2. The Importance of Tight Glycemic
Control
Stratton IM, et al. BMJ 2000; 321: 405-412
Every 1% of HbA1c is important in the reduction of risk in
patients with type 2 diabetes (UKPDS)
Relative risk
(n=3642)
Diabetes-related death
Fatal and nonfatal
myocardial infarction
Microvascular
complications
Amputations or death
caused by peripheral
vascular disorders
Per 1% HbA1c
reduction
1%
p<0.001
21%
14%
37%
43%
3. Healthy eating, weight control, increased physical activity & diabetes education
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-ior
or
or GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable
therapy‡
GLP-1-RAMealtime Insulin
Insulin (basal)
+
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
HbA1c
≥9%
Metformin
intolerance or
contraindication
Uncontrolled
hyperglycemia
(catabolic features,
BG ≥300-350 mg/dl,
HbA1c ≥10-12%)
4. Management of Hyperglycemia in
Type 2 Diabetes, 2015:
A Patient-Centered Approach
Update to a Position Statement of the AmericanDiabetes Association (ADA)
and the European Association for the Study of Diabetes (EASD)
Diabetes Care 2015;38:140–149
Diabetologia 2015;58:429–442
5. Approach to management
of hyperglycemia: more
stringent
less
stringent
Patient attitude and
expected treatment efforts
highly motivated, adherent,
excellent self-care capacities
less motivated, non-adherent,
poor self-care capacities
Risks potentially associated
with hypoglycemia, other
adverse events
low high
Disease duration newly diagnosed long-standing
Life expectancy long short
Important comorbidities absent severefew / mild
Established vascular
complications
absent severefew / mild
Resources, support system readily available limited
Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)
6. Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Healthy eating, weight control, increased physical activity
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Major side effect(s)
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months,
proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:
Insulin#
(multiple daily doses)
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination
(order not meant to denote any specific preference):
If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination
(order not meant to denote any specific preference):
Adapted Recommendations: When Goal is to Minimize Costs
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]
9. K+
K+
GlimepirideGlibenclamide
Solubilisation
Glibenclamide Glimepiride
65 kDa
140 kDa
65 kDa
140 kDa
cell membrane
Sulfonylurea
receptor
Potassium channels
Glimepiride binds to the 65 kDa subunit of the sulfonylurea receptor;
glibenclamide binds to the 140 kDa subunit
Kramer W et al., Biochim Biophys Acta 1994;1191: 278-290
Hypothetical Model of Sulfonylurea
Receptor in -cells
10. 1st Action
Pancreatic : Insulin Secretion
• Glimepiride binds and dissociates rapidly to a different receptor than other
sulfonylureas[1,2]
e
e
Ca2+
[Ca2+]
Pancreatic B-cell
v
v
v
v
v
v
v v
K+ + ATP
KATP-channel
Insulin
secretion
SULFONYLUREASulfonylureas bind SUR1
receptors on β-cells
Close ATP-sensitive
K+ channels
Increased Ca2+ influx
Insulin-containing secretory
granules translocate to cell
surface
Insulin release[2]
1Kramer W, et al. Biochimica etl Biophysica Acta 1994; 1191: 278-290; 2Rosak C. J Diabetes Complications 2002;16:123-32
Glimepiride binds to SURx
Receptors on β-cells
Glimepiride
11. Acting on Both Phases of Insulin
Secretion
Glimepiride: The only sulfonylurea to treat
fasting and postprandial hyperglycemia
First Phase Second Phase
Insulin secretion
Before treatment After Glimepiride treatment
Incrementalplasmainsulin
(pmol/L)
0
50
100
p=0.04
First and second phase insulin secretion
before and after treatment with Glimepiride
p=0.02
+Glimepiride
+Glimepiride
Korytkowski M et al. Diabetes Care 2002; 25(9):1607-11.
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
Glimepiride on insulin
secretion
12. Glimepiride Controls Glycemia with
Less Insulin Secretion
• For an equivalent glycemic effect, Glimepiride induces a lower
secretion of insulin
Mean variation of insulin and
glycemia over a 36-h period
Mean ratio between increased level
of insulin and reduced glycemia
5
10
15
0
1
2
3
Glimepiride Glibenclamide Gliclazide Glipizide
20
0
Glycemic
variation(%)
Insulinemia
(U/mL)
GlimepirideGlibenclamide Glipizide Gliclazide
0.00
0.05
0.10
0.15
0.20
n=16
n=13
n=14
n=16
Ratio
Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37
Sulfonylureas tested in
fasted male beagle
dogs to determine
ratios of mean plasma
insulin release/ blood
glucose decrease
13. 1Müller & Wied. Diabetes. 1993;42: 1852-1867; 2Mori et al. Diabetes Obes Metab 200; epub ahead of print
The extrapancreatic effect of Glimepiride
Rate limiting step for glucose utilization is
glucose uptake via GLUT4 transporter
Glimepiride ↑ translocation of GLUT4
transporters from low-density microsomes
to plasma membrane
of insulin-resistant fat and muscle cells1
Glimepiride ↑ GLUT4 protein and glucose
utilization in oxidative muscles in vivo2
Glimepiride appears to ↑ peripheral
glucose uptake1,2 and to mimic
the action of insulin1
2nd Action
Extra-Pancreatic: Insulin Resistance
14. Glimepiride reduces Insulin Resistance
Inukai K, et al. Diabetes Res Clin Pract 2005; 68: 250-257
0
1
2
3
4
5
HOMA-IR
6
6.5
7
7.5
8
HbA1c (%)
Baseline 6 months
Gliclazide or
glibenclamide
(n=52)
all patients BMI ≥ 25 BMI < 25
Glimepiride
(n=120)
all patients BMI ≥ 25 BMI < 25
Glimepiride
(n=120)
*
* *
Mean homeostasis model of insulin resistance (HOMA-IR) and
HbA1c (%) levels at baseline and after 6 months of treatment
*p< 0.05 vs baseline
Glimepiride maintains glycemic control and improves insulin sensitivity in
patients switching from gliclazide or glibenclamide
Gliclazide or
glibenclamide
(n=52)
Multicentre study in 172
Japanese patients in
whom glycemia was
inadequately controlled
(HbA1c ≥7%) by
gliclazide or
glibenclamide. Patients
were randomly assigned
to continue their usual
sulfonylurea or switch to
Glimepiride and were
followed for 6 months.
Baseline HbA1c: 7.5%
gliclazide/glibenclamide
; 7.6% Glimepiride
16. Glimepiride Sustained Glycemic Control
Mean change in HbA1c from baseline
HbA1c(%)
4 months 12 months 18 months
-1.4*
-1.5*
-1.7*
*p<0.0001
Weitgasser R, et al. Diabetes Res Clin Pract 2003; 61(1): 13-9
0
-0.2
-0.4
-0.8
-1.0
-1.2
-1.4
-1.6
-1.8
>1%
sustained
reduction
in HbA1c
1% reduction in
HbA1c means 37%
reduction in risk of
microvascular
complications,
according to UKPDS
study
Open-label study in 284 T2DM patients treated with
Glimepiride 0.5 to > 4 mg once daily for 1.5 years;
baseline HbA1c 8.4%
17. Efficacy: Glimepiride + Insulin
Combination• Reduced insulin requirement and faster glycemic control and with insulin +
Glimepiride vs insulin + placebo
Randomized, double-
blind, 24-week study in
T2DM subjects with
body weight >130%
ideal and in
secondary
sulfonylurea failure.
Patients were
randomized to
placebo + insulin or
Glimepiride + insulin.
Riddle et al. Diabetes Care 1998;21:1052-1057
* p<0.001; † p<0.05 vs Glimepiride
Placebo + Insulin (n=62) Glimepiride + Insulin (n=70)
Units/day
Weeks
0
25
50
75
100
0 4 8 12 16 20 24
†
*
*
* * * *
78 U/day
49 U/day
-38%
Mean insulin dosage required to
restore glycemic control
Weeks
18. • Glimipride is an effective tool in management of
type2 DM either as monotherapy or added to
other non SU drugs or insulin.
• Glimipride addresses more than one
pathophysiological target of type 2DM :
increase both 1st&2nd phase of insulin release.
Increase insulin sensitivity.
• Controls Glycemia with Less Insulin Secretion.
• Improve tt.adherence:
once daily,modest cost,less frequent side effects
and sustained action.
Sammary
20. Management of Hyperglycemia in
Type 2 Diabetes, 2015:
A Patient-Centered Approach
Update to a Position Statement of the AmericanDiabetes Association (ADA)
and the European Association for the Study of Diabetes (EASD)
Diabetes Care 2015;38:140–149
Diabetologia 2015;58:429–442
21. Add ≥2 rapid insulin* injections
before meals ('basal-bolus’†
)
Change to
premixed insulin* twice daily
Add 1 rapid insulin* injections
before largest meal
• Start: Divide current basal dose into 2/3 AM,
1/3 PM or 1/2 AM, 1/2 PM.
• Adjust: é dose by 1-2 U or 10-15% once-
twice weekly until SMBG target reached.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
• Start: 10U/day or 0.1-0.2 U/kg/day
• Adjust: 10-15% or 2-4 U once-twice weekly to
reach FBG target.
• For hypo: Determine & address cause;
ê dose by 4 units or 10-20%.
Basal Insulin
(usually with metformin +/-
other non-insulin agent)
If not
controlled after
FBG target is reached
(or if dose > 0.5 U/kg/day),
treat PPG excursions with
meal-time insulin.
(Consider initial
GLP-1-RA
trial.)
low
mod.
high
more flexible less flexible
Complexity
#
Injections
Flexibility
1
2
3+
If not
controlled,
consider basal-
bolus.
If not
controlled,
consider basal-
bolus.
• Start: 4U, 0.1 U/kg, or 10% basal dose. If
A1c<8%, consider ê basal by same amount.
• Adjust: é dose by 1-2 U or 10-15% once-
twice weekly until SMBG target reached.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
• Start: 4U, 0.1 U/kg, or 10% basal dose/meal.‡
If
A1c<8%, consider ê basal by same amount.
• Adjust: é dose by 1-2 U or 10-15% once-twice
weekly to achieve SMBG target.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
Figure 3.
Approach
to starting
& adjusting
insulin in
T2DM
Diabetes Care 2015;38:140-149;
Diabetologia 2015;58:429-442
22. • The risk for hypoglycemia in type 2 diabetes is
low, and newer insulin analogs have
demonstrated even lower rates of hypoglycemia
than older insulin products.
• Although weight gain can be expected with insulin
(similar to that seen with secretagogues), the
benefits of glycemic control clearly exceed the
small increases in body weight.
23
23. • Of note, insulin has been shown to reduce mortality
postmyocardial infarction,and more than 10 years
of follow-up in the United Kingdom Prospective
Diabetes Study (UKPDS) have clearly shown no
increase in cardiovascular risk.
• Finally, although multiple daily injections may be
required for patients with advanced, uncontrolled
diabetes, simpler insulin regimens are often highly
effective if initiated earlier in the course of diabetes
24
24. Basal Insulin Therapy
• Usual first step in beginning insulin therapy
• Continue oral agents and add basal insulin to optimize FPG
• A1C of up to 9.0% usually brought to goal (7%) by addition of
basal insulin therapy to oral agents
• Easy and generally safe: patient-directed treatment algorithms
with small risk of serious hypoglycemia
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.
ADA/EASD Management of hyperglycemia in type 2 diabetes: A patient-centered approach. Diabetologia (2012) 55:1577–1596
25. Types of basal insulin
Intermediate-
Acting
(e.g. NPH, lente)
Long-Acting
(e.g. ultralente)
Long-Acting
Analogues
(glargine, detemir)
Onset 1-3 hr(s) 3-4 hrs 1.5-3 hrs
Peak 5-8 hrs 8-15 hrs
No peak with glargine,
dose-dependent peak
with detemir
Duration Up to 18 hrs 22-26 hrs
9-24 hrs (detemir);
20-24 hrs (glargine)
Rossetti P, et al. Arch Physiol Biochem 2008;114(1): 3 – 10.
26. • Recombinant human insulin analogue1
• Basal (long-acting) insulin1
• Relatively constant peakless concentration/time profile over
24 hours1,2
• Once-daily SC administration1
• For adult and paediatric (aged 6 years) patients with type 1
diabetes2 and adults with type 2 diabetes
• Less nocturnal hypoglycaemia1
• More flexible dosing1
Insulin Glargine
27. Insulin Glargine Structure
1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.
2. McKeage K et al. Drugs. 2001;61:1599-1624.
Substitution
Extension
A chain
B chain
1
15105
10 15
20 Asn
30
Gly
Arg Arg
5 10 15 19 25
1
• Asparagine at position A21 replaced by glycine
– Provides stability
• Addition of 2 arginines at the C-terminus of the B chain
– Soluble at slightly acidic pH
28. Injection of an acidic solution
(pH 4.0)3
Microprecipitation of insulin glargine
in subcutaneous tissue (pH 7.4)3
Slow dissolution of free insulin glargine
hexamers from microprecipitates
(stabilised aggregates)3
Protracted action3
1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.
2. McKeage K et al. Drugs. 2001;61:1599-1624.
3. Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.
Insulin Glargine
Mechanism of Action
The mechanics of sustained release1,2
29. PK/PD: Insulin Glargine has a flatter action profile
and a longer duration of action than NPH
Lepore M, et al. Diabetes 2000;49(12):2142–2148
Randomized four-way crossover euglycaemic clamp study comparing
the pharmacokinetics and pharmacodynamics of Insulin Glargine with
three commonly used basal insulin regimens (NPH, ultralente, CSII) in
patients with T1DM
30. Insulin glargine consistently achieves mean
HbA1C ≤ 7%
1. Riddle M, et al. Diabetes Care 2003;26:3080. 2. Gerstein HC, et al. Diabetes Med 2006;23:736. 3.
Bretzel RG, et al. Lancet 2008;371:1073. 4. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364. 5.
Schreiber SA, et al. Diabetes Obes Metab 2007;9:31.
Baseline Study end
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
T-T-T1
(n = 367)
INSIGHT2
(n = 206)
APOLLO3
(n = 174)
INITIATE4
(n = 58)
Schreiber5
(n = 12,216)
HbA1C(%)
8.6 8.6 8.7 8.78.8
7.0 7.0 7.0 6.8 7.0
∆ -1.6 ∆ -1.6 ∆ -1.7 ∆ -2.0 ∆ -1.7
32. 33
Treat-to-Target: Insulin Glargine can be rapidly titrated
to achieve target glycaemic control
Starting daily dose
10 IU
Forced weekly titration using
predefined algorithm and
based on self-monitored FBG
Riddle MC, et al. Diabetes Care 2003;26(11):3080–3086
Mean daily dose at endpoint (IU/kg)
• NPH: 0.42
• Insulin Glargine: 0.48
• Randomized study in 756 insulin-naïve patients with T2DM who added
Insulin Glargine or NPH to their existing OAD therapy
33. •Basal insulin begun at a low dose (e.g., 0.1–0.2 units/kg per
day).
• A single injection of basal insulin administered before the
evening meal or at bedtime, at an initial dose of 0.1units/kg.
This will ensure that changes in blood glucose levels will be
gradual.
• Under special conditions, such as significant hyperglycemia
(HbA1c ≥9%) and/or obesity, a starting dose of 0.2 units/kg
may be used.
•An alternative, non-weight-based option is to start most
individuals empirically with 10 units, or in obesity up to 20
units, of basal insulin (i.e., long-acting or intermediate-acting).
How to Initiate Basal Insulin
34. Initiate& Titrate basal insulin
FPG, fasting plasma glucose
Nathan DM, et al. Diabetes Care 2009;32:193-203.
Initiate insulin with a single injection of a basal insulin
(Glargine)
Check
FPG
daily
In the event of hypoglycemia or
FPG level <3.89 mmol/L
(<70 mg/dL)
• Reduce bedtime insulin dose
by 4 units, or by 10% if >60
units
• Bedtime or morning long-acting insulin OR
• Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 units/kg
INITIATE
• Increase dose by 2 units every 3
days until FPG (70–130 mg/dL)
• If FPG is >180 mg/dL, increase
dose by 4 units every 3 days
TITRATE
Continue regimen and
check HbA1c every 3 monthsMONITOR
35. 1.2.3 study: insulin glargine with addition of one, two or
three daily doses of glulisine
Subjects:
• Insulin naïve (785 entered study, 343 randomized) T2D (HbA1c ≥8.0%)
• Receiving 2 or 3 OHAs for ≥3 months (OHAs continued except sulfonylurea)
Randomization (subjects
with HbA1c >7.0%, n=434)
24 weeks
Insulin glargine
(n=785)
14 weeks
Additional insulin glulisine once daily (n=115)
Additional insulin glulisine twice daily (n=113)
Additional insulin glulisine three times daily (n=115)
Sanofi-aventis data on file (1.2.3 study)
Mean study entry values:
• HbA1c (%): 9.8
• BMI (kg/m2): 35.0
36. 1.2.3 study: intensification of Basal insulin
with mealtime glulisine injections improves glycemic
control
Sanofi-aventis data on file (1.2.3 study)
HbA1c in all subjects (n=785) = 9.8 at run in and 7.3 at randomization
Run in Randomization Wk 8 Wk 16 Wk 24
7.40
7.0
HbA1c(%)
10.19
10.19
10.16
7.44
7.29
8.0
9.0
10.0
Glulisine 1x
Glulisine 2x
Glulisine 3x
Responders in the whole
population (n=785)
Evolution of HbA1c in the
randomized population (n=343)
0
20
40
60
80
Subjects who
achieved
HbA1c <7.0%
with glargine
during run in
Additional
subjects who
achieved
HbA1c <7.0%
with glulisine
added to
glargine
All subjects
(n=785)
%achievingHbA1c<7.0
23%
37%
Glargine
(alone)
Glargine plus glulisine
(patients with HbA1c >7%)
37. 1.2.3 study: The Basal Plus strategy is associated with a
reduced level of hypoglycaemia
p=NS for all other pairwise comparisons
Sanofi-aventis data on file (1.2.3 study)
x1 x2 x3
0
1
2
3
4
5
Meanbodyweightchange
frombaseline(kg)
3.7 3.8 3.9
Glulisine
0
5
10
15
20
x1 x2 x3
Glulisine
Confirmedsymptomatichypo
(event/patient-year)
12.2
12.9
17.1
p=0.043
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
Severeorserioushypo
(event/patient-year)
x1 x2 x3
Glulisine
0.10
0.30
0.26
•At study end, the mean insulin dose (glargine + glulisine) was 84 +27, 80 + 50
and 81 + 66 U/day in the glulisine x1, x2 and x3 groups, respectively.
38. Summary
• Early and Tight management of type 2 DM is highly recommended to avoid
complications.
• Individualize treatment based upon patient needs, resources, and lifestyle
considerations
• CVS Safety issue must be considered in all patients.
• Structured patient Education &SMBG can minimize the hypoglycemia.
• Overcome the causes for patient resistance to insulin therapy with provider
belief and communication strategies
• Recognize when prandial insulin is required to avoid clinical inertia and the
concept of overbasalization
• Be willing to change strategies as needed to achieve goals i.e:
AVOID CLINICAL INNERTIA
