Download triple drug regimen

Smart Approach to Post Prandial Glycemic Peaks :
Glimepiride, Metformin & Voglibose Combination in
T2DM
Dr. Mohammed Riyaz M.D (Medicine), Masters in Endocrinology(UK)
Chief Endocrinologist & Medical Director (EDSC)
Flow of contents
 Type 2 diabetes population requiring stringent glycemic control
 Triple drug combination in the management of type 2 diabetes mellitus
 Postprandial hyperglycemia and glycemic variability
 Role of alfa glucosidase inhibitors in triple drug combination
 Amaryl MV: A triple drug combination of glimepiride, metformin and
voglibose
Introduction
 Prevalence of diabetes mellitus is rising world over, so the related burden
of mortality and morbidity1
 Diabetes and its complications are also associated with significant
economic burden1
 Glycemic control reduces complications of diabetes1
 The United Kingdom Prospective Diabetes Study (UKPDS) of patients
with type 2 diabetes showed that, intensive glycemic control results in a
25% reduction of microvascular complications2
1.
2.
Expert Opin. Drug Metab. Toxicol. (2010) 6(2):225-235
Lancet 1998;352(9131):837-53
Triple drug therapy in the management of type 2
diabetes mellitus
Lifestyle
changes
Entry HbA1c
<7.5%
>7.5%
>9% with no
symptoms
Oral
monotherapy
Oral dual
therapy
Oral dual or
triple
therapy
HbA1c >6.5% in 3
months
Endocrine practice. May/June 2013;19;suppl 2: 1-48
If goal not achieved in 3 months with dual
therapy: Triple therapy
Metformin: A first line agent for type 2 diabetes
Parameter
Efficacy
Risk of hypoglycemia
Effect on body weight
Costs
Metformin
High
Low
Neutral/weight loss
Low
Metformin, if not contraindicated and if tolerated, is the
preferred initial pharmacological agent for type 2 diabetes
American Diabetes Association.Approaches to glycemic treatment. Sec. 7.In Standards of Medical Care in Diabetesd2015.
Diabetes Care 2015;38(Suppl. 1):S41–S48
Combination therapy for type 2 diabetes
Metformin
or
Sulfonylurea
+
or
Thiozolidinedione
or
DPP4
inhibitor
or
SGLT2
inhibitor
or
GLP-1 receptor
agonist
Insulin
(basal)
Each new class of noninsulin agents added to initial therapy
lowers HbA1c around 0.9–1.1%.
American Diabetes Association.Approaches to glycemic treatment. Sec. 7.In Standards of Medical Care in Diabetesd2015.
Diabetes Care 2015;38(Suppl. 1):S41–S48
SU + Metformin : Effective combination for t2dm
Metformin
Increases insulin
secretion
Extensive experience
+
Sulfonylurea
Reduces microvascular
risk (UKPDS)
Economical
American Diabetes Association.Approaches to glycemic treatment. Sec. 7.In Standards of Medical Care in Diabetesd2015.
Diabetes Care 2015;38(Suppl. 1):S41–S48
Glimepiride: a Preferred Sulfonylurea
Improves the
relative
insulin
secretory
deficit
Minimal
hypoglycemia
& weight gain
High on
efficacy:
Upto 2.5%
HbA1c
Reduction
Pleiotropic
Benefits (antioxidative,
antiinflammat
ory,
angiogenic
properties)
Expert Opin. Drug Metab. Toxicol. (2010) 6(2):225-235; J Assoc Physicians India. 2004 Jun;52:459-63.
Cardiovascular Diabetology 2014, 13:15
Glimepiride is Different from
Other Sulfonylureas
Among interventions to preserve or “rejuvenate” β-cells, is the induction of β-cell “rest” by
selective activation of ATP-sensitive K+ (KATP) channels.
Most Sulphonylureas
Glimepiride used at an optimum dose, causes no β-cell hyperfunction (reduced β-cell
exhaustion) & no hyperinsulinemia due to its unique binding characteristics.
Comparison of Extrapancreatic Action of Glimepiride
and Other Sulfonylureas
Glimepiride has greatest extrapancreatic activity among sulfonylureas
Mean increase in plasma insulin (PI) and mean % decrease
in blood glucose (BG) over 6 hours after single dose
PI/BG ratio
Sulfonylurea
Glimepiride®
0.03 (n=16)
Glibenclamide
0.16 (n=16)
Gliclazide
0.07 (n=14)
Glipizide
0.11 (n=13)
0
5
10
15
20
Mean plasma insulin increase (µU/ml) PI
Mean blood glucose decrease (%) BG
Müller G et al. Diabetes Res Clin Pract 1995;28 (suppl):S115-S137
Sulfonylureas tested
in fasted male beagle
dogs to determine
ratios of mean
plasma insulin
release/ blood
glucose decrease
Glimepiride and CV safety
Glimepiride is superior to other Sulfonylureas
in terms of reducing the risk of macrovascular diseases, despite achieving the same
glycemic control.
H. Onuma et al. / Journal of Diabetes Mellitus 4 (2014) 33-37
Comparison : Glimepiride vs DPP4 Inhibitors
Glimepiride
DPP4 Inhibitors
Efficacy:∆A1c(minus)
25-30%*
8-12%*
Efficacy:∆A1c(minus)
More or equal†
Less or equal†
Cost
Less
More
Cost Efficacy
More
Less
Hypoglycemia
++‡
CVD
Decreased#
+‡
No Change¶
*from Baseline in Premarketing trials
†2-6 mg Glimepiride vs Maximum DPP4 Inhibitors
‡Severe, Rare with both
#MI in UKPDS, ADOPT, ADVANCE,BARI trials[Diabetes Care,2015;38(1):166]
¶ Increased CHF [Clin Ther,2014;36(12):20729,CurrTreatOptionsCardiovascMed,2014;16(12):353]
• Glimepiride doses (1-3mg) vs max doses of DPP4I
• All efficacy variables – reduction in HbA1c, % patients
reaching HbA1c<7 & FPG reduction are consistently
favourable to glimepiride
• Weight variations ( ~2kg) not significantly different
• Serious adverse events not significantly different
• Greater effectiveness with glimepiride compared to
DPP4I and offers potential advantages in
management
Int J Clin Pract. 2015 Feb 16
Controlling glucose triad
Long term
average
glucose
level
HbA1c
Glucose
triad
Peak
glucose
level
Int J Cur Res Rev, Aug 2013; 05; 16:20-26
Postpra
ndial
glucose
Fasting
plasma
glucose
Basal
glucose
level
Postprandial hyperglycemia results in oxidative stress
through different mechanisms
Postprandial
hyperglycemia
 Protein nitration
PARP activation and ↑ of NAD+
↑NFK-B activation
↑ GAPDH activity
LDL oxidation
European Review for Medical and Pharmacological Sciences 2005; 9: 191-208
Overloaded mitochondrial
metabolism
Autoxidation
Early or reversible glycation
increased carbonylic stress
Oxidative
stress
Postprandial hyperglycemia: ADA-2015
 Elevated post challenge (two hour glucose tolerance test )
glucose values are associated with increased cardiovascular
risk independent of fasting plasma glucose
 Endothelial function is negatively affected
American Diabetes Association.Glycemic targets. Sec. 6. In Standards of Medical Care in Diabetesd2015. Diabetes Care
2015;38(Suppl. 1):S33–S40
Glycemic pentad in the management of diabetes
HbA1c
Quality of life
Glycemic
pentad
Glycemic
variability
Fasting blood
glucose
Postprandial
blood glucose
Glycemic pentad should to be considered in diabetes
management
Indian J Endocrinol Metab. 2013 Jul-Aug; 17(4): 611–619
Typical Indian Foods are rich in Carbohydrates and
may result in High PPG levels
Traditional Asian Indian diets are carbohydrate-rich
Sometimes even up to 80% percent of the macronutrient composition comes
from carbohydrate
High glucose load leads to higher prandial glycemic excursion
JAPI Nov 2010; 58:665
Triple Combination therapy for type 2 diabetes
Metformin
+
Sulfonylurea
Reduces postprandial
glucose excursions
No hypoglycemia
+
Alfa glucosidase
inhibitor
Non-systemic
Reduced CV events (?)
American Diabetes Association.Approaches to glycemic treatment. Sec. 7.In Standards of Medical Care in Diabetesd2015.
Diabetes Care 2015;38(Suppl. 1):S41–S48
Alfa (α) glucosidase inhibitors
• α-glucosidase inhibitors are oral drugs used in the management
of type 2 diabetes mellitus with postprandial hyperglycemia
• Prevent digestion and absorption of carbohydrates by
inhibiting the terminal step of carbohydrate digestion at the
brush border of the intestinal epithelium
• Carbohydrate absorption is shifted more distally in the
intestine and therefore delayed
Int J Med Res. 2011; 1(2): 121-129
AGIs reduce absorption of carbohydrates
With AGIs
Without AGIs
Carbohydrates
Carbohydrate
absorption
Jejunum
Ileum
Jejunum
Ileum
without AGIs
with AGIs
Carbohydrate
absorption
Duodenum
Jejunum
Ileum
Place of AGIs in therapy to control PPG
At the diagnosis when
PPG is high
Start with AGI – alternative to
metformin
Patients uncontrolled on
metformin monotherapy
with high PPG
Add AGI if PPG is high with
monotherapy
Patients uncontrolled on
dual therapy with PPG
Start with AGI – if PPG is high
on dual therapy
Place of alfa glucosidase inhibitors in the
management of type 2 diabetes
Lifestyle measures
Usual approach
At each step, if not to target (generally
HbA1c ‹7.0 %)
Alternative approach
Consider first line
Metformin
SU or AGI
Consider second line
SU
Consider third line or
Basal/premix insulin
Consider fourth line
Basal + meal
time insulin
International Diabetes Federation ; 2012 Clinical Guidelines
or
AGI/DPP-4
inhibitor or
TZD
Metformin (if not
used first line)
or
AGI/DPP-4
inhibitor or TZD
Basal/pre-mix
insulin (later basal
+ meal time)
AGI/DPP-4
inhibitor or TZD
Voglibose
 Competitive α glucosidase inhibitor (α-GIs) discovered in 1981 and available for
treatment of DM in Japan since 19941
 Inhibitory activity on maltose and sucrose is 190-270 times higher than acarbose and
100 times higher than miglitol1
 Specifically targets postprandial hyperglycemia, with little or no risk of
hypoglycemia2
 Negligible renal excretion2
 Can be used as monotherapy or in combination with other antidiabetic agents2
 Mobilize endogenous pool of insulinotropic GLP-1; inhibits overwork of pancreatic
beta-cells and has insulin-sparing effect2
1. Journal of Clinical and Diagnostic Research. 2013 Dec, Vol-7(12): 3023-3027
2. Expert Opin. Pharmacother. 2014; 15(8):1181-1190
Voglibose: Reduces oxidative stress and
hyperlipidemia
In obese type 2 diabetes patients, voglibose reduces
Oxidative
stress
generation
Soluble
intercellular
adhesion
molecule
PPG and
hyperlipidemia
Satoh N, Shimatsu A. Metabolism. 2006 Jun;55(6):786-93.
Triple drug combination with voglibose
for controlling PPH
Patients uncontrolled on dual therapy (like Met+SU) and
who have post-prandial hyperglycemia.
Non-compliance: A significant challenge in type
2 diabetes
A study of 600 type 2 diabetes patients
Only 16.6% patients were adherent to prescribed anti-diabetic drugs
85%
90.00%
80.00%
71.60%
% of patients
70.00%
60.80%
60.00%
50.00%
40.00%
30.00%
20.00%
18.30%
10.00%
0.00%
Did you ever forget to take Were you careless at times When you felt better, did Sometimes, if you felt worse
your medication?
about taking your
you sometimes stop taking when you took medicine did
medication?
your medication?
you stop taking it?
JIACM 2014; 15(1): 26-9
Need of fixed dose combination
 Non-adherence was highly
significantly (p < 0.001) associated
with frequent dosing and multiple
drugs1
 More than half of patients desired
less number frequency of
medications1
Reduced pill
burden
Increased
adherence
Different
strengths of
FDCs
• Better adherence
• Better glycemic control
• Reduced disease management cost
• Dosing flexibility
Fixed-dose combination decreases
the risk of medication noncompliance and can translate into
better clinical outcomes2
JIACM 2014; 15(1): 26-9
Am J Med. 2007 Aug;120(8):713-9
Adv Ther 2012; Jan 29 (1): 1-13
Dosing of three individual agents
• Glimepiride
– After oral administration, glimepiride is rapidly absorbed, and
bioavailability is practically 100% and is essentially
unaffected by food1
– Glimepiride may be taken before or after meal with similar
results. 2
• Metformin
– Recommended and approved for use with meals.3
• Voglibose
– Usual starting dose is 0.2 mg three times daily with meals. 4
.1.xpert Opin. Drug Metab. Toxicol. (2010) 6(2):225-235) 2. Vascular Health and Risk Management 2012:8 463–472 3.
Metformin Prescribing information 4. Expert Opin. Pharmacother. (2014) 15(8))
Amaryl MV
 Indication
– As third line treatment of Type II diabetes mellitus in adult patients
when diet, exercise and the single agents and second line therapy with
two drugs do not result in adequate glycemic control
 Dosage & Administration
– Usual recommended dose for adults: 1 tablet of Amaryl MV twice a
day before meals. Additionally, voglibose tablets may be taken before
the remaining meal, as prescribed by the physician.
 Available as
– Amaryl® MV 1mg : Each uncoated bilayered tablet contains Metformin
hydrochloride IP 500mg (in sustained release form) + Glimepiride IP
1mg + Voglibose IP 0.2mg
– Amaryl® MV 2mg : Each uncoated bilayered tablet contains Metformin
hydrochloride IP 500mg (in sustained release form) + Glimepiride IP
2mg + Voglibose IP 0.2mg
Summary
 Control of glucose triad (HbA1c, fasting blood glucose level
and postprandial blood glucose level) is important in reducing
complications of diabetes mellitus
 Combination of glimepiride, metformin and voglibose controls
glucose triad and is well tolerated
 Fixed dose combination of drugs from different classes helps
in better control of glycemia and offers advantages of
convenience, and potential for improved compliance