=15)
Glibenclamide
(n=15)
p = 0.01 p = NS
p = 0.049
0
15. Efficacy of Glipizide, Glyburide, and Glimepiride
Monotherapy in T2DM Patients With History of CAD
Overall mortality in the subgroup with a
documented history of CAD, treated with
sulfonylurea monotherapy
Increased overall mortality risk
with glyburide vs. glimepiride
(hazard ratio 1.36 [95% CI: 0.96 –
1.91]) and glipizide versus
glimepiride (1.39 [0.99 –1.96]) in
those with CAD
Glimepiride may be the
preferred SU in T2DM
patients with underlying
CAD.
Mocanu MM, et al. Circulation. 2001;103(25):3111-3116.
16. CAROLINA Trial Reassures on CV Safety of Modern Sus
There was no significant
difference in occurrence of
3P-MACE in patients treated
with glimepiride as compared
to those treated with linagliptin
(12.0% vs. 11.8%), with a
hazard ratio of 0.98 (95.47%
CI 0.84–1.14, p < 0.001 for
noninferiority).
Rosenstock J, et al. JAMA. 2019;321(1):69–79.
CAROLINA: Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Type 2
Diabetes; 3P- MACE: 3-point major cardiovascular event; CI: Confidence interval; SUs:
Sulfonylureas; CVOT: Cardiovascularoutcometrial.
18. As compared to older SUs, Glimepiride
• Has lower risk of hypoglycemic events
• Exhibits a higher exchange rate and lower binding affinity to β cells
• Secretes smaller amounts of insulin in the fasting state or post-prandially
Agent used No of events Person years Incidence rate
Metformin 836 205351 4.1%
Glimepiride 28 2629 10.7%
Gliclazide 389 27433 14.2%
Glipizide 14 1273 11%
Glibenclamide 22 610 36.1%
Compared ToOlder SUs, Glimepiride has a Lower Risk of
Hypoglycemic Events
van Dalem J, et al. BMJ. 2016;354:i3625.
19. Glimepiride: Decoding the Misinformation and
Missing Information
Increased risk of
hypoglycemia
Increased CV risk
Poor efficacy
Weight gain
Glimepiride is associated with lesser hypoglycemic effects, as it is associated with lower
stimulation of insulin secretion and has lower binding affinity and quick association and
dissociation with SU receptor subunits of KATP-channels
Modern Sus, such as glimepiride have a good tolerability CV profile and are assured by recent
CAROLINA trial
The efficacy of glimepiride in lowering hyperglycemic conditions in type 2 diabetes mellitus
patients as monotherapy or combination therapy is well established
Opposed to conventional Sus, glimepiride is reported to have weight reducing or neutralizing
effects
Shunmugavelu M, et al. JAPI. 2019; 24-26
20. Despite All Myths, Glimepiride is Reported have a good
tolerability to Use Across Different Patient Profiles
Not effective in
special population
Beta cell depletion
Pleiotropic Benefits
Unlike other Sus, glimepiride is well tolerated in various T2DM patients such as elderly,
mainourished or debilitated patients. With regular monitoring for signs and symptoms of
hypoglycemia, glimepiride can be used in patient with renal impairment
Glimepiride stimulates insulin release from beta cells of the pancreas, improvement in both
firs and second phase insulin secretion of beta cells has been reported with glimepiride
Glimepiride has numerous extrapancreatic pleiotropic effects. It stimulates liipogenesis and
glycogenesis and has insulin-sensitizing effects. It also possesses potent anti-inflammatory,
antioxidative and angiogenic properties
Shunmugavelu M, et al. JAPI. 2019; 24-26
21. Practical Tips For Using SUs
1. Practice a ‘start low, step-up slow’ approach, up titrating gradually.
2. SU titration should be based on glucose monitoring:
• once in two weeks –for responders with no hypoglycemia
• once a week –for non-responders, with or without hypoglycemia
3. Timing of administration of SUs before the first, and subsequent major meals of the day, is
important. Importance of adherence must be explained.
4.Patients/ family members should be educated on sick day management, need to carry diabetes
identity cards, recognition and management of hypoglycemia, including de-escalation of SU doses, if
required.
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 Sep-Oct;19(5):577-96.
22. Key Conclusion
• 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
• Modern SU, such as Glimepiride provide promising efficacy and safety in the
management T2DM
• CAROLINA provides a strong evidence that modern sulfonylurea (Glimepiride) is
not guilty increasing cardiovascular risk
• Person-centred care, i.e., careful choice of SU, appropriate dosage, timing of
administration, and adequate patient counseling, will ensure that deserving
patients are not deprived of the advantages of this well-established class of anti-
diabetic agents
The key messages of this module are as follows:
FDCs have merits and demerits, and some FDCs are irrational
Reluctance to increase “pill burden” is a key reason for poor control of HbA1c.
Monotherapy is inadequate to maintain the target glycemic level in the long run.
Combination therapies offer better glycemic control than monotherapies.
FDC is better than individual combination therapies in terms of patient adherence, efficacy, and cost advantage.
Triple FDCs offer reduced pill burden, improved compliance, and better glycemic control.
Triple FDC of metformin, sulfonylurea, and voglibose targets fasting plasma glucose and postprandial glucose, and thereby improves all five components of the glycemic pentad.
A multi-step approach is required to prevent irrational FDCs
